8. Therapie des invasiven Plattenepithelkarzinoms der Haut – Aktinische Keratose und Plattenepithelkarzinom der Haut
M. Felcht, H. Breuninger, F. Bechara, S. Dengler, R. Gutzmer, A. Hauschild, L. Kofler, O. Kölbl, U. Leiter, D. Nashan, D. Vordermark, K. Wermker
8.1 Chirurgische Therapie des Primärtumors
Dem untersuchenden Pathologen/Dermatopathologen sollen folgende Risikofaktoren des PEK mitgeteilt werden, wenn sie vorliegen: Rezidiv, Tumordurchmesser >2 cm, Lokalisation Ohr, Lippe oder Schläfe, Immunsuppression und Hinweis auf perineurale Invasion, keine Verschieblichkeit vom Untergrund.
- Konsens
- Starker Konsens (100%)
Die chirurgische Therapie des Primärtumors soll nach folgendem Algorithmus (Abbildung 4) erfolgen:
- Konsens
- Starker Konsens (94,1%)
Obwohl es in der Literatur keinen Zweifel daran gibt, dass die chirurgische Entfernung eines Plattenepithelkarzinoms der Haut die Methode der Wahl ist [334], besteht für die genaue Gestaltung der Exzision und der darauffolgenden histologischen Untersuchung nur geringer Konsens.
Bei der Durchsicht der vorhandenen Leitlinien bezüglich der lokalen Therapie des PEK der Haut fällt auf, dass es weiterhin Diskrepanzen gibt hinsichtlich der Beurteilung von Risikofaktoren, die das lokoregionäre Verhalten der PEK beeinflussen und auch hinsichtlich der Modalitäten der lokalen Therapie. Das hängt damit zusammen, dass die vorhandene Literatur zu diesen Themen fast durchweg aus retrospektiven und auch zum Teil kleinen Studien besteht, die oft zu heterogenen Ergebnissen kommen.
8.1.1 Risikofaktoren für den loko-regionalen Progress und tumorspezifisches Überleben
Die Kenntnis der Faktoren, die zum lokalen Rezidiv und regionären Metastasierung führen, ist für die Operationsplanung von Bedeutung. Ein Tumor mit hohem Potential zur lokalen Infiltration ist anders zu behandeln als ein solcher mit geringem Potential.
Zur Analyse von Risikofaktoren wurden sowohl retrospektive als auch wenige prospektive Studien durchgeführt. Allerdings mangelt es für Letztere immer noch an Studien mit ausreichend großen Patientenzahlen. Bislang wurden 7 prospektive Studien publiziert [21][335][20][336][62][337]; drei davon mit Patientenzahlen von 502 bis 1.434 unterschiedlicher Zeiträume aus einer Institution [21][335][20]. Eine kürzlich veröffentlichte Studie mit 745 Tumoren war zwar multizentrisch, jedoch waren zum Großteil eher low-risk PEK eingeschlossen (95% waren gut differenziert, 85% kleiner als 2 cm Durchmesser) [337]. Zwei weitere prospektive Studien untersuchten 210 und 224 Patienten [336][62]. Eine weitere prospektive Studie mit 1.010 Patienten analysierte den Risikofaktor Immunsuppression [30]. Alle anderen Studien sind retrospektiv mit Patientenzahlen von 69 bis 1468 Patienten [338][339][340][57][341][342][343][344][345][54][346][347][63][348][63][349][350][351] In 7 Reviews wird die vorhandene Literatur bewertet [352][353][354][33][355][356][356][357]. Hier zeigt sich, dass die Kollektive unterschiedlich zusammengesetzt sind. Damit sind die Raten der Lokalrezidive und die der Metastasierung durch diese großen Unterschiede sehr schwer zu bewerten, auch hinsichtlich der Risikofaktoren.
Mehrere Arbeiten weisen auf eine Insuffizienz AJCC Klassifikation hin, um lokale Rezidive oder Metastasierung vorherzusagen [344][355][358][359][337]. Dies hat dazu geführt, dass alternative Klassifizierungssysteme vorgeschlagen wurden [360].
Insgesamt lassen sich, wie schon Rowe 1992 ausführte, folgende wichtige Risikofaktoren festhalten:
- Tumordurchmesser >20 mm
- Infiltrationstiefe >Level 3
- Entdifferenzierung
- Perineurale Invasion
- Lokalisation Ohr und Unterlippe
- Immunsuppression
- histologische Tumordicke >6 mm
- Desmoplasie
Unklar ist derzeit, wie die einzelnen Faktoren zu gewichten sind. Nach den bisher vorliegenden Publikationen sind die Tumordicke ab 6 mm, die Desmoplasie und eine perineurale Invasion die stärksten prognostischen Faktoren insbesondere für die Lokalrezidivierung, aber auch der Metastasierung [33][351].
8.1.1.1 Tumordurchmesser
Der klinische Tumordurchmesser von 2 cm ist in allen Publikationen ein prognostischer Faktor zur groben Orientierung, außer in einer [336]. In den meisten Publikationen wurde der Tumordurchmesser als Risikofaktor dargestellt. In wenigen werden die Rate der Lokalrezidive und der Metastasierung für diese Grenze errechnet. Bei Tumoren ≥2 cm Durchmesser traten Lokalrezidive zwischen 2-7% auf [20][343][63][352], eine regionale Metastasierung zu 9-16% [20][63] bzw. bei Rowe 30% [352]. Aus diesem Grund wird eine standardmäßige Angabe des klinischen Durchmessers in den europäischen Empfehlungen zum PEK empfohlen.
Der Tumordurchmesser alleine bietet aber nicht genug Informationen über tatsächliche "high-risk"-Tumoren. Daher braucht es, wie die Publikationen zeigen, zusätzlich histologische Informationen (Differenzierung, perineurale Invasion, Invasionstiefe bzw Tumordicke) sowie sowie Informationen über patientenbezogene Faktoren [361].
8.1.1.2 Tumordicke
Nach AJCC wird die Tumordicke vom Stratum granulosum bzw. dem Boden einer Ulzeration bis zur tiefsten Infiltration gemessen [354]. Die Messung am tiefsten Punkt der Ulzeration ist kritisch zu bewerten, da stark ulzerierte Tumoren dann eine geringere Tumordicke aufweisen und dadurch mit niedrigerem Risiko bewertet werden, obwohl das Gegenteil der Fall sein könnte. Eine Studie zur Wertigkeit einer Ulzeration ist nach Kenntnis der Autoren bisher nicht publiziert worden. Die Tumordicke wird in den o.g. Studien immer von der höchsten Erhebung (dort Stratum granulosum) unabhängig von einer Ulzeration bis zur tiefsten Infiltration gemessen [20][63][352].
Die Tumordicke gemessen am histologischen Schnitt ist zwar vom Tumordurchmesser abhängig, ist aber in multivariaten Analysen ein stärkerer prognostischer Faktor als der Tumordurchmesser. In 7 weiteren Studien wird die Tumordicke ebenfalls analysiert (von 3-7 mm) [336][62][346][353][354][355][33]. In der alten 7. Edition der AJCC-Klassifikation wird eine Tumordicke von mehr als 2 mm als high-risk Faktor genannt [347][33]. Die Tumordicke >2 mm war in der Literatur 1990 [339] als Grenze einer ab 2 mm beginnenden Möglichkeit der Metastasierung eingeführt und in weiteren Publikationen bestätigt worden. Diese Grenze ist kritisch zu werten, da damit der überwiegende Teil der PEK als Hochrisiko-Tumor gewertet würde. Die 8. Edition der AJCC-Klassifikation wurde dahingehend geändert, dass für Kopf-Hals-Tumoren eine Tumordicke ≥6 mm gilt. Dies ist in praktisch allen Klassifikationssystemen auch so Konsensus [360].
8.1.1.3 Infiltrationstiefe
Die Infiltrationstiefe ist in aller Regel von der Tumordicke abhängig. Je dicker ein Tumor, desto größer ist seine Infiltrationstiefe, es sei denn er wächst rein exophytisch, was selten vorkommt. Die Eindringtiefe wird v.a. in Bezug auf die anatomische Schichtung (insbesondere ab Clark-Level V, entsprechend Infiltration und Überschreiten der Subcutis) als prognostischer Faktor angesehen [336][57][347][63][352][353][354][33][355].
Die Tumordicke ist jedoch der Infiltrationstiefe als prognostischer Faktor überlegen. Im Stagingsystem nach Breuninger [358], welches als prädiktiver Wert einer Metastasierung sich in einer unabhängigen Analyse einer norwegischen Gruppe den anderen Klassifikationssystemen überlegen zeigte, wird die Infiltrationstiefe nicht berücksichtigt [359].
8.1.1.4 Entdifferenzierung und Desmoplasie
Die Entdifferenzierung wird in fast allen Publikationen als prognostischer Faktor beschrieben. In den EDF-EADO-EORTC Empfehlungen werden sowohl Entdifferenzierung als auch Desmoplasie als eigenständige Risikofaktoren genannt [360]. Trotzdem wird in der Mehrzahl der Publikationen Desmoplasie nicht erwähnt. Dabei unterscheidet sich die Häufigkeit der Desmoplasie je nach untersuchten Patientenkollektiv. Desmoplasie wurde 1997 in einer großen prospektiven Studie als eigenständiger Risikofaktor für das Auftreten von Lokalrezidiven und die regionäre Metastasierung eingeführt [335]. In denjenigen Publikationen, welche Desmoplasie als Risikofaktor untersuchen, ist wiederum die Entdifferenzierung kein signifikanter Faktor [335][20][21]. Es ist anzunehmen, dass Desmoplasie in den meisten Studien als entdifferenzierter Typ mit den anderen Formen der Entdifferenzierung bewertet wurde [57][55]. Desmoplasie wird auch in einer weiteren Studie analysiert [355], und wird in einigen Leitlinien als prognostischer Faktor genannt [362][104][362][362]. In der oben beschriebenen norwegischen Studie, in der die unterschiedlichen Klassifikationssysteme verglichen wurden, waren die Klassifikationssysteme, welche Desmoplasie nicht berücksichtigten, in ihrer prädiktiven Wertigkeit hinsichtlich Metastasierung unterlegen [359]. Die hohe Lokalrezidivrate liegt auch daran, dass sich gerade die Desmoplasie durch Einzelzell-Infiltration oft dem histologischen Nachweis in der vom Tumor abgelegenen Peripherie entzieht [363]. Eine Evaluation der Ränder mittels immunhistochemischer Färbungen ermöglicht es daher eine höhere Rate an Tumorausläufern zu detektieren [364].
8.1.1.5 Perineurale Infiltration
Die perineurale Infiltration (PNI) ist durchgängig als high-risk Faktor anerkannt. Wichtig ist, dass diese mikroskopisch, klinisch als auch radiologisch nachweisbar sein kann [360].
Die Häufigkeiten des Auftretens werden sehr unterschiedlich angegeben. Sie reichen von 1% bis 100% [342][365]. Eine hohe PNI (55-64%) ist in stark selektierten Kollektiven zu finden [347][65][366], hiervon in 64% bei einem Kollektiv von immunsupprimierten Patienten. In den meisten Publikationen wird die PNI in 2% und 10% der Tumoren detektiert [55][57][336][367][368][344][62][345][369]. Einige Publikationen zeigen ein erhöhtes Auftreten von PNI bei desmoplastischen PEK [335][57][370]. Eine Arbeit fand PNI ausschließlich bei desmoplastischen Tumoren [371]. Ein wesentlicher Faktor scheint hier außerdem der Tumordurchmesser zu sein. Karia et al. zeigten ein signifikant höheres Risiko für lokale Rezidivierung bei einem perineuralen Wachstum um Nerven mit einem Durchmesser > 0,1 mm im Vergleich zu geringeren Nervendurchmessern [19]. Von den etablierten Klassifikationssystemen für kutane PEK führt lediglich die Klassifikation des Brigham and Women’s Hospital den Cut-Off von 0,1 mm Nervendurchmesser als gesonderten Risikofaktor.
8.1.1.6 Lokalisation
Die Lokalisation als prognostischer Faktor wird unterschiedlich bewertet. Die Ohr (-region) und das Unterlippenrot wurden in zahlreichen Studien als prognostische Faktoren analysiert [20][62][341][342][344][346][347][63][352][353][354][33]. In der Meta-Analyse von Thompson et al., welche über 23.000 PEK einschloss, zeigte sich das höchste Risiko für Lokalrezidivierung an Schläfe, Lippe und Ohr [33]. Darüberhinaus werden neben Schläfe, Skalp, Nase und auch Wange in zahlreichen Publikationen als high-risk Lokalisationen identifiziert [342][347][63][354][33][351][33]. Einzig drei Arbeiten sehen den Rumpf als eigenen Risikofaktor [340][354][351]. In einer großen prospektiven Arbeit mit 1434 Patienten starben 40 aufgrund des PEK [21]. 35/40 verstorbenen Patienten hatten das PEK in der Kopf-Hals-Region. Demensprechend war in der alten europäischen Leitlinie die gesamte Kopf-Hals-Region als high risk oder intermediate risk klassifiziert worden, einzig Rumpf und Extremitäten waren low risk [361]. In den neuen Empfehlungen sind einzig die Regionen Schläfe, Ohr und Lippe [360]. Zwei Studien sehen die Lokalisation nicht als prognostischen Faktor [57][345].
8.1.1.7 Immunsuppression
8.1.1.8 Weitere Faktoren
Wenn ein bereits vorbehandeltes PEK vorliegt, wird dies in einigen Publikationen als Risikofaktor bewertet [361]. Das kann an einer insuffizienten Erstbehandlung liegen oder an der hohen lokalen Malignität des Tumors, die per se schon häufiger zu Lokalrezidiven führt, unabhängig von der Behandlungsmodalität [335][20][21]. Dieses Phänomen Malignität des Tumors vs. insuffiziente Lokalbehandlung lässt sich in der Literatur oft nicht trennen [336][57][343][372]. Auch soll die Art der Behandlung den Verlauf beeinflussen.
8.1.2 Chirurgische Therapie und histologische Schnittrandkontrolle
8.1.2.1 Exzision bei Tumoren mit Durchmesser kleiner 10 mm
Bei kleinen Tumoren <10 mm eignet sich die Kürettage mit der scharfen 7-mm-Ringkürette oder eine tiefe horizontale Abtragung („Shave“-Exzision). Beide Methoden gewährleisten eine scharfe Abtragung, wodurch für die histopathologische Untersuchung ein übersichtliches Präparat zur Verfügung gestellt wird. Es gibt hierfür in der Literatur keine Studien. Der Durchmesser des Exzidates sollte jedoch nicht unter 5 mm liegen. Das untere Korium oder knapp die Subkutis sollte zur Tiefe hin erreicht werden. Wurde der Tumor so in toto entfernt, führt die folgende Sekundärheilung, wenn sie an der entsprechenden Lokalisation möglich ist, zu sehr guten ästhetischen Ergebnissen [373][374]. Darüber hinaus können entzündliche Prozesse nach beispielsweise horizontaler Abtragung oder Kürettage zu einer Regression verbliebener Tumoranteile führen [375].
Bei größeren und dickeren Tumoren soll die Tiefe mindestens bis tief in die Subkutis reichen, wenn immer möglich mindestens 6 mm tief. Das lässt eine Beurteilung der Tumordicke und der Differenzierung zu und somit eine genauere prognostische Einschätzung durch die Histopathologen. Jedoch ist zu beachten, dass dabei nicht immer eine Desmoplasie erkannt werden kann, da sie in Teilarealen auftreten kann. Das gleiche gilt für PNI, welche häufig nur in der Tumorperipherie zu erkennen ist.
8.1.2.2 Histologische Sicherung vor einer größeren Exzision
Oft ist die Diagnose eines PEK oder zumindest eines epithelialen malignen Tumors klinisch schon sehr sicher zu stellen und somit eine Operationsindikation gegeben. In diesen Fällen wäre die Probebiopsie eine unnötige Belastung für die Patienten. Ist dennoch eine Probebiopsie notwendig, so eignet sich am besten eine Stanze mit 6 mm Durchmesser, gesetzt am höchsten Punkt des Tumors. Eine spindelförmige Exzision ist die Alternative. Da auch eine Probebiopsie oftmals histopathologisch schwierig einzuordnen ist oder nicht alle notwendigen histologischen Parameter erhoben werden können (siehe Exzision von Tumoren mit Durchmesser kleiner 10mm), ist ein Schnitt durch den gesamten Tumor aufschlussreicher. Das gelingt am besten durch eine klinisch vollständige Tumorexzision. Hier ist eine Markierung (beispielweise bei 12 Uhr bezogen auf die Körperachse) sinnvoll, damit die spätere Orientierung im Falle einer R1-Resektion möglich ist. Bei kompletter Exzision sollte eine Aufarbeitung der Schnittränder folgen, um eine R0- oder R1-Resektion zu sichern.
8.1.2.3 Histologische Schnittrandkontrolle: lückenlose vs. nicht-lückenlose Aufarbeitung des Tumorexzidates
Die Befundung der histologischen Präparate kann entweder am Gefrierschnitt oder am Paraffin-eingebetteten Material erfolgen. Paraffinschnitte sind der Goldstandard was Sensitivität und Spezifität angeht, besonders beim PEK der Haut, da sich die Zellen des Stratum spinosum nicht so intensiv anfärben wie die Zellen des Stratum basale. Weitere Methoden wie die konfokale Lasermikroskopie oder "Rapid Lump Examination" wurden nicht für das PEK der Haut überprüft [376][377].
Das eingebettete Präparat kann auf unterschiedliche Arten aufgearbeitet werden. Hier wird insbesondere der konventionelle Aufschnitt von einer 3D-Histologie unterschieden. Im Gegensatz zum konventionellen Aufschnitt des Exzidates durch parallele, lamellenartige, serielle Schnitte (Brotlaibtechnik), die diagnostische Lücken haben, werden bei der 3D-Histologie die kompletten Exzidat-Außenränder in einbettungsfähige Streifen abgetrennt oder als solche nachexzidiert und nach den Regeln der Uhrzeit auf der Außenseite plan gedrückt. So erreicht man eine Verwandlung der dreidimensionalen Schnittflächen des Exzidates zu zweidimensionalen histologischen Präparaten mit lückenloser Ansicht der schnittkanten des Exzidates [378]. Der Zeitaufwand für Aufschnitt und Untersuchung ist für die Randschnittkontrolle im Vergleich zu Brotlaibtechnik umso geringer, je größer das Präparat ist [379].
Eine Arbeit hat prospektiv untersucht, ob die unterschiedlichen Aufarbeitungstechniken zu Unterschieden in der Rezidivhäufigkeiten beim Basalzellkarzinom führen [380]. Die Rezidivhäufigkeit war signifikant geringer, wenn eine lückenlose Aufarbeitung erfolgte. Mit Einschränkungen lässt sich dies möglicherweise auf das PEK übertragen. Jedoch ist kritisch anzumerken, dass dieser Unterschied einzig beim nodulären Basalzellkarzinom signifikant war, da insgesamt die Anzahl der Rezidive sehr gering war und die nodulären Basalzellkarzinome die größte Subgruppe ausmachte. Darüber hinaus kann der Abstand zwischen den Lamellen in der Brotlaibtechnik sicherlich noch enger als 5 mm (wie in der Arbeit angewandt) gesetzt werden.
8.1.2.4 Lokale Exzision mit weitem Resektionsabstand und nachfolgender lamellenartiger serieller Aufarbeitung
Beim Verfahren der Exzision mit weitem Resektionsabstand (englisch „wide local excision“, WLE) wird der Primärtumor mit einem gewissen Sicherheitsabstand exzidiert. Die Größe des Sicherheitsabstandes ist bei dieser Form der Resektion nicht standardmäßig definiert und eine breite Varianz in der Literatur beschrieben (4 bis 10 mm, maximal 50 mm) [381][382][383][384][361]. In der aktuellen europäischen Leitlinie wird für die WLE Technik die Entnahme eines klinischen Sicherheitsabstandes von 5 mm für low-risk PEK und von 6-10 mm für high-risk PEK empfohlen [384]. Ein größerer Resektionsabstand gleicht die im Folgenden beschriebene Unsicherheit der histologischen Untersuchung aus und erhöht auch die Rate an kompletten Exzisionen schon beim ersten Eingriff.
Die Aufarbeitung mittels Brotlaib-Histologie (Serienschnitttechnik/ Brotlaibschnitte) erfolgt im Paraffinschnittverfahren mit lamellenartigem, seriellem Aufschneiden des Tumorpräparates. Bei einer konventionellen histologischen Untersuchung durch die genannte Brotlaib-Histologie wird die Breite der Lamellen in der vorliegenden Literatur außer in zweien nicht angegeben, obgleich die Qualität der histologischen Untersuchung wesentlich davon abhängt [367][382]. Da die Untersuchung mit Brotlaibschnitten technikbedingt lückenhaft („diagnostische Lücken“) ist, werden bei der Erstexzision eines Tumors von den Chirurgen meist eher großzügige Resektionsabstände gewählt, deshalb der Begriff (WLE). Dadurch entstehen größere Defekte [385]. Aus diesem Grund wird in der aktuellen europäischen Leitlinie darauf hingewiesen, dass beispielsweise in der Kopf-Hals-Region die Anwendung der gewebesparenden MKC Technik mit lückenloser dreidimensionaler Schnittrandkontrolle sinnvoll sein kann [384].
Zu den Resektionsabständen für die WLE ist die Datenlage in der Literatur relativ schmal. Die wichtigste und am meisten dazu zitierte Studie ist die von Brodland 1992, die besagt, dass Tumoren mit <20 mm Durchmesser mit 4 mm Resektionsabstand zu den klinisch sichtbaren Tumorgrenzen zu 96% R0 exzidiert werden können [386]. Bei Tumoren mit ≥20 mm wird dies mit einem Resektionsabstand von 6 mm immer erreicht. Vergrößert man den Resektionsabstand auf 9 mm, wird eine R0-Resektion zu 100% erreicht. Eine Limitierung dieser Studie ist, dass hier vorwiegend low-risk Tumoren untersucht wurden. Eine neuere, prospektive Untersuchung bestätigt diese Annahme, da hier bis zu 49% der PEK mit PNI einen Resektionsabstand von 6 mm und mehr benötigten [55]. Im Mittel werden Resektionsabstände von 6,5 mm angeben [62][382][387][388]. Der Benefit eines größeren Resektionsabstandes wird deutlich durch eine kürzlich veröffentlichte retrospektive Arbeit, in der gezeigt werden konnte, dass die Entnahme eines Sicherheitsabstandes von mehr als 5 mm bei Hochrisikoplattenepithelkarzinomen, das tumorspezifische Überleben verbessert [389]. Philipps et al. geben jedoch an, dass keine Angaben zum klinischen Resektionsabstand verfügbar waren, weshalb die verfügbaren Daten auf den histologischen Resektionsrändern (angegeben durch den Pathologen) basieren [389]. In den anderen oben zitierten Publikationen zur WLE werden keine Angaben zum Resektionsabstand gemacht.
In einigen Arbeiten wird auch der Frage nachgegangen, wie häufig eine R1-Resektion bei der Erstexzision stattfand. Hier werden Raten von 1-16% genannt. Im Mittel liegt sie bei ca. 6% [387][390][391][392]. Weiter wird untersucht, ob initiale R1-Exzision die Anzahl der Rezidive beeinflusst. Die Daten hierzu sind mit 8-68% Rezidiven sehr uneinheitlich [390][388]. Eine retrospektive Arbeit an einem sehr großen Kollektiv (n=1468) von Patienten hat untersucht, ob es Subgruppen gibt, bei denen die einfachere Technik der WLE häufiger positive Schnittränder aufweisen. Dies war signifikant häufiger bei PEK, die bei älteren Patienten oder im Kopf-Hals-Bereich auftraten, vorbehandelt waren, einen größeren Durchmesser oder hohe Tumordicke aufwiesen [349]. Hieraus kann man schlussfolgern, dass die relativ einfache Methode der WLE bei PEK, die nicht die obigen Faktoren aufweisen, eine sinnvolle Methode sein kann.
Der Vorteil der Methode ist, dass man den Tumor auf fast allen Schnitten in seiner Ausprägung erkennen kann. Der Nachteil ist die lückenhafte Aufarbeitung der Ränder mit daraus resultierenden falsch negativen Befunden. Bedauerlich ist, dass nicht genau definiert ist, wie breit der Abstand zwischen den Lamellen sein darf. Dies ist gerade bei großen, multifokal wachsenden Tumoren problematisch. Wenn man bei sehr großen Tumoren den Abstand zwischen den Lamellen klein hält, entstehen schnell sehr viele Schnitte, die es zu befunden gilt. Die Definition, wie groß der histologische Abstand des Tumors vom Schnittrand sein sollte, um noch eine R0-Resektion zu befunden, variiert in den Studien der WLE von 1 bis 4 mm [345][54][390]. Weniger als 1mm ist in nur ganz wenigen Arbeiten als R0 definiert worden [387].
8.1.2.5 Mikrographisch kontrollierte Chirurgie
Bei der Entwicklung der lückenlosen Schnittrandmethode sind in der Literatur unterschiedliche Verfahren angegeben. F. Mohs hat als Erster 1941 die Chlorzinkätzung eingeführt [393]. Bereits 1963 hat Drepper als erster systematisch flache Exzidate aus dem Wundgrund im Paraffinschnittverfahren an ihrer Außenseite histologisch untersucht, um damit Tumorausläufer zu erfassen [394]. Mohs hat dieses Verfahren „Microscopic Controlled Surgery“ benannt [395][396]. In Deutschland hat sich danach der Begriff als „mikroskopisch kontrollierte Chirurgie“ (MKC) etabliert [397][398].
In der aktuellen AWMF-Leitlinie zu MKC ist diese als eine Technik definiert, dessen Ziel es ist, eine histologisch nachgewiesene vollständige Entfernung maligner Tumoranteile (R0-Resektion) bei größtmöglicher Schonung der gesunden Umgebung zu erreichen [398]. In der AWMF-Leitlinie sind unterschiedliche Techniken aufgezählt, die alle als MKC subsummiert werden. Sicher als MKC dürfen solche Techniken bezeichnet werden, bei denen eine lückenlose Beurteilung der Schnittränder erfolgt. Darüber hinaus werden in Deutschland teilweise auch nicht-lückenlose Techniken mit eng gesetzten Lamellen als MKC bezeichnet, obwohl dies der ursprünglichen Idee einer lückenlosen Befundung des Exzidat-Außenrandes widerspricht.
Der Großteil der veröffentlichten lückenlosen MKC Studien beim PEK stammt aus Ländern, in denen hauptsächlich die Befundung an Gefrierschnitten erfolgt. Dies umfasst Originalarbeiten [338][63][352][353][337]und Übersichtsarbeiten [399][400][356]. In Deutschland erfolgt die MKC zum Großteil am Paraffin-eingebetteten Material [398]. Für die lückenlose MKC an Paraffin-eingebetteten Präparaten wurde auch der Begriff 3D-Histologie [401] bzw. in den USA “complete circumferential peripheral and deep margin assessment (CCPDMA)” vorgeschlagen [402]. Auch zu dieser Technik mit Befundung an Paraffinschnitten gibt es mehrere Studien [335][20][21][369][403] („slow Mohs-surgery“). In einer Studie wurde untersucht, ob Befunde beim Basalzellkarzinom, die initial an einem Gefrierschnitt durchgeführt wurden, identisch sind mit Befunden an Paraffin-aufgearbeiteten Präparaten [367]. Dies war in 158/160 (98,8%) der Fälle der Fall. Trotzdem muss festgehalten werden, dass die Befundung von PEK am Gefrierschnitt nicht einfach ist und auch mehr Schwierigkeiten aufweist als beim Basalzellkarzinom aufgrund des unterschiedlichen Färbeverhaltens in einer HE-Färbung. In der aktuellen europäischen Leitlinie wird deshalb nach einer initialen Befundung an einem Gefrierschnitt, die Kontrolle an Paraffin-aufgearbeiteten Schnitten empfohlen [384].
Die Frage, wie häufig bei der primären Tumorexzision eine R1-Resektion vorliegt, wird nur bei einer der Publikationen genannt und beträgt hier 43% [55]. Dies erscheint im Vergleich zur WLE recht hoch, was bei den kleinen initialen Exzisionsabständen im Konzept einer hautsparenden Operationstechnik aber nicht verwundert. Es wurde nicht geprüft, ob dies die Rezidivrate beeinflusst.
Der Vorteil der Methoden ist die hohe Sensitivität, Tumorausläufer zu erkennen. Jedoch ist dabei zu bedenken, dass beispielsweise desmoplastische Tumoren durch Einzelzell-Infiltration gekennzeichnet sind, die sich dem histologischen Nachweis in der vom Tumor abgelegenen Peripherie entziehen können. Nichtsdestotrotz lässt sich festhalten, dass bei dieser Methode der primäre Sicherheitsabstand meist klein gehalten wird (1-5 mm, je nach Tumordurchmesser und Lokalisation), da insgesamt die Sensitivität, Tumorausläufer nachzuweisen, hoch ist. Dies ermöglicht signifikant kleinere Defekte, was in bestimmten Lokalisationen wie der Gesichtsregion von Vorteil sein kann [385]. Daneben kann es aus rein praktischer Sicht sinnvoll sein, die lückenlose MKC bei sehr großen Tumoren anzuwenden, da eine Brotlaibtechnik (mit engen Lamellen) die Befundung sehr vieler Schnitte notwendig macht. Dies ist aber natürlich von den individuellen Standortgegebenheiten abhängig, denn eine nur temporäre Anwendung einer lückenlosen MKC kann ebenfalls zeitaufwendig sein. Der Nachteil ist, dass lediglich die Ebene des Schnittrandes dargestellt wird und das Tumorzentrum getrennt, entweder nach Kürettage wie bei Mohs-Chirurgie oder vom verbleibenden Rest nach Abtrennung der Außenseiten untersucht werden muss. Und bei der MKC Methode können vermehrt Nachoperationen erforderlich sein, um eine R0 Situation zu erreichen.
8.1.2.6 Wann ist eine mikrographisch kontrollierte Chirurgie mit lückenloser Aufarbeitung der Schnittränder anzustreben?
Bei allen folgenden Überlegungen bzgl. chirurgischer R0 Resektion mit/ohne Sicherheitsnachresektion, ist es wichtig das tumorspezifische Überleben mit dem Gesamtüberleben zu vergleichen. Es zeigt sich, dass nur ca. 2% der Patienten mit kutanen PEK tatsächlich am PEK versterben und ca. 40% an anderen Ursachen [21][404][403]. Man darf hoffen, dass dies zukünftig noch seltener wird, denn mit der Immuntherapie gibt es vielversprechende Therapieoptionen. Allerdings werden diese bei einem Teil der Patienten nicht ohne weiteres angewendet werden können, so dass es notwendig ist, in diesen Gruppen inoperable Komplikationen so weit zu verhindern wie möglich (bspw. Immunsupprimierte).
Die lokalen Rezidiv-Raten nach WLE, schwanken stark zwischen 0-53% [352][404]. Innerhalb der gleichen Publikationen können bei gleicher Therapiemethode die Raten lokaler Rezidivierung ebenfalls um das Vielfache schwanken, je nach untersuchtem Subkollektiv [343][352][390][405]. Die Mehrheit der Publikationen nennt Raten von 2-13% [336][340][352][369][369][367][369][406][369][388][369][407][369][408][348][348][409][350][350][410].
In einer prospektiven Studie, in der 277 PEK mit WLE und nachfolgender Brotlaib-Histologie behandelt wurden, betrug die regionäre Metastasierungsrate 23% [336]. Ähnliche regionale Metastasierungsraten von 5-47% finden sich in retrospektiven Studien [341][343][345][346][347][352][368][404][406]. Andere Studien zeigen geringere Metastasierungsraten von 2-4% [62][340][345][367]. Insgesamt ist zu beachten, dass diese Methode häufiger durch Mund-Kiefer- und Gesichtschirurgen angewendet wurde, welche die größeren Tumoren behandelten und somit die Patienten per se ein größeres Risiko hatten, Metastasen zu entwickelten. Es besteht also offensichtlich ein Bias zu Ungunsten der WLE. Ein Vergleich der genannten Studien ist kaum möglich, da oftmals die Risiko-Faktoren der Tumoren nicht genannt werden [352][65][399][400][411]bzw. die Angaben über die Metastasierungsrate fehlen [372][390][391][408].
Die lokalen Rezidiv-Raten der MKC schwanken zwischen 0-33% [352][337]. Die meisten Publikationen geben Rezidivraten zwischen 2-8% an [400][20][352][412][403][408][291][413][414][415][416][350]. Betrachtet man spezifisch die Lokalrezidivrate zwischen nicht-desmoplastischen und desmoplastischen PEK, so unterscheidet sich diese signifikant mit 4 vs. 26% [417].
Insgesamt erscheint somit die Rezidivrate nach MKC niedriger als nach WLE mit einer durchschnittlichen Rezidivrate von 2-13% (s.o.) jedoch gibt es Risikokonstellationen (wie beispielweise Desmoplasie), bei denen es trotz lückenloser MKC häufig zu Rezidiven kommen kann. Die Annahme einer insgesamt niedrigeren Rezidivrate nach MKC wird unterstützt durch zwei kürzlich veröffentlichte retrospektiv vergleichende Arbeiten, die zeigen, dass sowohl die Lokalrezidivrate als auch die Metastasierungsrate bei MKC niedriger sind als bei WLE [350][418]. Jedoch fehlen bei beiden Arbeiten die Details zur genauen Aufarbeitung der WLE-behandelten Präparate insbesondere wie groß der Abstand zwischen den einzelnen Lamellen war. Daneben fehlen Angaben zur Verteilung von Differenzierung [350]bzw. Desmoplasie [350][418]. Bemerkenswert ist aber, dass in beiden Arbeiten die MKC-behandelten Kollektive ein signifikant schlechteres Risikoprofil aufwiesen und beispielsweise größere Tumoren enthielten, welche tiefere Strukturen infiltrierten [350] oder häufiger immunsupprimiert waren [418]. Andere Arbeiten, konnten keine signifikante Überlegenheit der MKC bzgl. Rezidivrate nachweisen [408][405]. Dies kann daran liegen, dass abhängig vom untersuchtem Subkollektiv bei gleicher Therapiemethode die Raten lokaler Rezidive um das Vielfache schwanken können [335][20].
Niedrige Metastasierungsraten von 0-7% sind nach Mohs Chirurgie beschrieben [338][63][413][414][415][20][62][369][369][407][369][414][416][416][418][337]. Jedoch sind bei vielen der vorliegenden Daten mit Mohs Chirurgie eher kleinere Tumoren behandelt worden [400]. Besonders deutlich wird dies in einer viel zitierten prospektiven Studie bei der es in keinem Fall der 1263 untersuchten PEK zu einer lokoregionäre Metastasierung kam [412]. Wichtig ist zu beachten, dass auch neuere Studien mit zum Großteil kleineren Tumoren zeigen, dass MKC weder ein Lokalrezidiv noch Metastasierung zu 100% sicher verhindern können [350][337][418]. Und auch der Anteil der Patienten, die aufgrund des PEK versterben, ist nach MKC niedriger als nach WLE jedoch nicht ausgeschlossen [405]. Wenn Desmoplasie vorliegt, so ist – trotz MKC – das Risiko an einem PEK zu versterben, 8-fach erhöht [21]. All dies impliziert, dass auch nach lückenloser MKC die Entnahme eines zusätzlichen Sicherheitsnachresektates nach R0-Exzision für gewisse Risikopatienten durchaus sinnvoll sein könnte, insbesondere da ein Wiederauftreten des PEK [334] oder Metastasenbildung mit einer schlechten Prognose assoziiert ist.
Schon 1992 forderte Friedman [381] in einem Kommentar zum Review von Rowe et al. [352] prospektiv randomisierte Studien für die unterschiedlichen Therapiemodalitäten. Eine solche gibt es bis heute noch nicht [400]. Für Deutschland kommt erschwerend hinzu, dass unterschiedliche Zentren verschiedene Techniken der MKC anwenden bzw. teilweise Techniken als MKC bezeichnet werden, die mit unvollständiger Darstellung der Schnittränder einhergehen [419]. Häufig ist dem Operateur der Abstand zwischen den einzelnen Lamellen bei Brotlaib-Technik aufgearbeiteten Präparaten nicht bekannt, so dass er nicht wirklich beurteilen kann, wie verlässlich ein R0 Befund ist, wenn dieser anhand Brotlaibtechnik-aufgearbeitetem Histologie erfolgte.
Im Fazit ergibt sich, dass es aus oben genannten Gründen (Fehlen von guten randomisierten, multizentrischen Studien mit ähnlichen Kohorten; unterschiedliche Techniken der MKC; lückenlose vs. nicht-lückenlose Aufarbeitung und Formaldehyd-fixiert vs. Gefrierschnitt) schwierig ist, zu sagen, wann eine MKC definitiv anzustreben ist. Gleichzeitig ist diese Frage sehr wichtig aufgrund der Tatsache, dass auch die neuen Immuntherapien nicht bei allen hilfreich sind bzw. eingesetzt werden können (bspw. Organtransplantierte), teuer sind und zahlreiche Nebenwirkungen haben. Insgesamt muss man festhalten, dass eine generelle Empfehlung alle PEK mit lückenloser MKC zu behandeln aktuell als nicht gerechtfertigt erscheint. Andererseits erscheint die gezielte Anwendung dieser Technik für bestimmte Hochrisikopatienten als sinnvolle Option.
8.2 Operatives Vorgehen nach R0-Resektion
8.2.1 Sicherheitsnachresektat nach R0-Resektion
Der Verlauf eines PEK der Haut kann verkompliziert werden durch lokales Wiederauftreten (lokale Rezidivrate), lokale Metastasenbildung in der Haut, Metastasenbildung in den regionalen Lymphknoten oder durch Fernmetastasen. Optimalerweise sollte die Entnahme eines Sicherheitsnachresektates, das Risiko eine dieser Komplikationen zu entwickeln, reduzieren.
Die Interpretation und ein Vergleich der oben beschriebenen Studien ist jedoch durch die Anwendung der unterschiedlichen Exzisionstechniken und histologischen Schnittrandkontrollen in Deutschland und auch durch die unterschiedlich angewendeten Techniken der MKC schwierig. Gleichzeitig zeigen jedoch die allermeisten der Studien, dass nach beiden Methoden (WLE und MKC) prinzipiell das Risiko sowohl für ein Lokalrezidiv als auch Metastasierung für Hochrisikoplattenepithelkarzinome nicht 0% beträgt. Ein Wiederauftreten des PEK geht mit einer schlechten Prognose einher, insbesondere wenn dieser Befund inoperabel ist [21][334]. Treten mehrere Risikofaktoren gleichzeitig auf, so verschlechtert dies zusätzlich das Gesamtüberleben [21].
In der aktuellen europäischen Leitlinie wird nach WLE bei low-risk PEK die Entnahme eines klinischen Sicherheitsabstandes von 5 mm und bei high-risk PEK von 6-10 mm zu den Seiten hin empfohlen [384]. Zur Tiefe wird eine Exzision des subkutanen Fettgewebes und bei entsprechender Lokalisation eine Mitnahme der Galea aponeurotica empfohlen [384]. Daten hierfür liegen praktisch nicht vor [361]. In der Schottischen Leitlinie wird nach WLE für ein low-risk PEK die Entnahme von mind. 4 mm und für high-risk PEK von mind. 6 mm empfohlen [362]. Weder die europäische, noch die schottische Leitlinie, kommentieren, ob nach lückenloser MKC die zusätzliche Entnahme eines Sicherheitsnachresektates bei bestimmten Hochrisikopatienten doch sinnvoll ist.
Aufgrund der Wichtigkeit der Frage bezüglich der Sicherheitsnachresektatabstände nach Exzision eines PEK, wurde versucht, anhand der eingeschränkten Datenlage Empfehlungen zu formulieren. Dabei wurde auch berücksichtigt, dass i.) unterschieden werden muss zwischen lückenloser vs. nicht-lückenloser Aufarbeitung und ii.) auch eine lückenlose Aufarbeitung der Schnittränder nicht davor schützt, dass sich Tumorzellen aus dem Primarius gelöst haben und in der direkten Peripherie des Tumors befinden können.
8.2.2 Wundverschluss nach Bestätigung der R0-Resektion
Solange eine R0-Resektion histologisch nicht bestätigt ist, soll ein Wundverschluss nur erfolgen, wenn die Resektionsräder postoperativ eindeutig zuzuordnen sind (z.B. keine Verschiebelappen).
- Konsens
- Starker Konsens (100%)
Evidenztabellen (1)
Therapie PEK chirurgisch + strahlentherapeutisch
Der histologische Befund im Paraffinschnittverfahren steht frühestens am Folgetag nach der Exzision zur Verfügung. Dabei werden auch die Areale subtotaler Exzision mitgeteilt. Die Wahrscheinlichkeit einer subtotalen Exzision steigt proportional mit der Tumorgröße und umgekehrt proportional mit dem Exzisionsabstand. Für die WLE wurde oben ausgeführt, dass die Raten der R1-Resektionen nach der Erstexzision zwischen 1-16%, im Mittel bei 6% liegen [387][390][391][392]. Nach MKC ist die Rate höher (bis 43% [55]) wegen der eher kleinen Resektionsabstände. Bei letzterem Verfahren wird international meist das Kryostat-Schnittverfahren angewandt. Eine Nachexzision kann dann zeitnah erfolgen.
Bei ungünstiger Lokalisation oder sehr großen Tumoren empfiehlt es sich, den Defekt bis zum Nachweis tumorfreier Schnittränder noch nicht plastisch zu verschließen. Das gilt insbesondere, wenn lokale Lappenplastiken geplant werden, da durch sie die Randabschnitte des Defektes mitunter verschoben werden können, was die spätere Zuordnung einer Nachexzision erschwert.
8.3 Wächterlymphknotenbiopsie
Es liegen keine validen Daten zur prognostischen und therapeutischen Wertigkeit der SLNB vor.
Evidenztabellen (1)
Therapie PEK chirurgisch + strahlentherapeutischEine Möglichkeit zur minimalinvasiven Lymphknotendiagnostik stellt die Entfernung eines oder mehrerer Wächterlymphknoten dar (sog. Sentinel-Lymphknoten, sentinel lymph node(s)=SLN) dar. Mittels eines radioaktiven Tracers oder eines Farbstoffes, welcher peritumoral infiltriert wird, werden Lymphabfluss und SLN dargestellt, welche daraufhin operativ entfernt und histopathologisch untersucht werden (Wächterlymphknotenbiopsie, sentinel lymph node biopsy, SLNB). Die Gütekriterien (Sensitivität, Spezifität, negativer prädiktiver Wert, falsch negative Rate) der SLNB beim PEK der Haut zeigen eine Sensitivität von 79%, eine Spezifität von 100% und einen negativ prädiktiven Wert von 96%, so dass das Verfahren rein technisch als zuverlässig eingestuft werden kann [423][420][424][425]. Vorteilhaft kann gerade im Kopf-Hals-Bereich und auch bei Rezidivtumoren oder nach Voroperationen die Möglichkeit der Darstellung auch untypischer Lymphabflusswege sein [426][427][428].
Dabei muss berücksichtigt werden, dass bei der primären therapeutischen Exzision von großen Tumoren (>20 mm Durchmesser, in der Literatur als high-risk Tumoren bezeichnet) ggf. mit Sicherheitsnachresektat naturgemäß relativ große Defekte entstehen. Damit wird der Lymphabstrom im Kopf-Hals-Bereich mit seiner komplizierten Lymphgefäßversorgung in aller Regel verändert. Das macht eine eventuell indizierte SLNB möglicherweise insuffizient, denn der Ort der Injektion entspricht dann nicht mehr nahe dem Tumorzentrum. Wenn also eine Lymphabstromszintigrafie im Rahmen einer SLNB geplant wird, sollte vor der Tumorexzision eine adäquate Probebiopsie erfolgen, um das Metastasierungsrisiko durch die histologischen Parameter so gut wie möglich zu bestimmen. Die Größe von >20 mm Durchmesser ist ohne Zusatzinformationen relativ unscharf und schließt noch viele low-risk Tumoren ein. Man würde dann durch eine SLNB nur mit diesem einzigen Parameter bei oft alten Patienten eine Überdiagnostik riskieren.
Nichtsdestotrotz kann eine generelle Empfehlung zur SLNB derzeit nicht ausgesprochen werden, da ausreichende und genügend valide Daten zur prognostischen und therapeutischen Wertigkeit einer SLNB fehlen [429][430][431][432][433][104]. Bisherige Studien konnten noch keine Vorteile bei SLNB bezüglich krankheitsspezifischem und Gesamtüberleben sowie metastasenfreiem Überleben mit statistischer Signifikanz beweisen [434].
Die meisten verfügbaren Daten befassen sich mit dem Einsatz der SLNB bei Hochrisikoprofil (siehe Kapitel 6.1.1 Risikofaktoren für den loko-regionalen Progress und tumorspezifisches Überleben). Zahlreiche Studien führen einen potenziellen Nutzen (Detektion klinisch okkulter Mikrometastasen, Vermeidung unnötig umfangreicher Lymphadenektomien mit höherer Morbidität im Vergleich zur SLNB) beim high-risk PEK, bei dem mit einem Metastasierungsrisiko >10% zu rechnen ist, an. Eine rezente Arbeit untersuchte 720 Patienten mit Hochrisiko-PEK, von denen 150 eine SLNB erhielten [435]. Es konnte gezeigt werden, dass Patienten, welche eine Wächterlymphknotenbiopsie erhielten, keinen Vorteil hinsichtlich weiterer Metastasierung oder tumorspezifischem Tod zeigten. Damit zeigt sich weiterhin kein Benefit einer SLN-Entnahme beim PEK der Haut, obwohl natürlich Komplikationen der SLNB (siehe Studien beim Mammakarzinom und Melanom) selten sind (3-5%) und primär Lymphödeme, Infektionen, Hämatome, Serome, kutane Lymphfisteln und Nahtdehiszenzen beinhalten [436][428][429][104][437][438][439][440].
8.4 Prophylaktische und therapeutische Lymphadenektomie
Eine regionäre (therapeutische) Lymphadenektomie sollte bei einer klinisch manifesten Lymphknotenmetastase erfolgen.
- Empfehlungsgrad
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Evidenzlevel
- 3
- Konsens
- Starker Konsens (100%)
- Literatur
- [433] [441] [442] [443] [444]
Evidenztabellen (1)
PEK LK DissektionFür das kutane PEK ist ein (prospektiver) Nutzen einer prophylaktischen (elektiven) Lymphknotendissektion in Bezug auf krankheitsspezifisches und Gesamtüberleben bisher nicht belegt [443][445]. Ein Nutzen ist erst ab einer Metastasierungshäufigkeit von über 20% zu erwarten, für den Kopf-Hals-Bereich konnte eine Studie hier einen zu erwartenden Nutzen erarbeiten [444]. (Nutzwert „utility“ für jede Behandlung ist ein Gewichtungsschema für den erwarteten Wert jedes Gliedes des Entscheidungsbaums. Utilities sind numerische Werte, die die Präferenz einer Person für unterschiedliche Gesundheitsergebnisse nach der Behandlung darstellen. Jeder Versorgungszustand hat einen Zahlenwert zwischen 0 und 1; der Tod wird traditionell mit 0 bewertet, während ein krankheitsfreier Zustand ohne signifikante Auswirkungen der Behandlung mit 1 bewertet wird.). Lediglich bei sehr fortgeschrittenen Stadien (wie z.B. einer Schädelbasisnähe oder nodaler Metastasierung im Parotisgebiet) berichten einzelne Studien (retrospektive Fallserien) über einen Benefit durch eine elektive Neck-Dissection im Kopf-Hals-Bereich [446][447].
In den europäischen konsensusbasierten Leitlinien wird eine therapeutische Lymphknotendissektion bei klinisch (cN+ im Staging, Makrometastase) oder histologisch gesicherter Metastase (pN+, Mikro- oder Makrometastase im SLN, durch Feinnadelbiopsie oder durch Lymphknotenentfernung gesicherte Metastase) empfohlen [104]. Sie umfasst in der Regel und nach Empfehlung der meisten Autoren neben der Region bzw. dem Level der gesicherten Metastase auch die jeweils direkt angrenzenden Level (Adaptation aus der S3-Leitlinie „Mundhöhlenkarzinom“ [445]. Ausreichende Daten für eine evidenzbasierte Entscheidung zum Ausmaß (Level, Radikalität) der notwendigen therapeutischen Lymphadenektomie bei cN+/ pN+-Situation existieren nicht [448][449]. Die Datenlage rechtfertigt eine therapeutische Lymphadenektomie bei cN+ /pN+ durch eine zu erwartende bessere lokoregionäre Tumorkontrolle und – je nach Ausmaß der nodalen Metastasierung – partiell auch des krankheitsspezifischen Überlebens, wobei eine adjuvante Radiatio bei pN+ zusätzlich durchgeführt wurde [450][451][448][428][442][447][452][453][454].
Eine therapeutische Lymphknotendissektion soll nur dann erfolgen, wenn bezüglich des Allgemeinzustandes (Operabilität) und im Rahmen des Gesamtkonzeptes ein operatives Vorgehen möglich und sinnvoll erscheint. Dieses setzt die Intention einer R0-Resektabilität der Metastase(n) voraus (lokale Operabilität). Sind allgemeine und lokale Operabilität nicht gegeben, sollte nicht-operativen Therapiemodalitäten im Rahmen einer interdisziplinären Tumorboard-Entscheidung der Vorzug gegeben werden.
8.5 Lymphadenektomie im Kopf-Hals-Bereich
In der Kopf-Hals-Region besteht in der Literatur keine Einigkeit über das Ausmaß einer Lymphknotenausräumung. Entscheidender Faktor ist insbesondere die Lokalisation des Primärtumors.
Für einige wenige Lokalisationen wird ein recht konstanter Lymphabflussbereich beschrieben, so z.B. für den Bereich der Unterlippe der Lymphabfluss in die submentalen und submandibulären Lymphknoten sowie hoch-zervikalen Lymphknoten (Level Ia, Ib und II nach Robbins et al.) [455][456][457][458].
Die meisten Lokalisationen weisen einen sehr variablen Lymphabfluss auf. So werden allein für die Ohrregion verschiedenste Lymphdrainagewege beschrieben: nach retroaurikulär und okzipital, nach infraaurikulär, in die zervikalen Level II, III und IV sowie in die parotidealen Lymphknoten [459][460][461]. Auch für andere Regionen des Kopf-Hals-Bereiches trifft dieser variable Lymphabfluss, der bei mittelliniennaher Lokalisation des Tumors auch die kontralateralen Lymphabstromgebiete mit einschließen kann, zu [441][462][443][463][464]. So konnte gezeigt werden, dass bei Hauttumoren des Kopf-Hals-Bereiches in 7% ein kontralateraler Wächterlymphknoten vorliegt [465]. Insbesondere der Lymphabfluss in das Parotisgebiet ist auch unter klinisch-chirurgischen Gesichtspunkten durch Nähe zum N. facialis von Bedeutung, welcher wenn irgend möglich im Rahmen einer Lymphadenektomie/ Parotidektomie erhalten und geschont werden sollte [466][467][466][467].
Wenn möglich, sollte eine schonende, sog. selektiv-funktionelle Ausräumung unter Erhalt der funktionell bedeutsamen Strukturen (insbesondere Nerven, Muskeln und Gefäße) erfolgen. Nur bei ausgedehnter Metastasierung werden radikale Dissektionen empfohlen mit dann erhöhter Morbidität. In Analogie zum Mundhöhlenkarzinom sind die Ergebnisse einer selektiven Neck-Dissection bezüglich Tumorkontrolle, krankheitsspezifischem und Gesamtüberleben denen einer modifiziert-radikalen oder radikalen Neck-Dissection nicht unterlegen (Adaptation aus der S3-Leitlinie zum Mundhöhlenkarzinom) [468][469][470][471][472].
8.6 Strahlentherapie und postoperative Radiatio
Bei lokal nicht in sano resezierbaren Tumoren oder inoperablen Patienten sollte eine Radiotherapie durchgeführt werden.
- Empfehlungsgrad
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Evidenzlevel
- 3
De-novo-Recherche
- Konsens
- Starker Konsens (100%)
- Literatur
- [405] [473] [474] [475] [476] [477]
Evidenztabellen (1)
PEK StrahlentherapieProspektiv randomisierte Studien, welche die Effektivität einer primären Radiotherapie hinsichtlich lokaler Tumorkontrolle und Überleben der Patienten im Vergleich zu anderen lokalen Therapiemodalitäten vergleichen, liegen nicht vor. Retrospektive Untersuchungen zeigen jedoch eine hohe lokale Tumorkontrolle nach primärer Bestrahlung. Mendenhall berichtet für ein 245 Patienten umfassendes Kollektiv von einer Lokalrezidivrate von 6,0%/ 10,5%/ 12,8% nach 5/ 10/ 15 Jahren. Dabei war die Lokalrezidivrate abhängig von der initialen Tumorgröße. Bei T1-Tumoren lag sie nach 15 Jahren bei 1,7%, bei T2-Tumoren nach 5/ 10/ 15 Jahren bei 7,4%/ 14,2%/ 19,0% und bei T3-Tumoren nach 5/ 10 Jahren bei 25%. Mendenhall empfiehlt daher bei größeren Tumoren eine Bestrahlungsdosis von 70 Gy, bei kleineren eine von 60-70 Gy [478]. Lansbury kommt in einer 14 meist retrospektive Studien umfassenden Metaanalyse über 1018 primär bestrahlte Patienten mit kutanen PEK zu ähnlichen Ergebnissen [405]. Für Studien mit einer mittleren Beobachtungszeit von 2 bis 5 Jahren berichtet er von einer durchschnittlichen Rezidivrate von 6,1%.
Inwieweit bei großen oder initial lymphogen metastasierten Tumoren eine simultane Chemotherapie die Effektivität einer primären Radiotherapie steigern kann, ist nicht an großen Patientenkollektiven mit kutanen PEK geklärt.
In der Literatur ist eine Vorgehensweise in Analogie zur Behandlung fortgeschrittener mukosaler PEK [474][475] beschrieben. So berichtet Nottage von 21 Patienten, welche in einer prospektiven Phase-II-Studie primär bestrahlt (Gesamtdosis 70 Gy, Einzeldosis 2 Gy) und simultan mit Chemotherapie (Cisplatin 40mg/ m2 oder Carboplatin AUC2 wöchentlich) behandelt wurden. Von 19 auswertbaren Patienten entwickelten 10 eine komplette Remission, 2 Tumoren waren nach Radiochemotherapie operabel und konnten komplett reseziert werden [476]. Tanvetyanon et al. berichteten bei 67 Patienten, dass eine adjuvante Radiochemotherapie mit Cisplatin signifikant das Risiko eines Rezidivs in einer multivariablen Analyse senkte: Hazard-Ratio (HR) 0,31. Allerdings wurde kein Unterschied im Gesamtüberleben festgestellt [479]. Für ein sehr kleines Patientenkollektiv mit rezidivierenden Tumoren berichtet Sharon von der Möglichkeit neben einer Platin-basierten Chemotherapie auch alternativ eine Therapie mit Antikörpern (Cetuximab) simultan zur Radiotherapie durchführen zu können [477]. Die Strahlentherapie mit entweder gleichzeitigem Platin oder Cetuximab scheint ähnliche klinische Ergebnisse bei Patienten mit lokal fortgeschrittenem kutanen PEK des Kopf-Hals-Bereichs zu bieten.
Eine postoperative Radiotherapie sollte durchgeführt werden bei:
- R1- bzw. R2-Resektion (bei fehlender Möglichkeit der Nachresektion)
- Ausgedehntem Lymphknotenbefall (>1 befallenem Lymphknoten, Lymphknotenmetastase >3cm, Kapseldurchbruch)
- Intraparotidealem Lymphknotenbefall
- Empfehlungsgrad
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Evidenzlevel
- 2
De-novo-Recherche
- Konsens
- Starker Konsens (100%)
- Literatur
- [104] [473] [479] [366] [368] [480] [481] [482] [483] [484] [485]
Evidenztabellen (1)
PEK StrahlentherapieEine adjuvante Radiotherapie sollte bei Vorliegen einer ausgedehnten Perineuralscheideninfiltration durchgeführt werden.
- Empfehlungsgrad
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Evidenzlevel
- 2
De-novo-Recherche
- Konsens
- Starker Konsens (100%)
- Literatur
- [104] [366] [368] [473] [479] [480] [481] [482] [483] [485] [484]
Änderungshinweis
Eine adjuvante Radiotherapie sollte bei Vorliegen von Risikofaktoren durchgeführt werden: Knapper Resektionsrand (<2 mm, bei fehlender Möglichkeit der Nachresektion) Ausgedehnter PerineuralscheideninfiltrationEvidenztabellen (1)
PEK StrahlentherapieEine adjuvante Radiotherapie kann bei knappem Resektionsrand erwogen werden.
- Empfehlungsgrad
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Evidenzlevel
- 2
De-novo-Recherche
- Konsens
- Starker Konsens (90,5%)
- Literatur
- [104] [366] [368] [473] [479] [480] [481] [482] [483] [485] [484]
Änderungshinweis
Eine adjuvante Radiotherapie sollte bei Vorliegen von Risikofaktoren durchgeführt werden: Knapper Resektionsrand (<2 mm, bei fehlender Möglichkeit der Nachresektion) Ausgedehnter PerineuralscheideninfiltrationDie aktuelle Datenlage lässt keine Empfehlung für eine Kombination einer adjuvanten Radiotherapie mit einer Systemtherapie zu.
Evidenztabellen (1)
PEK StrahlentherapieFür die folgende Überarbeitung im Rahmen der Aktualisierung der Leitlinie 2020/2021 erfolgte eine systematische Update-Recherche für den Zeitraum Januar 2017 bis Mai 2021. Systematische Reviews, randomisierte Studien und Fallserien > 200 Patienten wurden einbezogen.
Eine generelle postoperative Radiotherapie des kutanen PEK ist nicht indiziert, sondern sollte nur bei Vorliegen von Risikofaktoren für ein lokales oder lokoregionäres Rezidiv angeboten werden. Zu den Risikofaktoren, welche in der Literatur teilweise widersprüchlich diskutiert werden, gehören R1- oder R2-Resektion, knapper Resektionsrand (<2 mm bei fehlender Option einer Nachresektion), Rezidivtumor, maximale Tumorgröße (>2 cm), maximale Eindringtiefe (>4 mm), Infiltration von Fettgewebe, PNI und ausgedehnter lymphogener Befall (>1 befallener Lymphknoten, Kapseldurchbruch) [365][481][368][489][362][479][480][366][490].
In einem aktuellen systematischen Review mit Metaanalyse wurde der Einfluss der postoperativen Radiotherapie bei Patienten mit kutanem PEK betrachtet (n=2605 Patienten, n=20 Studien) [485]. Die adjuvante Strahlentherapie erreichte signifante Verbesserungen des Gesamtüberlebens (OR 2,94; 95% KI, 1,75-4,91; p<0.0001), des krankheitsfreien Überlebens (OR 2,17; 95% KI, 1,23-3,83; p=0,008) und der Rezidivrate (OR 0,56; 95% KI, 0,36-0,85; p=0,006). In der Subgruppe von Patienten mit freien Schnitträndern führte die postoperative Strahlentherapie zu einem verbesserten krankheitsfreien Überleben (OR 2,53; 95% KI 1,24-5,14; p=0,01), das Gesamtüberleben wurde nicht analysiert. Im Gesamtkollektiv identifizierte eine multivariate Analyse von Risikofaktoren für das Gesamtüberleben folgende signifikante Faktoren: Einsatz der Strahlentherapie (Verbesserung mit HR 0,47; 95% KI, 0,34-0,65; p<0,00001) sowie PNI (HR 1,61; 95% KI, 1,24-2,09; p=0,0004), positive Schnittränder (HR 2,34; 95% KI 0,34-0,65; p=0,0008) und Immunsuppression (HR 3,02; 95% KI 2,14-4,25; p<0,00001) [485].
Ein weiterer systematischer Review mit Metaanalyse evaluierte den Stellenwert der postoperativen Strahlentherapie bei Patienten mit kutanem PEK der Kopf-Hals-Region und regionärer Lymphknotenmetastasierung (n=3534 Patienten aus 20 Beobachtungsstudien und einer randomisierten Studie) [484]. Die adjuvante Radiotherapie war in der Metaanalyse signifikant mit einem verbesserten Gesamtüberleben assoziiert (HR 0,45, 95% KI 0,26-0,78; p=0,005), während als signifikante Risikofaktoren Immunsuppression (HR 2,66, 95% KI 2,26-3,13; p<0,0001), Kapseldurchbruch (HR 1,90, 95% KI 1,12-3,22; p=0,02), der Anteil befallener Lymphknoten (HR 1,91, 95% KI 1,09-3,35; p=0,02) und das Alter (HR 1,03, 95% KI 1,00-1,07; p=0,05) ermittelt wurden. Der Einsatz der postoperativen Strahlentherapie war auch mit einem verbesserten krankheitsspezifischen Überleben assoziiert (HR 0,52, 95% KI 0,33-0,84; p=0,008).
Eine postoperative Radiotherapie nach R1- oder R2-Resektion sowie nach knapper Resektion (<2 mm) ohne die Möglichkeit einer Nachresektion wird als obligat angesehen [368][362][104][479][480]. In einer Metaanalyse konnten für knappe oder unklare Resektionsränder zwar keine unterschiedlichen Lokalrezidivraten zwischen alleiniger Operation und Operation und postoperativer Radiotherapie festgestellt werden. Die Autoren leiten aber die Effektivität einer postoperativen Radiotherapie ab aufgrund der Tatsache, dass bei beiden Therapiemodalitäten die Rezidivraten gleich waren, obwohl die bestrahlten Patienten größere Tumoren aufwiesen [368]. Daher empfiehlt Veness in dieser Situation eine Radiotherapie mit einer Gesamtdosis von 50-60 Gy [480]. Es liegt keine Literatur vor, welche die maximale Tumorgröße oder Infiltrationstiefe als obligate Indikationen für eine postoperative Radiotherapie angibt. Beide Risikofaktoren müssen daher als fakultativ angesehen werden und können gegebenenfalls im Sinne einer Individualentscheidung herangezogen werden. Obwohl keine prospektiven Studien zur PNI als Indikation für eine postoperativen Radiotherapie vorliegen, weisen 2 Reviews sowie 3 weitere Publikationen darauf hin, dass das Lokalrezidivrisiko bei PNI durch eine postoperative Radiotherapie reduziert werden kann [365][481][368][104][366][490]. Dabei sind das Ausmaß der Infiltration und die Größe des infiltrierten Nervs von Bedeutung. Han gibt für eine mikroskopische PNI lokale Kontrollraten von 78-87%, für makroskopische PNI von 50-55% an, während nach postoperativer Radiotherapie die lokale Kontrolle bei selektierten Patienten bei 100% lag [481]. Bei Vorliegen eines ausgedehnten Befalls der zervikalen Lymphknoten (>1 befallener Lymphknoten, Lymphknotenmetastase >3cm, Kapseldurchbruch) ist eine postoperative Radiotherapie obligat [491][492][442][493][483][454][482]. Dadurch werden nicht nur die Lokalrezidivrate [492][442][493][483][454][482] und das krankheitsfreie Überleben [483][454], sondern auch das Gesamtüberleben verbessert [442][493][483][454][482]. In einer 122 Patienten umfassenden retrospektiven Studie betrugen die Lokalrezidivrate, das 5-Jahres krankheitsfreie Überleben und das Gesamtüberleben für die alleinig operierten Patienten 55%, 34% und 27%, für die zusätzlich postoperativ bestrahlten 23%, 74% und 66% [482]. Die Bestrahlungsdosis lag dabei zwischen 50 und 60 Gy [442]. Eine besondere Situation liegt bei intraparotidealen Lymphknotenmetastasen vor, da hier immer eine postoperative Radiotherapie empfohlen wird [494][495]. Literaturangaben über die Vorgehensweise bei Lymphknotenmetastasen der Axilla und der Leistenregion sind spärlich und orientieren sich im Wesentlichen an der Indikation zur postoperativen Radiotherapie in der Halsregion [494].
Zur Frage der Rolle einer postoperativen Radiochemotherapie bei Vorliegen von Risikofaktoren kann die randomisierte Phase-III-Studie TROG 05.01 herangezogen werden, die n=310 Patienten mit makroskopisch komplett reseziertem (R0 oder R1) kutanem Hochrisiko-PEK der Kopf-Hals-Region nach folgenden Kriterien einschloss: Vorliegen von intraparotidealer Lymphknotenmetastase oder Lymphknotenmetastase mit mindestens einem der Kriterien (≥ 2 Lymphknoten oder Kapseldurchbruch oder größter Lymphknoten > 3cm) oder fortgeschrittener Primärtumor (> 5cm oder T4 oder In-Transit Metastase) [486]. Verglichen wurde die postoperative Strahlentherapie mit 60-66 Gy mit einer Radiochemotherapie 60-66 Gy mit Carboplatin wöchentlich AUC 2 (maximal 6 Gaben). Im primären Endpunkt Freiheit von lokoregionärem Rezidiv zeigte sich kein Vorteil der Radiochemotherapie, sie betrug nach 5 Jahren für die alleinige Strahlentherapie 83% und für die Radiochemotherapie 87% (HR 0,84, 95% KI 0,46-1,55; p=0,58). Auch das 5-Jahres-Gesamtüberleben war vergleichbar, es betrug für die Strahlentherapie 76% und für die Radiochemotherapie 79% (HR 0,95, 95% KI 0,58-1,57) [486].
Ein Review zeigte 2019 ebenfalls keinen Benefit in der Ergänzung von Carboplatin im Rahmen einer adjuvanten Radiotherapie voroperierter Patienten verglichen mit der single Radiotherapie. Eine retrospektive Analyse von 104 Patienten mit lokal fortgeschrittenem kutanen PEK, die bereits operativ inklusive Parotidektomie und Neck-Dissection versorgt worden waren, konnte keinen signifikanten Unterschied bezüglich der Rezidivfreiheit zwischen Radiochemotherapie vs. Radiotherapie feststellen bei einem 2-Jahres-krankheitsfreien Überleben von 65% vs. 58% (p=0.43) [487].
In einer Propensity-Score-gematchten Analyse wurde der Effekt einer Kombination von postoperativer Strahlentherapie mit Cetuximab bei kutanem Hochrisiko-PEK (wenig differenziert, PNI, lymphovaskuläre Invasion, positiver Schnittrand, Lymphknotenbefall, Rezidiv, Immunsuppression oder Lokalisation Ohr / Wange / Lippe) der Kopf-Hals-Region betrachtet (n=68) [488]. Sowohl das 5-Jahres-Gesamtüberleben (80% vs. 61%) als auch das 5-Jahres-progressionsfreie Überleben (66% vs. 29%) waren vorteilhaft für die Gruppe mit Cetuximab, die Unterschiede waren aber nicht signifikant.
Zusammenfassend zeigt sich in mehreren Studien mit heterogenen und teils sehr kleinen Patientenkollektiven für die platinbasierten Chemotherapien in Kombination mit Radiotherapie kein oder kein statistisch signifikanter Benefit bezüglich Gesamtüberleben, krankheitsspezifischem Überleben und Rezidivfreiheit im Vergleich zur Radiotherapie alleinig. Der Einsatz von EGFR-Rezeptorantagonisten in Kombination mit Radiotherapie ist insbesondere zu diskutieren bei Patienten, die Kontraindikationen für den Einsatz von Checkpoint-Inhibitoren sowie ein erhöhtes Risiko für Lokalrezidive und Metastasierung aufweisen wie z.B. organtransplantierte Patienten.
Die Kombination von Checkpoint-Inhibitoren und Radiotherapie ist bislang beim kutanen PEK wenig untersucht. Mehrere klinische Studien überprüfen derzeit den Einsatz dieser therapeutischen Option in der Adjuvanz unter Einsatz unterschiedlichen Checkpoint-Inhibitoren. Ergebnisse dieser Studien müssen für künftige therapeutische Empfehlungen abgewartet werden.
Bei einem lokalen oder lokoregionären Rezidiv gelten die gleichen Kriterien für die Indikation zu einer postoperativen Radiotherapie wie in der primären Situation [496].
8.7 Therapie des lokalen bzw. loko-regionären Rezidivs
Ein lokoregionäres Rezidiv soll, wenn klinisch lokal möglich, chirurgisch entfernt werden.
- Konsens
- Starker Konsens (100%)
Evidenztabellen (1)
PEK LokalrezidivDabei soll die Mikrographisch kontrollierte Chirurgie (MKC) zur Anwendung kommen.
- Empfehlungsgrad
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Evidenzlevel
- 2
De-novo-Recherche
- Konsens
- Starker Konsens (100%)
- Literatur
- [473] [481] [493] [495] [104] [355] [366] [368] [479] [482] [483] [496] [364]
Evidenztabellen (1)
PEK LokalrezidivFalls sich im Verlauf der Resektion eine nicht weiter resektable R1- bzw. R2-Situation ergibt, sollte eine Nachbestrahlung an der R1- bzw. R2-Lokalisation erfolgen (siehe Kapitel 6.5 Strahlentherapie und postoperative Radiatio).
- Empfehlungsgrad
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Evidenzlevel
- 2
De-novo-Recherche
- Konsens
- Starker Konsens (100%)
- Literatur
- [355] [493] [495] [496] [364]
Evidenztabellen (1)
PEK LokalrezidivBei interdisziplinär festgestellter Inoperabilität sollte eine Strahlentherapie erfolgen (siehe Kapitel 6.5 Strahlentherapie und postoperative Radiatio).
- Empfehlungsgrad
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Evidenzlevel
- 3
De-novo-Recherche
- Konsens
- Starker Konsens (100%)
- Literatur
- [355] [493] [495] [496] [364]
Evidenztabellen (1)
PEK LokalrezidivZur Therapie eines lokalen bzw. lokoregionären Rezidivs sollte die Indikation zur Elektrochemotherapie oder eine Systemtherapie geprüft werden, sofern keine chirurgischen oder strahlentherapeutischen Optionen zur Verfügung stehen.
- Konsens
- Konsens (93,3%)
Evidenztabellen (1)
PEK LokalrezidivLokalrezidive haben oft eine ausgedehntere, irreguläre subklinische Infiltration als Primärtumoren, die mit der Brotlaib-Histologie nur unzureichend erfasst wird. Desmoplastische PEK rezidivieren häufiger trotz Anwendung einer lückenlosen MKC [364][355]. Tod an einer lokalen Infiltration ist bei diesem Typ nicht selten [21]. Somit ist bei Rezidiven nach MKC nach chirurgischer Therapie eine Nachbestrahlung empfehlenswert. Insgesamt wird entsprechend der Literatur bei Nachbestrahlung die Rezidivrate verringert und ein längeres rezidivfreies Überleben erreicht, verglichen mit einer alleinigen chirurgischen Therapie [481][368][473][104][479][480][483][482][366].
Sollte eine Inoperabilität vorliegen und eine Radiatio nicht möglich sein, kann eine Elektrochemotherapie zur Verbesserung der lokalen Tumorkontrolle erfolgen, die Ansprechrate wurde mit 46% angegeben [497][498][499]. Des Weiteren kann geprüft werden, ob eine Systemtherapie möglich ist (siehe Kapitel 6.7 Therapie im fernmetastasierten Stadium).
8.8 Therapie im fortgeschrittenen (lokal fortgeschrittenen bzw. metastasierten) Stadium
8.8.1 Indikation zur Systemtherapie
Im Falle einer (Fern-) Metastasierung oder einer lokal fortgeschrittenen Erkrankung, die nicht oder nur mit größeren Einschränkungen der Funktionalität durch operative oder strahlentherapeutische Interventionen kontrolliert werden kann, soll die Indikation zur Systemtherapie geprüft werden.
- Konsens
- Starker Konsens (100%)
Evidenztabellen (1)
PEK SystemtherapieDie Indikation zur Systemtherapie sollte in einem interdisziplinären Tumorboard gestellt werden.
- Konsens
- Konsens (89%)
Es besteht ein internationaler Konsens darüber, dass metastasierte Hauttumorerkrankungen im Allgemeinen und fortgeschrittene kutane PEK im Speziellen in einem interdisziplinären Tumorboard diskutiert werden sollen.
Die Möglichkeit des Einschlusses in klinische Studien sollte in jedem Fall geprüft werden.
Während eine Fernmetastasierung klar durch radiologische Kriterien (RECIST) in der Bildgebung definiert ist, fällt die Definition einer „lokal fortgeschrittenen PEK-Erkrankung“ schwerer. In den klinischen Studien zur Zulassung der PD-1-Antikörper Cemiplimab (REGN-1540) bzw. Pembrolizumab (KEYNOTE-630) wurde der Studieneinschluss nur dann möglich, wenn ein interdisziplinäres Tumorboard potenzielle Patienten diskutiert hatte. Nur wenn im Tumorboard keine kurative Option (Operation oder Strahlentherapie) gesehen wurde oder diese nur mit größeren Einschränkungen der Funktionalität durchgeführt werden könnte, wurde der Studieneinschluss möglich. Vor allem sollte die Sinnhaftigkeit einer Operation im Vergleich zu den Aussichten einer systemischen Therapie sorgfältig abgewogen werden.
Eine international akzeptierte Definition der lokal fortgeschrittenen PEK-Erkrankung gibt es aber bis dato nicht. Beim Basalzellkarzinom wurde kürzlich durch die European Association of Dermato-Oncology eine Unterteilung beim fortgeschrittenen Basalzellkarzinom vorgestellt, die 5 Subgruppen unterscheidet. Auch die Deutsche Leitlinie zum Basalzellkarzinom enthält eine Begriffsdefinition für die „lokal fortgeschrittene Erkrankung“. Die EADO erarbeitet derzeit an einer PEK-Datensammlung einen ähnlichen internationalen Expertenkonsensus auch beim fortgeschrittenen PEK.
Zusammengefasst sollte jeder Patient mit einem fernmetastasierten oder einem lokal fortgeschrittenen PEK in einem interdisziplinären Hauttumorboard vorgestellt und die Lokal- und Systemtherapieoptionen sorgfältig in Bezug auf Nutzen und Risiken abgewogen werden. Hierbei soll stets der Einschluss in eine klinische Studie geprüft.
8.8.2 Durchführung der Systemtherapie
Bei Patienten mit lokal fortgeschrittenem oder metastasiertem PEK soll in der Erstlinie eine Immuntherapie mit einem für diese Indikation zugelassenen PD‐1‐Inhibitor angeboten werden.
- Konsens
- Starker Konsens (100%)
Bei Progress unter PD‐1‐Blockade oder bei Kontraindikationen gegen diese Art von Immuntherapie soll eine EGFR‐gerichtete Therapie oder Chemotherapie angeboten werden.
- Konsens
- Starker Konsens (100%)
Besteht eine Indikation zur Systemtherapie, dann liegt für PD1-Inhibitoren die beste Datenlage aus allerdings nur unkontrollierten Studien vor (siehe hier). PEK weisen eine sehr hohe Mutationslast auf [500], welche bei anderen Tumorentitäten mit einem Ansprechen auf PD1-Inhibitoren assoziiert sind. Daten mit dem PD1-Antikörper Cemiplimab und Pembrolizumab (siehe hier) zeigen Ansprechraten von 41-50%, die mediane Dauer des Ansprechens war nach einer medianen Nachbeobachtung von 8.1-22.4 Monaten noch nicht erreicht (siehe hier).
In einer retrospektiven monozentrischen Fallserie der Universitätshautklinik Tübingen wurden 57 Patienten mit fortgeschrittenem PEK erfasst, die eine Systemtherapie erhalten hatten [501]. Bei dem Vergleich des Gesamtüberlebens von 20 Patienten, die zu irgendeinem Zeitpunkt eine Immuntherapie erhalten hatten, mit 37 Patienten, die keine Immuntherapie, sondern Chemotherapie und/oder EGFR-Inhibitor erhalten hatten, zeigte sich ein signifikanter Vorteil für die Patienten mit Immuntherapie. Das deutet darauf hin, dass die Immuntherapie in Bezug auf das Gesamtüberleben vorteilhaft sein könnte.
Eine weitere retrospektive Fallserie 6 deutscher Hauttumorzentren berichtete 46 Patienten mit fortgeschrittenem PEK, welche einen PD1-Inhibitor erhalten hatten [502]. Die Ansprechrate war 58.7% und war unabhängig davon, ob ein lokal fortgeschrittenes oder metastasiertes Stadium vorlag. Medianes PFS und OS waren nicht erreicht, das PFS nach 12 Monaten war 58.8%. Als ungünstige Faktoren für einen Benefit von der Checkpoint-Blockade zeigten sich ein erhöhtes LDH und eine Lokalisation des Primärtumors im Bereich der Beine.
Zusammengefasst scheint die Ansprechrate von PD1-Inhibitoren höher zu sein bei Patienten mit fortgeschrittenem PEK auf chronisch lichtgeschädigter Haut (mit hoher Mutationslast) ohne Vorbehandlung, während Vorbehandlung und Primärtumoren auf nicht-lichtexponierter Haut (mit geringerer Mutationslast) niedrigere Ansprechraten zeigen.
Tabelle 36: Laufende Therapiestudien mit dem Einsatz von PD1-Blockern beim kutanen PEK (NBZ=Nachbeobachtungszeit)
|
Therapie |
Linie |
Studienphase |
Anzahl auswertbare Patienten |
Mediane Ansprechdauer (Monate) |
Ansprechraten |
Referenz |
|
Cemiplimab |
Jede |
1 |
26 |
nicht erreicht (mediane NBZ 11.1 Monate) |
50% |
Migden et al., 2018 [503] |
|
Cemiplimab (Kohorte 1, Gewichtsadaptierte Dosis alle 2 Wochen) |
Jede |
2 |
59 (mit Metastasen) |
nicht erreicht (mediane NBZ 16.5 Monate) |
49.2% |
Migden et al., 2018 [503] Rischin et al., 2020 [504] |
|
Cemiplimab (Kohorte 2, Gewichtsadaptierte Dosis alle 2 Wochen) |
Jede |
2 |
78 (lokal fort-geschritten) |
nicht erreicht (mediane NBZ 9.3 Monate) |
44% |
Migden et al., 2020 [505] |
|
Cemiplimab (Kohorte 3, fixe Dosis alle 3 Wochen) |
Jede |
2 |
56 (mit Metastasen) |
nicht erreicht (mediane NBZ 8.1 Monate) |
41.1% |
Rischin et al., 2020 [504] |
|
Pembrolizumab (CARSKIN) |
1. |
2 |
39 |
nicht erreicht (mediane NBZ 22.4 Monate) |
41% |
Maubec et al., 2020 [506] |
|
Pembrolizumab |
Jede |
2 |
29 |
|
|
|
|
Pembrolizumab+ Strahlentherapie |
Postoperativ adjuvant |
2 |
37 |
|
|
|
|
Pembrolizumab (Keynote 629) |
Jede |
2 |
105 |
nicht erreicht (mediane NBZ 11.4 Monate) |
34% |
Grob et al., 2020 [507] |
Neben den Studien zu den PD-1 Inhibitoren gibt es zumeist ältere Daten für verschiedene Chemotherapien und EGFR-Inhibitoren.
Ein 2011 publiziertes systematisches Review zur Systemtherapie des lokal fortgeschrittenen kutanen PEK fasst 28 Studien mit 119 Patienten zusammen, die in den Jahren 1970-2011 publiziert wurden [508]. Dabei wurde als wichtige Limitierung klar, dass es nur unkontrollierte Studien mit wenigen Patienten zu dieser Fragestellung gibt, das „Level of Evidence“ wurde mit 2-3 bewertet (2=randomized trial or (exceptionally) observational study; 3=non-randomized controlled cohort/follow-up study, Non -randomized controlled cohort/follow-up study) und entspricht einer Empfehlung B (entsprechende Level 2 oder 3 Studien) bzw. C (Level 4 Studien oder Extrapolation von Level 2 oder 3 Studien). Daher sind die Daten zur Effizienz mit (starken) Unsicherheiten behaftet. Über die verschiedenen Therapien hinweg wurde eine mittlere Zeit bis zum Ansprechen von 9 Wochen bei einer Gesamtansprechrate von 72% und einer mittleren Ansprechdauer von 42 Wochen gesehen.
In einer 2018 publizierten retrospektiven Fallserie wurden in 24 deutschen und österreichischen Zentren insgesamt 190 Patienten mit fortgeschrittenem PEK aus den Jahren 2010 und 2011 dokumentiert [509]. 78 Patienten hatten ein lokal fortgeschrittenes PEK, 114 Patienten ein metastasiertes PEK. 32 Patienten erhielten eine Systemtherapie, wobei verschiedene Chemotherapeutika und EGFR-Inhibitoren alleine oder in Kombination zum Einsatz kamen. Die Ansprechrate lag bei 26%, die mittlere Dauer des Ansprechens bei 5 Monaten.
Tabelle 37: Therapiestudien zum Einsatz von Chemotherapeutika, Interferon alpha und 13-cis Retinsäure bei kutanem PEK
|
Therapie |
Linie |
Studienphase |
Anzahl auswertbare Patienten |
Mediane Ansprechdauer (Monate) |
Ansprechraten |
Referenz |
|
Cisplatin + Doxorubicin |
Zum Teil neoadjuvant |
2 |
12 |
8.6 |
58% |
Guthrie et al., 1990 [510] |
|
Cisplatin + 5-Fluorouracil + Bleomycin |
vorbehandelt |
2 |
13 |
11.7 |
84% |
Sadek et al., 1990 [511] |
|
Cisplatin + 5-Fluorouracil |
1. |
2 |
7 |
11.8 |
86% |
Khansur et al., 1991 [512] |
|
Orales 5-Fluorouracil |
1. |
2 |
15 |
30 |
14% |
Cartei et al., 2000 [513] |
|
Interferon alpha + 13-cis Retinsäure |
1. |
2 |
28 |
5 |
68% |
Lippman et al., 1992 [514] |
|
Interferon alpha+ 13-cis Retinsäure+ Cisplatin |
1. |
2 |
35 |
9 |
34% |
Shin et al., 2001 [515] |
|
70 Gray Radiotherapie +Carboplatin |
1., nur lokal fortgeschritten, inkl. regionäre Lymphknoten-metastasen |
2 |
19 |
Nicht berichtet |
100% (53% komplette Remission) |
Nottage et al., 2017 [476] |
Mit den o.g. Limitationen stellt sich hier das PEK als chemosensitiv dar mit Ansprechraten >50% auf eine Platin-basierte Chemotherapie. Allerdings sollte hier immer ein möglicher Bias hinsichtlich der Publikation der erfolgreichen Behandlungen berücksichtigt werden. Die Ansprechraten sind höher bei einer Poly-Chemotherapie oder einer Radiochemotherapie. Allerdings ist die Dauer des Ansprechens häufig unklar und gerade bei den genannten Poly-Chemotherapie-Schemata ist mit einer vermehrten Toxizität zu rechnen.
Eine retrospektive Fallserie untersuchte eine isolierte Extremitätenperfusion bei inoperablem PEK [516]. Bei 21 Patienten wurde das Bein, bei 9 Patienten der Arm mit Melphalan perfundiert, bei 2 Patienten zusätzlich mit TNFα. Von 27 evaluierbaren Pateinten zeigten 16 (59%) eine komplette Remission, 6 (22%) eine partielle Remission und 5 (19%) eine progressive Erkrankung. 7 Patienten mit Ansprechen entwickelten im Verlauf ein Rezidiv bzw. einen erneuten Progress nach im Median 9 Monaten. Somit könnte die isolierte Extremitätenperfusion eine Therapieoption bei entsprechender Tumorlokalisation sein.
Bezüglich einer Monotherapie mit EGFR-Inhibitoren (siehe hier) liegen die Ansprechraten zwischen 25% und 45%, die mediane Ansprechdauer beträgt wenige Monate (progressionsfreies Überleben: ca. 4 Monate, Gesamtüberleben ca. 8 Monate). Hohe Ansprechraten wurden für die Kombination Cetuximab und Strahlentherapie berichtet. Eine Publikation fasste 8 eigene und 24 Patienten aus der Literatur zusammen [517]. 29 der 34 Patienten sprachen auf die Therapie an. Hier stellt sich allerdings die Frage, inwieweit dieses Ergebnis nicht auch mit alleiniger Strahlentherapie erreicht worden wäre bzw. die zusätzliche Cetuximab-Gabe notwendig war. Eine andere retrospektive Studie verglich den Einsatz einer Strahlentherapie plus Cetuximab vs. Strahlentherapie plus Platin-haltige Chemotherapie und zeigte ähnliche Therapieerfolge in beiden Armen [477].
Tabelle 38: Therapiestudien mit dem Einsatz von EGFR-Blockern beim kutanen PEK
|
Therapie |
Linie |
Studienphase |
Anzahl auswertbare Patienten |
Mediane Ansprechdauer (Monate) |
Ansprechraten |
Referenz |
|
Cetuximab |
1. |
2 |
36 |
6.8 |
28% |
Maubec et al., 2011 [518], |
|
Panitumumab |
1/2 |
2 |
16 |
6 |
31% |
Foote et al., 2014 [519], |
|
Gefitinib |
Neo-adjuvant |
2 |
22 |
Nicht berichtet |
45% |
Lewis et al., 2012 [520], |
|
Erlotinib + Strahlentherapie |
1 |
1 |
15 |
Nicht berichtet |
Nicht berichtet |
Heath et al., 2013 [521], |
|
Lapatinib |
Neo-adjuvant |
1 |
8 |
Nicht berichtet |
25% |
Jenni et al., 2016 [522], |
|
Dacomitinib |
1./2. |
2 |
42 |
10.3 |
28% |
Cavalieri et al., Eur J Cancer 2018 [523] |
|
Erlotinib |
1./2. |
2 |
29 |
5.3 |
10% |
Gold et al., Cancer 2018 [524] |
Als Besonderheit ist bei Patienten mit fortgeschrittenem oder metastasiertem PEK zu beachten, dass es sich häufig um ältere Patienten mit relevanten Komorbiditäten handelt; so ist z.B. eine chronisch-lymphatische Leukämie ein Risikofaktor für eine rasche Progression des PEK. Eine retrospektive Studie konnte zeigen, dass auch bei Patienten mit hämatologischen Neoplasien eine PD1-gerichtete Checkpoint-Blockade erfolgversprechend sein kann, wobei hier die Effizienz geringer zu sein scheint als bei Patienten ohne hämatologische Zweiterkrankung [525].
Unabhängig vom Alter sind Patienten mit Zustand nach Organtransplantation mit einer damit einhergehenden iatrogenen Immunsuppression zu erwähnen. Während bei Nierentransplantierten die Umsetzung der Immunsuppression auf ein mTOR-haltiges-Regime in mehreren Studien einen positiven Effekt in der Primär- und Sekundärprävention neuer epithelialer Hauttumoren hatte, ist der Effekt einer Umstellung auf mTOR-Inhibitoren bei manifesten epithelialen Hauttumoren unklar [526][527][528][529]. Bei inoperablen oder metastasierten PEK kann auch hier eine PD1-Checkpoint-Inhibition diskutiert werden, jedoch besteht hier das Risiko einer Organabstoßung [530].
Zusammengefasst soll aktuell bei einem PEK mit Indikation zur Systemtherapie eine Immuntherapie mit einem PD1-Inhibitor durchgeführt werden, wenn kein Einschluss in eine klinische Studie möglich ist. Derzeit laufen eine Reihe klinischer Studien z.B. mit Kombinationen aus Checkpoint-Blockade und EGFR-Blockade (Avelumab + Cetuximab, AliCe-Studie, EUDRACT-Nummer 2018-001708-12). Bei Progress der Erkrankung unter einer Immuntherapie oder Kontraindikationen gegen eine Immuntherapie soll die Indikation einer Chemotherapie oder EGFR-gerichteten Therapie geprüft werden. Dabei können auch Schemata in Anlehnung an Therapien des mukosalen PEK (HNSCC) bzw. des Mundhöhlenkarzinoms Anwendung finden [430][531][532]wie Cetuximab plus Platinderivat [533].
8.9 Palliativmedizinische Versorgung
Für Patienten mit fortgeschrittenem PEK sind die Kommunikation zur Palliation, die Vorstellung möglicher Behandlungskonzepte und Absprache zu realistischen Zielen unerlässlich. Versorgungsstrukturen im Umfeld und im Sinne des Patienten sind zu eruieren.
Durch ein Tumorwachstum bedingte Funktionsverluste, eingeschränkte Mobilität und Stigmatisierung sind zu berücksichtigen. Maligne zerfallende Tumoren betreffen 5-14% der Tumorpatienten. Tumorulzeration, Nekrosen und Superinfektionen verursachen zusätzliche psychische Belastungen [534]. Eine mikrobielle Besiedlung wird durch einen Tumorzerfall begünstigt. Exsudat, Blutungen, Fötor werden zur Bürde [384]. Lokale Maßnahmen können flankierend antitumoral eingesetzt werden [535][536].
Palliativversorgung ist definiert als ein Ansatz zur Verbesserung der Lebensqualität von Patienten und ihren Familien, die mit Problemen konfrontiert sind, welche mit einer lebensbedrohlichen Erkrankung einhergehen. Dies geschieht durch Vorbeugen und Lindern von Leiden durch frühzeitige Erkennung, sorgfältige Einschätzung und Behandlung von Schmerzen sowie anderen Problemen körperlicher, psychosozialer und spiritueller Art. Bezüglich palliativmedizinischer Aspekte, unabhängig der zugrunde liegenden Diagnose, wird auf die erweiterte S3-Leitlinie Palliativmedizin des Leitlinienprogramms Onkologie verwiesen [537].
Patienten und Patientinnen mit unheilbaren PEK bedürfen einer palliativen Versorgung; dazu gehören Schmerztherapie und häufig auch ein Wundmanagement. Ernährung und gastrointestinale Beschwerden einschließlich Gewichtsabnahme, Schlafstörungen, Fatigue und körperliche Schwäche sind weitere zugehörige und gängige Themen [384][538][537]. Abhängig von Tumorlokalisation, Tumorgröße und dem Ausmaß der Erkrankung können weitere physische und psychische Probleme hinzukommen. Die psychoonkologische Versorgung adressiert psychische, soziale und spirituelle Konflikte. Ängste und Ungewissheit, wie die Krankheit und Sterben verlaufen, können rechtzeitig und Sorgen mindernd in die Kommunikation aufgenommen werden.
Physische Einschränkungen und Probleme wie auch psychosoziale Belange, Prävention von Komplikationen und der Erhalt der Lebensqualität stehen im Fokus. Die Wünsche der Patienten sind in Abstimmung mit den Angehörigen zu berücksichtigen. Ein multiprofessionelles und interdisziplinäres Management soll rechtzeitig auf den Weg gebracht werden.
Evidenztabellen
Therapie PEK chirurgisch + strahlentherapeutisch
|
Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments |
LoE |
|
Ahmed et al 2014 |
Analyze the feasibility and reliability sentinel lymph node biopsy (SLNB) for cutaneous head and neck SCC (HNSCC).
Identify risk factors associated with a positive SLN. |
Systematic review; n= 221 articles; were screened of these 11 publications with 73 patients were selected; 3 case series; 8 prospective cohorts. |
MEDLINE, PubMed, Cochrane, and ASCO databases searches conducted (1946-2013). |
Analyze the feasibility and reliability SLNB for HNSCC.
Identify risk factors associated with a positive SLN. |
Studies ranged from 1 to 15 patients (median 5). Median age was 74 years. Median follow-up was 21.5 months. Average tumor size was 3.09 cm. At least 1 SLN was identified in 100% of patients (median 2). Ten (13.5%) had a positive SLN; no additional metastatic nodes were identified in 9 patients receiving completion lymphadenectomy. Three of 63 (4.76%) failed regionally following a negative SLNB. HNSCC SLNB is feasible and reliable for staging, with a false omission rate of 4.7% mirroring melanoma.
Tumor diameter was not associated with SLN status (P = .09; 95% CI, –.27 to 3.02). Risk factors (tumor depth, perineural invasion, location, differentiation) were not consistently recorded. Prospective studies documenting high-risk features are required to further define its role. |
|
2 |
|
Allen et al 2015 |
To define the predictive value and role of SLNB combined with the different high-risk factors to determine which patients could benefit from SLNB. |
Retrospective review; n=173 |
Patients with cutaneous SCC (cSCC) in whom SLNB was performed, published in the year 2000 until May 2012. |
Sensitivity, specificity and negative predictive value (NPV) for the cumulative results for each risk factor. |
Sensitivity for the total cohort was 79%, specificity was 100% and negative predictive value was 96%. The sensitivity, specificity and NPV were 78.26%, 100% and 95.14%, respectively, for tumor size >2 cm. Sensitivity, specificity and NPV for a tumor localized at a high-risk area were 72.63%, 100% and 96.74%, respectively. Specificity was 100% as was NPV for immunosuppression. SLNB has a high NPV and low false-negative rate and carries a low risk of complications. SLNB proves to enhance prognostic information of high-risk cSCC. Longer follow-up times are needed to evaluate the efficacy on OS and DFS. |
|
2 |
|
Bobin et al 2018 |
To identify factors for survival in PM from CSCC of the head and neck |
Retrospective study; n= 35 |
Cutaneous SCC of the head and neck with parotid metastases diagnosed between 2005 and 2015 |
Overall and specific survival; prognostic factors for parotid metastases. |
Thirty-five patients were included. Mean time to onset of PM was 13 months. Overall 1-, 2- and 5-year survival was respectively 70, 66 and 59%. Independent prognostic factors comprised immunodepression, age at treatment, positive CSCC margins, macroscopic facial nerve involvement, and metastatic cervical adenopathies. |
|
3 |
|
Chabrillac et al 2019 |
To identify prognostic factors associated with sentinel lymph node positivity |
Retrospective study; n= 74 |
Patients with high-risk cSCC undergoing sentinel lymph node biopsy |
Risk factors statistically associated with sentinel lymph node positivity |
Seventy-four patients were included. Five (6.8%) procedures failed. Of the 69 patients assessed, the positive sentinel lymph node biopsy rate was 11.6% (n=8) with a false negative rate of 5.7% (n=4). The positivity of sentinel lymph node biopsy was associated with tumour size (p=0.0194). |
Sentinel lymph node biopsy is an effective staging procedure for clinically N0 high-risk cutaneous squamous cell carcinoma, with acceptable morbidity. To date, 2 risk factors of sentinel lymph node positivity have been identified with statistical significance: tumour size and poor tumour differentiation. |
3 |
|
Daniels et al 2020 |
To investigate the effect of the treatment package time (TPT) defined as the interval between date of surgery and completion of postoperative radiation therapy (PORT) on tumor control and survival outcomes in node-positive cHNSCC treated with curative surgery and PORT |
Retrospective study; n= 152 |
Node-positive cHNSCC patients involving either the parotid or cervical nodes treated with curative intent surgery with macroscopic tumor clearance followed by standard fractionation PORT from 2001 to 2014. |
OS, cHNSCC specific survival (CSS), PFS, and freedom from locoregional failure (FFLRF). |
152 patients met the inclusion criteria. The 5-year OS, CSS, PFS, and FFLRF were 62% (95% confidence interval [CI], 54-71), 78% (95% CI, 71-87), 54% (95% CI, 46-64), and 76% (95% CI ,68-85), respectively. In a multivariable model, TPT ³14 weeks was associated with worse outcomes in all endpoints (OS [hazard ratio (HR) 4.93; 95% CI, 2.54-9.56, P < .001], CSS [HR 6.09; 95% CI, 2.33-15.92; P Z .001], PFS [HR 4.29; 95% CI, 2.21-8.34; P < .001], and FFLRF [HR 4.63; 95% CI, 1.71-12.51; P=0.007]). Immunosuppression and the presence of ³ 2 pathologically involved lymph nodes were also significant adverse factors for both OS and FFLRF, although extracapsular extension was also associated with lower FFRLF. Delays to commencing PORT rather than treatment breaks accounted for the majority of cases with prolonged TPT. |
Prolongation of TPT to 14 weeks or longer may confer a lower probability of locoregional control and survival in patients with lymph node-positive cHNSCC treated with surgery and PORT. Timely referral and commencement of PORT is necessary to maximize long-term disease outcomes. |
3 |
|
Demir et al 2011 |
To evaluate and identify the role of lymphoscintigraphy and sentinel lymph node biopsy in patients with high-risk cutaneous SCC (cSCC). Tumor size greater than 2 cm, depth of invasion greater than 4 mm grade 2 differentiation or greater, perineural invasion and recurrent tumors were also regarded as high-risk characteristics |
Prospective study; n= 19 |
Patients with high-risk cSCC treated in one center |
To evaluate and identify the role of lymphoscintigraphy and sentinel lymph node biopsy in patients with high-risk cSCC. |
A total of 26 SLNs and 32 secondary lymph nodes were imaged on LS and were marked. During surgery, 29 SLNs, 21 secondary lymph nodes and three non-active lymph nodes were excised. In total, 53 lymph nodes were removed surgically. A histopathological study revealed that all lymph nodes were negative for metastasis. Patients were followed up for an average of 41.1 ± 22.2 months (7–80 months). Until the time of data collection, 14 patients were alive and had no regional lymph node or distant metastasis. Local recurrence was seen in only one patient, operated upon 38 months ago.
The feasibility of determining SLNs using LS and an intraoperative gamma probe in patients with cSCC was shown. Unnecessary elective lymph node dissection and possible complications could be avoided in 19 patients. |
|
4 |
|
Durham et al 2016 |
To evaluate a single institution’s experience with use of SLNB for regional staging of SCC on the head and neck (HNSCC). |
Retrospective review; n=53
|
Patients with HNSCC, at high risk for nodal metastasis based on National Comprehensive Cancer Network (NCCN) risk factors, and treated with wide local excision (WLE) and SLNB from December 1, 2010, through January 30, 2015 in one institution. |
Sentinel node (SN) identification rate
SLNB positivity rate
Local recurrence
Regional nodal recurrence
Distant recurrence.
|
In 53 patients with 54 tumors the SN identification rate was 94%. The SLNB positivity rate was 11.3%. On more thorough tissue processing and IHC, metastatic SCC was identified in 2 of 5 (40%) cases previously deemed negative. After reclassification of these cases, the adjusted SLNB positivity rate was 15.1%. The adjusted rate of false omission was 7.1% (95% CI, 2%-19%). Nodal disease developed in 20.8% overall. Angiolymphatic invasion (Cohen d, 3.52; 95% CI, 1.83-5.21), perineural invasion (Cohen d, 0.81; 95% CI, 0.09-1.52), and clinical size (Cohen d, 0.83; 95% CI, 0.05-1.63) were associated with the presence of nodal disease. |
Rigorous study of SLNB for cutaneous SCC incorporating prospectively-collected comprehensive data sets based on standardized treatment algorithms is justified with potential to modify clinical practice. Our study demonstrates the critical importance of serial sectioning and IHC of the SLNB specimen for accurate diagnosis. Use of the NCCN guidelines may facilitate identification of patients with SCC at high risk for nodal metastasis.
|
3 |
|
Feinsten et al 2019 |
To characterize the risk factors for and clinical course of cutaneous SCC with nodal metastasis |
Retrospective study; n= 53 |
Patients with cSCC and nodal metastasis |
Disease-free survival rate after treatment of nodal disease |
Most patients were men (84.6%, 44/52), and almost all primary tumors were on the head and neck (96.2%, 51/53). Most primary tumors were characterized by known “high-risk features” including perineural invasion (56.6%, 30/53), diameter ³2 cm (54.7%, 29/53), invasion beyond subcutaneous fat (43.4%, 23/53), and poor differentiation (32.1%, 17/53). In addition, many tumors were recurrent (52.8%, 28/53), and many patients were immunosuppressed (30.8%, 16/52). Disease-free survival after treatment of nodal disease was 7.5% (4/53) at 5 years. |
|
3 |
|
Fukushima et al 2014 |
To evaluate the efficacy of sentinel node biopsy for cutaneous SCC (cSCC) |
Retrospective study; n= 54 patients |
Patients with SCC who underwent SLNB in the Kumamoto University Hospital between 2006 and 2012 |
To evaluate the efficacy of sentinel node biopsy for cSCC |
The positive rate of SLNB in SCC was 7.4%. If the cases were limited to more than T2, the positive rate was 12.9%. Three of 41 patients who was estimated negative LN metastasis by the preoperative tests had micrometastases (7.3%). Among 13 patients who were suggested to have metastasis in the preoperative tests, only one patient had histological metastasis. One patient with SCC located in the lower lip showed negative SLNB and subsequently developed node recurrence.
In conclusion, the efficacy of SLNB in SCC is comparable to that of melanoma in the positive rate. There are two kinds of benefit, avoidance of unnecessary complete lymph node dissection and early detection of metastasis. |
|
4 |
|
Gore et al 2016 |
To determine the rate of sentinel lymph node metastasis in cutaneous SCC with 1) tumor size>2 cm; (2) invasion into subcutaneous fat or tumor thickness >5 mm; (3) poorly differentiated tumor; (4) perineural invasion (PNI); (5) lymphovascular invasion (LVI); (6) local recurrence in the setting of adequate prior resection margins; (7) ear or lip location; (8)Immuno-compromise (post-organ transplant, chemotherapy); and(9) carcinoma in a preexisting scar. to examine whether the accepted clinicopathological factors should be considered “high-risk,” and to decide whether a randomized controlled trial is feasible. |
Prospective study; n=57 patients |
Patients from one center with high-risk cutaneous SCC were assessed with sentinel node biopsy (SNB) either at the time of primary cutaneous tumor resection or at secondary wide local excision between 2010 and 2013. |
Rate of nodal metastasis in “high-risk” cutaneous SCC.
To examine whether the accepted clinicopathological factors should be considered “high-risk” |
Of 57 patients, 8 (14%) had nodal metastasis. During a mean of 19.4 months, 9 patients developed recurrence and 6 died of cutaneous SCC.
Significant predictors of metastasis are the number of high-risk factors (p5.008), perineural invasion (PNI; p5.05), and lymphovascular invasion (LVI; p5.05).
Lymph node metastasis occurs in 14% of patients with high-risk cutaneous SCC. A clinical trial with over 1300 patients would be required for a randomized controlled trial with 80% power to detect a significant difference in DFS. |
|
3 |
|
Haisma et al 2016 |
To identify independent risk factors for lymph node metastasis in patients with cHNSCC and to evaluate the impact of lymph node metastasis on prognosis. |
Retrospective study; n= 36 patients with 545 primary cHNSCC |
Patients with primary cHNSCC treated between 2000 and 2012 at a tertiary care center (University Medical Center Groningen, the Netherlands). |
Disease-specific survival and OS |
Three hundred thirty-six patients with 545 primary cHNSCCs were included. The median follow-up period was 43 months (range, 1-176 months). lymph node metastasis occurred in 55 patients (16.4%). The following independent risk factors of cHNSCC for the development of lymph node metastasis were identified: location on the ear, tumor diameter [50 mm, moderate and poor differentiation, and tumor thickness [2 mm. There was a significant decline in disease-specific survival and overall survival in patients with lymph node metastasis compared to patients without lymph node metastasis. |
Lymph node metastases from cHNSCC are common with diminished survival rates. This study confirmed some well-known risk factors, but also found moderate differentiation as an independent risk factor for lymph node metastasis. |
3 |
|
Hirshoren et al 2017 |
To describe the clinical outcomes and prognostic factors for patients with node-positive cutaneous head and neck SCC (cHNSCC) who underwent lymphadenectomy. |
Retrospective single-center study; n=149 lymphadenectomies |
Patients with node-positive cHNSCC treated surgically at a single tertiary center between June 1, 2001, and December 31, 2014. |
OS
Locoregional control rates
Prognostic factors |
The median number of positive lymph nodes from 149 lymphadenectomies was 2 in the neck and 1 in the parotid gland. The 5-year OS and locoregional control rates were 50% and 77%, respectively. OS was worse among older patients (hazard ratio [HR], 1.04; p = .015), immunosuppressed patients (HR, 2.06; p = .034), and patients with a high total lymph node ratio (calculated from the number of positive lymph nodes divided by the total number of nodes; multivariate analysis [MVA]; HR, 1.13; p = .019). |
|
3 |
|
Kofler et al 2020 |
To analyze the role of the SLNB in lymph node status and survival |
Retrospective study; n= 720 |
Patients with high-risk SCC (tumor thickness > 5 mm) |
Proportion of distant metastasis and tumor-specific survival |
A total of 11.11% of the patients showed lymph node metastasis in the course of their treatment, with no difference in the proportion of patients in the SLNB group (11.9%) and the observation group (11.4%) (p = 0.873). The proportion of distant metastasis also did not differ between the groups (p = 0.898). In 3.96% of the patients in the SLNB group, metastasis was found in the sentinel lymph node. Tumor-specific death was observed in 7.14% of the patients in the SLNB group and 4.74% in the observation group (p = 0.269). |
|
3 |
|
Krediet et al 2015 |
To evaluate risk factors for metastasis in patients with cutaneous SCC (cSCC) in a large cohort study with long-term follow-up and to determine the value of SLNB. |
Retrospective review; n=143 |
Patients who underwent excision of cSCC between January 2005 and August 2009 at a tertiary referral center |
To evaluate risk factors for metastasis in patients with cSCC in a large cohort study with long-term follow-up.
To determine the value of SLNB. |
The risk for metastases from a cSCC is associated with tumor thickness > 4 mm and tumor recurrence. All metastases occurred within 2 years after excision. SLNB seems to have a low sensitivity for metastases of cSCC. Despite a negative SLNB, some patients developed metastatic disease, underlining the necessity of close follow-up of high-risk patients in the first 2 years after excision, regardless of SLNB status.
Based on our data SLNB does not provide diagnostic value for patients with cSCC. |
|
3 |
|
Maruyama et al 2016 |
Effects of SLNB on the further course of cSCC |
Prospective study; n= 169 |
Patients who underwent treatment for cSCC between 2004 and 2015 in the Department of Dermatology, Tsukuba University Hospital. |
Efficacy of sentinel lymph node biopsy for cSCC.
Compared the outcomes with those in cSCC patients who did not undergo concurrent SLNB. |
Patients who were followed up for at least 6 months or developed metastases within the follow-up period were included. Forty-nine patients underwent sentinel lymph node biopsy, whereas 120 patients did not, including 13 who exhibited clinical lymph node metastases before treatment.
Of these 49 patients, nine (18.4%) presented with sentinel lymph node metastasis, which occurred after treatment in three (6.1%) of them (false-negative). Among the 107 patients who did not undergo lymph node biopsy, 12 (11.2%) developed post-treatment metastases. The metastasis-free and DSS rates were not significantly different in those who did or did not undergo sentinel lymph node biopsy. Patients with clinical lymph node metastases had a higher risk compared with those without. Patients with T2–T4 tumors had a higher risk compared with those with T1 tumors. When selecting for those with T2 tumors or greater, the same lack of relationship was observed. In this small retrospective cohort, in patients with cutaneous squamous cell carcinoma, there were no significant differences in metastasis-free and DSS rates between those who did or did not undergo sentinel lymph node biopsy, regardless of T staging. |
|
3 |
|
McLaughlin et al 2017 |
To determine the rate of regional lymph node involvement in patients with cutaneous head and neck squamous cell carcinoma (cHNSCC) |
Retrospective chart review; n= 30 solid organ transplant patients; 383 cHNSCC resections |
All solid organ transplant recipients who underwent surgery between 2005 and 2015 for a cHNSCC at the Hospital of the University of Pennsylvania Department of Dermatology and/or Otorhinolaryngology |
Rate of regional lymph node involvement;
Time from first diagnosis to regional lymphatic disease |
The average age of the patient was 63. Seven patients (5%) developed regional lymph node metastases (3 parotid, 4 cervical lymph nodes). The mean time from primary tumor resection to diagnosis of regional lymphatic disease was 6.7months. Six of these patients underwent definitive surgical resection followed by adjuvant radiation; one patient underwent definitive chemoradiation. 6 of the 7 patients died of disease progression with a mean survival of 15months. The average follow-up time was 3years (minimum 6months).
Solid organ transplant recipients with cutaneous squamous cell carcinoma of the head and neck develop regional lymph node metastasis at a rate of 5%. Regional lymph node metastasis in this population has a poor prognosis and requires aggressive management and surveillance. |
This is the largest study to date of cutaneous SCC in solid organ transplant patients. In addition, all of these lesions were limited to the head and neck. Despite the low rate of regional lymph node involvement demonstrated in these patients, their extremely poor prognosis makes managing a N0 neck in an immunocompromised patient a difficult clinical dilemma. |
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Navarrete-Dechent et al 2015 |
To perform a review of the currently available evidence, in the form of systematic reviews, meta-analysis, trials, and case series and analyzed the features that define a high-risk cutaneous SCC (HRcSCC) and the feasibility of performing sentinel lymph node biopsy in this group of patients |
Retrospective review; n= 156 articles found; 16 articles included all types of studies (systematic reviews, meta-analysis, trials, and case series ) published to date in English and Spanish |
Patients included in publications in the MEDLINE database published through November 25, 2014 found using the key words: ‘‘squamous’’ or ‘‘non-melanoma’’ or ‘‘non-melanoma’’ or ‘‘squamous cell carcinoma’’ AND ‘‘cutaneous’’ or ‘‘skin’’ AND ‘‘sentinel lymph node.’’ |
To perform a review of the currently available evidence, analyzed the features that define a group of cSCC patients who are at risk of developing nodal metastasis and might benefit from SLNB |
This systematic review identified an overall positive rate for SLNB of 13.9% (32 of 231 patients) and a false-negative rate of 4.6% (10 of 215 patients) in cSCC. The authors usually stated that patients had high-risk factors for lymph node involvement. However, these high-risk factors were not homogeneous and not always adequately detailed. Takahashi et al documented survival in 26 patients with HRcSCC with 23.1% (6 of 26) having a positive SLNB. This study included patients with external genital squamous cell carcinoma (SCC). The authors reported a 3-year survival 100% for SLN-negative SCC cases but only 20.8% for SLN-positive cases. Four patients died during the follow-up, all having a positive SLNB, 3 of 3 external genital SCC, and 1 of 3 cSCC. Patients with cSCC are at risk of developing nodal metastasis, death, or both, especially if risk factors are present. SLNB may identify occult nodal metastases in patients at risk. Its utility in cSCC is still to be confirmed because it is considered to be more precise than imaging procedures and less invasive than lymph node dissection and may ultimately emerge as the gold standard for HRcSCC staging. |
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1 |
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Quinn et al 2019 |
To analyze costs and survival in patients with cHNSCC based on their tumor and nodal metastasis staging and whether or not they received an SLNB |
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To determine the most cost-effective strategy for the treatment of patients with cHNSCC using one-way, two-way, and probabilistic sensitivity analyses were performed to validate the results. |
Not performing an SLNB results in 12.26 QALYs and a cost of $3712.98. Performing an SLNB resulted in a 0.59 decrease in QALYs and an increase in cost of $1379.58 for an incremental cost-effectiveness ratio of -2338.27. This trend remained the same across all tumor stages and remained consistent within most sensitivity analyses. |
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4 |
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Ross et al 2006 |
To review reported SCC in which sentinel lymph node biopsy (SLNB) whether SLNB proofs as a staging tool for patients with high-risk SCC. |
Retrospective review; n= 692 |
Patient's results of SLNB in patients with cutaneous SCC reported in the English medical literature. A total of 607 patients with anogenital SCC and 85 patients with non-anogenital SCC were included in the analysis. |
The percentage of cases with a positive sentinel lymph node (SLN) was calculated. False-negative and no detection rates were tabulated. Rates of local recurrence, nodal and distant metastasis, and disease-specific death were reported. |
A SLN could not be identified in 3% of anogenital and 4% of non-anogenital cases. SLNB was positive in 24% of anogenital and 21% of non-anogenital patients. False-negative rates as determined by completion lymphadenectomy were 4% (8/213) and 5% (1/20), respectively. Most false-negative results were reported in studies from 2000 or earlier in which the combination of radioisotope and blue dye was not used in the SLN localization process. Complications were reported rarely and were limited to hematoma, seroma, cutaneous lymphatic fistula, wound infection, and dehiscence. |
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4 |
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Samsanavicius et al 2018 |
To determine cSCC micrometastases when non-invasive examination methods do not detect them |
Retrospectve study; n= 88 |
Patients with cSCC and no distant or regional lymph node metastases detected during instrumental tests, grouped into low- and high-risk CSCC groups, who underwent one-stage surgery – radical tumour excision and sentinel lymph node/nodes biopsy (SLNB) |
Detection rate of cSCC micrometastases. |
153 SLN were detected and excised in 88 patients. Micrometastases were found in five SLNs of three patients with high-risk CSCC. The rate of micrometastases was 3.4%; however, in the high-risk group it was 6.5%. The mean diameter of CSCC with micrometastases in SLN was 5.6 ± 3.5 cm, and that without micrometastases was 1.5 ± 1.1 cm (p = 0.003). The depth of CSCC according to Breslow in the patients with detected micrometastases in SLN was 3.5 ± 1.2 mm, and that without detected micrometastases was 2.2 ± 1.4 mm (p = 0.047). Patients with micrometastases in sentinel lymphatic nodes under- went radical lymphadenectomy. There was neither recurrence of CSCC metastases in regional lymph nodes nor distant metastases during the research period detected. |
In patients with cSCC the rate of micrometastases directly correlates with the depth and diameter of the tumour. In patients with high-risk cSCC the rate of micrometastases is 6.5%. |
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Schmitt et al 2014 |
To define factors closely associated with positive SLNB findings in non-anogenital cSCC. |
Retrospective review; n= 130 patients for AJCC staging; n= 117 for the alternative system |
Patients with non-anogenital cSCC and SLNB. |
To evaluate the positive SLNB findings by cSCC stage, quantified as the number and percentage of positive nodes.
To analyze which stages in the American Joint Committee on Cancer (AJCC) criteria and a recently proposed alternative staging system are most closely associated with positive SLNB findings in non-anogenital cSCC. |
A positive SLN was identified in 12.3%of all patients. All cSCCs with positive SLNs were greater than 2 cm diameter. The AJCC criteria identified positive SLNB findings in 0 of 9 T1 lesions (0%), 13 of 116 T2 lesions (11.2%), and 3 of 5 T4 lesions (60.0%). No T3 lesions were identified. The alternative staging systems identified positive SNLB findings in 0 of 9 T1 lesions (0%), 6 of 85 T2a lesions (7.1%), 5 of 17 T2b lesions (29.4%), and 3 of 6 T3 lesions (50.0%). Rates of positive SLNB findings in patients with T2b lesions were statistically higher than those with T2a lesions (P = .02, Fisher exact test) in the alternative staging system.
Our findings suggest that most cSCCs associated with positive SLNB findings occur in T2 lesions (in both staging systems) that are greater than 2 cm in diameter. The alternative staging system appears to more precisely delineate high-risk lesions in the T2b category that may warrant consideration of SLNB. Future prospective studies are necessary to validate the relationship between tumor stage and positive SLNB findings and to identify the optimal staging system. |
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Skulsky et al 2017 |
To evaluate surgical procedures as SLNB for high-risk cSCC defined as ((>2 cm), a deeply invasive lesion (>2 mm), incomplete excision, high-grade/desmoplastic lesions, perineural invasion (PNI), lymphovascular invasion, immunosuppression |
Embase, CENTRAL, and MEDLINE were searched for published studies, clinical trials, and guidelines on high-risk cutaneous SCC of the head and neck. Reference lists from the relevant articles acquired were also searched. The search date range used January 2016 as the end date; no start date was specified. The following terms are examples of terms that were combined in the database searches: “high-risk cutaneous squamous cell carcinoma, guidelines, excision margins, organ transplant, immuno- suppression, depth, recurrence, sirolimus, cyclosporine, azathioprine, sentinel lymph node biopsy, superficial parotidectomy, elective neck dissection, and Mohs micrographic surgery.” All records obtained from our searches were screened by title and abstract for selection. |
Patients with high-risk cSCC |
To compare two different guidelines (NCCN and AJCC) in what concerns SCC high-risk features discrepancies and omissions.
The following aspects were evaluated:
Tumor size Depth of invasion Recurrent setting Poorly differentiated lesions Histopathological subtype Perineural invasions Lymphovascular invasion High-risk anatomical location Immunosuppressed sate Incomplete excision |
The AJCC TNM staging system considers the following high-risk features when determining the primary tumor (T) classification: depth (>2mm thickness or Clark level ≥IV), anatomic location, poor histological differentiation, and perineural invasion (PNI). Tumors are classified as T2 in 2 ways: (1) tumors > 2 cm in greatest dimension, or (2) any size tumor with ≥2 high-risk features. NCCN has also identified several high-risk features of cSCC. High-risk cSCC, as per NCCN Guidelines refers to a greater propensity for local recurrence and/or metastasis. NCCN classifies cSCC as high-risk if≥1 feature is present. Currently, there is no unanimous consensus on the high-risk features of cSCC. Although NCCN Guidelines and the AJCC TNM classification system share some overlapping high-risk features of cSCC, significant discrepancies exist. In comparison with NCCN Guidelines, the AJCC omits several high-risk features associated with poor clinical outcomes, including immunosuppression, lymphovascular invasion, recurrent tumors, and certain prominent high-risk anatomic locations. Notably, neither NCCN nor the AJCC include incomplete excision as a feature warranting a tumor’s treatment as high-risk cSCC. As a compounding factor, there are no guidelines for managing the deep tumor margin. |
Future studies are required to evaluate the extent to which the inclusion of these additional high-risk features would improve tumor staging and prognostic outcomes. Ultimately, a consensus on the definition of high-risk features of cSCC needs to be reached in order to produce accurate and practical treatment guidelines that will enhance patient care. |
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Takahashi et al 2014 |
To investigate the usefulness of and indication criteria for SNB for cutaneous SCC (cSCC) |
Retrospective review; n= 26 |
Patients who were diagnosed with high-risk cSCC and underwent SNB at our hospital from July 2005 to April 2012 |
To investigate the usefulness of and indication criteria for SNB for cSCC |
Of the 26 patients, recurrence or metastasis was observed in 5 cases (19.2%). Six cases (23.1%) were sentinel node (SN) metastasis-positive. All cases that were SN metastasis-negative survived, and 4 of 6 SN metastasis-positive (66.7%) cases died of the original disease. The 3-year survival rates of all cases, SN metastasis-negative cases, and SN metastasis-positive cases were 82.2%, 100%, and 20.8%, respectively. Tumor thickness was a significant risk factor for SN metastasis (p=0.049). Recurrence occurred in 4 of 7 cases involving external genitalia, 3 of which died. The 3-year survival rates of external genitalia and non-genital cases were 47.6% and 94.1%, respectively (p= 0.016). SNB aided the early discovery and treatment of latent lymph node metastasis and helped predict whether SN metastasis had occurred, and therefore helped predict patient prognosis. These results suggest that thickness of the primary lesion is an indication criterion for the use of SNB in cases of cSCC. SNB should be considered in cases where tumor thickness is ≥ 2 mm and actively performed in cases ≥ 5 mm. |
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Tejera-Vaquerizo et al 2019 |
To analyze the frequency of SLN metastasis in published series of cSCC in the context of the eighth edition of the American Joint Committee on Cancer (AJCC-8) and the Brigham and Women’s Hospital (BWH) staging criteria |
Retrospective analysis; n= 153 |
Studies included in the analysis were those evaluating patients with cSCC who underwent SLN biopsy and that described biopsy results. |
Rate of SLN metastases |
In total, 153 patients with 24 positive SLN biopsies (15.7%) were included. Based on the AJCC-8 criteria positivity rates in the T2 and T3 categories were 8.3% (1/12 patients) and 25% (8/32), respectively. Using the BWH system there were, 2/33 in category T2a (6.5%), and 5/17 in category T2b (29.8%). On applying the same criteria to tumors of the trunk and extremities the results were similar. |
It would seem reasonable to recommend SLN biopsy for patients with AJCC-8 Stage T3+ disease or BWH Stage T2b/T3 disease. Both the AJCC-8 and the BWH systems would appear to be useful for staging cSCC of the trunk and extremities. |
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Tseros et al 2016 |
To analyze the correlation between lymph node ratio (LNR) and outcome - time to disease progression (TTDP) and OS - in patients who have undergone surgery for metastatic cutaneous nodal HNSCC. |
Retrospective study; n= 238 |
Patients with metastatic cutaneous nodal HNSCC. |
TTDP and OS. |
In total, 193 males and 45 females with a median of age 68 years were identified, with a mean recorded LNR of 0.15. On multivariate analysis, an LNR cutpoint of 0.21 was a significant predictor of decreased TTDP (HR 2.34, 95 % CI: 4.40–0.49; p = 0.009] and OS (HR 2.75, 95 % CI 1.57–4.82; p< 0.001). Forty-nine of 238 patients (2 %) developed recurrence, with most recurrences being regional (29 of 49; 59 %). A total of 17 % of patients with an LNR £0.21 recurred compared with 40 % for patients with an LNR >0.21. |
LNR is potentially an independent predictor of outcome in patients with metastatic cutaneous nodal SCC. The clinical relevance of this finding requires further validation. |
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Vasan et al 2018 |
To validate the prognostic significance of the lymph node ratio in metastatic cHNSCC |
Retrospective study; n= 326 |
Patients with cHNSCC with parotid and/or cervical nodal metastases was performed. |
OS and disease-free survival |
Data reported included 77 recurrences and 101 deaths. A lymph node ratio of 6% was a significant predictor of shorter DFS (HR 1.62; 95% CI: 1.11-2.38; P=0.01) and OS (HR 1.63; 95% CI 1.03-2.58; P=0.04) on multivariable analysis. |
The lymph node ratio is an independent prognosticator of survival out- comes in patients presenting with metastatic head and neck cutaneous SCC. A lymph node ratio >6% is a significant threshold to categorize patients into low and high risk. |
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PEK LK Dissektion
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Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments |
LoE |
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Amoils et al 2019 |
To describe outcomes in one institution, including patterns of metastasis, clinicopathologic factors related to survival, and failure rates. To stratify results by treatment modality. |
Retrospective review; n=80 |
Patients treated for regionally metastatic cutaneous HNSCC |
OS, failure rates, results by treatment modality |
On multivariate regression, cutaneous primary >2 cm (p = .03) and extracapsular spread (ECS; p = .01) were significantly associated with decreased OS. Location of regional metastasis (neck vs parotid vs both) did not affect OS (p = .2), nor did the presence of a cutaneous primary at the time of presentation (p = .9). The 3-year survival was 43%, 52%, and 49% for surgery alone, adjuvant radiation, and adjuvant chemoradiation, respectively. Fifty-one percent of patients had a recurrence of their disease. |
Regionally metastatic cutaneous HNSCC is an aggressive disease associated with high recurrence rates. Patients with tumors >2 cm and ECS have poorer OS despite adjuvant therapy. |
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Bergstrom et al 2008 |
To review the available information on the high-risk SCC patients treatment To define patients which may benefit from lymph node dissection |
Review |
n.a. |
n.a. |
Staging systems, which account only for the horizontal diameter and invasion of subcutaneous structures of cSCC may not be adequate to stratify risk and predict metastasis.
Selective neck dissection or sentinel lymph node biopsy: elective neck dissection remains the standard of care for invasive SCC of the head and neck. |
New data from SCC studies help to predict high-risk SCCs and, as in malignant, how to take advantage of SLNB to diagnose metastatic disease. The current tumor node metastasis classification could be refined to better predict which are “bad actors”. The role of HPV in SCC carcinogenesis continues to be elucidated and represents a potential approach to targeted therapy and prevention. |
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Cannon 2016 |
To investigate the factors associated with elective neck dissection (END) in this population and the survival difference with END com- pared with observation for patients with a cN0 neck. |
Retrospective; n= 59. Case series with chart review |
Patients were treated surgically for head and neck cSCC with skull base invasion via perineural spread with a cN0 neck from 2004 to 2014. |
Primary outcomes were disease-free survival (DFS) and overall survival (OS). |
Fifty-nine patients met inclusion criteria: 28 underwent an END and 31 underwent neck observation. Free tissue transfer reconstruction was significantly associated with END (P <.001 patients treated with an end had significantly improved dfs and p=".042)" os compared those who were observed a reduced rate of regional recurrence the occult nodal metastasis identified was is approxi- mately equal to failure neck obser- vation group> |
END was more commonly used in cases requir- ing free tissue transfer. The use of END for head and neck cSCCs that have invaded the skull base is not routinely per- formed but was found to be associated with a survival advantage and reduced regional recurrence rate. |
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Ebrahimi et al 2010 |
To analyze the distribution of regional nodal metastases according to the primary tumor location in patients with cutaneous squamous cell carcinoma of the head and neck (cSCCHN). |
Retrospective study; n= 295 neck dissections |
Patients with clinically evident regional metastases from cSCCHN between 1987 and 2009 from one institution |
To analyze the distribution of regional nodal metastases according to primary tumor location in patients with cSCCHN |
Level I involvement in the absence of level II or III only occurred in patients with facial primaries. In patients with clear nodes in level II–III, the risk of level IV–V involvement was 0.0% for external ear primaries, 2.7% for face and anterior scalp, and 15.8% for posterior scalp and neck. In patients undergoing parotidectomy for metastatic cSCCHN with a clinically negative neck, the results of this study support selective neck dissection including level I–III for facial primaries, level II–III for anterior scalp and external ear primaries, and levels II–V for posterior scalp and neck primaries. |
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Forest et al 2010 |
Review of clinical and pathological information of patients treated for metastatic cutaneous SCC (cSCC) to the parotid and/or neck was conducted. Potential prognostic factors were analyzed using univariate and multivariate analyses. A staging system was elaborated and externally validated. |
Retrospective study; n=215 patients |
Patients with treated with curative intent between 1987 and 2007 for metastatic HN cSCC to the parotid and/or neck were identified. |
To identify potential prognostic factors using univariate and multivariate analyses.
To elaborate a staging system and validated it externally. |
All patients had surgery as their primary treatment; 148 had parotidectomy with neck dissection, 50 parotidectomy alone, and 18 neck dissection alone. One hundred seventy-five patients received postoperative radiotherapy.
On univariate analysis, the number of involved lymph nodes (P < .001), maximal size (P=.01), and extracapsular spread (P=.003) were found to be significant predictors of survival. On Cox regression, the number of involved lymph nodes as single or multiple (P=.006) was significant. The N1S3 staging system incorporates involved lymph nodes from the parotid and neck (single or multiple) and the size (< or >3 cm). This system demonstrates a significant predictive capacity for locoregional control (P < .001), DSS (P<.0001 and os n1s3 was tested on a different cohort of patients the results confirmed those obtained from our primary analyses.>
The N1S3 system stages patients according to the number of involved lymph nodes and size, and incorporates parotid as 1 of the regional levels. These 2 predictors are easily applied to both clinical and pathological data. |
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Girardi et al 2019 |
To evaluate the prognostic features among patients with head and neck cutaneous squamous cell carcinoma exhibiting regional metastasis. |
Retrospective study; n=38 |
Patients with head and neck cutaneous squamous cell carcinoma with parotid and/or neck metastasis |
Disease recurrence and death due to the disease |
Thirty-eight cases of head and neck cutaneous squamous cell carcinoma with parotid and/or neck metastasis were identified. Overall, 18 (47.3 %) patients showed parotid metas- tasis alone, 12 (31.5 %) exhibited neck metastasis alone and 8 (21.0 %) had both. A primary tumor in the parotid zone (Hazard Ratio - HR = 5.53; p = 0.02) was associated with improved disease-specific survival. Poorer disease-specific survival was observed in patients with higher primary tumor diameter (HR = 1.54; p = 0.002), higher depth of invasion (HR = 2.89; p = 0.02), invasion beyond the subcutaneous fat (HR = 5.05; p = 0.002), neck metastasis at first presenta- tion (HR = 8.74; p < 0.001), number of positive lymph nodes (HR = 1.25; p = 0.004), and higher TNM stages (HR=7.13; p = 0.009). Patients presenting with isolated parotid metastasis dur- ing all follow-ups had better disease-specific survival than those with neck metastasis or both (HR = 3.12; p = 0.02). |
Head and neck cutaneous squamous cell carcinoma with parotid lymph node metas- tasis demonstrated better outcomes than cases with neck metastasis. |
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Kovatch et al 2019 |
To report one institutional experience, management, and outcomes of cutaneous periauricular squamous cell carcinoma (SCC). |
Retrospective chart review; n=112 |
Patients undergoing treatment of cutaneous peri-auricular SCC from 2000 to 2016 |
Overall survival, disease-specific survival, and disease-free survival at 3 years |
A total of 112 patients had a median follow-up of 24.5 months, a mean 6 SD age of 75.7 6 10.6 years, and a strong male predominance (93.8%). Site distribution shows 87 (77.7%) auricular, 26 (23.2%) preauricular, and 10 (8.8%) post- auricular lesions. Of auricular lesions, tumors involved the tragus (n = 3, 3.4%), helix/antihelix (n = 47, 54.0%), conchal bowl (n = 31, 35.6%), external auditory canal (n = 18, 16.1%), and lobule (n = 3, 3.4%). Most patients presented at stage I (52.7%) versus stages II (28.6%), III (6.3%), and IV (12.5%). Patients were largely treated surgically with primary tumor resection ranging from wide local excision to lateral temporal bone resection (6 parotidectomy and neck dissection), with 17.0% and 5.4% receiving adjuvant radiation and chemoradia- tion, respectively. Metastatic spread was seen to the parotid (25.9%) and neck (26.8%), with most common cervical spread to level II. Overall survival, disease-specific survival, and disease-free survival at 3 years were 62%, 89%, and 56%, respectively. Nodal disease was associated with worse disease-specific survival (P < .001) and disease-free survival (P = .042). Pre- and postauricular sites were associated with worse overall survival (P = .007) relative to auricular sites. |
Among cutaneous SCC, periauricular subsites pose treatment challenges related to surrounding anatomy and represent a unique tumor population. The reported propensity toward recurrence and patterns of metastasis may better guide the treatment of aggressive tumors to include regional nodal dissection. |
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Martinez et al 2007 |
To review the available literature regarding the use of elective node dissection (END) in the management of both cutaneous SCC (cSCC) and head and neck SCC (HNSCC). |
Review article |
Patients with cSCC and HNSCC that underwent END |
To review the available literature regarding the use of elective node dissection (END) in the management of both cSCC and HNSCC. |
Many surgical specialists recommend that END be routinely performed in patients with N0 HNSCC when the risk of occult metastases is estimated to exceed 20%; however, patients who undergo END have no proven survival benefit over those who are initially staged as N0 and undergo therapeutic neck dissection (TND) after the development of the apparent regional disease. There is a lack of data regarding the proper management of regional nodal basins in patients with N0 CSCC. In the absence of evidence-based data, the cutaneous surgeon must rely on clinical judgment to guide the management of patients with N0 high-risk CSCC of the head and neck.
Appropriate workup for occult nodal disease may occasionally be warranted in patients with high-risk cSCC. END may play a role in only a very limited number of patients with high-risk cSCC. |
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Oddone et al 2009 |
To propose a prognostic score model using a prospective study of patients with regional metastatic cutaneous squamous cell carcinoma of the head and neck. |
Prospective study; n=250 patients |
Patients between 1980 to 2005 who had metastatic cSCC to lymph nodes of the HN (parotid and/or cervical) and who were treated with curative intent were eligible for inclusion in this study from one center. |
To propose a prognostic score model using a prospective study of patients with regional metastatic cutaneous squamous cell carcinoma of the head and neck. |
At a median follow-up of 54 months (range, 1.3-212 months) 70 of 250 patients (28%) developed recurrent disease: Most were regional recurrences (51 of 70 patients; 73%) in the treated lymph node basin. After regional recurrence, a majority (73%) died of disease. The following 4 variables were associated significantly with survival: immunosuppression (hazard ratio [HR], 3.13; 95% confidence interval [CI], 1.39-7.05), treatment (HR, 0.32; 95% CI, 0.16-0.66), extranodal spread (HR, 9.92; 95% CI, 1.28-77.09), and margin status (HR, 1.85; 95% CI, 1.85-3.369); and those 4 variables (immunosuppression, treatment, extranodal spread, and margin status) were used to calculate the ITEM score. The 5-year risk of dying from disease for patients with high-risk (>3.0), moderate-risk (>2.6-3.0), and low-risk (≤2.6) ITEM scores were 56%, 24%, and 6%, respectively. Fifty-six of 250 patients (22%) died from another cause. |
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3 |
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Silberstein et al 2015 |
To find the rate of cervical lymph node metastasis in the series of patients with cutaneous SCC of the head and neck (cHNSCC) and to identify those who may need SLNB. |
Retrospective review; n= 572 patients; 725 cHNSCC |
Patients treated at the Soroka University Medical Center with a diagnosis of cHNSCC during the years 1998 to 2005. |
To find the rate of cervical lymph node metastasis in the series of patients with cHNSCC and to identify those who may need SLNB. |
A total of 572 patients with 725 cHNSCC were included in the study group. During the follow-up period, 10 (1.3%) patients developed lymph node metastases and no patients developed distant metastases. The probability of lymph node metastasis within 6 years for T1 and T2 tumors was 1.09% and 5.46%, respectively (p = .0387). Because of the relatively low incidence of cervical lymph node metastases in patients with cHNSCC, SLNB for clinically N0 patients is not justified. |
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3 |
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Sood et al 2019 |
To determine if the number of metastatic lymph nodes is an independent prognostic factor in metastatic cSCCHN and whether it provides additional prognostic information to the American Joint Committee on Cancer (AJCC) staging. |
Retrospective analysis; n=101 |
Patients undergoing curative-intent treatment for metastatic cSCCHN to parotid and/or neck nodes by surgery +/− radiotherapy at Liver- pool Hospital, Sydney, Australia. |
Disease-free survival and risk of distant metastases |
The mean number of nodal metastases was 2.5 (range 1–12). On multivariate analysis, an increasing number of nodal metastases significantly predicted reduced DFS (hazard ratio 1.17; 95% confidence interval 1.05–1.30; P = 0.004), with a 17% increased risk of recurrence or death for each additional node. This remained significant in multivariate models adjusted for AJCC 8th edition nodal and TNM stages. Number of nodal metastases was also associated with risk of distant metastatic failure (hazard ratio 1.21; 95% confidence interval 1.05–1.39; P = 0.009).
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Increasing number of nodal metastases is associated with decreased DFS and increased risk of distant metastases in metastatic cSCCHN, with a cumulative risk increase with each additional node. It provides additional prognostic information to the AJCC stag- ing, which may be improved by incorporating information on the number of nodal metasta- ses beyond the current single versus multiple distinctions. |
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Takeda et al 2013 |
To compare pre-surgical aspects data between two groups: patients with lymph node metastasis and patients without lymph node metastasis |
Retrospective review; n=164 patients |
Patients with cSCC from one center |
Detection rate from lymph node metastasis of the SLNB |
The following factors were compared between the patients with lymph node metastasis group and the group with no lymph node metastasis: age, sex, tumour size, symptom period, lesions, and local recurrence. Detection rate from sentinel lymph biopsy node metastasis using the blue dye technique was evaluated. Among all subjects, lymph node metastasis was observed in 17 cases (10.4%). Lower lip SCC was observed only in the higher metastasis rate. Significant local recurrence occurred more frequently in the lymph node metastasis group. For other factors, no significant difference was observed between the lymph node metastasis group and the no lymph node metastasis group. A sentinel lymph node biopsy was performed in 21 cases, two false-negative cases were observed, and local recurrence and lymph node metastasis were observed postoperatively. Operation should be given to the lower lip SCC and local recurrence cases considering lymph node metastasis. It is hard to say that the sentinel lymph node biopsy of cSCC using the blue dye technique has sufficient detection rates. |
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3 |
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Wang et al 2018 |
To compare differences in risks of recurrence, metastasis, and death from cSCCs on the vermilion vs cutaneous lip. |
Retrospective cohort study; n= 303 |
Patients with primary cSCCs of the lip (138 cutaneous, 172 vermilion) diagnosed between 2000 and 2015 at 2 academic tertiary care centers in Boston, Massachusetts. |
Development of local recurrence, nodal metastasis, distant metastasis, disease-specific death, and all-cause death |
Of the 303 study participants with 310 SCCs. Of the lip, 153 (50.5%) were men,and 150 (49.5%) were women; median age at diagnosis, 68 years (range, 27-93 years). Outcomes were as follows for vermilion vs cutaneous locations: local recurrence, 6.4% (11 of 172) vs 2.9% (4 of 138); nodal metastasis, 7.6% (13 of 172) vs 1.5% (2 of 138); distant metastasis, 0.6% (1 of 172) vs 0.7% (1 of 138); disease-specific death, 3.5% (6 of 172) vs 2.9% (4 of 138); and all-cause death, 26.7% (46 of 172) vs 29.0% (40 of 138). The difference was statistically significant for nodal metastasis (P = .01). In multivariable analysis, nodal metastasis was associated with vermilion lip location (subhazard ratio, 5.0; 95% CI, 1.1-23.8) and invasion beyond fat (fascia or beyond for vermilion lip) (subhazard ratio, 4.4; 95% CI, 1.3-14.9). |
The risk of nodal. Metastasis is 5-fold greater for cSCCs on the vermilion lip compared with those on the cutaneous lip. Squamous cell carcinomas of the cutaneous lip have a nodal metastasis risk similar to cSCCs in general (1.5%). Thus, vermilion involvement appears responsible for the increased risk associated with cSCC of the lip. Vermilion involvement may merit radiologic nodal staging and inclusion in future tumor staging since it was independently associated with higher-risk cSCC of the lip region. |
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Wang et al 2013 |
To compare recurrence and survival in patients undergoing either selective neck dissection or modified radical neck dissection to treat metastatic cutaneous head and neck squamous cell carcinoma (cHNSCC) to the cervical lymph nodes (levels I–V) only. |
Retrospective review; n=122 patients |
Patients undergoing neck dissection for metastatic cHNSCC between 1980 and 2008 from one center. |
To compare recurrence and survival in patients undergoing either selective neck dissection or modified radical neck dissection to treat metastatic cHNSCC to the cervical lymph nodes (levels I–V) only. |
There were 122 eligible patients: 96 males (79%) and 26 (21%) females (median age, 66 years). Sixty-six patients (54%) underwent selective neck dissection and 56 (46%) modified radical neck dissection. The former patients had a lower rate of regional recurrence compared with the latter (17 vs 23%, respectively). There was no significant difference in five-year OS (61% vs 57%, respectively) or five-year DFS (74% vs 60%, respectively), comparing the two groups. OS and DFS were significantly improved by the addition of adjuvant radiotherapy .No difference was found in outcome in patients undergoing selective versus modified radical neck dissection. Adjuvant radiotherapy significantly improved outcome. |
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3 |
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Wermker K et al 2015 |
To identify predictive factors for lymph node metastasis (LNM) in SCC of the lip and to establish a prediction model identifying patients at high LNM risk. |
Retrospective analysis; n=326 |
Patients with malignancies of the lip (ICD10-codes C00.1eC00.8) and histologically secured SCC, treated surgically between 2001 and 2011 from one institutional database. |
To formulate a prediction model for LNM using binary logistic and Cox regression analysis |
Lymph node metastasis occurred in 26 (8%) patients. Regression analysis revealed tumor extent, tumor depth and grading as the most important factors in the correct classification of LNM in 94.2% of patients. A prediction model taking tumor depth and grading into account allowed for stratification of patients into high and low-risk groups (sensitivity 92.3%, specificity 78.3%, negative predictive value 99.2%). |
This new prediction model was able to identify patients with lip cancer who had a high risk of LNM with a good level of accuracy.
This algorithm is easy to apply as part of the decision process for elective and selective lymph node dissection in SCC of the lip. |
3 |
|
Wong et al 2014 |
To examine the tradeoffs and benefits of different management approaches in the stage N0 patient. |
Retrospective analysis; n=30 patients |
Patients with stage N0 cutaneous squamous cell carcinoma of the head and neck (cSCCHN) from one center |
To compare different management approaches in the stage N0 patient: surveillance, elective node irradiation, and elective node dissection. |
Sensitivity analysis was performed and the effect on the expected utility was examined. When the probability of occult metastasis was[19 %, elective nodal irradiation resulted in a higher expected utility than observation. When the probability of occult metastasis exceeds 25 %, elective node dissection has a higher expected utility compared to observation. Given the currently available evidence, a wait-and-see approach is justified in patients with a probability of occult metastases < 19 %. |
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3 |
|
Wu et al 2020 |
To describe outcomes of a single institution experience with sentinel lymph node biopsy (SLNB) for high-risk cutaneous squamous cell carcinoma of the head and neck. |
Retrospective analysis; n=83 |
Patients who presented with clinically node-negative cutaneous squamous cell carcinoma of the head and neck between December 2007 and May 2018 |
The main outcomes were SLNB result, lymph node spread, recurrence-free survival, disease-specific survival, and overall survival. |
Eighty-three patients underwent successful SLNB, and one patient underwent selective neck dissection for intraoperatively identified occult lymph node metastasis. Five patients (6%) had a sentinel node-positive for tumor, of whom 4/5 received further treatment (neck dissection, radiation, and/or systemic therapy) with no further recurrence at the time of last follow-up. SLNB had a negative predictive value of 95% to 100%. Recurrent tumor at presentation, tumor arising from an area of chronic inflammation, and immunosuppression were significantly associated with increased risk of subsequent recurrence, with a mean follow-up of 19.9 months. |
SLNB can be used to identify regional lymph node metastases in cutaneous squamous cell carcinoma of the head and neck with a high negative predictive value (95%–100%). Factors associated with recurrence were tumor being locally recurrent at presentation, arising from an area of chronic inflammation, and immunosuppression. |
4 |
|
Xiao et al 2018 |
To analyze the superiority of wait-and-see policy and elective neck dissection in treating cN0 patients with facial cutaneous cell carcinoma (cSCC). |
Prospective study; n=111 |
Patients with cSCC and clinically negative parotid and neck metastasis disease from one center |
Regional control and disease-specific survival rates between 3 groups: 1) wait and see; 2) superficial parotidectomy and 3) superficial parotidectomy and elective neck dissection |
The occult parotid and neck metastasis rate was 20% and 16%, respectively. There was neck node metastasis without parotid metastasis in only 1 patient. All the node metastasis occurred in level II. Regional recurrence was noted in 16 (16%) patients, and 6 patients died of the disease. In the group undergoing superficial parotidectomy and elective neck dissection, 2 patients had neck node metastasis, and there was no disease-related death, further survival analysis indicated it had better regional control and disease-specific survival rates compared with the other 2 groups. |
Superficial parotidectomy and elective neck dissection are suggested for patients with T3–4 facial cutaneous squamous cell carcinoma |
3 |
PEK Strahlentherapie
|
Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments |
LoE |
|
Amaral et al 2019 |
To describe and analyze patients and primary tumour characteristics, local and systemic treatments, as well as survival outcomes. |
Retrospective analysis; n= 195 |
Patients with advanced cSCC diagnosed between 01/2011 and 06/2018 in one center |
Survival rates |
The median follow-up was 21 months [IQR = (10.0; 21.0)]. The median age at time of advanced disease diagnosis was 78 years [IQR = (72; 84)], with 40.5% of the patients in stage III and 59.5% in stage IV. One hundred and forty-five patients had resectable tumours. In this group the median overall survival (mOS) was 59 months (95% CI: 28.2–89.8), significantly higher than the mOS in patients with inoperable tumour [n = 50; mOS: 19 months (96% CI: 7–31, P <0.0001)]. Patients receiving immunotherapy (n = 20) showed a statistically significant better survival compared to those treated with other systemic therapies (n = 37; mOS not reached vs. mOS: 22 months (95% CI: 6.5–43.5), P = 0.034). For patients without systemic therapy, a combination of surgery and radiotherapy provided better outcomes compared to radiotherapy alone or best supportive care (P<0.001). |
Surgical complete resection should be the first therapeutic option for patients with acSCC. For patients with inoperable tumour, first-line immunotherapy should be preferably considered. |
3 |
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Amoils et al 2019 |
To describe outcomes in one institution, including patterns of metastasis, clinicopathologic factors related to survival, and failure rates. To stratify results by treatment modality. |
Retrospective review; n= 80 |
Patients treated for regionally metastatic cutaneous HNSCC |
OS, failure rates, results by treatment modality |
On multivariate regression, cutaneous primary >2 cm (p = .03) and extracapsular spread (ECS; p = .01) were significantly associated with decreased OS. Location of regional metastasis (neck vs parotid vs both) did not affect OS (p = .2), nor did the presence of a cutaneous primary at the time of presentation (p = .9). The 3-year survival was 43%, 52%, and 49% for surgery alone, adjuvant radiation, and adjuvant chemoradiation, respectively. Fifty-one percent of patients had a recurrence of their disease. |
Regionally metastatic cutaneous HNSCC is an aggressive disease associated with high recurrence rates. Patients with tumors >2 cm and ECS have poorer OS despite adjuvant therapy. |
4 |
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Arbab et al 2019 |
To evaluate outcomes and patterns of recurrence following radiation therapy (RT) for cutaneous squamous cell carcinoma (cSCC) of the head and neck |
Retrospective analysis; n= 111 |
Patients with head and neck cSCC patients treated with RT |
Recurrence rate |
With a median follow-up of 7 months, there were 29 (26%) recurrences, 73% of which were nodal (n = 21). Immunosuppression (IS) was the only factor associated with recurrence (47% in IS, 22% in non-IS, P = .04), and also with time to recurrence in multivariate analysis (HR 5.5; P = .03). No factors were associated with recurrence among patients who received definitive RT. The majority of patients who recurred were salvaged with surgery (n = 20, 69%). |
In a cohort of cSCC treated with radiotherapy, there was an association between IS and increased failure risk. The majority of failures were salvaged surgically. |
3 |
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Canueto et al 2020 |
To evaluate the usefulness of postoperative radiotherapy (PORT) in the treatment of CSCC with perineural invasion (PNI) to determine which patients would best benefit from this type of treatment. |
Retrospective multicenter cohort; n= 110 |
Patients with CSCCs and with PNI |
Types of PNI associated with poor outcome and the effectiveness of PORT on different groups of CSCC with PNI. Assessed for the usefulness of PORT depending on the surgical margin status (either clear or positive). |
Postoperative radiotherapy showed clear benefit over observation in CSCC with PNI and positive margins after surgery, where the management by observation increased the risk of poor outcome events 2.43 times (P = 0.025), and especially in those with positive margins and PNI ≥0.1 mm, where the risk of poor prognosis is eight times greater following management by observation (P = 0.0065). Multivariate competing risk analysis preserved statistical significance. |
The use of PORT on patients with CSCC with PNI and positive margins after surgery, especially in PNI ≥0.1 mm, significantly improves long-term outcome. The benefit of PORT in cases with clear margins is not as evident, especially in those with PNI of small-calibre nerves. |
3 |
|
Chen et al 2007 |
To report the clinical outcome of patients treated with radiation therapy for parotid-area metastases from cutaneous squamous cell carcinoma of the head and neck (cHNSCC). |
Retrospective study; n= 36 patients |
Patients treated with radiation therapy for parotid-area metastasis from primary skin cancer of the head and neck from 1970 to 2003 |
Clinical outcomes |
Thirty patients (83%) were treated postoperatively after gross total tumor resection. Median dose to the parotid area was 60 Gy (range, 50–72 Gy). Treatment of clinically N0 necks consisted of surgical dissection (7 patients), irradiation (15 patients), and observation (14 patients).
The 5-year estimate of local (parotid) control was 86% in patients treated using surgery with postoperative therapy and 47% in patients treated using radiation therapy alone. Three of 4 patients with tumors that relapsed locally after surgery and postoperative radiation received a dose of less than 60 Gy. Elective neck irradiation decreased the incidence of subsequent nodal failures from 50% to 0% and significantly improved neck control (p < 0.001). The 5-year OS rate was 63%. Surgery followed by radiation therapy to doses of at least 60 Gy results in effective local control for patients with parotid area metastasis from cutaneous squamous cell carcinoma. Routine irradiation of the clinically N0 neck is recommended. |
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2 |
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Chua et al 2002 |
To report on the patterns of recurrence, outcome and predictors for locoregional recurrence following treatment at our institution. Locoregional recurrence was defined as disease relapse above the clavicles. |
Retrospective review; n=52 |
Patients with head and neck SCC (HNSCC) treated within the department of Radiation Oncology, Westmead Hospital, Sydney between 1980–1997. |
Patterns of recurrence, predictors for local recurrence. |
Only extranodal spread (P = 0.02) was identified as an independent predictor for locoregional recurrence on multivariate analysis. The cumulative locoregional recurrence rates were 28 and 45% at 2 and 5 years, respectively. The 5-year cause-specific survival rate in this study was 65%. We conclude that parotid lymph-node metastases from cHNSCC are associated with a high rate of locoregional recurrence and cause-specific mortality despite surgery and adjuvant radiotherapy. The role of altered fractionation after surgery as a means to further enhance locoregional control warrants further investigation. |
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2 |
|
Dona et al 2003 |
To report on the patterns of recurrence, outcome and predictors for locoregional recurrence of cutaneous SCC metastatic to the parotid and neck lymph nodes, following surgery and high dose adjuvant radiotherapy |
Retrospective review; n=74 |
Patients treated for metastatic cutaneous squamous cell carcinoma to the parotid with surgery and adjuvant radiotherapy at Westmead Hospital, Sydney, between 1983 and 2000. |
Patterns of recurrence, outcome and predictors for locoregional recurrence. |
24% developed locoregional recurrence, with a median time to relapse of 7.5 months. The most common site for recurrence was the treated parotid region and upper neck. Most relapsed patients died. No variable independently predicted for locoregional recurrence on multivariate analysis. The 5-year absolute and cause-specific survival rates were 58% and 72%, respectively. |
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3 |
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Erkan et al 2017 |
To analyze the outcomes of multimodal treatment entailing the en bloc surgical resection and postoperative radiotherapy for previously untreated patients as well as the outcomes of the salvage treatment for previously treated patients with clinical perineural invasion (PNI) of the trigeminal and facial nerves from cutaneous squamous cell carcinoma of the head and neck (cHNSCC) at a single institution |
Retrospective review; n= 21 |
Patients with clinical PNI from cHNSCC between the years 2006 and 2012 in one center. |
DFS
OS
Correlation of OS and DFS with surgical factors, such as margin status, previous treatment, zone involvement, and trigeminal involvement (branch-specific), as well as the pretreatment and post-treatment pain scores |
Of 21 patients with clinical PNI from cHNSCC, 7 patients (33%) were previously treated for their disease with primary radiotherapy. Negative tumor margins were achieved in 18 patients (86%). Three of the 7 patients (43%) undergoing salvage surgery had positive margins. One-year and 3-year DFS for previously untreated patients was 91% and 67%, respectively, whereas 1-year and 3-year DFS was 72% and 28%, respectively, for the previously treated patients. Previous radiotherapy, ophthalmic nerve involvement, and positive margins portended poorer survival outcomes in this study. |
The retrospective study of this rare clinical entity demonstrates that multimodal treatment can achieve favorable survival outcomes. |
3 |
|
Goyal et al 2017 |
To evaluate the role of concurrent systemic therapy to postoperative radiation therapy (RT) for locally advanced cutaneous head and neck squamous cell carcinoma (LA-cHNSCC). |
Retrospective study; n=32 |
Patients with LA-cHNSCC after surgical resection with one or more high-risk features. |
Local regional control (LRC), distant control (DC), and acute and late toxicities; progression-free survival (PFS) and overall survival (OS). |
While comparing patients receiving RT with systemic therapy (n = 14) vs RT alone (n = 18), LRC was 92.9% vs 72.2% (p = 0.20), DC 92.9% vs 94.4% (p = 1.0), median PFS 17.7 months vs 34.4 months (p = 0.48), and median OS 20.9 months vs 34.4 months (p = 0.03), respectively. On univariate analyses, use of concurrent systemic therapy was associated with an increased risk of death with an HR of 3.5 [95% confidence interval (CI): 1.04 - 11.6] (p = 0.04), while patients treated for recurrent disease who had previously treated superficial primaries had improved OS with an HR of 0.10 [95% CI: 0.01-0.80] (p = 0.03). There were no significant differences in acute or chronic toxicities between groups. |
Patients receiving postoperative RT alone for LA-cHNSCC had better OS than patients receiving concurrent systemic therapy. There were no differences in any other endpoints evaluated. |
4 |
|
Han et al 2007 |
To evaluate the effectiveness of adjuvant RT in treating SCC with perineural invasion (PNI). |
Literature review; n=554; n= 10 articles |
Patients with SCC and PNI described in 10 published articles |
Effectiveness
|
For SCC with PNI, the local control rate after MMS with or without RT was from 92% to 100% compared with a control rate from 38% to 100% after standard excision with or without RT. A better prognosis was associated with negative pretreatment MRI or CT findings than with positive radiographic evidence of PNI. Primary SCC with PNI was associated with better local control than recurrent SCC with PNI. When treatment outcomes were stratified by PNI type, SCC with microscopic PNI and SCC with extensive PNI had local control rates from 78% to 87% and from 50% mto 55%, respectively. Adjuvant RT was associated in selected patients with 100% local control. |
Few studies addressed the effectiveness of adjuvant RT in patients who have SCC with PNI. Although RT has been established as an adjuvant treatment for selected patients, the extent of nerve involvement by tumor, particularly in the setting of other high-risk features, may be helpful in defining its role. |
1 |
|
Harris et al 2019 |
To assess indications for adjuvant radiation therapy in patients with CSCC |
Retrospective analysis; n=349 |
Patients with head and neck CSCC treated with primary resection with or without adjuvant radiation therapy at 2 tertiary referral centers from January 1, 2008, to June 30, 2016. |
Disease-free survival (DFS) and overall survival (OS) |
A total of 349 patients had tumors that met the inclusion criteria (mean [SD] age, 70 [12] years; age range, 32-94 years; 302 [86.5%] male), and 191 (54.7%) received adjuvant radiation therapy. The 5-year Kaplan-Meier estimates were 59.4% for DFS and 47.4% for OS. Patients with larger, regionally metastatic, poorly differentiated tumors with perineural invasion (PNI) and younger immunosuppressed patients were more likely to receive adjuvant radiation therapy. On Cox proportional hazards multivariate regression, patients with periorbital tumors (hazard ratio [HR], 2.48; 95% CI, 1.00-6.16), PNI (HR, 1.90; 95% CI, 1.12-3.19), or N2 or greater nodal disease (HR, 2.16; 95% CI, 1.13-4.16) had lower DFS. Immunosuppressed patients (HR, 2.17; 95% CI, 1.12-4.17) and those with N2 or greater nodal disease (HR, 2.43; 95% CI, 1.42-4.17) had lower OS. Adjuvant radiation therapy was associated with an improved OS for the entire cohort (HR, 0.59; 95% CI, 0.38-0.90). In a subset analysis of tumors with PNI, adjuvant radiation therapy was associated with improved DFS (HR, 0.47; 95% CI, 0.23-0.93) and OS (HR, 0.44; 95% CI, 0.24-0.86). Adjuvant radiation therapy was also associated with improved DFS (HR, 0.36; 95% CI, 0.15-0.84) and OS (HR, 0.30; 95% CI, 0.15-0.61) in patients with regional disease. |
Among patients with advanced CSCC, receipt of adjuvant radiation therapy was associated with improved survival in those with PNI and regional disease. |
3 |
|
Hirshoren et al 2018 |
To identify the patterns of recurrence, with attention paid to the incidence of parotid bed recurrence following protocols used at one institution. |
A retrospective cohort study of parotidectomy with or without neck dissection for metastatic cSCC. |
Patients with metastatic cSCC involving the parotid gland who underwent a curative-intent parotidectomy (superficial or total), with or without neck dissection, between 2003 and 2014. |
Overall survival and regional recurrence associated with surgical extent and adjuvant treatment. |
Of 78 patients, 65 underwent superficial parotidectomy. Median follow-up was 6.5 years. Sixty-four patients (82%) patients received adjuvant radiotherapy. Cervical lymph nodes were involved in 6 (24%) elective neck dissections. Involved preauricular, facial, external jugular, and occipital nodes occurred in 36.9%. Adjuvant radiotherapy was associated with improved 5-year survival—50% (95% CI, 36%-69%) versus 20% (95% CI, 6%-70%)—and improved 2- year regional control: 89% (95% CI, 67%-100%) versus 40% (95% CI, 14%-100%). The ipsilateral parotid bed recurrence rate was 3.7% for those who received adjuvant radiotherapy and 27% for those who did not receive radiotherapy. |
This study supports surgery plus adjuvant radiotherapy as a standard of care for metastatic cSCC. The low incidence of parotid bed recurrence with this approach suggests that routine elective deep lobe resection may not be required. |
4 |
|
Jambusaria-Pahlajani et al 2009 |
To compare reported outcomes of high-risk SCC treated with surgical monotherapy (SM) with those of surgery plus adjuvant radiotherapy (S+ART). |
Systematic review; n= 2,449 |
Medline reports of high-risk SCC treated with SM or S+ART that reported outcomes of interest: local recurrence, regional or distant metastasis, or disease-specific death, between January 1, 1980, and June 30, 2006. Case reports containing less than 5 cases were excluded |
Local recurrence, regional
Distant metastasis
Disease-specific death. |
There were no controlled trials. Of the 2,449 cases of high-risk SCC included, 91 were treated with S+ART. Tumor stage and surgical margin status before ART were unreported. In 74 cases of perineural invasion (PNI), outcomes were statistically similar between SM and S+ART. In 943 SCC cases in which clear surgical margins were explicitly documented. Risk of local recurrence in cases with documented clear margins versus unreported margins was 5% versus 8% (p=.005), regional metastasis 5% versus 14% (p=.001), distant metastasis 1% versus 7%(p=.001), and disease-specific death 1% versus 7% (p=.001). |
High cure rates are achieved in high-risk cutaneous SCC when clear surgical margins are obtained. Current data are insufficient to identify high-risk features in which ART may be beneficial. In cases of PNI, the extent of nerve involvement appears to affect outcomes, with the involvement of larger nerves imparting a worse prognosis. |
1 |
|
Lansbury et al 2013 |
To assess the effects of treatments for non-metastatic invasive SCC of the skin using evidence from observational studies, given the paucity of evidence from randomized controlled trials. |
Systematic review of observational studies; n=118 papers; |
Patients with non-metastatic invasive SCC of the skin reported in observational studies in Medline or Embase, to December 2012. |
Effects of treatments for non-metastatic invasive SCC of the skin
Recurrence |
Pooled estimates of recurrence of SCCs were lowest after cryotherapy (0.8% (95% confidence interval 0.1% to 2%)) and curettage and electrodesiccation (1.7% (0.5% to 3.4%)), but most treated SCCs were small, low-risk lesions. After Mohs micrographic surgery, the pooled estimate of local recurrence during variable follow-up periods from 10 studies were 3.0% (2.2% to 3.9%), which was non-significantly lower than the pooled average local recurrence of 5.4% (2.5% to 9.1%) after standard surgical excision (12 studies), and 6.4% (3.0% to 11.0%) after external radiotherapy (7 studies). After an apparently successful initial response of SCCs to photodynamic therapy, pooled average recurrence of 26.4% (12.3% to 43.7%; 8 studies) was significantly higher than other treatments. Evidence was limited for laser treatment (1 study) and for topical and systemic treatments (mostly single case reports or small non-comparative series with limited follow-up). |
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1 |
|
Manyam et al 2018 |
To report survival outcomes of immunosuppressed and immunocompetent stage I-IV cSCC-HN patients treated with surgery and postoperative RT |
Retrospective study; n=205 |
Immunosuppressed and immunocompetent patients from 3 institutions who underwent surgery and also received postoperative RT for primary or recurrent, stage I through IV cSCC-HN between 1995 and 2015 |
Overall survival, locoregional recurrence-free survival, and progression-free survival |
Of 205 patients, 138 (67.3%) were immunocompetent, and 67 (32.7%) were immuno- suppressed. Locoregional recurrence-free survival (47.3% vs 86.1%; P < .0001) and progression-free survival (38.7% vs 71.6%; P = .002) were significantly lower in immunosuppressed patients at 2 years. The 2-year OS rate in immunosuppressed patients demon- strated a similar trend (60.9% vs 78.1%; P = .135) but did not meet significance. On multivariate analysis, immunosuppressed status (hazard ratio [HR], 3.79; P < .0001), recurrent disease (HR, 2.67; P = .001), poor differentiation (HR, 2.08; P = .006), and perineural invasion (HR, 2.05; P = .009) were significantly associated with locoregional recurrence. |
Immunosuppressed patients with cSCC-HN had dramatically lower outcomes compared with immunocompetent patients, despite receiving bimodality therapy. Immune status is a strong prognostic factor that should be accounted for in prognostic systems, treatment algorithms, and clinical trial design. |
3 |
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McDowell et al 2016 |
To review outcomes of current management in a tertiary center to target future strategies |
Retrospective study; n=132 |
Patients with metastatic cHNSCC involving the parotid gland, undergoing radical surgery and adjuvant radiotherapy during 2000–2014 |
Overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) |
One hundred and thirty-two patients met the inclusion criteria. Median follow-up was 5.0 years. Five-year overall (OS), cancer-specific (CSS) and progression free survival (PFS) were 44% (95% Confidence Interval (CI) 34– 53%), 64% (95% CI 52–74%) and 37% (95% CI 28–47%) respectively. Locoregional control (LRC) was 68% (95% CI 55–77%) at 5 years. Immunosuppressed patients fared worse (compared with immunecompetent) with five-year OS, CSS, and PFS of 14% versus 53% (HR = 3.19; 95% CI 1.91– 5.34), 40% versus 71% (Hazard Ratio (HR) = 2.92; 95% CI 1.38–6.19) and 10% versus 46% (HR = 2.51; 95% CI 1.52–4.14) respectively. On multivariate analysis, immune status strongly predicted OS (P < 0.001), CSS (P = 0.003), DMFS (P < 0.001) and PFS (P < 0.001), but not LRC. Largest lymph node size was the only significant factor predictive for LRC on multivariate analysis (P = 0.02). |
Despite multimodality treatment metastatic cHNSCC involving the parotid shows moderate rates of recurrence. Immunosuppressed patients with this disease have a particularly poor prognosis, demonstrating lower rates of CSS with similar rates of LRC compared to their immunocompetent counterparts. |
3 |
|
Mendenhall et al 2009 |
To discuss the role of radiotherapy (RT) in the treatment of cutaneous SCC and BCC of the head and neck. |
Literature review |
Patients with BCC and SCC treated with RT |
Radiotherapy outcomes – cosmetic, local control, cure rate |
The likelihood of cure with a good cosmetic outcome is high for patients with early-stage cancers treated with definitive RT. The probability of local control is higher for previously untreated cancers and is inversely related to tumor size. The likelihood of cure for patients with perineural invasion (PNI) is related to the presence of symptoms and to the radiographic extent of disease. It decreases as the tumor extends centrally towards the central nervous system. Patients with incidental PNI have a local control rate of 80% to 90% compared with about 50% to 55% for those with clinical PNI. The optimal treatment for patients with clinically positive nodes is surgery and postoperative RT. The likelihood of cure for those with positive parotid nodes is approximately 70% to 80%. |
Definitive RT is useful for treating early-stage skin cancers where resection would result in a significant cosmetic and/or functional deficit. Postoperative RT is indicated in situations where the probability of residual disease after surgery is high and the chance of successful salvage is modest.
Patients with parotid-area node metastases are optimally treated with surgery and postoperative RT. |
4 |
|
Miller et al 2019 |
To examine the clinical outcomes in a cohort of patients with cSCC who completed adjuvant radiotherapy (ART) after Mohs micrographic surgery or wide local excision with negative margins. |
Retrospective study; n=32 |
Patients with cSCC treated in the Mayo Clinic Department of Radiation Oncology from March 10, 1998, through April 26, 2013. Inclusion criteria were age >18 years, resection with negative histologic surgical margins, and completion of ART |
Rates of local recurrence (LR), lymph node metastasis (NM), and disease-specific death (DSD) |
Thirty-two patients met the inclusion criteria: 15 patients died, 12 without evidence of disease related to cSCC. Three patients developed recurrent disease, all with poorly differentiated cSCC, >2 cm in clinical diameter, perineural invasion, and Brigham and Women’s (BWH) stage T2b/T3; 2 of 3 patients were immunosuppressed; and 2 of 3 patients died of cSCC-related causes. |
These data suggest that the combination of surgical resection and ART is a reasonable option for Brigham and Women’s T2b/T3 tumors. |
4 |
|
Nottage et al 2016 |
To present one group evaluation of the outcomes of concurrent chemoradiotherapy (CRT) in patients with locally advanced cutaneous squamous cell carcinoma (cSCC). |
Prospective phase II study; n=21 |
Patients with locally or regionally advanced SCC of the skin unsuitable for surgery, who received definitive radiotherapy (RT; 70 Gy in 35fractions) and concurrent weekly platinum-based chemotherapy (cisplatin 40 mg/m2 or carboplatin area under the curve 2). |
Primary endpoint was complete response (CR) |
Twenty-one patients were enrolled in this study. Eighteen patients had a locally advanced primary or nodal disease in the head and neck region with 66% having stage IV non-metastatic disease. Of 19 evaluable patients, 10 achieved a CR to definitive CRT with 2 further patients rendered disease-free by salvage surgery for an overall CR of 63%. |
This is the only prospective series of CRT for cSCC. A high CR rate was documented in patients with locoregional advanced disease who were unable to undergo surgery. |
3 |
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Palmer et al 2018 |
To investigate the safety, tolerability and preliminary efficacy of radiotherapy plus cetuximab in high-risk CSCC patients. |
Retrospective study; n= 68 |
Patients with high-risk CSCC diagnosed between 2006 and 2013 |
Safety, tolerability, PFS and OS rates |
Median follow-up for living patients was 30 months. Patients in the cetuximab group were more likely to have advanced N stage, positive margins and recurrent disease. After propensity score matching the groups were well balanced. Six patients experienced ≥ grade 3 acute toxicity in the cetuximab group. The 1-year, 2-year and 5-year progression-free survival (PFS) for patients in the cetuximab group were 86%, 72% and 66%, respectively. The 1-year, 2-year and 5-year overall survival (OS) for patients in the cetuximab group was 98%, 80% and 80%, respectively. |
Although limited by small numbers, the combination of cetuximab and radiotherapy in CSCC appears well-tolerated there were more long-term survivors and less distant metastasis in the cetuximab group. These promising findings warrant further studies. |
4 |
|
Porceddu et al 2018 |
To determine whether the addition of concurrent chemotherapy to postoperative radiotherapy (CRT) improved locoregional control in patients with high-risk cutaneous squamous cell carcinoma of the head and neck. |
This was a multicenter, open-label, randomized, phase III clinical trial; n= 321 |
Patients with high-risk cutaneous squamous cell carcinoma of the head and neck. |
The primary objective was to determine whether there was a difference in freedom from locoregional relapse (FFLRR) between 60 or 66 Gy (6 to 6.5 weeks) with or without weekly carboplatin (area under the curve 2) after resection of gross disease. Secondary efficacy objectives were to compare disease-free survival and overall survival. |
Three hundred twenty-one patients were randomly assigned, with 310 patients commencing al- located treatment (radiotherapy [RT] alone, n = 157; CRT, n = 153). Two hundred thirty-eight patients (77%) had high-risk nodal disease, 59 (19%) had a high-risk primary or in-transit disease, and 13 (4%) had both. Median follow-up was 60 months. Median RT dose was 60 Gy, with 84% of patients randomly assigned to CRT completing six cycles of carboplatin. The 2- and 5-year FFLRR rates were 88% (95% CI, 83% to 93%) and 83% (95% CI, 77% to 90%), respectively, for RT and 89% (95% CI, 84% to 94%) and 87% (95% CI, 81% to 93%; hazard ratio, 0.84; 95% CI, 0.46 to 1.55; P = .58), respectively, for CRT. There were no significant differences in disease-free or overall survival. Locoregional failure was the most common site of first treatment failure, with isolated distant metastases as the first site of failure seen in 7% of both arms. Treatment was well tolerated in both arms, with no observed enhancement of RT toxicity with carboplatin. Grade 3 or 4 late toxicities were infrequent. |
Although surgery and postoperative RT provided excellent FFLRR, there was no observed benefit with the addition of weekly carboplatin. |
2 |
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Ruiz et al 2020 |
To compare surgery plus adjuvant radiation therapy (S1ART) to surgical monotherapy (SM) for primary cSCCs with LCNI and other risk factors |
Retrospective study; n= 62 |
Patients with cSCC diagnosed at Brigham and Women’s Hospital (BWH) during January 1, 2000-December 31, 2017 |
LR, NM, distant metastasis, and disease-specific death |
In total, 62 cSCCs were included in matched analysis (31 S1ART and 31 SM) and 33 cSCCs in the LCNI analysis (16 S1ART and 17 SM). There were no significant differences in local recurrence, metastasis, or death from disease in either analysis. Risk of local recurrence was low (8%, 7/89), with 3 of the local recurrences being effectively treated upon recurrence. |
Adjuvant radiation did not improve outcomes compared with SM due to a low baseline risk of recurrence, although adjuvant radiation for named nerve invasion and LCNI of ³3 nerves has been shown to improve outcomes in a prior study. Randomized studies are needed to define the subset of cSCC for whom adjuvant radiation has utility. |
4 |
|
Strassen et al 2017 |
To determine whether surgical concepts are warranted in the collective of old patients with cutaneous (cSCC) |
Retrospective study; n=67 |
Patients with cutaneous HNSCC treated in one department between January 2008 and December 2013 |
OS
Recurrence-free interval (RFI) |
The cohort was divided into patients with/without adjuvant therapeutic regimens.
The median recurrent free interval and the median OS after recurrent disease therapy were 27 and 59 months (data not shown), respectively. There was a significant difference between patients who underwent surgery with adjuvant radiotherapy and patients without adjuvant treatment.
Patients with adjuvant treatment demonstrated a 5y-RFI and OS rate of 78 and 79 %, respectively, while patients without adjuvant therapy showed a 5y-RFI and OS rate of 30 and 46 % (p = 0.02; p<0.05). The distribution of T and N stages differed significantly between the groups. Patients who underwent adjuvant radiotherapy presented with limited T stages (T0–1), but advanced N stages (N2a–2b). Patients without adjuvant treatment concepts showed higher T stages (T1–2) and limited N stages (N0–1) (p=0.001; p<0.0001). There were no differences in patient’ age (patients receiving adjuvant therapy: 76 years vs patients not receiving adjuvant therapy: 80 years; p = 0.07) and comorbidities (p=0.9). |
While the benefit of elective parotidectomy and/or neck dissection—particularly in high-risk patients (pN+, G3/ G4, tumour thickness >6 mm)—in the long-term preservation of neuronal structures, RFI and, OS has to be analyzed in a prospective randomized trial, our study demonstrated a favorable RFI/OS in patients with cSCC recurrent disease who underwent surgical concepts and adjuvant radiotherapy. Locoregional metastases in the lymphatic basin might be more frequent than previously expected.
Sonographic staging and follow-up screening of the cervical lymphatic basin might, therefore, be beneficial even in patients presenting with small primary tumors. |
3 |
|
Stratigos et al 2020 |
To make recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC) |
Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. |
EDF–EADO–EORTC guideline |
Treatment |
Lymph node dissection is recommended for cSCC with cytologically or histologically confirmed regional nodal involvement. Radiotherapy should be considered as curative treatment for inoperable cSCC, or for non-surgical candidates. |
|
1 |
|
Tang et al 2013 |
To report outcomes, failure patterns, and toxicity after stereotactic radiosurgery (SRS) for recurrent head and neck cutaneous squamous cell carcinoma with gross perineural invasion (GPNI). |
Retrospective study; n=10 |
Patients from one center, who received SRS as part of retreatment for recurrent head and neck cutaneous squamous cell carcinoma with GPNI, between December 2003 and September 2009. |
PFS rate
OS rate
Failure patterns
Toxicity |
At a median 22-month follow-up, the 2-year PFS and OS rates were 20% and 50%, respectively. Seven patients exhibited local failures, all of which occurred outside both SRS and EBRT fields. Five local failures occurred in previously clinically uninvolved cranial nerves (CNs). CN disease spreads through 3 distinct patterns: among different branches of CN V; between CNs V and VII; and between V1 and CNs III, IV, and/or VI. Five patients experienced side effects potentially attributable to radiation. |
Although there is excellent in-field control with this approach, the rate of out-of-field failures remains unacceptably high. We found that the majority of failures occurred in previously clinically uninvolved CNs often just outside treatment fields. Novel treatment strategies targeting this mode of perineural spread are needed. |
3 |
|
Tanvetyanon et al 2015 |
To report the efficacy of postoperative concurrent chemotherapy and radiotherapy for high-risk cutaneous squamous cell carcinoma of the head and neck (cSCCHN). |
Retrospective cohort study; n=61 |
Patients with cSCCHN who underwent adjuvant radiation or concurrent chemoradiation. Patients must have had stage III/IV with high-risk features, including metastatic involvement of >=2 lymph nodes, positive margins, or extracapsular invasion. |
RFS
Risk of recurrence
OR |
27 (44%) received adjuvant radiation and 34 (56%) received adjuvant chemoradiation. The median recurrence-free survivals were 15.4 and 40.3 months, respectively. Adjuvant chemoradiation significantly decreased the risk of recurrence or death in a multivariable analysis: hazard ratio (HR) 0.31 (p= .01). However, a difference in OS was not found. |
For high-risk cSCCHN, adjuvant chemoradiation was associated with better recurrence-free survival than adjuvant radiation alone. |
3 |
|
Terra et al 2017 |
First to determine the local control rate (LC) of HNcSCC after radiotherapy, both as primary modality or when complete surgery is not possible. Secondly, to determine which specific patient, tumour or treatment characteristics are prognostic for local recurrence (LR). |
Retrospective analysis |
Patients who had primary HNcSCC or recurrent HNcSCC (after surgery with curative intent) over the period 2000– 2014 were selected from the database of the Department of Radiation Oncology. The patients were analyzed in two groups: I) primary RT (RT as primary modality) and II) postoperative RT (RT when radical surgery cannot be performed or when perineural invasion is present). Primary RT is defined as RT for primary HNcSCC or recurrent HNcSCC, after surgery (52 tumours in 48 patients), and postoperative RT as RT after incomplete resection or when perineural invasion was present (99 tumours in 90 patients). |
Local control rate and local recurrence rate |
Primary RT.
A total of 52 tumours in 48 patients were included. The male-to-female ratio was 3:1, and the median age was 81 years (range 50–100). Median follow-up duration was 23 months (95% CI: 20.9–29.9). A clinical target volume margin of 1 cm was generally applied. All patients were treated five times per week.
Postoperative RT. A total of 99 tumours in 90 patients were included. There were more males (70.7%), and the median age was 76 years (range 39–106). The median follow-up was 24 months (95% CI: 24.9–35.8). A relatively large number of tumours had unfavourable characteristics such as poor differentiation (23.2%) and perineural growth (31.3%). A margin of 1 cm was generally applied. All patients were treated five times per week.
LC and LR Primary RT.
Two- and five-year LCs were both 82.5%. LR was 15.4% (8 of 52 tumours recurred). The median time to recurrence was five months (range 2–15).
Postoperative RT. The two- and five-year LCs were 81.4% and 75.4%, respectively. LR was 18.2% (18 of 99 tumours recurred). The median time to recurrence was five months (range 0–50).
Prognostic factors
Primary RT.
Kaplan–Meier estimates did not show statistically significant prognostic factors for local recurrence. The extension (T3) and poor differentiation grade were significantly associated with a higher risk of local recurrence. Multivariable analyses identified these three factors as independent predictors of higher LR after RT (hazard ratios of 4.3, 3.9 and 3.5, respectively), |
Radiotherapy is an effective treatment modality for HNcSCC patients for whom surgery would impair functional or cosmetic outcomes and may be the preferred choice of treatment for elderly patients when surgery is expected to cause major side-effects. HNcSCCs larger than 2 cm in diameter (T2), with extradermal invasion (T3) or a poor differentiation grade, have a higher chance of recurrence after postoperative RT. |
4 |
|
Trosman et al 2020 |
To review the oncologic outcomes of patients with high-risk HNcSCC treated with surgery and to identify risk factors for treatment failure. |
Retrospective cohort analysis; n=104 |
Patients treated for HNcSCC with definitive surgery involving at least parotidectomy and neck dissection at a tertiary care academic center from 2011 to 2017 |
The primary outcome was disease-free survival (DFS) |
One-hundred four patients with a median age of 68 years (range = 42–91 years) were reviewed. Twenty-one patients were treated with surgery alone, 45 patients underwent adjuvant radiotherapy (RT), and 38 patients underwent adjuvant chemoradiotherapy (CRT). The 2-year DFS for patients treated with surgery, surgery + RT, and surgery + CRT were 71%, 65%, and 58%, respectively, with no significant difference between the groups (P = .70). On multivariate analyses, tumor size (P = .006) and perineural invasion (PNI, P = .04) independently predicted recurrence. The addition of chemotherapy did not appear to improve DFS, neither for those patients with extranodal extension and/or positive margins (P = .93) nor for the entire cohort (P = .43). |
Advanced HNcSCC has a high recurrence rate despite adjuvant treatment. Tumor size >2 cm was a strong independent risk factor for recurrence. Out of the traditional mucosal HNcSCC risk factors, PNI was most strongly associated with worse DFS. There was no observed survival benefit to the addition of chemotherapy. |
4 |
|
Varra et al 2018 |
To identify factors associated with disease recurrence and report failure patterns and survival outcomes in patients with nodal metastases from cutaneous squamous cell cancer of the head and neck (cSCC-HN) treated with surgery and postoperative radiotherapy (RT). |
Retrospective analysis; n= 76 |
Patients with cSCC-HN with metastasis to cervical and/or parotid lymph nodes, treated with surgery and postoperative RT between 2002 and 2017. |
Overall survival, disease-free survival and disease recurrence |
This study included 76 patients (57 immunocompetent and 18 immunosuppressed) with a median follow-up of 18 months. Overall survival, disease-free survival (DFS), and disease recurrence (DR) at 2 years were 60%, 49%, and 40%, respectively. Immunosuppressed patients had significantly lower 2-year DFS (28% vs. 55%; p=0.003) and higher DR (61% vs. 34%; p=0.04) compared to immunocompetent patients. Analysis of immunocompetent patients demonstrated extracapsular extension (ECE) as the only factor associated with DR (p<0.0001). |
Patients with nodal metastases from cSCC-HN have suboptimal outcomes. ECE and immunosuppression were significantly associated with DR. |
4 |
|
Veness 2005 |
To discuss the treatment of patients with high-risk cutaneous SCC (cSCC) and, where applicable, also present the current role of radiotherapy in the management of these patients |
Review article |
n.a. |
n.a. |
Elective treatment of lymph nodes: The majority of patients with cSCC will not develop nodal metastases. The elective treatment of lymph nodes in all patients is inappropriate. Patients with adequately excised and previously untreated lesions are usually not candidates for further treatment. Patients with more than one high-risk factor (deeply invasive >4–5 mm, >2 cm in diameter), especially in the recurrent setting, should be considered at risk of developing nodal metastases. In such cases, elective treatment to first echelon nodes may be of benefit. At a minimum, patients should be followed closely (2–3 months) for at least 2–3 years. If radiotherapy is used to treat a primary high-risk lesion (definitive or adjuvant), consideration should be given to encompassing first echelon nodes in the treatment field.
METASTATIC SCC TO LYMPH NODES: Patients with metastases to parotid lymph nodes should undergo a parotidectomy and neck dissection. The extent of both the parotidectomy and neck dissection depends on the extent of clinical disease. Essentially, all patients should also be recommended adjuvant RT (60 Gy) to the parotid bed, and in many cases, to the lower neck. Similarly, patients with operable metastases to cervical lymph nodes should undergo a comprehensive neck dissection followed by adjuvant RT. Single modality treatment alone, either surgery or RT, is associated with a worse outcome. Close follow-up for at least 3–4 years is imperative if early loco-regional recurrence is to be potentially salvaged. The benefits from the addition of chemotherapy, altered fractionation or routine radical parotidectomy are currently unproven and not recommended.
INCOMPLETELY EXCISED SCC: Ideally, 4–5 mm excision margins are desirable. Margins <2 mm should be considered inadequate and warrant further treatment. It is not recommended to wait and watch ‘expectantly’ as a minority of patients will recur and increase a patient’s risk of developing nodal metastases. If function is not compromised, re-excision should be considered. If re-excision is not appropriate, a course of adjuvant RT (55–60 Gy) is likely to provide excellent local control without compromising function. All patients should be followed up regularly for at least 4–5 years to monitor for recurrence.
PERINEURAL INVASION: Patients with established palsies and/or involvement of the cavernous sinus or skull base are incurable. However, radiotherapy may palliate debilitating neuropathic-type symptoms. Following the reporting of perineural invasion of a cranial nerve, or branch of a cranial nerve, patients should be considered candidates for wide-field radiotherapy to encompass the potential neural pathway which often extends back to the brainstem.
IMMUNOSUPPRESSION: The basic tenets of obtaining adequate surgical margins and examining for perineural invasion are especially applicable to this group of patients. Although routine prophylactic treatment to regional lymph nodes cannot be recommended, adjuvant RT to incompletely excised SCC, or those with perineural invasion, should be strongly considered. Close liaison with a transplant physician is important. |
|
4 |
|
Veness et al 2005 |
To present further supportive evidence on the addition of adjuvant RT for treatment of patients with cutaneous SCC (cSCC) |
Retrospective review; n=167 |
Patients with metastatic cSCC to the parotid and/or cervical lymph nodes (levels I–V) were identified, treated with surgery alone or surgery and adjuvant RT with curative intent, between 1980 and 2002 in one Australian center |
Relapse
DFS rates
OS rates |
Median age was 67 years (range, 34–95) in 143 men and 24 women with a minimum follow-up of 24 months. Patients underwent surgery (21/167; 13%), or surgery and adjuvant RT (146/167; 87%). The majority (98/167; 59%) of metastatic nodes were located in the parotid and/or cervical nodes. The remaining 69 (41%) had metastatic cervical nodes (levels I–V). Forty-seven patients (28%) had recurrences, with the majority (35/47; 74%) as locoregional failures. On multivariate analysis, spread to multiple nodes and single-modality treatment significantly predicted worse survival. Patients undergoing combined treatment had a lower rate of locoregional recurrence (20% vs. 43%) and a significantly better 5-year DFS rate (73% vs. 54%; P =.004) compared to surgery alone. |
In patients with metastatic cutaneous head and neck SCC, surgery and adjuvant RT provide the best chance of achieving locoregional control and should be considered best practice. |
3 |
|
Veness et al 2003 |
To present the experience of one Australian center on treating cutaneous SCC (cSCC) metastatic to cervical non-parotid lymph nodes. |
Retrospective review; n=74 |
Patients diagnosed with previously untreated metastatic cSCC to cervical lymph nodes (level I-V) |
Recurrence
Time to relapse and recurrence rate. |
34% of patients developed recurrent disease, predominantly locoregional (22 of 25). Median time to recurrence was 5.2 months (2 - 34.3). Increasing nodal size (>=3cm; p=0.01), metastatic spread to multiple nodes (p=0.5) and the presence of extranodal spread (p= 0.01) all predicted for worse survival. Patients undergoing combined modality treatment had a lower relapse rate (15%) and a significantly better DFS (p=0.01) when compared to single modality treatment. |
|
3 |
|
Wang et al 2012 |
To compare the outcome of surgery against surgery plus radiotherapy in patients with metastatic cutaneous head and neck squamous cell carcinoma (HNSCC) to cervical nodes. |
Retrospective analysis; n=122 |
Patients who were treated for metastatic cutaneous HNSCC involving the cervical nodes (levels I–V), between 1980 and 2008 in one center |
Recurrence
DFS
5y-DFS
5y-OS |
After surgery alone, 11 patients (55%) developed recurrence compared with 23 patients (23%) after surgery plus RT. On multivariate analysis, the following variables were significantly associated with DFS: immunosuppression (p= .002), treatment modality (p< .001), extracapsular spread (p=.009), and pathological nodal stage (p=.04). Patients undergoing surgery plus RT had a significantly better 5-year DFS (74% vs 34%; p= .001) and 5-year OS (OS; 66% vs 27%; p =.003) compared with surgery alone. |
|
3 |
|
Warren et al 2016 |
To report the outcomes after surgery and postoperative RT for perineural spread of head and neck cutaneous SCC (cHNSCC) |
Retrospective review; n=50 |
Patients with clinical PNI from cSCCHN treated with surgery and postoperative radiotherapy (PORT) between 2000 and 2011 and a minimum of 24 months follow-up, from one Australian center. |
Recurrence-free survival (RFS)
5y disease-specific free survival (DSFS)
OS |
Fifty patients (mean age, 60 years) with median follow-up of 50 months were included in this study. A total of 54.8% of known primary tumors had incidental PNI. Ten percent had nodal disease at presentation. MRI neurogram was positive in 95.8%. RFS at 5-years was 62%. Five-year DSFS and OS were 75% and 64%, respectively. There were no perioperative deaths. |
This report demonstrates that long-term survival is achievable in patients with clinical PNI from cSCCHN after surgery and postoperative RT |
3 |
|
Waxweiler et al 2011 |
To review the current relevant evidence for the use of adjuvant RT (ART) in patients with cutaneous SCC (cSCC), specifically, as it relates to those cSCCs that undergo perineural invasion (PNI). |
Retrospective review |
PubMed publications obtained using the search terms ‘‘squamous cell carcinoma,’’ ‘‘cutaneous squamous cell carcinoma,’’ ‘‘radiotherapy,’’ and ‘‘perineural invasion’’ for reports dealing with cSCC with PNI. |
n.a. |
There is no strong evidence for or against the use of surgical excision (SE) with ART versus SE alone in the treatment of cSCC with PNI. Certain researchers suggest treating all cSCC with PNI, even microscopic, with ART, while others would disagree. Even the subject experts who write the National Comprehensive Cancer Network (NCCN) guidelines on cSCC have had difficulty agreeing upon exactly when ART should be utilized. Emerging ART technologies such as hyperfractionation, MRI fusion, and intensity-modulated radiotherapy, while offering hope for the future, will only further complicate this issue. |
|
4 |
|
Wray et al 2015 |
To report the efficacy of elective nodal radiotherapy to the regional nodes as an alternative to parotid or neck surgery |
Retrospective study; n=71 |
Consecutively treated adults patients with SCC of the face, ears, or scalp from one institution |
Acute and late toxicity and regional control |
Median follow-up was 4.5 years for all patients. The actuarial regional control rate at 5 years was 96 %. There were no (0 %) grade 3 or higher complications from elective nodal irradiation. |
Elective nodal irradiation in patients with high-risk SCC of the face, ears, and scalp was safe and effective. |
4 |
|
Zaorsky et al 2017 |
To characterize the cosmetic outcomes and local recurrence (LR) rates of various hypofractionated radiation therapy (RT) regimens for skin basal and squamous cell cancers (BCCs/SCCs). |
Systematic review: A PICOS /PRISMA/MOOSE selection protocol was performed to identify 344 articles published between 1985–2016 evaluating patients with T1–2 N0 SCCs/BCCs treated with definitive RT. Biologically equivalent doses with a/b = 3 (BED3s) were calculated. The primary endpoint was post- treatment cosmesis. Mixed-effects regression models were used to estimate weighted linear relationships between BED3 and cosmetic outcomes. |
Patients with skin basal and squamous cell cancers (BCCs/SCCs) treated with hypofractionated radiation therapy (RT) regimens |
Cosmetic outcomes and local recurrence |
A total of 21 studies were identified detailing the treatment of 9729 skin BCC/SCC patients, across seven countries, with external beam RT (n = 9255) or brachytherapy (n = 474). Median follow-up was 36 months (range: 12–77). Median dose was 45 Gy/11 fractions (interquartile range: 37.5 Gy/6–55 Gy/18) at 4 Gy/fraction (interquartile range: 2.5–6 Gy); most hypofractionated 18.75 Gy/1. There was a trend to decreased ‘‘good” cosmesis with higher total dose: -3.4% ‘‘good” cosmesis/10 Gy BED3, p=0.01. Similarly, there was a trend to increased ‘‘fair” cosmesis with higher dose: +3.8% ‘‘fair” cosmesis/10 Gy BED3, p = 0.006. At a BED3 of 100 Gy, the expected rate of ‘‘good” cosmesis is 79% (95% confidence interval: 70%, 88%). Hypofractionated schedules produced similar cosmesis to conventionally fractionated schedules, at the same BED3. Fewer than 8% of patients experienced ‘‘poor” cosmesis, independent of dose or fractionation regimen. |
Hypofractionated RT has favorable cosmesis for patients with skin BCCs/SCCs. We recommend clinicians consider these commonly-used regimens, which all have BED3 of $100 Gy: 50 Gy/15 fractions, 36.75 Gy/7 fractions, or 35 Gy/5 fractions, as they result in ‘‘good” cosmesis in 80% of patient |
|
PEK Lokalrezidiv
|
Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments |
LoE |
|
Amoils et al 2017 |
To describe outcomes at one institution, including patterns of metastasis, clinicopathologic factors related to survival, and failure rates for patients treated for regionally metastatic cutaneous head and neck SCC (cHNSCC)
To stratify results by treatment modality.
To evaluate the following hypothesis in this population: 1) use of adjuvant therapy would be important; 2) radiotherapy and chemotherapy have a survival benefit |
Retrospective study; n=80 |
Patients surgically treated for regionally metastatic cHNSCC between 2009 and 2014, available in Stanford Cancer Institute Research Database |
The effect of various clinicopathologic variables on OS
Outcomes by treatment modality |
On multivariate regression, cutaneous primary >2 cm (p = .03) and extracapsular spread (ECS; p = .01) were significantly associated with decreased OS. Location of regional metastasis (neck vs. parotid vs. both) had no effect on OS (p = .2), nor did the presence of a cutaneous primary at the time of presentation (p = .9). The 3-year survival was 43%, 52%, and 49% for surgery alone, adjuvant radiation, and adjuvant chemoradiation, respectively. Fifty-one percent of patients had a recurrence of their disease. |
Regionally metastatic cHNSCC is an aggressive disease associated with high recurrence rates. Adjuvant therapy may provide clinical benefit but patients with tumors >2 cm and ECS have poorer OS despite adjuvant treatment. |
3 |
|
Canon et al 2017 |
To investigate the factors associated with elective neck dissection (END) in this patients with skull base invasion from cSCC via perineural spread
To identify the survival difference with END compared with observation for patients with a cN0 neck |
Retrospective study; n=59 |
Patients treated surgically for cHNSCC with skull base invasion via perineural spread with a cN0 neck from 2004 to 2014 in one center |
DFS
OS |
Fifty-nine patients met inclusion criteria: 28 underwent an END and 31 underwent neck observation. Free tissue transfer reconstruction was significantly associated with END ( P < .001). Patients treated with an END had significantly improved 5-year DFS (57% and 32%, P = .042) and OS (60% and 37%, P = .036) compared with those who were observed and a significantly reduced rate of regional recurrence (9% and 37%, P = .024). The rate of occult nodal metastasis identified with END was 36% and is approximately equal to the regional failure rate of the neck observation group (37%). |
END was more commonly used in cases requiring free tissue transfer. The use of END for head and neck cSCCs that have invaded the skull base is not routinely performed but was found to be associated with a survival advantage and reduced regional recurrence rate. |
3 |
|
Chen et al 2007 |
To analyze the management of parotid-area metastasis from cutaneous squamous cell carcinoma with radiation therapy |
Retrospective study; n=36 |
Patients treated with radiation therapy for cutaneous squamous cell carcinoma involving the parotid-area lymph nodes |
Local (parotid) control
OS |
After treatment, 7 patients experienced a subsequent parotid resulting in a 5-year local (parotid) control rate of 76%. Of 30 patients treated using surgery and post-operative radiation therapy, 4 patients experienced local recurrence, resulting in a 5-year local (parotid) control rate of 86%. OS rate for the entire patient population at 5 years was 63% |
The present study shows that surgery and postoperative radiation therapy result in excellent rates of local-regional control for patients with parotid-area metastasis. Based on this analysis, a dose of 60 Gy or greater to the parotid region, as well as routine inclusion of the draining lymphatics of the ipsilateral neck in the radiation field, is recommended. |
3 |
|
Foote et al 2014 |
This study evaluated the Efficacy and safety of single-agent panitumumab in the treatment of patients with cutaneous SCC (cSCC) not suitable for local therapy |
Single center prospective phase II study; n=16 |
Patients who received single-agent panitumumab at the Princess Alexandra Hospital, Brisbane, Australia |
Best overall response rate (ORR)
Evaluation of safety
Toxicity
PFS |
The best overall response rate (ORR; PR or CR) was 31% with a further 6 of 16 patients achieving stable disease. The duration of overall response was a median 6 months. The 6-week disease control rate (DCR) was 69%. With a median follow-up of 24 months, 10 patients died due to progressive disease, 6 were alive, 1 patient with no evidence of disease at the time of analysis. The median OS was 11 months and median PFS was 8 months |
This study reports that some patients were slow to respond to therapy. In this study of panitumumab, most of the patients had been pre-treated; 12 patients had previous surgery, 14 of 16 patients receiving previous radiotherapy and 7 of 16 patients having prior chemotherapy. The best ORR was 31%, with a DCR at 6 weeks of 69% and duration of response being 6 months. |
4 |
|
Fujimura et al 2017 |
To determine the effective and safe dose of PEP and the curative rate of intra-arterial administration of peplomycin (IA-PEP) |
Retrospective study; N=24 |
Patients with cutaneous SCC (cSCC) on the lips who were treated with IA-PEP in one dermatology department |
Efficacy
Safety |
IA-PEP reduced the tumor mass in all 24 cases (100%). A complete response occurred in 17 patients (70.8%), and a partial response occurred in seven (29.2%). Moreover, 17 patients (70.8%) were cured, three patients developed cervical lymph node metastasis (12.5%), and four developed local recurrence (16.7%). Three out of the 24 patients developed interstitial pneumonia (12.5%). |
Low-dose IA-PEP administered through a superficial temporal artery was a highly effective treatment that achieved a curative response for 70.8% of patients with cSCC on the lips. Nevertheless interstitial pneumonia can occur, even with low doses of PEP |
3 |
|
Goh et al 2010 |
The aim of this retrospective study was to look at the treatment and outcome of patients with metastatic cutaneous SCC (cSCC) to the axilla and groin nodes treated at Westmead Hospital, Sydney |
Retrospective study; n=26 |
Patients treated between 1980 and 2007 |
Recurrence and survival |
Seven patients (27%) developed a recurrence with a median time to recurrence of 2.2 months. The lungs were the most common site of first recurrence (four patients). The median survival of patients was 18.5 months |
In this study, patients were treated with radical intent with all patients proceeding to surgery and half also receiving adjuvant nodal radiotherapy. Although not well reported, the decision not to offer combined treatment may have been related to the concern of the surgeon in regards to limb edema. |
3 |
|
Gonzalez et al 2017 |
To compare the AJCC-7 and BWH staging systems for cutaneous SCC (cSCC) in immunosuppressed patients |
A single-institution retrospective cohort study; n=106 |
cSCC in immunosuppressed patients |
Risks of local recurrence nodal metastasis in-transit metastasis
To report poor outcomes |
One hundred six patients had 412 primary invasive cSCC. Eighty-five percent were AJCC-7 T1, and 15% T2. Risks of NM and PO for AJCC-7 T1 versus T2 were 0.9% versus 5% and 12.8% versus 23.3%, respectively, p < .05. Eighty-one percent of tumors were BWH T1, 18% T2a, 1% T2b, and 0.2% T3. Risk of LR for BWH T1 versus T2a was 11.4% versus 20.3%, p < .01. Risk of NM increased from 0.3% for T1 to 4.1%, 25%, and 100% for T2a, T2b, and T3, p < .05. Ninety percent of PO occurred in low-stage BWH T1/T2a. |
Low T-stage cSCC accounts for most poor outcomes. Brigham and Women’s Hospital staging criteria better risk stratifies cSCC in immunosuppressed patients for risk of nodal metastasis and local recurrences.
Additional studies are needed to quantify the increase in the risk of poor outcomes for the same T-stage cSCC in immunocompetent versus immunocompromised patients. Better risk stratification of low T-stage cSCC in immunosuppressed patients is needed. Alternatively, immune status can potentially be included as part of the staging criteria to reflect the inherently higher risk of poor outcomes associated with immuno- suppression. In the meantime, vigilant detection and definitive treatment of even low T-stage cSCC in immunosuppressed patients are recommended. |
3 |
|
Han et al 2007 |
To evaluate the effectiveness of adjuvant XRT in treating SCC with PNI |
Literature review, focused on large studies in major dermatologic journals |
Patients treated for SCC with PNI from the 1960s to 2005 |
Local control rates
5-year survival rate |
Patients who underwent standard excision with or without receiving XRT had local control rates that ranged from 38% to 87%. The 5-year cause-specific and absolute survival rates ranged from 50% to 61% in imaging-positive patients and from 86% to 100% in imaging-negative patients |
Although most studies reviewed here included between 9 and 135 patients, only 1 report was a meta-analysis of 70 studies. The disparate methodologies of these cited articles render their results and conclusions difficult to validate or compare |
3 |
|
Harris et al 2017 |
To evaluate which factors are predictive of recurrence and nodal spread and survival in patients with cutaneous head and neck SCC (cHNSCC) treated surgically |
Retrospective review; n=212
|
Patients with cHNSCC treated between January 1998 and June 2014. All patients undergoing primary surgery, with or without adjuvant therapy, with curative intent for cSCC were included. Patients were excluded if they had distant metastases at presentation, were treated with palliative intent, and had <3 months of follow-up. |
5-years DFS
DSS
OS
Associations of patient and tumor characteristics with recurrence and survival
Factors independently associated with the presence of nodal metastasis at presentation |
A total of 212 patients met inclusion criteria, with a mean age of 70.4 years; 87.3% were men. Mean tumor diameter was 3.65 cm, with an average depth of invasion of 1.38 cm. The mean follow-up time was 35 months (median, 21.5), and over that period 67 recurrences were recorded, 49 of which were local. The 5-year Kaplan-Meier estimate of DFS for the cohort was 53.2%. On Cox multivariate analysis, recurrent disease, perineural invasion (PNI), and poorly differentiated histology were independent predictors of recurrence. On multinomial logistic regression, patients with primary tumors on the ear, cheek, temple, or lip, as well as those with PNI, were more likely to present with nodal metastasis.
Analysis of OS and DSS was limited given incomplete cause of death data and the advanced age of the patient cohort. |
For advanced cHNSCC, patients with recurrent disease, PNI, and poorly differentiated tumors are at the highest risk for local recurrence. Patients with tumors or the ear, cheek, temple, or lip, as well as those with PNI, are at increased risk of harboring nodal disease. |
3 |
|
Hong et al 2005 |
To present diagnostic methods, the interval between index lesion and metastasis, treatment methods, and outcome |
Retrospective review; n=20 |
Patients confirmed to have parotid bed metastases of squamous cell carcinoma treated in the University of Wisconsin Tumor Registry and Head and Neck Oncology Tumor Board, during a period of 10y from 1989 to 1999 |
Treatment
Recurrence
Survival |
After the diagnosis of parotid bed metastases, 14 (70%) of 20 patients underwent primary surgery with postoperative radiotherapy to the parotid bed and ipsilateral neck. Three patients (15%) manifested local recurrence in the parotid bed during their follow-up period. The minimum follow-up time for patients in this series was 24 months. Cumulative OS was 12 of 20, or 60%. |
Most patients in this series underwent superficial parotidectomy, with total parotidectomy reserved for the 20% of patients with partially fixed lesions or preoperative facial nerve involvement. This rationale is based on several studies, which have demonstrated that most intraparotid lymph nodes lie lateral to the facial nerve. |
3 |
|
Khan et al 2018 |
To assess LR and LN metastasis in the same cohort of patients at 5 years in an attempt to examine time to recurrence and to identify risk factors that could predict recurrence. |
Retrospective analysis; n= 598 SCCs; 633 cutaneous squamous cell cancer (SCC) excisions |
Surgically excised cutaneous SCC from 4 centers |
Rates of local recurrence (LR) and lymph node (LN) metastasis |
We report 5-year outcomes from 598 SCCs (95% follow-up rate). The total recurrence rate (LR and LN metastasis) was 6.7% (n = 40) at 5 years, with 96% of these occurring within 2 years. Median time to LR was 9 months (1–57), with 76.9% (n = 20) undergoing further wide local excision. Median time to LN metastasis was 5.5 months (1–18 months). There were two cases of disease-related death. Only 15% (n = 6) of incomplete excisions recurred. Interestingly, 19.1% (n = 9) of 47 SCCs with perineural invasion on original histopathology recurred versus only 5.6% (n = 31) of the 551 SCCs without perineural invasion (p = 0.005). |
This study is one of the largest studies to date following up 598 SCC excisions at 5 years with total recurrence rates comparable to those in current published literature. We report perineural invasion as a significant predictor of recurrence and that 96% of total recurrence occurred within 2 years. This is in contrast to current UK guidelines (75% at 2 years, 95% at 5 years), thus suggesting that a shorter length of hospital follow-up may be reasonable. |
3 |
|
Korhonen et al 2020 |
To determine the rate of local recurrences and metastases of cutaneous squamous cell carcinomas in a previously defined patient cohort in Finland. |
Retrospective analysis; n= 774 patients with 1,131 cutaneous SCC |
All patients in the Pirkanmaa region of Finland diagnosed with cSCC in 2006–2015 |
Rate of local recurrence and metastases in cSCC |
Overall, 4.2% (48/1,131) of the tumours were metastatic and 2.2% (25/1,131) had a local recurrence. Three of the metastatic tumours and 8 of the recurrent tumours had an invasion depth of ≤2 mm. The majority of metastases (28/48; 58%) were found within 3 months of the diagnosis of cutaneous squamous cell carcinoma. |
The study demonstrated recurrences and metastases even in the case of thin cutaneous squamous cell carcinomas and in high-risk cases close monitoring should be organized during the first years after diagnosis. |
3 |
|
Jol et al 2002 |
To investigate the results of our treatment policy, we present our institutional experience in the management of regional neck node metastases of cutaneous head and neck squamous cell carcinoma (cHNSCC) |
Retrospective study; n=41 |
Patients with cHNSCC diagnosis, treated between 1977 and 1997 |
OS |
Seventy-six percent of the regional metastases occurred within the first 2 years, but a delay of more than 5 years was also observed. Parotid gland (56%), neck levels II (39%) and V (22%) were most frequently involved. Twenty-four percent of patients treated with curative intent failed at the regional site. Five years OS was 46%, with a median survival of 49 months. No survival differences emerged between patients treated by surgery alone and patients receiving adjuvant radiotherapy |
Although the present study was not set up to analyze prognostic parameters, it seems that the correlation between T-stage and the risk for regional metastases was not so outspoken in our material |
3 |
|
Lu et al 2015 |
Presentation of institutional experience with radiation and concurrent systemic therapy consisting of either Pt-based chemotherapy or Cx in patients with high-risk cutaneous head and neck SCC (cHNSCC) |
Single-institution retrospective review, n= 23 |
Patients from the Kaiser Permanente Los Angeles Medical Center Between 2005 to 2014 |
PSF
OS |
The majority (87%) of patients had stage III/IV disease and 9 (39%) patients had unresectable disease. All patients were being treated for recurrent disease. Aside from median age (59 Pt vs. 71 Cx, P = 0.04), there were no significant differences in patient and tumor characteristics between those receiving Pt versus Cx therapy. At mean follow-up of 24 months, locoregional recurrence and distant failure were observed in 52% and 17% of all patients, respectively. Estimated 2-year DFS and OS in the Cx versus Pt groups were: 50% versus 30% (P = 0.25), and 73% versus 40% (P = 0.32), respectively |
To our knowledge, this study is the first to report on the use of Cx with concurrent radiotherapy for this patient population. To date, only a handful of retrospective reports have been published describing the use of concurrent radiation and systemic therapy for locally advanced cHNSCC |
3 |
|
Oh et al 2020 |
To determine risk factors for recurrence including various patient factors in Asian patients with cSCC treated with Mohs micrographic surgery (MMS) |
Retrospective study; n= 237 |
cSCC patients treated with MMS at a single tertiary referral center from 2000 to 2017 |
Rate of recurrence of cSCC after MMS |
Two hundred and thirty-seven patients were included and 36 showed recurrence (20 with local recurrence, 16 with distant metastasis). History of organ transplantation, diabetes, other malignancies and poorly differentiated histology correlated with cSCC recurrence. |
History of organ transplantation and cryotherapy at the cSCC site were related to higher local recurrence rates, and poor differentiation related to higher distant metastasis in Asian cSCC patients treated with MMS. |
3 |
|
Manyam et al 2017 |
The current study is an effort to validate preliminary findings in a large cohort from 3 institutions and to further elucidate the association between immune status and disease-related outcomes in patients with cutaneous HNSCC (cHNSCC) |
Multi-institutional study; n=205 |
Patients from 3 institutions who underwent surgery and also received postoperative RT for primary or recurrent, stage I through IV cHNSCC between 1995 and 2015.
138 patients were immunocompetent and 67 were immunosuppressed |
Locoregional RFS and PFS
OS |
RFS (47.7% vs 86.1%) and PFS (38.7% vs 71.6%) were significantly lower in immunosuppressed patients at 2 years. OS rate in immunosuppressed patients demonstrated a similar trend but did not meet significance. Immunosuppressed patients with cHNSCC had dramatically lower outcomes |
Immunosuppressed status is strongly associated with inferior locoregional control and PFS in patients with high-risk cHNSCC who undergo surgery and receive postoperative RT. These findings underscore the need for improved prognostic systems, increased multidisciplinary management and clinical trials investigating methods of intensified therapies for these patients. |
3 |
|
Palme et al 2003 |
To test ta new clinical staging system in patients with metastatic cutaneous squamous cell carcinoma (cSCC) |
Retrospective analysis; n=126 |
Patients treated for metastatic cSCC involving the parotid and/ or neck between 1987 and 1999 with a minimum of 2 years follow-up |
Locoregional recurrence
DSS |
Of the 126 patients, disease involved the parotid gland in 81 patients, of whom 14 also had clinical neck disease, while 45 patients had neck involvement only. The 5-year local control rate was 80% and this varied statistically significantly with P stage. The 5-year DSS rate was 68%. |
|
3 |
|
Popovtzer et al 2020 |
To report the feasibility and safety of diffusing alpha-emitter radiation therapy (DaRT), which entails the interstitial implantation of a novel alpha-emitting brachytherapy source, for the treatment of locally advanced and recurrent squamous cancers of the skin and head and neck |
Prospective first-in-human, multicenter clinical study; n=28 patients; 31 lesions |
All patients with biopsy-proven squamous cancers of the skin and head and neck with either primary tumors or recurrent/previously treated disease by either surgery or prior external beam radiation therapy |
The primary objective was to determine the feasibility and safety of this approach, and the secondary objectives were to evaluate the initial tumor response and local progression-free survival. |
Acute toxicity included mostly local pain and erythema at the implantation site followed by swelling and mild skin ulceration. For pain and grade 2 skin ulcerations, 90% of patients had resolution within 3 to 5 weeks. Complete response to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 78.6%); 6 lesions (6/28, 21.4%) manifested a partial response (>30% tumor reduction). Among the 22 lesions with a complete response, 5 (22%) developed a subsequent local relapse at the site of DaRT implantation at a median time of 4.9 months (range, 2.43-5.52 months). The 1-year local progression-free survival probability at the implanted site was 44% overall (confidence interval [CI], 20.3%-64.3%) and 60% (95% CI, 28.61%-81.35%) for complete responders. Overall survival rates at 12 months post-DaRT implantation were 75% (95% CI, 46.14%-89.99%) among all patients and 93% (95% CI, 59.08%-98.96%) among complete responders. |
Alpha-emitter brachytherapy using DaRT achieved significant tumor responses without grade 3 or higher toxicities observed. Longer follow-up observations and larger studies are underway to validate these findings. |
2 |
|
Ruiz et al 2017 |
To review utilization of radiologic imaging of high-stage cutaneous SCC (cSCC) to evaluate whether imaging impacted management and outcomes. |
Retrospective study; n=98 patients; 108 high-stage cSCC |
Patients diagnosed with cutaneous SCC from January 1, 2000, through May 30, 2013 treated in the Brigham and Women’s Hospital. |
Disease-related outcomes (DRO): local recurrence, nodal metastasis, death from disease |
Imaging (mostly computed tomography, 79%) was utilized in 45 (46%) patients and management was altered in 16 (33%) patients who underwent imaging. Patients that received no imaging were at higher risk of developing nodal metastases (nonimaging, 30%; imaging, 13%; P = .041) and any DRO (nonimaging, 42%; imaging, 20%; P = .028) compared to the imaging group. Imaging was associated with a lower risk for DRO (subhazard ratio, 0.5; 95% CI 0.2-0.9; P = .046) adjusted for BWH T stage, sex, and location. |
Limitations: Single institution retrospective design and changes in technology over time.
Radiologic imaging of high-stage cSCC may influence management and appears to positively impact outcomes. Further prospective studies are needed to establish which patients benefit from imaging. |
3 |
|
Skulsky et al 2017 |
To review the high-risk features included in NCCN and AJCC guidelines, as well as their notable discrepancies and omissions. To provide a brief overview of current prophylactic measures, surgical options, and adjuvant therapies for high-risk cutaneous SCC (cSCC). |
Embase, CENTRAL, and MEDLINE were searched for published studies, clinical trials, and guidelines on high-risk cutaneous SCC of the head and neck. Reference lists from the relevant articles acquired were also searched. The search date range used January 2016 as the end date; no start date was specified. The following terms are examples of terms that were combined in the database searches: “high-risk cutaneous squamous cell carcinoma, guidelines, excision margins, organ transplant, immunosuppression, depth, recurrence, sirolimus, cyclosporine, azathioprine, sentinel lymph node biopsy, superficial parotidectomy, elective neck dissection, and Mohs micrographic surgery.” All records obtained from our searches were screened by title and abstract for selection. |
Patients with high-risk cSCC |
To compare two different guidelines (NCCN and AJCC) in what concerns SCC high-risk features discrepancies and omissions.
The following aspects were evaluated: Tumor size Depth of invasion Recurrent setting Poorly differentiated lesions Histopathological subtype Perineural invasions Lymphovascular invasion High-risk anatomical location Immunosuppressed sate Incomplete excision |
The AJCC TNM staging system considers the following high-risk features when determining the primary tumor (T) classification: depth (>2mm thickness or Clark level ≥IV), anatomic location, poor histological differentiation, and perineural invasion (PNI). Tumors are classified as T2 in 2 ways: (1) tumors > 2 cm in greatest dimension, or (2) any size tumor with ≥2 high-risk features. NCCN has also identified several high-risk features of cSCC. High-risk cSCC, as per NCCN Guidelines refers to a greater propensity for local recurrence and/or metastasis. NCCN classifies cSCC as high-risk if≥1 feature is present. Currently, there is no unanimous consensus on the high-risk features of cSCC. Although NCCN Guidelines and the AJCC TNM classification system share some overlapping high-risk features of cSCC, significant discrepancies exist. In comparison with NCCN Guidelines, the AJCC omits several high-risk features associated with poor clinical outcomes, including immunosuppression, lymphovascular invasion, recurrent tumors, and certain prominent high-risk anatomic locations. Notably, neither NCCN nor the AJCC includes incomplete excision as a feature warranting a tumor’s treatment as high-risk cSCC. As a compounding factor, there are no guidelines for managing the deep tumor margin. |
Future studies are required to evaluate the extent to which the inclusion of these additional high-risk features would improve tumor staging and prognostic outcomes. Ultimately, a consensus on the definition of high-risk features of cSCC needs to be reached to produce accurate and practical treatment guidelines that will enhance patient care. |
1 |
|
Strassen et al 2017 |
To determine whether surgical concepts are warranted in the collective of old patients with cutaneous head and neck SCC (cHNSCC) |
Retrospective study; n=67 |
Patients who underwent surgical procedure due to recurrent disease of cHNSCC in one department between January 2008 and December 2013 |
OS
Recurrence-free interval (RFI) |
The cohort was divided into patients with/without adjuvant therapeutic regimens.
The median recurrent free interval and the median OS after recurrent disease therapy were 27 and 59 months (data not shown), respectively. There was a significant difference between patients who underwent surgery with adjuvant radiotherapy and patients without adjuvant treatment.
Patients with adjuvant treatment demonstrated a 5y-RFI and OS rate of 78 and 79 %, respectively, while patients without adjuvant therapy showed a 5y-RFI and OS rate of 30 and 46 % (p = 0.02; p<0.05). The distribution of T and N stages differed significantly between the groups. Patients who underwent adjuvant radiotherapy presented with limited T stages (T0–1), but advanced N stages (N2a–2b). Patients without adjuvant treatment concepts showed higher T stages (T1–2) and limited N stages (N0–1) (p = 0.001; p<0.0001). There were no differences in patient’ age (patients receiving adjuvant therapy: 76 years vs patients not receiving adjuvant therapy: 80 years; p = 0.07) and comorbidities (p = 0.9). |
While the benefit of elective parotidectomy and/or neck dissection—particularly in high-risk patients (pN+, G3/ G4, tumor thickness >6 mm)—in the long-term preservation of neuronal structures, RFI and, OS has to be analyzed in a prospective randomized trial, our study demonstrated a favorable RFI/OS in patients with cSCC recurrent disease who underwent surgical concepts and adjuvant radiotherapy. Locoregional metastases in the lymphatic basin might be more frequent than previously expected.
Sonographic staging and follow-up screening of the cervical lymphatic basin might, therefore, be beneficial even in patients presenting with small primary tumors. |
3 |
|
Stratigos et 2020 |
to make recommendations on cutaneous SCC (cSCC) diagnosis and management |
Retrospective review; search with terms ‘cutaneous squamous cell carcinoma’ using the PubMed, EMBASE and Cochrane Library was conducted. Articles included systematic reviews, pooled analyses and meta-analyses |
EDF–EADO–EORTC guideline |
Risk factor
Clinical presentation and diagnosis
Overall prognosis |
The most prominent risk factors for cSCC include sun exposure, advanced age, and UVR-sensitive skin. The most common clinical appearance of invasive cSCC is an actinic keratosis that becomes hyperkeratotic or its base becomes infiltrated, or else becomes tender or ulcerated. The overall prognosis for the majority of patients with cSCC is excellent, with an overall five-year cure rate of greater than 90%, which is much better than other SCCs of the head and neck area |
The present EDF–EADO–EORTC guidelines represent a European consensus-based interdisciplinary set of recommendations (S2 level) addressing all aspects of management of invasive cSCC, from the diagnosis of primary tumor to the systemic treatment of locally advanced or metastatic disease. The recommendations are based on current standards of care, existing guidelines and the expert panel opinion |
1 |
|
Sun et al 2019 |
To report survival outcomes in patients with cSCC-HN after disease recurrence after surgery and postoperative radiotherapy and to investigate the association of immune status with disease-related outcomes. |
Retrospective study; n=205 |
Patients who underwent surgical resection and postoperative radiotherapy for primary or recurrent stage I to IV (nonmetastatic) cSCC-HN between January 1, 1995, and December 31, 2014 |
Overall survival |
Of the 205 patients in the original cohort, 72 patients (63 men and 9 women; median age, 71 years [range, 43-91 years]) developed disease recurrence after surgery and postoperative radiotherapy. Forty patients (55.6%) were immunosuppressed, and 32 patients (44.4%) were immunocompetent. Locoregional recurrence was the most common first pattern of failure for both groups (31 immunosuppressed patients [77.5%]; 21 immunocompetent patients [65.6%]). After any recurrence, 1-year overall survival was 43.2% (95% CI, 30.9%-55.4%), and median survival was 8.4 months. For patients for whom information on salvage treatment was available (n = 45), those not amenable to surgical salvage had a significantly poorer median cumulative incidence of survival compared with those who were amenable to surgical salvage (4.7 months; 95% CI, 3.7-7.0 months vs 26.1 months; 95% CI, 6.6 months to not reached; P = .01), regardless of their immune status. |
Results of this study suggest that patients with cSCC-HN who experience disease recurrence after definitive treatment with surgery and postoperative radiotherapy have poor survival, irrespective of immune status. Survival rates are low for patients with recurrent disease that is not amenable to surgical salvage. The low rate of successful salvage underscores the importance of intensifying upfront treatment to prevent recurrence. |
3 |
|
Tang et al 2013 |
To report outcomes, failure patterns, and toxicity after stereotactic radiosurgery (SRS) for recurrent head and neck cutaneous squamous cell carcinoma (cHNSCC) with gross perineural invasion (GPNI). |
Retrospective study; n=10 |
Patients who received SRS as part of retreatment for recurrent head and neck cHNSCC with GPNI, between December 2003 and September 2009 were included |
Median follow-up
PFS |
At a median 22-month follow-up, the 2-year progression-free and OS rates were 20% and 50%, respectively. At last follow-up, 7 patients had died and patients 1, 3, and 8 were alive at 23, 69, and 22 months, respectively |
The drawbacks of our study include its retrospective nature and heterogeneity in treatment and patient characteristics. In addition, we only scored CN involvement when both imaging and associated symptomatic manifestations were present. Some study patients exhibited clinical findings interpretable as CN involvement outside of those listed. However, as these symptoms lacked the corresponding imaging findings, we did not score such instances as GPNI. |
3 |
|
Xu et al 2018 |
To assess changes resulting from the American Joint Committee on Cancer (AJCC) eighth edition for cutaneous squamous cell carcinoma (SCC) and evaluate pertinent excluded factors |
Retrospective analysis; n=101 |
Patients receiving surgery and postoperative radiotherapy (PORT) with or without concurrent systemic therapy for cutaneous SCC from 2007-2016 |
Locoregional recurrence, overall survival (OS), and cause-specific mortality rates |
The 2-year locoregional recurrence, overall survival (OS), and cause-specific mortality rates were 25%, 72%, and 13%, respectively. The AJCC eighth edition upstaged T classification in 50% of patients and overall stage in 39%. In multivariate analysis, immunosuppression and in-transit metastasis were associated with locoregional recurrence. Older age and in-transit metastasis were associated with worse OS. In univariate analysis (limited by the number of events), cause-specific mortality was associated with a positive margin, in-transit metastasis, and the seventh edition dichotomized T classification and overall stage. |
In-transit metastasis was significantly associated with locoregional recurrence, OS, and cause-specific mortality. Efforts should be made to define in-transit metastasis in the staging system. |
3 |
PEK Systemtherapie
|
Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments |
LoE |
|
Adelstein et al 2000 |
To report the mature results from a phase III randomized trial comparing radiation therapy and concurrent chemoradiotherapy in patients with stage III and IV squamous cell carcinoma of the head and neck |
Randomized, phase III study; n=100 |
Patients with stage III or IV disease, included between March 1990 and June 1995 |
Median follow-up
DFS |
After completing all therapy including surgery, 82% of the patients in Arm A and 98% of the patients in Arm B had been rendered disease-free (P= 0.02). At a median follow-up of 5 years (range, 3–8 years), the 5-year Kaplan–Meier projections for OS for Arm A versus Arm B were 48% versus 50% (P =0.55) |
These results demonstrate the importance of assessing multiple endpoints in any evaluation of the role of chemotherapy for patients with this tumor. It also must be pointed out that this study did not address the role of primary surgical resection in the management of these patients. |
2 |
|
Amaral et al 2019 |
To describe and analyze patients and primary tumour characteristics, local and systemic treatments, as well as survival outcomes. |
Retrospective analysis; n=195 |
Patients with advanced cSCC diagnosed between 01/2011 and 06/2018 in one center |
Survival rates |
The median follow-up was 21 months [IQR = (10.0; 21.0)]. The median age at time of advanced disease diag- nosis was 78 years [IQR = (72; 84)], with 40.5% of the patients in stage III and 59.5% in stage IV. One hundred and forty-five patients had resectable tumours. In this group the median overall survival (mOS) was 59 months (95% CI: 28.2–89.8), significantly higher than the mOS in patients with inoperable tumour [n = 50; mOS: 19 months (96% CI: 7–31, P <0.0001)]. Patients receiving immunotherapy (n = 20) showed a statistically significant better survival compared to those treated with other systemic therapies (n = 37; mOS not reached vs. mOS: 22 months (95% CI: 6.5–43.5), P = 0.034). For patients without systemic therapy, a combination of surgery and radiotherapy provided better outcomes compared to radiotherapy alone or best supportive care (P <0.001). |
Surgical complete resection should be the first therapeutic option for patients with acSCC. For patients with an inoperable tumour, first-line immunotherapy should be preferably considered. |
3 |
|
Brewster et al 2007 |
To conduct a phase III trial of adjuvant 13-cis-retinoic acid (13cRA) plus interferon alfa (IFN-alfa) for preventing tumor recurrence and second primary tumors (SPTs) of SCC among patients with aggressive skin SCC. |
Randomized controlled clinical trial; n=66 |
Patients who were recruited consecutively and observed prospectively at The University of TexasM.D.Anderson Cancer Center (Houston, TX) from 1996 to 2002 |
Median follow-up |
At 21.5 months median follow-up, treatment did not improve the time to tumor recurrence and SPT versus control (hazard ratio, 1.13; 95% CI, 0.53 to 2.41), time to tumor recurrence (HR, 1.08; 95% CI, 0.43 to 2.72), or time to SPT (HR, 0.89; 95% CI, 0.27 to 2.93). Adjuvant 13cRA and IFN-alfa was moderately tolerable; 29% of patients in the treatment arm required dose reductions for grade 3 or 4 toxicities |
When we designed the trial in 1996, we projected that the event (recurrence or SPT) -free rate at 2 years would be 34% based on the available retrospective data from M.D. Anderson Cancer Center (subsequent prospective data showed a disease-specific survival of 70% in similar patients observed for a median of 22 months). Therefore, our study was underpowered to detect an HR of 0.32 for the study endpoint or to detect a significant difference between arms in either recurrence or SPT alone, limiting the interpretation of our results |
2 |
|
Caponigro et al 2002 |
To evaluate response data for Cisplatin, Raltitrexed, Levofolinic Acid and 5-FU treatment |
Phase II randomized study |
Patients receive either CDDP 60 mg/m2 and raltitrexed 2.5 mg/m2 on day 1 and LFA 250mg/m2 and 5-FU 900mg/m2 on day 2 (arm A) or CDDP 65 mg/m2 and methotrexate 500 mg/m2 on day 1, and LFA 250 mg/m2 and 5-FU 800 mg/m2 on day 2 (arm B) |
Response data |
An interim analysis was performed when 36 patients were evaluable in each arm. In arm A, 10 CR (28%) and 19 partial responses (PR) (53%) were observed, for an overall response rate of 81%. In arm B, 3 CR (8%) and 12 PR (34%) were observed, for an overall response rate of 42%. The difference in both CR and overall response rate between the two arms was statistically significant (p = 0.03 and 0.001, respectively). |
Although response data for our experimental arm look encouraging, the hypothesis of a 35% activity, expressed as the capability to induce a CR, cannot be accepted according to our statistical methods. The achievement of a CR following primary chemo-therapy is an important prognostic factor for these patients, and, if a survival advantage is to be expected with induction chemotherapy followed by locoregional treatment, the achievement of an CR after primary chemotherapy is an important step. |
2 |
|
Cavalieri et al 2018 |
To investigate the role of oral pan-HER inhibitor dacomitinib in In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) |
Open-label, multicentric, uncontrolled phase II trial |
Patients with diagnosis of R/M sSCC; n=42 |
Primary endpoint was the best response rate (RR) to dacomitinib, defined as the sum of partial response (PR) and complete response (CR) frequencies. |
Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3e4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup |
In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. The safety pro- file was comparable to previous experiences in other cancers. Molecular pt selection could improve the therapeutic ratio. |
3 |
|
Cavalieri et al 2019 |
To explore the possible role of PD-L1 expression in predicting response to anti-EGFR agents. |
Retrospective analysis; n=28 |
Patients with unresectable R/M sSCC treated with EGFR pathway inhibitors from 2010 to 2016. |
|
Twenty-eight R/M sSCCs were analyzed (19 treated with dacomitinib, 9 with CT-cet). TC and IC were negative in 82 and 45% of cases, respectively; 15% sSCCs were both TC and IC positive. Progression-free survival (PFS) was longer in IC-positive cases (median 7.5 months vs. 2.1 in IC0, p = 0.02). No statistically significant differences were observed be- tween PD-L1 expression and both overall survival and response rates. |
PD-L1 expression in microenvironment predicted better PFS. The combination of EGFR inhibitors and ICB could help to deepen the knowledge about the interrelations between the EGFR and PD-1/PD-L1 pathways. |
4 |
|
Chow et al 2016 |
The current study aimed to report the safety and efficacy of a Fixed-dose regimen in an all-comer population of patients with R/M HNSCC, regardless of PD-L1 or HPV status, from a larger head and neck SCC (HNSCC) expansion cohort of the KEYNOTE-012 trial |
Phase Ib, multicenter, nonrandomized, multicohort study; n=118 |
Patients with advanced solid tumors treated with pembrolizumab between June 12, 2014, and October 8, 2014 |
Overall response rate (ORR) PFS
OS |
Of 132 patients enrolled, median age was 60, and 57% received two or more lines of therapy for R/M disease. ORR was 18% (95% CI, 12 to 26) by central imaging vendor and 20% (95% CI, 13 to 28) by investigator review. Median duration of response was not reached (range, > 2 to > 11 months). Six-month progression-free survival and overall survival rates were 23% and 59%, respectively. By using tumor and immune cells, a statistically significant increase in ORR was observed for PD-L1–positive versus –negative patients (22% v 4%; P= .021). Treatment-related adverse events of any grade and grade>3 events occurred in 62% and 9% of patients, respectively. |
A limitation of this study is the lack of a consistent method used to determine HPV status. HPV association was determined by the site investigator by using the method of their choice; p16 IHC was used by the majority of sites. Whereas p16 IHC is a useful surrogate for HPV infection in oropharyngeal HNSCC, it has limited utility outside of the oropharynx where HPV is less prevalent. For that reason, patients with non-oropharyngeal HNSCC were considered to be HPV-negative regardless of p16 status |
3 |
|
Clement et al 2016 |
This report evaluates afatinib efficacy and safety in pre-specified subgroups of patients aged ≥65 and <65 years. |
Phase III, open-label trial; n= 483 |
Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m2/week intravenous methotrexate |
PF
OS
ORR |
Of 483 randomized patients, 27% were aged ≥65 years and 73% <65 years at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older and younger patients [2.6 versus 1.6 months, P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months and 6.7 versus 6.2 months. ORRs with afatinib vs. methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%–77%) and diarrhea (70%–80%) with afatinib, and stomatitis (43%) and fatigue (31%–34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each sub-group 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups. |
Although patient numbers in then older subgroup were smaller than the overall population andnyounger subgroup (particularly the methotrexate arm due to the 2:1 randomization scheme), and the study was not powered for formal statistical comparison of predefined subgroups, there is no indication that the benefit observed with afatinib would be adversely affected by advancing age |
2 |
|
Cooper et al 2012 |
To report the long-term outcome of RTOG 9501 trial |
Prospective randomized trial; n=410 |
Patients with high-risk resected head and neck cancers |
local-regional control
OS |
At 10 years, the local-regional failure rates were 28.8% vs. 22.3% (P=. 10), DFS was 19.1% vs. 20.1% (P=. 25), and OS was 27.0% vs. 29.1% (P=.31) for patients treated by RT vs. RT þ CT, respectively. In the unplanned subset analysis limited to patients who had microscopically involved resection margins and/or extracapsular spread of disease, local-regional failure occurred in 33.1% vs. 21.0% (P=.02), DFS was 12.3% vs. 18.4% (P=.05), and OS was 19.6% vs. 27.1% (P=.07), respectively. |
Now, with a median follow-up of 9.4 years for surviving patients, this analysis of RTOG 9501 shows no statistically significant differences for any of the major endpoints of L-R control (the primary endpoint), DFS, or OS (secondary endpoints). More-over, the longer follow-up has blunted the differences in outcome that were originally observed. We are unable to analyze the potential effect of HPV infection on the outcome of this trial. Not recognized at the time this trial was designed and conducted, HPV-positive cancers are associated with a better prognosis, could have diluted the RTOG “high risk” group, and could have confounded the results. |
2 |
|
Del Campo et al 2011 |
This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). |
Randomized phase II study; n=107 |
Therapy-naive patients with locally advanced SCCHN were randomized |
Objective response rate
Safety |
In a subset of 40 patients that received X4 weeks of lapatinib or placebo, the objective response rate (ORR) was 17% (n¼4/24) vs. 0% (n¼0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib. |
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2 |
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Fonseca et al 2005 |
The present study compares the efficacy and safety of a new combination of cisplatin/docetaxel versus the 5-FU + cisplatin regimen in patients with squamous cell carcinoma of the head and neck (SCCHN) |
A randomized phase II study; n=83 |
Chemotherapy-naıve patients |
Overall response rate
Median survival |
Among 76 patients evaluable for response, the overall response rate in arm A was 70% (complete response (CR) 26%, partial response (PR) 44%) and in arm B 69% (CR16%, PR54%), respectively. Median survival in arm A was 7.6months (95%CI: 5.8–11.1) and 9.9months (95%CI: 7.4–14.6) for arm B. The most frequent grade 3/4 toxicity in arm A was neutropenia (34.1%) and diarrhea (9.8%) versus mucositis (29.3%) and neutropenia (19.5%) in arm B |
In conclusion, in our phase II trial, both schedules, cisplatin/docetaxel and cisplatin/5-FU, are active and useful combinations in patients with locally advanced SCCHN. The high response rates, and recent results of a phase III trial with better survival for docetaxel combination, justify further evaluation of those chemotherapy combinations in major patient populations. Both schedules are well tolerated, with significant but different toxicity patterns, which are generally well manageable. |
2 |
|
Gilbert et al 2012 |
To evaluate the activity of bortezomib administered before irinotecan, versus the activity of bortezomib alone, followed by the addition of irinotecan at the time of progression |
Randomized phase II 2-arm trial; n=71 |
Patients with histologically documented incurable, locally advanced, or metastatic squamous cell carcinoma of the head and neck. Patients were allowed up to 1 prior therapy for incurable, advanced disease, but treatment must have been completed at least 4 weeks before study entry. Patients could not have been previously treated with irinotecan or bortezomib. |
Response rate |
The response rate of bortezomib and irinotecan was 13%. One patient had a partial response to bortezomib alone (response rate 3%). No responses were seen in patients with the addition of irinotecan at the time of progression on bortezomib. |
The objective response rates in this study were 13.1% (a 90% CI of 3.6%–30.3%) with irinotecan and bortezomib (arm A) and 2.6% (a 90% CI of 0.4%–22.1%) with bortezomib alone (arm B). For either arm, the observed response rate was not different than the null hypothesis (15% and 5% for arm A and arm B, respectively). Although the 90% confidence intervals for either arm include the targeted true response rates, the wide interval is probably due to the small number of patients on either arm. |
2 |
|
Gold et al 2018 |
To determine the response rate to therapy with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with locoregionally recurrent or metastatic CSCC that was not amenable to curative treat- ment (NCT01198028) |
An open-label, uncontrolled, single-center phase 2 study, N=39 |
Patients with histologically or cytologically confirmed CSCC that was not amenable to curative intent therapy, with either distant metastases or locoregional disease for which curative resection or definitive radiation were not feasible. |
The primary endpoint was overall response rate according to RECIST 1.1 criteria. Other endpoints included toxicity, PFS and OS |
A total of 39 patients received treatment during the trial; 29 of these patients were evaluable for response. ORR 10% (3/29); all responses were partial responses. DCR: 72% (21/29). The median PFS was 4.7 months (95% CI, 3.5-6.2 months); the median OS: 13 months (95% CI, 8.4-20.5 months). No unexpected toxicities were seen. |
Erlotinib therapy was feasible for most patients with incurable CSCC and was associated with expected toxicities. However, only a modest response rate of 10% was observed. Further study of EGFR tyrosine kinase inhibitors in this patient population is not warranted. |
3 |
|
Gregoire et al 2011 |
To assess the efficacy and safety of gefitinib given concomitantly and/or as maintenance therapy to standard cisplatin/radiotherapy for previously untreated, unresected, stage III/IV non-metastatic SCCHN |
A phase II, randomized, double-blind, placebo-controlled study; n=226 |
Patients with III/IV non-metastatic SCCHN treated with gefitinib 250mg/ day, 500 mg/day or placebo in two phases, followed by a maintenance phase (gefitinib or placebo alone). |
Primary endpoint was local disease control rate (LDCR) at 2 years;
Secondary endpoints were LDCR at 1 year, objective response rate, progression-free survival, OS, and safety and tolerability |
Gefitinib (250 and 500 mg/day) did not improve 2-year LDCR compared with placebo either when given concomitantly with chemoradiotherapy (32.7% vs. 33.6%, respectively; OR 0.921, 95% CI 0.508, 1.670 [1-sided p = 0.607]) or as maintenance therapy (28.8% vs. 37.4%, respectively; OR 0.684, 95% CI 0.377, 1.241 [1-sided p = 0.894]). Secondary efficacy outcomes were broadly consistent with the 2-year LDCR results. In both doses, gefitinib was well-tolerated and did not adversely affect the safety and tolerability of concomitant chemoradiotherapy. |
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2 |
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Grob et al. 2020 |
To evaluate Pembrolizumab in recurrent or metastatic cutaneous SCC |
Prospective single-arm study, Phase II, multicenter N=105 |
patients with recurrent or metastatic cSCC not amenable to surgery or radiation |
Primary endpoint: ORR Secondary endpoints: DOR, DCR, PFS, OS, and safety. |
Median FU: 11.4 months (0.4 to 16.3). ORR:34.3% (95% CI, 25.3; 44.2%) 4 CR, 32 PR, DCR: 52.4% (95% CI, 42; 62.2%) Median DOR: not reached ( 2.7 to 13.11 months); Median PFS: 6.9 months (95% CI, 3.1: 8.5). Median OS: not reached (95% CI, 10.7; not reached) Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n=56) of patients. |
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2 |
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Halim et al 2012 |
To compare concomitant chemoradiotherapy based on weekly low-dose gemcitabine versus weekly low-dose paclitaxel in locally advanced head and neck squamous cell carcinoma |
Prospective randomized phase III study; n=216 |
Patients with locally advanced, unresected stage III/IVA/IVB head and neck cancer |
Median follow-up
Response
Survival |
The median follow-up was 22 months. The scheduled protocol was exactly applied in 88 (80%) of patients in group A and in 96 (91%) of patients in group B (P = 0.02). Partial and complete response occurred in 86 out of 110 patients (78%) in group A and in 94 out of 106 patients (89%) in group B (P = 0.038). The 2-year progression-free survival figures were 54 and 64% of groups A and B, respectively however, the 2-year OS figures were 56 and 67%, respectively |
Although group B showed statistically significant better progression-free and OS, the differences between the survival figures were not enormous. |
2 |
|
Harrington et al 2013 |
To assess the activity and safety of concurrent chemoradiotherapy (CRT) and lapatinib followed by maintenance treatment in locally advanced, unresected stage III/IVA/IVB head and neck cancer |
Randomized Phase II study; n=67 |
|
Survival |
CRT dose intensities were unaffected by lapatinib: median radiation dose 70 Gy (lapatinib, placebo), duration 49 (lapatinib) and 50 days (placebo); median cisplatin dose 260 mg/m2 (lapatinib) and 280 mg/m2 (placebo). Lapatinib combined with CRT was well-tolerated. Grade 3/4 toxicities during CRT were balanced between arms, except for an excess of grade 3 diarrhea (6% vs. 0%) and rash (9% vs. 3%) and two grade 4 cardiac events in the lapatinib arm. CRR at 6 months post-CRT was 53% with lapatinib versus 36% with placebo in the intent-to-treat population. The progression-free survival (PFS) and OS rates at 18 months were 55% vs. 41% and 68% vs. 57% for the lapatinib and placebo arms, respectively. The difference between study arms was greatest in p16-negative disease (median PFS >20.4 months [lapatinib] vs. 10.9 [placebo]). |
Prior to the study, the consensus view of an expert panel was that a 10–15% superiority of lapatinib would be the minimum requirement to justify planning a randomized phase III study. Although the 17% absolute difference in the primary end-point favoring lapatinib meets this threshold, this has to be considered in light of using a non-standard end-point measure (CRR at 6 months) |
2 |
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Harrington et al 2009 |
This study (EGF100262) sought to establish the recommended phase II dose of lapatinib with chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). |
Phase I, open-label, cohort study; n=31 |
Patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). |
Dose-limiting toxicities
Overall response |
Dose-limiting toxicities (DLTs) included perforated ulcer in one patient in the 500-mg cohort and transient elevation of liver enzymes in one patient in the 1,000-mg cohort. No DLTs were observed in the 1,500-mg cohort. Therefore, the recommended phase II dose was defined as lapatinib 1,500 mg/d with chemoradiotherapy. The most common grade 3 to 4 adverse events were radiation mucositis, radiation dermatitis, lymphopenia, and neutropenia. No patients experienced drug-related symptomatic cardiotoxicity, and no interstitial pneumonitis was reported. The overall response rate was 81% (65% at the recommended phase II dose). |
This study has established the recommended phase II dose of lapatinib as 1,500 mg/d when combined with chemoradiotherapy in patients with LASCCHN. Furthermore, this dose is associated with an acceptable tolerability profile, similar to that observed with chemoradiotherapy alone. Given these findings, randomized phase II and III studies of lapatinib plus chemoradiotherapy have been initiated in LA SCCHN |
3 |
|
Huis in ’t Veld et al 2018 |
To evaluate the effectiveness of Tumour necrosis factor α (TNF) and melphalan-based isolated limb perfusion (TM-ILP) as a limb-saving strategy for locally advanced extremity cSCC. |
Retrospective analysis; n=30 |
Patients treated with TM-ILP for locally advanced cSSC of an extremity between 2000 and 2015. |
Effectiveness of TM-ILP as a limb saving strategy |
A total of 30 patients treated with TM-ILP for cSCC were identified, with a median age of 71 years (36–92) and 50% female. Response could not be evaluated in 3 patients. After a median follow-up of 25 months, the overall response rate was 81% (n = 22), with 16 patients having a complete response (CR, 59%). A total of 7 patients developed local recurrence, with a median time to recurrence of 9 months (Interquartile Range 7–10). Progressive disease was observed in 5 patients (19%). Limb salvage rate was 80%. The overall 2-year survival was 67%. |
TM-ILP should be considered as an option in patients with locally advanced cSCC in specialized centers, resulting in a high limb salvage rate. |
3 |
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Jehn et al 2008 |
To compare the safety and efficacy profiles of patients in the two treatment arms – cisplatin and cisplatin with liposomal formulation (lipoplatin). |
A randomized, multicenter phase III trial; n=46 |
Patients with histologically confirmed SCCHN, age between 18-75 years with sufficient renal function. |
Toxicities
Response rate |
Grade III and IV hematotoxicity were more frequent in the cisplatin arm (31.7% vs. 12%). The renal toxicity profile of both drugs also showed marked differences. In the cisplatin arm, 23.8% of patients suffered grade III toxicity. In contrast, no grade III or IV renal toxicity occurred in patients treated with lipoplatin. The efficacy results showed 38.8% objective partial remission in the cisplatin arm vs. 19% in the lipoplatin arm. However, 64% of the patients achieved stable disease while being treated with lipoplatin/5-fluorouracil (5-FU), vs. 50% in the cisplatin/5-FU arm. |
This ongoing study has shown so far that the lipoplatin formulation reduces both the hematological and non-hematological toxicity profiles of cisplatin to a clinically relevant extent when combined with 5-FU. However, the authors feel that the high percentage of renal toxicity associated with the cisplatin arm in this study, especially the three patients suffering acute renal failure, does not fully reflect the experience at our institution with this drug |
2 |
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Joseph et al 2019 |
To report the outcomes of using a combination of cetuximab with radiation therapy (Cetux-RT) to treat a selected group of patients with locally advanced (unresectable) cutaneous squamous cell carcinoma (LA-cSCC) |
Propective pilot study; n=8 |
Patients with LA-cSCC received curative-intent treatment with Cetux-RT |
Two-year efficacy and safety data |
The median age was 81 years (range, 55–87). The ECOG performance status of all patients was between 0 and 2. With a median duration of follow-up of 25 months (range 10–48 months), five patients remain in complete response. After a partial response, another patient has relapsed and is receiving palliative chemotherapy, while two patients have died during the period of follow-up (one of whom died following the progression of disease, the other of an unrelated cause). Treatment in this group of patients was well tolerated, with most toxicities ≤ grade 2, and no toxicities of grade 4/5 reported. |
Cetux-RT was well tolerated and provided durable disease control within this patient sample. Our data support the use of the Cetux-RT regimen for selected patients with inoperable LA-cSCC and adequate performance status. |
3 |
|
Lu et al 2015 |
To report the survival outcomes of patients with advanced cutaneous SCCHN treated with two chemotherapy regimens |
Retrospective study; n=23 |
Patients with locally advanced cutaneous SCCHN treated with radiation and concomitant platinum (Pt)-based chemotherapy or cetuximab (Cx). |
2-years DFS and OS |
The majority (87%) of patients had stage III/IV disease and 9 (39%) patients had unresctable disease. All patients were being treated for recurrent disease. Aside from median age (59 Pt vs. 71 Cx, P=0.04), there were no significant differences in patient and tumor characteristics between those receiving Pt versus Cx therapy. At mean follow-up of 24 months, locoregional recurrence and distant failure were observed in 52% and 17% of all patients, respectively. Estimated 2-year disease-free survival and overall survival in the Cx versus Pt groups were: 50% versus 30% (P=0.25), and 73% versus 40% (P = 0.32), respectively. |
Radiotherapy with either concurrent Pt or Cx appears to offer similar clinical outcomes in patients with locally advanced cutaneous SCCHN. |
3 |
|
Martins et al 2013 |
To evaluate the efficacy of adding EGFR inhibition to standard cisplatin-radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). |
A phase I/II randomized clinical trial conducted at the Brazilian National Cancer Institute; n= 204 |
Patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). |
Complete response rate (CRR)
PFS |
Patients on arm B had more rash, but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities. Arm A had a CRR of 40% and arm B had a CRR of 52% (P _ .08) when evaluated by central review. With a median follow-up time of 26 months and 54 progression events, there was no difference in PFS (hazard ratio, 0.9; P =.71). |
This randomized phase II trial showed that erlotinib did not improve the CRR or PFS in patients with locally advanced SCCHN when added to cisplatin-radiotherapy. Another possible explanation would be an imbalance in the number of p16-positive patients between the treatment arms because this was not a stratification factor. Results from the current study and RTOG 0522 suggest that EGFR-directed therapy in unselected patients does not lead to an improvement in outcome compared with cisplatin-radiotherapy alone |
2 |
|
Maubec et al 2011 |
To evaluate the efficacy and safety of cetuximab |
Open-label, uncontrolled phase II study; n=36 |
Patients with unresectable squamous cell carcinoma of the skin (SCCS) treated with cetuximab (initial dose of 400 mg/m2 followed by subsequent weekly doses of 250 mg/m2) for at least 6 weeks |
Disease control rate
PFS |
DCR at 6 weeks was obtained in 25 of 36 patients (69%; 95% CI, 52% to 84%) of the intention-to-treat population. The best responses were eight partial responses and two complete responses. There were no cetuximab-related deaths. There were three related serious adverse events: two grade 4 infusion reactions and one grade 3 interstitial pneumopathy. Grade 1 to 2 acne-like rash occurred in 78% of patients and was associated with prolonged PFS. |
As a first-line treatment in patients with unresectable SCCS, cetuximab achieved 69% DCR and may be considered as a therapeutic option especially in elderly patients. The low frequency of RAS mutations in SCCS makes SCCS tumors attractive for EGFR inhibition |
3 |
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Migden et al 2018 |
To report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). |
Phase 1 study was an open-label, multicenter study and a nonrandomized phase 2 study |
Patients with advanced cutaneous squamous-cell carcinoma and patients with advanced solid tumors |
Phase 1 study: The primary endpoint was the safety and side-effect profile of cemiplimab; phase 2 study: The primary endpoint was the response rate, as assessed by independent central review.
For both studies, secondary endpoints included the duration of response, progression-free survival, overall survival, and toxic effects. |
In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event. |
Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. |
2 |
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Migden et al 2020 |
To evaluate the safety and antitumor activity of cemiplimab in patients with locally advanced cSCC |
Prospective pivotal open-label, phase 2, single-arm trial |
Patients with locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0–1 |
Objective response, (proportion of patients with complete/partial response, as per RECIST 1.1 for radiological scans and WHO criteria for medical photography |
78 patients were treated with cemiplimab. The median duration of study follow-up was 9.3 months (IQR 5.1–15.7) at the time of data cutoff. An OR was observed in 34 (44%; 95% CI 32–55) of 78 patients. The BOR was 10(13%) patients with a CR and 24 (31%) with a PR. Grade 3–4 treatment-emergent AE occurred in 34 (44%) of 78 patients; the most common were hypertension in 6 (8%) patients and pneumonia in four (5%). SAE occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia. |
Cemiplimab showed antitumor activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma |
2 |
|
Montaudié et al 2020 |
To evaluated clinical outcomes of cetuximab as a single agent in patients with unresectable cutaneous squamous cell carcinoma (cSCC) |
Retrospective analysis; n=58 |
Patients with unresectable cutaneous squamous cell carcinoma (cSCC) |
Disease Control Rate (DCR) at 6 weeks according to RECIST criteria. Secondary endpoints included DCR at 12 weeks, objective response rate (ORR) at 6 and 12 weeks, progression-free survival (PFS), overall survival (OS), and safety profile |
Fifty-eight patients received cetuximab as monotherapy. The median age was 83.2 (range, 47.4 to 96.1). The majority of patients was chemotherapy naïve. The median follow-up was 11.7 months (95% CI: 9.6-30.1). The DCR at 6 and 12 weeks was 87% and 70%, respectively. The ORR was 53% and 42%, respectively, at 6 and 12 weeks. The median PFS and OS were 9.7 months (95% CI: 4.8-43.4) and 17.5 months (95% CI: 9.4-43.1), respectively. Fifty-one patients (88%) experienced toxicity, and 67 adverse events related to cetuximab occurred. Most of them (84%) were grade 1 to 2. |
Our study shows that cetuximab is safe and efficient for the treatment of patients, even elderly ones, with advanced cSCC. These results indicate that cetuximab is a promising agent to test in new combinations, especially with immune checkpoint inhibitors such as anti–PD-1 agents. |
3 |
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Reigneau et al 2015 |
To address the question of the efficacy of induction therapy with cetuximab as neoadjuvant treatment for locally advanced NMSC. |
Retrospective analysis; n=34 |
All consecutive patients with a diagnosis of unresectable locally advanced cutaneous SCC treated with neoadjuvant chemotherapy containing cetuximab +/- cisplatin and 5-FU between February 2008 and February 2013 in one institution |
The primary endpoint was the percentage of patients becoming amenable to surgery after three cycles of cetuximab and chemotherapy, or cetuximab monotherapy. The secondary endpoints were as follows: (i) the percentage of histological tumour responses; (ii) the treatments received after induction therapy; (iii) progression-free survival (PFS), and overall survival (OS), (iv) the characteristics of relapses. |
Thirty-four patients, with a median age of 745 years, were evaluated. Twenty-five patients received CC. After three cycles of CC, 23 of 25 patients whose tumours were initially unresectable became amenable to surgery (92%). A complete histological response was observed in 15 (65%) patients. The mean progression-free and mean overall survival in operated patients were 8.5 and 26.0 months, respectively. |
There was a good response in terms of resectability and tumour control in the majority of patients, with few relapses, despite the initially poor prognosis of these tumours in this elderly group of patients. However, this therapeutic strategy needs to be validated in a prospective, randomized study. |
3 |
|
Seiwert et al 2016 |
To assess the safety, tolerability, and antitumor activity of pembrolizumab |
Open-label, multicenter, multi-cohort phase 1b trial; n=60 |
Patients with PD-L1-positive squamous cell carcinoma of the head and neck |
Adverse events
Overall response |
23 patients (38%) were HPV-positive and 37 (62%) were HPV-negative. Pembrolizumab was well tolerated, with 10 (17%) of 60 patients having grade 3–4 drug-related adverse events, the most common of which were increases in alanine aminotransferase and in aspartate aminotransferase, and hyponatremia, each occurring in two of 60 patients; one patient developed a grade 3 drug-related rash. 27 (45%) of 60 patients experienced a serious adverse event. There were no drug-related deaths. The proportion of patients with an overall response by central imaging review was 18% (8 of 45 patients; 95% CI 8–32) in all patients and was 25% (4 of 16 patients; 7–52) in HPV-positive patients and 14% (4 of 29 patients; 4–32) in HPV-negative patients. |
This study is the first to report the efficacy and safety of an anti-PD-1 antibody in patients with advanced PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck. Pembrolizumab showed clinically significant activity in patients with heavily pretreated squamous cell carcinoma of the head and neck irrespective of HPV status. Greater antitumor activity was recorded in patients with squamous cell carcinoma tumors of the head and neck that expressed higher levels of PD-L1 and interferon-γ-related genes |
3 |
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Stratigos et al 2020 |
To make recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC) |
Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. |
EDF–EADO–EORTC guideline |
Treatment |
Anti-PD-1 antibodies are the first-line systemic treatment for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation therapy. |
|
1 |
|
Shin et al 2000 |
To assess the antitumor activity and toxicity profile of a combination of paclitaxel, ifosfamide, and carboplatin (TIC) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). |
Phase II Study; n=56 |
Patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). |
Survival rates |
A total of 32 patients (59%) responded to treatment; the complete response rate was 17% (9 of 54 patients). The median duration of the responses was 3.7 months (95% confidence interval [95% CI], 3.4–7.8 months) and that of complete responses was 9.7 months (95% CI, 7.4 months to the date of the last follow-up). The median duration of follow-up care in all patients was 13.5 months. Median survival time for all patients was 9.1 months (95% CI, 7.9–12.2 months). |
The TIC regimen had high antitumor activity in patients with recurrent or metastatic SCCHN. The activity of TIC in patients with recurrent or metastatic SCCHN should be confirmed in a phase III randomized trial |
3 |
|
Tortochaux et al 2011 |
To investigate the potential benefit of concurrent re-irradiation, fluorouracil and hydroxyurea versus methotrexate for patients treated with palliative intent for recurrent or second primary HNSCC in previously irradiated area |
Randomized phase III trial (GORTEC 98-03); n=57 |
Patients treated with palliative intent for recurrent or second primary HNSCC in previously irradiated area |
OS |
All patients died in the two arms with a maximal follow-up of 5 years. 4 complete responses were achieved in R-RT arm, re-irradiation did not improve OS compared with methotrexate (23% vs. 22% at 1 year, NS). Sixteen patients experienced clinical grade P3 late toxicities (>6 months), 11 in R-RT arm and five in Ch-T arm. |
There was no suggestion that concurrent re-irradiation, fluorouracil and hydroxyurea improved OS compared to methotrexate alone in patients treated with palliative intent for a recurrent or second primary HNSCC. |
2 |
|
Tsukuda et al 2010 |
We compared concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP), and 5-fluorouracil (5-FU) (TPF) with CCRT with CDDP, 5-FU, methotrexate and leucovorin (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) |
Randomized controlled phase II comparison study; n=100 |
Patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were enrolled. The TPF group received CCRT with the TPF regimen. In the PFML group, patients received CCRT with the PFML regimen |
Overall response rate
Safety |
The overall response rates after CCRT were 98 with 90% of pathologically complete response (pCR) in the TPF group and 94 with 77% in the PFML group. For grade 3/4 adverse events, mucositis was more frequent in the PMFL group, and the TPF group showed a higher incidence of hematological toxicity |
The use of multiagent CCRT including CDDP appears to be more efficacious than CCRT with CDDP alone. Both regimens showed high ORRs after CCRT completion (94%: PFML group; 98%: TPF group). The ORR, pCR rate and 3-year survival rate were almost identical to the results of previous studies on CCRT with PFML |
2 |
|
Vermorken et al 2014 |
Report the results of the ADVANTAGE study.
To identify potential biomarkers of response to the combined cilengitide/ cisplatin, 5-fluorouracil, and cetuximab (PFE) treatment. |
Randomized phase I/II ADVANTAGE trial; n=182 |
Patients treated with cilengitide combined (cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly) with PFE in recurrent or metastatic (R/M)- HNSCC |
PFS per investigator read
Secondary objectives: OS
ORR, disease control rates
Duration of response
Time-to-treatment failure (TTF)
Confirm the safety profile of cilengitide plus PFE
To determine the pharmacokinetic (PK) profile. |
Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median OS and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papilloma-virus) were predictive of outcome |
This study suggests that the combination of cilengitide and PFE offered no efficacy benefits compared with PFE alone in R/M HNSCCHN patients. Neither of the cilengitide-containing regimens demonstrated that a PFS benefit versus PFE alone and OS, OR, and disease control outcomes were similar across the three cohorts. Therefore, this combination cannot be recommended for further development in R/M-SCCHN patients. |
2 |
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