8. Therapy of invasive squamous cell carcinoma of the skin – Actinic keratosis and squamous cell carcinoma of the skin
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 Surgical therapy of the primary tumor
The following risk factors of SCC shall be reported to the examining pathologist/dermatopathologist if present: recurrence, tumor diameter >2 cm, localization ear, lip or temple, immunosuppression and evidence of perineural invasion, no displaceability from the subsurface.
- Consensus
- Strong consensus (100%)
Surgical therapy of the primary tumor shall be carried out according to the following algorithm ((Figure 4):
- Consensus
- Strong consensus (94,1%)
Although there is no doubt in the literature that surgical excision of SCC of the skin is the method of choice [333] there is little consensus for the exact design of the excision and subsequent histological examination.
In reviewing the existing guidelines regarding local therapy of SCC of the skin, it is noticeable that discrepancies continue to exist regarding the assessment of risk factors that influence the locoregional behavior of SCC and also regarding the modalities of local therapy. This is due to the fact that the existing literature on these topics consists almost entirely of retrospective and also partly small studies, which often result in heterogeneous results.
8.1.1 Risk factors for loco-regional progression and tumor-specific survival
Knowledge of the factors leading to local recurrence and regional metastasis is important for surgical planning. A tumor with high potential for local infiltration should be treated differently than one with low potential.
Both retrospective and few prospective studies have been carried out to analyze risk factors. However, for the latter, there is still a lack of studies with sufficiently large patient numbers. To date, 7 prospective studies have been published [21][334][20][335][62][336]; three of them with patient numbers ranging from 502 to 1,434 of different time periods from one institution [21][334][20]. A recently published study of 745 tumors was multicenter but included mostly rather low-risk SCC (95% were well differentiated, 85% smaller than 2 cm in diameter) [336]. Two other prospective studies examined 210 and 224 patients [335][62]. Another prospective study with 1,010 patients analyzed the risk factor immunosuppression [30]. All other studies are retrospective with patient numbers ranging from 69 to 1468 patients [337][338][339][57][340][341][342][343][344][54][345][346][63][347][63][348][349][350] In 7 reviews the existing literature is assessed [351][352][353][33][354][355][355][356]. From these, it can be seen that the collectives have different compositions. Thus, the rates of local recurrence and metastasis are very difficult to evaluate by these large differences, also with regard to risk factors.
Several papers point to an insufficiency AJCC classification to predict local recurrence or metastasis [343][354][357][358][336]. This has led to alternative classification systems being proposed [359].
Overall, as detailed by Rowe in 1992, the following important risk factors can be noted:
- Tumor diameter >20 mm
- Depth of infiltration >Level 3
- De-differentiation
- Perineural invasion
- Localization ear and lower lip
- Immunosuppression
- Histological tumor thickness >6 mm
- Desmoplasia
It is currently unclear how to weight the individual factors. According to the publications available to date, tumor thickness > 6 mm, desmoplasia and perineural invasion are the strongest prognostic factors, especially for local recurrence, but also for metastasis [33][350].
8.1.1.1 Tumor diameter
Clinical tumor diameter of 2 cm is a prognostic factor for rough guidance in all publications except one [335]. In most publications, tumor diameter was presented as a risk factor. In a few, the rate of local recurrence and metastasis are calculated for this limit. For tumors ≥2 cm in diameter, local recurrence occurred between 2-7% [20][342][63][351], regional metastasis at 9-16% [20][63] or at Rowe 30% [351]. For this reason, a standard indication of clinical diameter is recommended in the European recommendations on SCC.
However, tumor diameter alone does not provide enough information about actual "high-risk" tumors. Therefore, as the publications show, additional histological information (differentiation, perineural invasion, depth of invasion or tumor thickness) as well as information about patient-related factors is needed [360].
8.1.1.2 Tumor thickness
According to AJCC, tumor thickness is measured from the stratum granulosum or the base of an ulceration to the deepest infiltration [353]. Measurement at the deepest point of the ulceration is critical because severely ulcerated tumors then have a smaller tumor thickness and are thus rated at lower risk, although the opposite may be true. To the authors' knowledge, a study on the value of ulceration has not yet been published. Tumor thickness in the above studies is always measured from the highest elevation (stratum granulosum there) to the deepest infiltration regardless of ulceration [20][63][351].
Tumor thickness measured on histological section is dependent on tumor diameter, but is a stronger prognostic factor than tumor diameter in multivariate analyses. In 7 other studies, tumor thickness is also analyzed (from 3-7 mm) [335][62][345][352][353][354][33]. In the old 7th edition of the AJCC classification, tumor thickness greater than 2 mm is cited as a high-risk factor [346][33]. The tumor thickness >2 mm had been introduced in the literature in 1990 [338] as a limit of a possibility of metastasis starting at 2 mm and confirmed in further publications. This limit is critical because it would mean that the majority of SCC would be considered a high-risk tumor. The 8th edition of the AJCC classification has been amended to include a tumor thickness ≥6 mm for head and neck tumors. This is also consensus in virtually all classification systems [359].
8.1.1.3 Infiltration depth
The infiltration depth is generally dependent on the tumor thickness. The thicker a tumor, the greater its infiltration depth, unless it grows purely exophytic, which rarely occurs. The depth of infiltration is considered a prognostic factor, especially in relation to the anatomical stratification (especially from Clark level V, corresponding to infiltration and exceeding the subcutis) [335][57][346][63][351][352][353][33][354].
However, tumor thickness is superior to infiltration depth as a prognostic factor. In the staging system according to Breuninger [357], which was shown to be superior to the other classification systems as a predictive value of metastasis in an independent analysis of a Norwegian group, infiltration depth is not considered [358].
8.1.1.4 De-differentiation and desmoplasia
De-differentiation is described as a prognostic factor in almost all publications. In the EDF-EADO-EORTC recommendations, both dedifferentiation and desmoplasia are mentioned as independent risk factors [359]. Nevertheless, desmoplasia is not mentioned in the majority of publications. Thereby, the frequency of desmoplasia differs depending on the studied patient collective. Desmoplasia was introduced as an independent risk factor for the occurrence of local recurrence and regional metastasis in a large prospective study in 1997 [334]. In those publications investigating desmoplasia as a risk factor, again, dedifferentiation is not a significant factor [334][20][21]. It is likely that desmoplasia was evaluated as a de-differentiated type with the other forms of de-differentiation in most studies [57][55]. Desmoplasia is also analyzed in another study [354], and is mentioned as a prognostic factor in some guidelines [361][104][361][361][362]. In the Norwegian study described above, in which the different classification systems were compared, the classification systems that did not take desmoplasia into account were inferior in their predictive value with regard to metastasis [358]. The high local recurrence rate is also due to the fact that desmoplasia in particular often eludes histological detection in the periphery remote from the tumor due to single cell infiltration [363]. Therefore, evaluation of the margins by immunohistochemical staining faciliates a higher rate of detection of tumor extensions [364].
8.1.1.5 Perineural infiltration
Perineural infiltration (PNI) is consistently recognized as a high-risk factor. Importantly, it may be detectable microscopically, clinically as well as radiologically [359].
The frequencies of occurrence are reported very differently. They range from 1% to 100% [341][365]. A high PNI (55-64%) is found in highly selected collectives [346][65][366], of which in 64% in a collective of immunosuppressed patients. In most publications PNI is detected in 2% and 10% of tumors [55][57][335][367][368][343][62][344][369]. Some publications show an increased incidence of PNI in desmoplastic SCC [334][57][370]. One paper found PNI exclusively in desmoplastic tumors [371]. In addition, a major factor here seems to be tumor diameter. Karia et al. showed a significantly higher risk for local recurrence in perineural growth around nerves with a diameter > 0.1 mm compared to smaller nerve diameters [19]. Of the established classification systems for cutaneous SCC, only the Brigham and Women’s Hospital classification lists the cut-off of 0.1 mm nerve diameter as a separate risk factor.
8.1.1.6 Localization
Localization as a prognostic factor has been evaluated differently. The ear (region) and lower lip red have been analyzed as prognostic factors in numerous studies [20][62][340][341][343][345][346][63][351][352][353][33]. In the meta-analysis by Thompson et al. which included over 23,000 SCC, the highest risk for local recurrence was shown at the temple, lip and ear [33]. Furthermore, in addition to temple, scalp, nose and also cheek are identified as high-risk localizations in numerous publications [341][346][63][353][33][350][33]. Only three papers consider the trunk as a separate risk factor [339][353][350]. In a large prospective work with 1434 patients, 40 died due to SCC [21]. 35/40 patients who died had SCC in the head and neck region. Accordingly, in the old European guideline the entire head and neck region was classified as high risk or intermediate risk and only trunk and extremities were low risk [360]. In the new recommendations, only the temple, ear and lip regions are included [359]. Two studies do not consider localization as a prognostic factor [57][344].
8.1.1.7 Immunosuppression
8.1.1.8 Other factors
If a previously treated SCC is present, this is evaluated as a risk factor in some publications [360]. This may be due to insufficient initial treatment or to the high local malignancy of the tumor, which per se leads more frequently to local recurrence, regardless of the treatment modality [334][20][21]. This phenomenon malignancy of the tumor vs. insufficient local treatment often cannot be separated in the literature [335][57][342][372]. Also, the type of treatment is thought to influence the course.
8.1.2 Surgical therapy and histological incision margin control
8.1.2.1 Excision for tumors with diameter smaller than 10 mm
For small tumors <10 mm, curettage with the sharp 7-mm ring curette or deep horizontal ablation ("shave“ excision) is suitable. Both methods ensure sharp ablation, providing a clear specimen for histopathological examination. There are no studies for this in the literature. However, the diameter of the excised tissue should not be less than 5 mm. The lower corium or just under the subcutis should be reached for depth. If the tumor was removed in toto in this way, the subsequent secondary healing, if it is possible at the corresponding localization, leads to very good aesthetic results [373][374]. In addition, inflammatory processes can lead to regression of remaining tumor parts after horizontal ablation or curettage for example [375].
For larger and thicker tumors, the depth should reach at least deep into the subcutis, whenever possible at least 6 mm deep. This allows assessment of tumor thickness and differentiation and thus a more accurate prognostic assessment by histopathologists. However, it should be noted that this may not always detect desmoplasia, as it may occur in subareas. The same applies to PNI, which can often be detected only in the tumor periphery.
8.1.2.2 Histological backup before major excision
Often, the diagnosis of SCC or at least an epithelial malignant tumor can already be made clinically with a high degree of certainty and thus a surgical indication is given. In these cases, the sample biopsy would be an unnecessary burden for the patient. If a trial biopsy is nevertheless necessary, a 6-mm-diameter punch, set at the highest point of the tumor, is most suitable. A spindle-shaped excision is the alternative. Since even a specimen biopsy is often difficult to classify histopathologically or not all necessary histological parameters can be collected(see excision of tumors smaller than 10mm in diameter), an incision through the entire tumor is more informative. This is best achieved by a clinically complete tumor excision. A marker (for example, at 12 o'clock relative to the body axis) is useful for later orientation in case of R1 resection. In case of a complete excision, a reprocessing of the cut edges should follow in order to ensure an R0 or R1 resection.
8.1.2.3 Histological section margin control: gapless vs. non-gapless workup of excised tumor material
Histological specimens can be evaluated either on frozen section or on paraffin-embedded material. Kerosene sections are the gold standard in terms of sensitivity and specificity, especially for SCC of the skin, as the cells of the stratum spinosum do not stain as intensively as the cells of the stratum basale. Other methods such as confocal laser microscopy or "Rapid Lump Examination" have not been reviewed for SCC of the skin [376][377].
The embedded preparation can be processed in different ways. In particular, conventional slicing is distinguished from 3D histology. In contrast to conventional slicing of the excised material by parallel, lamellar, serial cuts (bread loaf technique), which have diagnostic gaps, in 3D histology the outer edges of the entire excised material are cut off into embeddable strips or re-excised as such and pressed flat on the outer side according to the rules of the clock. In this way, a transformation of the three-dimensional cut surfaces of the material into two-dimensional histological preparations with a gap-free view of the cut edges of the excised sample is achieved [378]. The larger the specimen, the less time is required for sectioning and examination for edge sectioning compared to bread loaf technique [379].
One paper prospectively investigated whether the different reprocessing techniques lead to differences in recurrence frequencies in basal cell carcinoma [380]. Recurrence frequency was significantly lower when gapless reprocessing was used. With limitations, this may be transferable to SCC. However, it should be critically noted that this difference was significant only in nodular basal cell carcinoma, since overall the number of recurrences was very low and nodular basal cell carcinoma constituted the largest subgroup. Furthermore, the spacing between the lamellae in the bread loaf technique can certainly be set even tighter than 5 mm (as applied in the study).
8.1.2.4 Local excision with wide resection margins and subsequent lamellar serial reprocessing
In the procedure of wide resection ("wide local excision“, WLE), the primary tumor is excised with a certain safety margin. The size of the safety margin is not standardly defined for this form of resection and a wide variance is described in the literature (4 to 10 mm, maximum 50 mm) [381][382][383][384][360]. The current European Guideline recommends removal of a clinical safety margin of 5 mm for low-risk SCC and 6-10 mm for high-risk SCC for the WLE technique [384]. A larger resection margin compensates for the uncertainty of histological examination described below and also increases the rate of complete excisions even at the first procedure.
Workup using bread loaf histology (serial sectioning technique/bread loaf sections) is carried out using the kerosene sectioning technique with lamellar, serial sectioning of the tumor specimen. In conventional histological examination via the aforementioned bread loaf histology, the width of the lamellae is not specified in the existing literature except in two cases, although the quality of the histological examination depends significantly on it [367][382]. Since examination with bread loaf sections is technically incomplete ("diagnostic gaps“), surgeons usually choose rather generous resection margins for the initial excision of a tumor, hence the term (WLE). This results in larger defects [385]. For this reason, the current European Guideline points out that, for example, in the head and neck region, the use of the tissue-saving MKC technique with gapless three-dimensional incision margin control can be useful [384].
The data in the literature on resection distances for WLE is relatively meagre. The most important and most cited study on this is that of Brodland 1992, which states that tumors with <20 mm diameter can be excised with 4 mm resection distance from the clinically visible tumor borders in 96% R0 [386]. For tumors with ≥20 mm, this is always achieved with a resection margin of 6 mm. If the resection margin is increased to 9 mm, 100% R0 resection is achieved. A limitation of this study is that predominantly low-risk tumors were investigated. A more recent prospective study confirms this assumption, as up to 49% of SCC with PNI required a resection margin of 6 mm or more [55]. On average, resection margins of 6.5 mm are reported [62][382][387][388]. The benefit of a larger resection margin is clearly demonstrated by a recently published retrospective work showing that taking a safety margin of more than 5 mm in high-risk SCC, improves tumor-specific survival [389]. However, Philipps et al. state that clinical resection margin data were not available, so the available data are based on histological resection margins (indicated by the pathologist) [389]. In the other publications on WLE cited above, no data on resection margins are provided.
Some papers also address the question of how frequently R1 resection occurred at initial excision. Rates of 1-16% are mentioned. On average, it is approximately 6% [387][390][391][392]. Further studies investigated whether initial R1 excision influences the number of recurrences. The data on this are very inconsistent with 8-68% recurrences [390][388]. One retrospective work on a very large collective (n=1468) of patients investigated whether there are subgroups in which the simpler technique of WLE has more frequent positive excision margins. This was significantly more common in SCC that occurred in older patients or in the head and neck region, were pretreated, had a larger diameter or high tumor thickness [348]. From this, it can be concluded that the relatively simple method of WLE can be a useful method in SCC that do not have the above factors.
The advantage of the method is that the tumor can be seen on almost all sections in its expression. The disadvantage is incomplete work-up of the margins with resulting false negative findings. It is regrettable that it is not precisely defined how wide the distance between the lamellae may be. This is especially problematic in large, multifocally growing tumors. Keeping the distance between the lamellae small in very large tumors quickly results in a large number of sections to be found. The definition of how large the histological distance of the tumor from the edge of the incision should be to still be considered an R0 resection varies from 1 to 4 mm in WLE studies [344][54][390]. Less than 1mm has been defined as R0 in very few papers [387].
8.1.2.5 Micrographically controlled surgery
In the development of the gapless cut edge method, different procedures are given in the literature. F. Mohs was the first to introduce chlorine zinc etching in 1941 [393]. As early as 1963, Drepper was the first to systematically examine flat excisions from the wound bed histologically on their outer surface using the kerosene section method, in order to detect tumor extensions [394]. Mohs named this procedure "Microscopic Controlled Surgery“ [395][396]. In Germany, the term subsequently became established (MKC) [397][398].
In the current AWMF guideline on MKC, this is defined as a technique the goal of which is to achieve histologically proven complete removal of malignant tumor components (R0 resection) while sparing the healthy environment as much as possible [398]. The AWMF guideline lists different techniques, all of which are subsumed as MKC. Techniques that can be safely described as MKC are those in which there is a gapless evaluation of the cut edges. In addition, in Germany, non-gapless techniques with closely set lamellae are sometimes also referred to as MKC, although this contradicts the original idea of a gapless assessment of the outer margin of the excised tissue.
The majority of published gapless MKC studies in SCC originate from countries where findings are mainly made on frozen sections. This includes original papers [337][63][351][352][336]and reviews [399][400][355]. In Germany, MKC is mostly carried out on paraffin-embedded material [398]. For the gapless MKC on paraffin-embedded specimens, the term 3D histology [401] or in the US “complete circumferential peripheral and deep margin assessment (CCPDMA)” has also been proposed [402]. There are also several studies on this technique with findings on kerosene sections [334][20][21][369][403] ("slow Mohs-surgery“). One study investigated whether findings in basal cell carcinoma initially carried out on a frozen section were identical to findings on paraffin-embedded specimens [367]. This was the case in 158/160 (98.8%) of the cases. Nevertheless, it must be stated that the diagnosis of SCC on frozen section is not easy and also presents more difficulties than in basal cell carcinoma due to the different staining behavior in an HE stain. Therefore, in the current European guideline, after initial diagnosis on a frozen section, control on paraffin-embedded sections is recommended [384].
The question of how often R1 resection is present in primary tumor excision is mentioned in only one of the publications and amounts here to 43% [55]. This seems quite high compared to WLE, but this is not surprising given the small initial excision distances in the concept of a skin-sparing surgical technique. It was not tested whether this influences the recurrence rate.
The advantage of the methods is the high sensitivity for detecting tumor extensions. However, it should be borne in mind that desmoplastic tumors, for example, are characterized by single-cell infiltration, which may elude histological detection in the periphery remote from the tumor. Nevertheless, it can be stated that with this method, the primary safety distance is usually kept small (1-5 mm, depending on tumor diameter and location), as overall the sensitivity to detect tumor extensions is high. This allows significantly smaller defects, which can be advantageous in certain localizations such as the facial region [385]. In addition, from a purely practical point of view, it may make sense to use gapless MKC for very large tumors, as a bread loaf technique (with narrow lamellae) necessitates the reporting of very many sections. However, this is of course dependent on the individual site conditions, as only temporary application of gapless MKC can also be time-consuming. The disadvantage is that only the plane of the incision margin is visualized and the tumor center must be examined separately, either after curettage as in Mohs surgery or from the remaining remnant after separation of the outer sides. And with the MKC method, increased re-operations may be required to achieve an R0 situation.
8.1.2.6 When should micrographically controlled surgery with gapless reprocessing of the incision margins be aimed for?
In all following considerations regarding surgical R0 resection with/without safety resection, it is important to compare tumor-specific survival with overall survival. It has been shown that only about 2% of patients with cutaneous SCC actually die from SCC and about 40% die from other causes [21][404][403]. One may hope that this will become even rarer in the future, as there are promising therapeutic options with immunotherapy. However, these will not be readily applicable in some patients, so that it is necessary to prevent inoperable complications in these groups as far as possible (e.g. immunosuppressed patients).
Local recurrence rates after WLE, vary widely between 0-53% [351][404]. Within the same publications, rates of local recurrence can also vary many times over for the same treatment modality, depending on the subcollective studied [342][351][390][405]. The majority of publications report rates of 2-13% [335][339][351][369][369][367][369][406][369][388][369][407][369][408][347][347][409][349][349][410].
In a prospective study in which 277 SCC were treated with WLE followed by bread loaf histology, the regional metastasis rate was 23% [335]. Similar regional metastasis rates of 5-47% are found in retrospective studies [340][342][344][345][346][351][368][404][406]. Other studies show lower metastasis rates of 2-4% [62][339][344][367]. Overall, it should be noted that this method was more commonly used by oral and maxillofacial surgeons who treated the larger tumors and thus patients were per se at greater risk of developing metastases. Thus, there is obviously a bias to the disadvantage of WLE. A comparison of the mentioned studies is virtually impossible, because often the risk factors of the tumors are not mentioned [351][65][399][400][411] or the information about the metastasis rate is missing [372][390][391][408].
Local recurrence rates of MKC vary between 0-33% [351][336]. Most publications report recurrence rates between 2-8% [400][20][351][412][403][408][290][413][414][415][416][349]. Looking specifically at the local recurrence rate between non-desmoplastic and desmoplastic SCC, it differs significantly with 4 vs. 26% [417].
Overall, the recurrence rate after MKC appears to be lower than after WLE with an average recurrence rate of 2-13% (see above), but there are risk constellations (such as desmoplasia) in which recurrences may occur frequently despite gapless MKC. The assumption of an overall lower recurrence rate after MKC is supported by two recently published retrospective comparative papers showing that both the local recurrence rate and the metastasis rate are lower with MKC than with WLE [349][418]. However, both papers lack details on the exact workup of the WLE-treated specimens, in particular the magnitude of the distance between the individual lamellae. In addition, data on the distribution of differentiation [349] or desmoplasia [349][418] are missing. However, it is noteworthy that in both studies, the MKC-treated collectives had a significantly worse risk profile and contained, for example, larger tumors that infiltrated deeper structures [349] or were more frequently immunosuppressed [418]. Other studies could not demonstrate a significant superiority of MKC in terms of recurrence rate [408][405]. This may be due to the fact that, depending on the subpopulation studied, the rates of local recurrence can vary many times over for the same treatment method [334][20].
Low metastasis rates of 0-7% have been described after Mohs surgery [337][63][413][414][415][20][62][369][369][407][369][414][416][416][418][336]. However, in much of the available data, Mohs surgery has tended to treat smaller tumors [400]. This is particularly evident in a much-cited prospective study in which locoregional metastasis did not occur in any case of the 1263 SCC studied [412]. It is important to note that even recent studies with mostly smaller tumors show that MKC cannot 100% reliably prevent either locoregional recurrence or metastasis [349][336][418]. Moreover, the proportion of patients who die due to SCC is lower after MKC than after WLE but death is not excluded [405]. If desmoplasia is present (despite MKC) the risk of dying from SCC is increased 8-fold [21]. All this implies that even after gapless MKC, removal of an additional safety resectate after R0 excision might well be reasonable for certain high-risk patients, especially since recurrence of SCC [333] or metastasis is associated with a poor prognosis.
As early as 1992, Friedman [381] published a commentary on the review by Rowe et al. [351] in which he called for prospective randomized trials for the different therapeutic modalities. There is still no such study [400]. For Germany it is aggravating that different centers use different techniques of MKC or some techniques are called MKC that are accompanied by incomplete visualization of the incision margins [419]. Often the surgeon is not aware of the distance between the individual lamellae in bread loaf technique processed specimens and therefore cannot really judge how reliable an R0 finding is, if this was based on bread loaf technique processed histology.
In conclusion, for the reasons mentioned above (lack of good randomised, multicenter studies with similar cohorts; different techniques of MKC; gapless vs. non-gapless workup and formaldehyde-fixed vs. frozen section), it is difficult to say when MKC should definitely be sought. At the same time, this question is very important due to the fact that even the new immunotherapies are not helpful or might not be able to be used in everyone (e.g., organ transplant patients), are expensive and have numerous side effects. Overall, it must be stated that a general recommendation to treat all SCC with gapless MKC does not seem justified at present. At the same time, the targeted use of this technique for certain high-risk patients seems to be a reasonable option.
8.2 Operative procedure after R0 resection
8.2.1 Safety resection after R0 resection
The course of SCC of the skin can be complicated by local recurrence (local recurrence rate), local metastasis to the skin, metastasis to the regional lymph nodes or distant metastases. Optimally, taking a safety resectate should reduce the risk of developing any of these complications.
However, interpretation and comparison of the studies described above is difficult due to the application of the different excision techniques and histological cut margin controls in Germany and also due to the differently applied techniques of MKC. At the same time, however, the vast majority of the studies show that after both methods (WLE and MKC), in principle, the risk of both local recurrence and metastasis for high-risk SCC is not 0%. Recurrence of SCC is associated with a poor prognosis, especially if this finding is unresectable [21][333]. If multiple risk factors occur simultaneously, this additionally worsens overall survival [21].
According to WLE, the current European guideline recommends removal of a clinical safety margin of 5 mm for low-risk SCC and 6-10 mm for high-risk SCC to the sides [384]. For depth, excision of the subcutaneous adipose tissue and, if localization is appropriate, entrainment of the galea aponeurotica is recommended [384]. Data for this are practically not available [360]. According to WLE, the Scottish guideline recommends excision of at least 4 mm for low-risk SCC and at least 6 mm for high-risk SCC [361]. Neither the European nor the Scottish guidelines comment on whether the additional collection of a safety resection specimen after gapless MKC is useful in certain high-risk patients.
Given the importance of the question regarding safety resectate intervals after excision of a SCC, an attempt was made to formulate recommendations based on the limited data available. It was also considered that i.) a distinction must be made between gapless vs. non-gapless resection and ii.) even gapless resection of the incision margins does not protect against the possibility that tumor cells have detached from the primarius and may be located in the immediate periphery of the tumor.
8.2.2 Wound closure after confirmation of R0 resection
As long as an R0 resection has not been histologically confirmed, wound closure shall only be performed if the resection margins can be clearly assigned postoperatively (e.g., no displacement flaps).
- Consensus
- Strong consensus (100%)
Evidence tables (1)
Therapie PEK chirurgisch + strahlentherapeutisch
The histological findings in the paraffin section are available at the earliest on the day after the excision. The areas of subtotal excision are also reported. The probability of subtotal excision increases proportionally with tumor size and inversely proportionally with excision distance. For WLE, it was stated above that rates of R1 resection after initial excision range from 1-16%, with a median of 6% [387][390][391][392]. After MKC, the rate is higher (up to 43% [55]) because of the rather small resection distances. For the latter procedure, the cryostat incision procedure is mostly used internationally. Re-excision can then be performed promptly.
In the case of unfavorable localization or very large tumors, it is advisable not to close the defect plastically until tumor-free incision margins have been demonstrated. This is especially true if local flap plastic surgery is planned, since it can sometimes displace the margins of the defect, making it difficult to assign a subsequent excision later.
8.3 Sentinel lymph node biopsy
There are no valid data on the prognostic and therapeutic value of sentinel lymph node biopsy available.
- Level of evidence
- 3
De novo research
- Consensus
- Strong consensus (100%)
- References
- [420] [421] [422] [423]
Evidence tables (1)
Therapie PEK chirurgisch + strahlentherapeutischOne option for minimally invasive lymph node diagnostics is the removal of one or more sentinel lymph nodes (SLN). By means of a radioactive tracer or a dye, which is infiltrated peritumorally, lymph drainage and SLN are visualized, which are then surgically removed and examined histopathologically (sentinel lymph node biopsy, SLNB). The quality criteria (sensitivity, specificity, negative predictive value, false negative rate) of SLNB in SCC of the skin show a sensitivity of 79%, a specificity of 100% and a negative predictive value of 96%, so that the procedure can purely technically be classified as reliable [423][420][424][425]. The possibility of imaging even atypical lymphatic drainage pathways can be advantageous especially in the head and neck area and also in recurrent tumors or after previous operations [426][427][428].
It must be taken into account that in the primary therapeutic excision of large tumors (>20 mm in diameter, referred to in the literature as high-risk tumors), if necessary with safety resectate, naturally relatively large defects arise. This generally alters the lymphatic drainage in the head and neck region with its complicated lymphatic vessel supply. This makes a possibly indicated SLNB possibly insufficient, because the site of injection then no longer corresponds closely to the tumor center. Thus, if lymphatic scintigraphy is planned as part of SLNB, an adequate trial biopsy should be performed before tumor excision to determine the risk of metastasis as best as possible by histological parameters. The size of >20 mm in diameter is relatively imprecise without additional information and still includes many low-risk tumors. One would then risk overdiagnosis by SLNB using only this single parameter in often elderly patients.
Nevertheless, a general recommendation for SLNB cannot be given at present because sufficient and sufficiently valid data on the prognostic and therapeutic value of SLNB are lacking [429][430][431][432][433][104]. Studies to date have not yet been able to prove any advantages with SLNB in terms of disease-specific and overall survival as well as metastasis-free survival with statistical significance [434].
Most of the available data address the use of SLNB in high-risk profiles (see 6.1.1 Risk factors for loco-regional progression and tumor-specific survival). Numerous studies cite a potential benefit (detection of clinically occult micrometastases, avoidance of unnecessarily extensive lymphadenectomies with higher morbidity compared with SLNB) in high-risk SCC, which is expected to have a metastatic risk >10%. A recent paper studied 720 patients with high-risk SCC, 150 of whom received SLNB [435]. It was shown that patients who received sentinel lymph node biopsy showed no benefit in terms of further metastasis or tumor-specific death. Thus, SLN removal for SCC of the skin continues to show no benefit, although of course complications of SLNB (see studies in breast cancer and melanoma) are rare (3-5%) and primarily include lymphedema, infection, hematoma, seroma, cutaneous lymphatic fistula, and suture dehiscence [436][428][429][104][437][438][439][440].
8.4 Prophylactic and therapeutic lymphadenectomy
Regional (therapeutic) lymphadenectomy should be performed when lymph node metastasis is clinically manifest.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 3
- Consensus
- Strong consensus (100%)
- References
- [433] [441] [442] [443] [444]
Evidence tables (1)
PEK LK DissektionFor cutaneous SCC, a (prospective) benefit of prophylactic (elective) lymph node dissection in terms of disease-specific and overall survival has not been proven so far [443][445]. A benefit can only be expected from a metastasis frequency of more than 20%, for the head and neck area a study could work out an expected benefit here [444] ("utility" for each treatment is a weighting scheme for the expected value of each member of the decision tree. Utilities are numeric values that represent a person's preference for different health outcomes after treatment. Each utility state has a numerical value between 0 and 1; death is traditionally assigned a value of 0, whereas a disease-free state with no significant effects of treatment is assigned a value of 1). Only in very advanced stages (such as skull base proximity or nodal metastasis in the parotid area) do individual studies (retrospective case series) report a benefit from elective neck dissection in the head and neck region [446][447].
European consensus-based guidelines recommend therapeutic lymph node dissection for clinically (cN+ in staging, macrometastasis) or histologically confirmed metastasis (pN+, micro- or macrometastasis in SLN, metastasis confirmed by fine needle biopsy or lymph node removal) [104]. As a rule and according to the recommendation of most authors, it includes not only the region or level of the confirmed metastasis but also the directly adjacent levels in each case (adaptation from the S3 guideline "Oral cavity carcinoma" [445]. Sufficient data for an evidence-based decision on the extent (level, radicality) of the necessary therapeutic lymphadenectomy in cN+/ pN+ situation do not exist [448][449]. Data justify therapeutic lymphadenectomy in cN+ /pN+ by expected better locoregional tumor control and – depending on the extent of nodal metastasis – partial also of disease-specific survival, whereas adjuvant radiotherapy in pN+ was additionally performed [450][D'Souza, J. et al. 2011][448][428][442][447][452][453][454].
Therapeutic lymph node dissection should only be performed if a surgical procedure seems possible and reasonable with regard to the general condition (operability) and in the context of the overall concept. This requires the intention of R0 resectability of the metastasis(es) (local operability). If general and local operability are not given, non-operative therapy modalities should be given preference in the context of an interdisciplinary tumor board decision.
8.5 Lymphadenectomy in the head and neck region
There is no consensus in the literature on the extent of lymph node clearance In the head and neck region. The decisive factor in particular is the localization of the primary tumor.
For a few localizations, a rather constant lymphatic drainage area is described, e.g., for the area of the lower lip, lymphatic drainage into the submental and submandibular lymph nodes as well as high-cervical lymph nodes (level Ia, Ib and II according to Robbins et al.) [455][456][457][458].
Most localizations exhibit highly variable lymphatic drainage. For example, a wide variety of lymphatic drainage pathways are described for the ear region alone: to retroauricular and occipital, to infraauricular, to cervical levels II, III and IV, and to parotidal lymph nodes [459][460][461]. This variable lymphatic drainage, which may include the contralateral lymphatic drainage areas if the tumor is located close to the midline, also applies to other regions of the head and neck [441][462][443][463][464]. Thus, it has been shown that in skin tumors of the head and neck region, a contralateral sentinel lymph node is present in 7% [465]. In particular, the lymphatic drainage into the parotid area is also important from a clinical-surgical point of view due to its proximity to the facial nerve, which should be preserved and spared if at all possible in the course of a lymphadenectomy/parotidectomy [466][467][466][467].
If possible, a gentle, so-called selective-functional excision should be performed while preserving the functionally significant structures (especially nerves, muscles and vessels). Only in cases of extensive metastasis are radical dissections recommended with then increased morbidity. In analogy to oral cavity carcinoma, the results of a selective neck dissection are not inferior to those of a modified-radical or radical neck dissection with regard to tumor control, disease-specific and overall survival (adaptation from the S3 guideline "Oral cavity carcinoma") [468][469][470][471][472].
8.6 Radiotherapy and postoperative radiotherapy
For tumors that are not locally resectable in sano or inoperable patients, radiotherapy should be performed.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 3
De novo research
- Consensus
- Strong consensus (100%)
- References
- [405] [473] [474] [475] [476] [477]
Evidence tables (1)
PEK StrahlentherapieProspective randomized studies comparing the effectiveness of primary radiotherapy in terms of local tumor control and patient survival compared to other local therapy modalities are not available. However, retrospective studies show high local tumor control after primary radiotherapy. Mendenhall reported a local recurrence rate of 6.0%/10.5%/12.8% at 5/10/15 years for a 245 patient collective. The local recurrence rate was dependent on the initial tumor size. For T1 tumors it was 1.7% after 15 years, for T2 tumors 7.4%/14.2%/19.0% after 5/10/15 years and for T3 tumors 25% after 5/10 years. Mendenhall therefore recommends a radiation dose of 70 Gy for larger tumors and 60-70 Gy for smaller ones [478]. Lansbury comes to similar conclusions in a meta-analysis comprising 14 mostly retrospective studies on 1018 primary irradiated patients with cutaneous SCC [405]. For studies with a median observation time of 2 to 5 years, he reports a median recurrence rate of 6.1%.
The extent to which simultaneous chemotherapy can increase the efficacy of primary radiotherapy in large or initially lymphogenically metastatic tumors has not been clarified in large patient collectives with cutaneous SCC.
An approach analogous to the treatment of advanced mucosal SCC has been described in the literature [474][475]. For example, Nottage reports 21 patients who received primary irradiation (total dose 70 Gy, single dose 2 Gy) and simultaneous chemotherapy (cisplatin 40 mg/m² or carboplatin AUC2 weekly) in a prospective phase II study. Of 19 evaluable patients, 10 developed complete remission and 2 tumors were operable after radiochemotherapy and could be completely resected [476]. Tanvetyanon et al. reported in 67 patients that adjuvant radiochemotherapy with cisplatin significantly reduced the risk of recurrence in a multivariable analysis: Hazard ratio (HR) 0.31. However, no difference in overall survival was observed [479]. For a very small patient population with recurrent tumors, Sharon reports the possibility of alternative therapy with antibodies (cetuximab) concurrent with radiotherapy in addition to platinum-based chemotherapy [477]. Radiotherapy with either concurrent platinum or cetuximab appears to offer similar clinical outcomes in patients with locally advanced cutaneous SCC of the head and neck.
Postoperative radiotherapy should be performed for:
- R1 or R2 resection (if further resection is not possible).
- Extensive lymph node involvement (>1 affected lymph node, lymph node metastasis >3 cm, capsule rupture)
- Intraparotid lymph node involvement
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2
De novo research
- Consensus
- Strong consensus (100%)
- References
- [104] [473] [479] [366] [368] [480] [481] [482] [483] [484] [485]
Evidence tables (1)
PEK StrahlentherapieAdjuvant radiotherapy should be performed in the presence of extensive perineural sheath infiltration.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2
De novo research
- Consensus
- Strong consensus (100%)
- References
- [104] [366] [368] [473] [479] [480] [481] [482] [483] [485] [484]
Change note
Adjuvant radiotherapy should be performed if risk factors are present: Scarce resection margin (<2 mm, in the absence of the possibility of resection) Extensive perineural sheath infiltration.Evidence tables (1)
PEK StrahlentherapieAdjuvant radiotherapy may be considered if the resection margin is close.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 2
De novo research
- Consensus
- Strong consensus (90,5%)
- References
- [104] [366] [368] [473] [479] [480] [481] [482] [483] [485] [484]
Change note
Adjuvant radiotherapy should be performed if risk factors are present: Scarce resection margin (<2 mm, in the absence of the possibility of resection) Extensive perineural sheath infiltration.Current data do not support a recommendation for combining adjuvant radiotherapy with systemic therapy.
Evidence tables (1)
PEK StrahlentherapieFor the following revision as part of the 2020/2021 guideline update, a systematic update search was performed for the period of January 2017 to May 2021. Systematic reviews, randomized trials, and case series > 200 patients were included.
General postoperative radiotherapy for cutaneous SCC is not indicated but should be offered only in the presence of risk factors for local or locoregional recurrence. Risk factors, some of which are discussed in contradictory fashion in the literature, include R1 or R2 resection, narrow resection margin (<2 mm in the absence of the option of resection), recurrent tumor, maximum tumor size (>2 cm), maximum penetration depth (>4 mm), infiltration of adipose tissue, PNI, and extensive lymphogenic involvement (>1 affected lymph node, capsular rupture) [365][481][368][489][361][479][480][366][490].
A recent systematic review with meta-analysis considered the impact of postoperative radiotherapy in patients with cutaneous SCC (n=2605 patients, n=20 studies) [485]. Adjuvant radiotherapy achieved significant improvements in overall survival (OR 2.94; 95% CI, 1.75-4.91; p<0.0001), disease-free survival (OR 2.17; 95% CI, 1.23-3.83; p=0.008), and recurrence rate (OR 0.56; 95% CI, 0.36-0.85; p=0.006). In the subgroup of patients with free incision margins, postoperative radiotherapy resulted in improved disease-free survival (OR 2.53; 95% CI 1.24-5.14; p=0.01); overall survival was not analyzed. In the overall population, multivariate analysis of risk factors for overall survival identified the following significant factors: Use of radiotherapy (improvement with HR 0.47; 95% CI, 0.34-0.65; p<0.00001) as well as PNI (HR 1.61; 95% CI, 1.24-2.09; p=0.0004), positive incision margins (HR 2.34; 95% CI 0.34-0.65; p=0.0008) and immunosuppression (HR 3.02; 95% CI 2.14-4.25; p<0.00001) [485].
Another systematic review with meta-analysis evaluated the value of postoperative radiotherapy in patients with cutaneous SCC of the head and neck region and regional lymph node metastasis (n=3534 patients from 20 observational studies and one randomized trial) [484]. Adjuvant radiotherapy was significantly associated with improved overall survival in the meta-analysis (HR 0.45, 95% CI 0.26-0.78; p=0.005), while immunosuppression (HR 2.66, 95% CI 2.26-3.13; p<0.0001), capsular rupture (HR 1.90, 95% CI 1.12-3.22; p=0.02), the proportion of affected lymph nodes (HR 1.91, 95% CI 1.09-3.35; p=0.02) and age (HR 1.03, 95% CI 1.00-1.07; p=0.05) were determined. The use of postoperative radiotherapy was also associated with improved disease-specific survival (HR 0.52, 95% CI 0.33-0.84; p=0.008).
Postoperative radiotherapy after R1 or R2 resection and after close resection (<2 mm) without the possibility of resection is considered mandatory [368][361][104][479][480]. A meta-analysis did not find different local recurrence rates between surgery alone and surgery and postoperative radiotherapy for close or unclear resection margins. However, the authors inferred the effectiveness of postoperative radiotherapy based on the fact that recurrence rates were the same for both treatment modalities, although the irradiated patients had larger tumors [368]. Therefore, Veness recommends radiotherapy with a total dose of 50-60 Gy in this situation [480]. There is no literature indicating maximum tumor size or infiltration depth as mandatory indications for postoperative radiotherapy. Therefore, both risk factors must be considered optional and may be used in terms of an individual decision if necessary. Although no prospective studies on PNI as an indication for postoperative radiotherapy are available, 2 reviews and 3 other publications indicate that the local recurrence risk in PNI can be reduced by postoperative radiotherapy [365][481][368][104][366][490]. The extent of infiltration and the size of the infiltrated nerve are important. Han reports local control rates of 78-87% for microscopic PNI, 50-55% for macroscopic PNI, while after postoperative radiotherapy local control was 100% in selected patients [481]. In the presence of extensive involvement of the cervical lymph nodes (>1 affected lymph node, lymph node metastasis >3cm, capsular rupture), postoperative radiotherapy is mandatory [491][492][442][493][483][454][482]. This not only improves the local recurrence rate [492][442][493][483][454][482] and disease-free survival [483][454], but also improves overall survival [442][493][483][454][482]. In a 122-patient retrospective study, the local recurrence rate, 5-year disease-free survival, and overall survival were 55%, 34%, and 27% for patients operated on alone and 23%, 74%, and 66% for those additionally irradiated postoperatively [482]. The irradiation dose ranged from 50 to 60 Gy [442]. A special situation exists in intraparotidal lymph node metastases, as postoperative radiotherapy is always recommended here [494][495]. Literature references on the procedure for lymph node metastases of the axilla and inguinal region are sparse and are essentially based on the indication for postoperative radiotherapy in the neck region [494].
On the question of the role of postoperative radiochemotherapy in the presence of risk factors, the randomized phase III trial TROG 05.01, which included n=310 patients with macroscopically completely resected (R0 or R1) high-risk cutaneous SCC of the head and neck region according to the following criteria: Presence of intraparotid lymph node metastasis or lymph node metastasis with at least one of the criteria (≥ 2 lymph nodes or capsule rupture or largest lymph node > 3cm) or advanced primary tumor (> 5cm or T4 or in-transit metastasis) [486]. Postoperative radiotherapy 60-66 Gy was compared with radiochemotherapy 60-66 Gy with carboplatin weekly AUC 2 (maximum 6 doses). The primary endpoint of freedom from locoregional recurrence showed no advantage of radiochemotherapy, being 83% for radiotherapy alone and 87% for radiochemotherapy at 5 years (HR 0.84, 95% CI 0.46-1.55; p=0.58). The 5-year overall survival was also comparable, being 76% for radiotherapy and 79% for radiochemotherapy (HR 0.95, 95% CI 0.58-1.57) [486].
A 2019 review also showed no benefit in adding carboplatin as part of adjuvant radiotherapy to preoperated patients compared with single radiotherapy. A retrospective analysis of 104 patients with locally advanced cutaneous SCC who had already undergone surgery including parotidectomy and neck dissection found no significant difference in recurrence-free survival between radiochemotherapy vs. radiotherapy with a 2-year disease-free survival of 65% vs. 58% (p=0.43) [487].
In a propensity score-matched analysis, the effect of combining postoperative radiotherapy with cetuximab for high-risk cutaneous SCC (poorly differentiated, PNI, lymphovascular invasion, positive incision margin, lymph node involvement, recurrence, immunosuppression, or ear/cheek/lip localization) of the head and neck region was considered (n=68) [488]. Both 5-year overall survival (80% vs. 61%) and 5-year progression-free survival (66% vs. 29%) were favorable for the cetuximab group, but the differences were not significant.
In summary, multiple studies with heterogeneous and sometimes very small patient populations show no or no statistically significant benefit for platinum-based chemotherapies in combination with radiotherapy in terms of overall survival, disease-specific survival, and relapse-free survival compared with radiotherapy alone. The use of EGFR receptor antagonists in combination with radiotherapy should be discussed especially in patients who have contraindications to the use of checkpoint inhibitors and an increased risk of local recurrence and metastasis such as organ transplanted patients.
The combination of checkpoint inhibitors and radiotherapy has been poorly studied in cutaneous SCC. Several clinical trials are currently evaluating the use of this therapeutic option in adjuvant setting using different checkpoint inhibitors. Results of these studies must await future therapeutic recommendations.
In local or locoregional recurrence, the same criteria for indication for postoperative radiotherapy apply as in the primary situation [496].
8.7 Therapy of local or locoregional recurrence
Locoregional recurrences shall be surgically removed if clinically possible.
- Consensus
- Strong consensus (100%)
Evidence tables (1)
PEK LokalrezidivMicrographically controlled surgery (MCS) shall be applied.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2
De novo research
- Consensus
- Strong consensus (100%)
- References
- [473] [481] [493] [495] [104] [354] [366] [368] [479] [482] [483] [496] [364]
Evidence tables (1)
PEK LokalrezidivIf a R1 or R2 situation that cannot be further resected arises during the course of resection, postoperative radiotherapy should be performed at the R1 or R2 localization (see chapter 6.5 Radiotherapy and postoperative radiotherapy).
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2
De novo research
- Consensus
- Strong consensus (100%)
- References
- [354] [493] [495] [496] [364]
Evidence tables (1)
PEK LokalrezidivIn case of interdisciplinary determinated inoperability, radiotherapy should be performed (see chapter 6.5 Radiotherapy and postoperative radiotherapy).
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 3
De novo research
- Consensus
- Strong consensus (100%)
- References
- [354] [493] [495] [496] [364]
Evidence tables (1)
PEK LokalrezidivFor therapy of local or locoregional recurrence, the indication for electrochemotherapy or systemic therapy should be considered if surgical or radiotherapeutic options are not available.
- Consensus
- Consent (93,3%)
Evidence tables (1)
PEK LokalrezidivLocal recurrences often have more extensive, irregular subclinical infiltration than primary tumors, which is inadequately detected by bread loafing histology. Desmoplastic SCC recur more frequently despite use of a gapless MCS [364][354]. Death from local infiltration is not uncommon in this type [21]. Thus, in case of recurrence after MCS after surgical therapy, postoperative irradiation is recommended. Overall, according to the literature, postirradiation reduces the recurrence rate and achieves longer recurrence-free survival compared with surgical therapy alone [481][368][473][104][479][480][483][482][366].
If inoperability is present and radiatio is not possible, electrochemotherapy can be given to improve local tumor control; the response rate has been reported to be 46% [497][498][499]. Furthermore, it can be evaluated whether systemic therapy is possible (see chapter 6.7 Therapy in distant metastatic stage).
8.8 Therapy in the advanced (locally advanced or metastasized) stage
8.8.1 Indication for systemic therapy
In case of (distant) metastasis or locally advanced disease that cannot be controlled by surgical or radiotherapeutic interventions or only with major limitations of functionality, the indication for systemic therapy shall be considered.
- Consensus
- Strong consensus (100%)
Evidence tables (1)
PEK SystemtherapieThe indication for systemic therapy should be made in an interdisciplinary tumor board.
- Consensus
- Consent (89%)
There is an international consensus that metastatic skin tumor diseases in general and advanced cutaneous SCC in particular should be discussed in an interdisciplinary tumor board.
The possibility of inclusion in clinical trials should be considered in all cases.
While distant metastasis is clearly defined by radiological criteria (RECIST) on imaging, the definition of "locally advanced SCC" disease is more difficult. In the clinical trials for approval of the PD-1 antibodies cemiplimab (REGN-1540) or pembrolizumab (KEYNOTE-630), study inclusion was only possible if an interdisciplinary tumor board had discussed potential patients. Only if no curative option (surgery or radiotherapy) was seen in the tumor board or if this could only be performed with major limitations in functionality, study inclusion was possible. Most importantly, the usefulness of surgery versus the prospects of systemic therapy should be carefully weighed.
However, an internationally accepted definition of locally advanced SCC disease does not exist to date. Recently, the European Association of Dermato-Oncology presented a subdivision of advanced basal cell carcinoma, which distinguishes 5 subgroups. The German guideline for basal cell carcinoma contains a term definition for the „locally advanced disease“ as well. In the context of a SCC data collection the EADO is currently working on a similar international expert consensus for advanced SCC.
In summary, every patient with distant metastatic or locally advanced SCC should present to an interdisciplinary skin tumor board and the local and systemic therapy options should be carefully weighed in terms of benefits and risks. Inclusion in a clinical trial should always be considered.
8.8.2 Implementation of systemic therapy
Patients with locally advanced or metastatic SCC shall be offered first-line immunotherapy with a PD‐1‐inhibitor approved for this indication.
- Consensus
- Strong consensus (100%)
In case of progression under PD‐1‐blockade or contraindications to this type of immunotherapy, EGFR‐directed therapy or chemotherapy shall be offered.
- Consensus
- Strong consensus (100%)
If there is an indication for systemic therapy, then the best data is available for PD1 inhibitors from, however, only uncontrolled studies (see here). SCC have a very high mutation burden [500], which are associated with a response to PD1 inhibitors in other tumor entities. Data with the PD1 antibody cemiplimab and pembrolizumab (see here) show response rates of 41-50%, median duration of response was not reached after a median follow-up of 8.1-22.4 months (see here).
A retrospective monocentric case series from the University Dermatology Clinic in Tübingen, Germany, included 57 patients with advanced SCC who had received systemic therapy [501]. When overall survival of 20 patients who had received immunotherapy at any time point was compared with 37 patients who had not received immunotherapy but had received chemotherapy and/or EGFR inhibitor, there was a significant advantage for the patients with immunotherapy. This suggests that immunotherapy may be beneficial in terms of overall survival.
Another retrospective case series of 6 German skin tumor centers reported 46 patients with advanced SCC who had received a PD1 inhibitor [502]. The response rate was 58.7% and was independent of whether there was a locally advanced or metastatic stage. Median PFS and OS were not reached, and PFS at 12 months was 58.8%. Unfavorable factors for benefit from checkpoint blockade included elevated LDH and localization of the primary tumor to the legs.
In summary, the response rate of PD1 inhibitors appears to be higher in patients with advanced SCC on chronically light-damaged skin (with high mutation burden) without pretreatment, whereas pretreatment and primary tumors on non-light-exposed skin (with lower mutation burden) show lower response rates.
Table 33: Ongoing therapeutic trials with the use of PD1 blockers in cutaneous SCC (FUI = follow-up interval)
|
Therapy |
Line |
Study phase |
Number of evaluable patients |
Median response duration (months) |
Response rates |
Reference |
|
Cemiplimab |
Any |
1 |
26 |
Not reached (median FUI 11.1 months) |
50% |
Migden et al., 2018 [503] |
|
Cemiplimab (cohort 1, weight-adjusted dose every 2 weeks) |
Any |
2 |
59 (with metastases) |
Not reached (median FUI 16.5 months). |
49.2% |
Migden et al., 2018 [503] Rischin et al., 2020 [504] |
|
Cemiplimab (Cohort 2, weight-adjusted dose every 2 weeks) |
Any |
2 |
78 (locally advanced) |
Not reached (median FUI 9.3 months) |
44% |
Migden et al., 2020 [505] |
|
Cemiplimab (Cohort 3, fixed dose every 3 weeks) |
Any |
2 |
56 (with metastases) |
Not reached (median FUI 8.1 months) |
41.1% |
Rischin et al., 2020 [504] |
|
Pembrolizumab (CARSKIN) |
1. |
2 |
39 |
Not reached (median FUI 22.4 months) |
41% |
Maubec et al., 2020 [506] |
|
Pembrolizumab |
Any |
2 |
29 |
|
|
|
|
Pembrolizumab+ radiotherapy |
Postoperative adjuvant |
2 |
37 |
|
|
|
|
Pembrolizumab (Keynote 629) |
Any |
2 |
105 |
Not reached (median FUI 11.4 months) |
34% |
Grob et al., 2020 [507] |
In addition to studies on PD-1 inhibitors, there are mostly older data for various chemotherapies and EGFR inhibitors.
A systematic review published in 2011 on systems therapy for locally advanced cutaneous SCC summarized 28 studies with 119 patients published from 1970-2011 [508]. It became clear as an important limitation that there are only uncontrolled studies with few patients on this question, the „level of evidence“ was rated 2-3 (2=randomized trial or (exceptionally) observational study; 3=non-randomized controlled cohort/follow-up study, Non -randomized controlled cohort/follow-up study) and corresponds to a recommendation B (corresponding level 2 or 3 studies) or C (level 4 studies or extrapolation of level 2 or 3 studies). Therefore, the efficiency data are subject to (strong) uncertainties. Across therapies, a median time to response of 9 weeks was seen with an overall response rate of 72% and a median duration of response of 42 weeks.
In a retrospective case series published in 2018, a total of 190 patients with advanced SCC from 2010 and 2011 were documented in 24 German and Austrian centers [509]. 78 patients had locally advanced SCC, and 114 patients had metastatic SCC. 32 patients received systemic therapy, using various chemotherapeutic agents and EGFR inhibitors alone or in combination. The response rate was 26%, and the median duration of response was 5 months.
Table 34: Therapeutic studies on the use of chemotherapeutic agents, interferon alpha, and 13-cis retinoic acid in cutaneous SCC
|
Therapy |
Line |
Study phase |
Number of evaluable patients |
Median response duration (months) |
Response rates |
Reference |
|
Cisplatin + doxorubicin |
Partly neoadjuvant |
2 |
12 |
8.6 |
58% |
Guthrie et al., 1990 [510] |
|
cisplatin + 5-fluoro-uracil + bleomycin |
pre-treated |
2 |
13 |
11.7 |
84% |
Sadek et al., 1990 [511] |
|
Cisplatin + 5-fluorouracil |
1. |
2 |
7 |
11.8 |
86% |
Khansur et al., 1991 [512] |
|
Oral 5-fluorouracil |
1. |
2 |
15 |
30 |
14% |
Cartei et al., 2000 [513] |
|
Interferon alpha + 13-cis retinoic acid |
1. |
2 |
28 |
5 |
68% |
Lippman et al., 1992 [514] |
|
Interferon alpha+ 13-cis retinoic acid+ cisplatin |
1. |
2 |
35 |
9 |
34% |
Shin et al., 2001 [515] |
|
70 Gray radiotherapy +carboplatin |
1, only locally advanced, incl. regional lymph node metastases |
2 |
19 |
Not reported |
100% (53% complete remission) |
Nottage et al., 2017 [476] |
With the above limitations, SCC is chemosensitive with response rates >50% to platinum-based chemotherapy. However, a possible bias regarding the publication of successful treatments should always be considered here. Response rates are higher with poly-chemotherapy or radiochemotherapy. However, the duration of response is often unclear and increased toxicity is to be expected especially with the mentioned poly-chemotherapy regimens.
A retrospective case series investigated isolated limb perfusion for unresectable SCC [Huis In 't Veld, EA et al. 2018]. In 21 patients, the leg was perfused with melphalan, in 9 patients the arm, in 2 patients additionally with TNFα. Of 27 evaluable patients, 16 (59%) showed complete remission, 6 (22%) partial remission, and 5 (19%) progressive disease. 7 patients with response developed relapse or re-progression during the course after a median of 9 months. Thus, isolated limb perfusion could be a therapeutic option in appropriate tumor location.
Regarding monotherapy with EGFR inhibitors (see here), response rates range from 25% to 45%, with a median response duration of a few months (progression-free survival: approximately 4 months, overall survival approximately 8 months). High response rates have been reported for the combination of cetuximab and radiotherapy. One publication summarized 8 patients of our own and 24 patients from the literature [517]. 29 of the 34 patients responded to therapy. However, this raises the question of the extent to which this result would not have been achieved with radiotherapy alone or whether the additional cetuximab administration was necessary. Another retrospective study compared the use of radiotherapy plus cetuximab vs. radiotherapy plus platinum-containing chemotherapy and showed similar therapeutic success in both arms [477].
Table 35: Therapeutic studies with the use of EGFR blockers in cutaneous SCC
|
Therapy |
Line |
Study phase |
Number of evaluable patients |
Median response duration (months) |
Response rates |
Reference |
|
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 |
Not reported |
45% |
Lewis et al., 2012 [520] |
|
Erlotinib + radiotherapy |
1 |
1 |
15 |
Not reported |
Not reported |
Heath et al., 2013 [521] |
|
Lapatinib |
Neo-adjuvant |
1 |
8 |
Not reported |
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] |
|
|
|
|
|
|
|
A special feature of patients with advanced or metastatic SCC is that they are often elderly patients with relevant comorbidities; for example, chronic lymphocytic leukemia is a risk factor for rapid progression of SCC. A retrospective study was able to show that PD1-targeted checkpoint blockade can also be promising in patients with hematologic neoplasms, although here the efficiency seems to be lower than in patients without secondary hematologic disease [525].
Irrespective of age, patients with post organ transplant condition with associated iatrogenic immunosuppression should be mentioned. While in renal transplant recipients conversion of immunosuppression to an mTOR-containing regimen had a positive effect in primary and secondary prevention of new epithelial skin tumors in several studies, the effect of conversion to mTOR inhibitors in manifest epithelial skin tumors is unclear [526][527][528][529]. In unresectable or metastatic SCC, PD1 checkpoint inhibition can also be discussed, but there is a risk of organ rejection [530].
In summary, currently in SCC with an indication for systemic therapy, immunotherapy with a PD1 inhibitor should be performed if inclusion in a clinical trial is not possible. A number of clinical trials are currently ongoing, e.g., with combinations of checkpoint blockade and EGFR blockade (avelumab + cetuximab, AliCe trial, EUDRACT number 2018-001708-12). In case of disease progression under immunotherapy or contraindications to immunotherapy, the indication of chemotherapy or EGFR-targeted therapy should be evaluated. Schemes following therapies for mucosal SCC (HNSCC) or oral cavity carcinoma may also apply [430][531][532] such as cetuximab plus platinum derivative [533].
8.9 Palliative care
For patients with advanced SCC, communication on palliation, presentation of possible treatment concepts, and agreement on realistic goals are essential. Care structures close and suitable to the patient are to be elicited.
Loss of function due to tumor growth, limited mobility and stigmatization must be taken into account. Malignant decaying tumors affect 5-14% of tumor patients. Tumor ulceration, necrosis and superinfection cause additional psychological distress [534]. Microbial colonization is favored by tumor decay. Exudate, bleeding, fetor become a burden [384]. Local measures can be used to flank antitumorally [535][536].
Palliative care is defined as an approach to improve the quality of life of patients and their families facing problems associated with life-threatening disease. This is done by preventing and relieving suffering through early recognition, careful assessment, and treatment of pain and other problems of a physical, psychosocial, and spiritual nature. Regarding palliative care aspects, regardless of the underlying diagnosis, reference is made to the expanded S3 guideline on palliative care by the German Guideline Program in Oncology [537].
Patients with incurable SCC require palliative care; this includes pain therapy and often wound management. Nutrition and gastrointestinal symptoms including weight loss, sleep disturbances, fatigue, and physical weakness are other associated and common topics [384][538][537]. Depending on tumor location, tumor size, and the extent of the disease, other physical and psychological problems may be added. Psycho-oncology care addresses psychological, social, and spiritual conflicts. Fears and uncertainties about the course of the disease and dying can be addressed in a timely and worry-reducing manner in communication.
Physical limitations and problems as well as psychosocial concerns, prevention of complications and preservation of quality of life are the focus. Patient wishes are to be taken into account in consultation with their relatives. Multi-professional and interdisciplinary management should be initiated in a timely manner.
Evidence tables
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. |
3 |
|
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. |
|
1 |
|
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 |
|
|
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. |
|
4 |
|
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. |
|
4 |
|
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%. |
4 |
|
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. |
|
4 |
|
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. |
1 |
|
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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3 |
|
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. |
3 |
|
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. |
3 |
|
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. |
3 |
PEK LK Dissektion
|
Study |
Aims |
Design |
Population |
Outcomes |
Results |
Comments |
LoE |
|
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 |
|
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. |
4 |
|
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. |
4 |
|
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. |
|
3 |
|
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. |
|
3 |
|
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. |
4 |
|
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. |
3 |
|
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. |
|
4 |
|
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. |
|
3 |
|
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. |
|
3 |
|
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).
|
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. |
3 |
|
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 |
|
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. |
3 |
|
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 |
|
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 |
|
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 |
|
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 |
|
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 |
|
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 |
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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 |
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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). |
|
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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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 |
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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 |
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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 |
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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 |
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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 |
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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. |
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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. |
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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. |
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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. |
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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 |
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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%. |
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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. |
|
2 |
|
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. |
|
2 |
|
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. |
|
2 |
|
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 |
|
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 |
|
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 |
|
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 |
|
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 |
|
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 |
|
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 |
|
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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