Postoperative Chemotherapie NSCLC Stadium III

Barlesi 2015

(22, 31)

08/2014 to 12/2017

Frankreich

RCT

efficacy of gemcitabine plus cisplatin with docetaxel plus cisplatin in completelly resected  NSCLC on quality of life

Inclusion Criteria:

· 18–75 yrs patients with completely resected (R0) Stage IB–III NSCLC, ECOG 0 or 1

· adequate bone marrow reserve and organ function, including calculated creatinine clearance of 45 ml/min

Exclusion Criteria:

· postoperative complications (acute respiratory distress syndrome, bronchial fistula or severe pneumonia)

· previous history of cancer within ≤ 5 years or clinically significant cardiac dysfunction, active infection or neurological/ psychiatric disorders

n=136

74% males

median age 57 (36-71)

Stage IB/II/III: 32/34/34%

bi(lobectomy): 85%

adenocarcinoma/Squamous cell carcinoma/others: 55/23/22%

minor postoperative complications: 15%

within 8 wks after surgery:

Cisplatin (75 mg/m², d1) plus gemcitabine (1250 mg/m², d1 and d8) (n=67)

vs.

Cisplatin (75 mg/m², d1) docetaxel (75 mg/m² d1) (n=69)

for three cycles (9 weeks)

Primary:

Quality of life (EORTC QLQ-C30, QLQ-LC12: raw scores from each functional and symptom scale were translated onto an overall scale from 0 to 100,.higher functional scores are indicative of global health scores better QoL, whereas lower symptom and single item scores reflected fewer symptoms)

Secondary:

overall survival, safety and cost

Quality of life:

·  (GHS) slightly improved from 63.5 vs. 62.7 at baseline to 64.5 vs. 65.4 after 3 months with no differences between groups (p=0.8)

· no significant differences for other functional scores between  groups

· Social function was not altered by the number of infusions (Days 1 and 8 for the GC arm)

· no differences for symptom scores, except for alopecia, where the CG showed a significantly higher score compared to IG

Safety:

· satisfactory compliance (80.6 vs. 85.5 % completed all the 3 planned cycles of CT)

· 32.8 vs.  21.7% experienced Grade 3/4 haematological toxicities with no significant difference between arms:

-    anaemia: 1.5 vs. 0%

-    neutropenia: 28.4 vs. 21.7 %

-    Thrombopenia: 9.0 vs. 1.4 %

· 32.8 vs. 26.1 % experienced non-haemotological toxicities:

-    asthenia: 7.5 vs. 7.2 %

-    nausea/vomiting: 10.4 vs. 7.2 %

-    infection: 3.0 vs. 1.4 %

-    neuropathy: 0 vs. 1.4 %

-    alopecia: fewer with IG: 3.0 vs. 13.0 % (p=0.03)

Overall survival:

· no differences between groups: median follow-up: 20.2 months, 1-year survival: 100 vs. 96.8% 2-year survival: 92.9 vs. 89.8%

· 15 (7 vs. 8) patients died in the course of study

2b

Abwertung aufgrund von Studienlimitationen, geringer Präzision und Indirektheit

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „In conclusion, DC or GC adjuvant chemotherapy for completely resected NSCLC might be an acceptable alternative to currently recommended combinations and might be compared with the VC regimen. This study did not demonstrate any significant negative QoL impact of DC and GC in resected lung cancer patients, and might be useful when discussing treatment options with such patients.“

Schlussfolgerung der Begutachterin: Multizentrische, in Frankreich durchgeführte Studie unter Einschluss von 136 NSCLC Patienten (Grad 1B-III, daher Abwertung aufgrund von Indirektheit) zur Bestimmung des optimalen Regimes einer CT nach vollständiger Resektion. Es fehlt eine nähere Beschreibung der Randomisation und Verblindung (z.B. in der Erfassung der Lebensqualität). Es existiert aber ein Protokoll in französischer Sprache (kein Zugriff auf Volltext). Die Studie wurde auf Empfehlung des Steering-Kommites vorzeitig aufgrund neuer ASCO-Empfehlungen für 4 (statt der hier untersuchten 3) Zyklen CT gestoppt (daher Abwertung aufgrund geringer Präzision). Ergebnisse zur Lebensqualität nach 93 Monaten liegen für 71% der Patienten vor, bei Gesamtüberleben werden in der Grafik viele Drop-outs sichtbar, welche nicht beschrieben werden (Abwertung aufgrund von schwerwiegenden Studienlimitationen), die Studie wurde von Lilly Oncology, Sanofi-Aventin, Amgen und mit öffentlichen Mitteln unterstützt.

Burdett 2015

(21)

Search from 1995 to 12/2013

Systematic Review

Effects of CT following surgery, or following surgery plus RT in patients with histologically diagnosed early stage NSCLC on OS, time to locoregional recurrence, time to distant recurrence and recurrence-free survival

Investigation of predefined patient subgroups benefit from cisplatin-based CT

Inclusion Criteria:

·  RCTs that compared OS, time to locoregional recurrence, time to distant recurrence and recurrence-free survival of additional adjuvant CT in patients with histologically diagnosed early stage NSCLC

·  published and unpublished completed trials with proper randomised

·  patient had undergone a potentially curative resection and not received previous CT

Exclusion criteria:

·  trials using long-term alkylating agents for >1 year

Surgery trials: mostly men with a median age of 61 (18-84) yrs

tended to have good performance status and

tumours of stage I-II adenocarcinomas or

squamous cell carcinomas.

Surgery+RT trials: mostly men, good performance status, median age of 59 yrs (range 27 to 81), stage III, squamous carcinomas

stage IIIA, IIB and IV (combined as stage III)

Risk of bias: inclusion of trials with adequate methods of randomization, no blinding, but OS is unlikely to be influenced, low reporting bias due to analysis of individual patient data

Surgery plus adjuvant CT:

o platinum plus

-vinca alkaloid/ etoposide

-or vinorelbine

-or taxane

o platinum plus vinca alkaloid + tegafur and uracil/tegafur other platinum regimens

o tegafur and uracil/tegafur plus other agent

o tegafur and uracil/tegafur

vs.

Surgery

median follow-up: 5.5 yrs

Surgery (plus RT)

vs.

Surgery (plus RCT) plus adjuvant CT:

o platinum plus vinca alkaloid/ etoposide

o platinum plus vinorelbine

o other platinum regimens

o antimetabolic agent only

median follow-up: 6.4 yrs

Primary:

OS

Secondary:

time to locoregional recurrence

time to distant recurrence

recurrence-free survival

Overall survival:

Surgery+adjuvant CT vs. surgery (N=35, N= 26 with individual patient data; IPD, n=8447 with 3223 deaths):

·    benefit of adding CT after surgery (HR 0.86; 95% CI 0.81 to 0.92; p< 0.0001) with small heterogeneity between results of different studies (I²=4%)

·    no influence of age group, sex, histology, PS and stage of the disease on the effect, for stage III survival was improved

·    with differences depending on CT category:

-     Platinum plus vinca alkaloid/ etoposide (N=9, n=2404): no difference: HR 0.94; 95%CI 0.84 to 1.05)

-     Platinum+vinorelbine (N=4, n=1304): benefit: HR 0.82; 95%CI 0.70 to 0.97)

-     Platinum+taxane (N=1, n=244): no difference: HR 0.77; 95%CI 0.57 to 1.05)

-     Other platinum regimes (N=4; n=699): no difference: HR 0.90; 95%CI 0.72 to 1.13)

-     platinum plus vinca alkaloid + tegafur and uracil/tegafur (N=8, n=1375): benefit: HR 0.79; 95%CI 0.67 to 0.93)

-     Tegafur and uracil/tegafur+other agent (N=1, n=83): harm: HR 1.79; 95%CI 1.00 to 3.20)

-     Tegafur and uracil/tegafur (N=7; n=2390): benefit: HR 0.76; 95%CI 0.64 to 0.90

·    absolute increase in survival of 4% (95%CI 3 to 6) at five years (5-yrs OS increased from 60 to 64%)

·    with no influence of subgroup analyses by age, sex, histological cell type, tumour stage, and performance status

·    for stage III, 5-year survival was improved by 5 % (95 % CI 3 to 8) from 30 to 25 %

·     

Surgery plus RT+ adjuvant CT vs. surgery+RT (N=15, N= 12 with IPD, n=2660 with 1909 deaths):

·    benefit of adding CT after surgery+RT (HR 0.88; 95% CI 0.81 to 0.97; p= 0.0009) with small heterogeneity between results of different studies (I²=0%)

·    no evidence of a differential effect by CT category,  the extent of resection achieved or timing of CT in relation to RT

·    absolute increase in survival of 4% at five years (5-yrs OS increased from 29 to 33%)

·    no influence of subgroup analyses by age, sex, histological cell type, tumour stage, and performance status

Recurrence-free survival

Surgery+adjuvant CT vs. surgery (n=5379 with 2519 events):

benefit of adding CT after surgery (HR 0.83; 95% CI 0.77 to 0.90; p< 0.0001)

Surgery+RT+adjuvant CT vs. surgery+RT (n=2247 with 1673 events):

benefit of adding CT after surgery (HR 0.85; 95% CI 0.77 to 0.93; p=0.0006)

Time to locoregional recurrence

Surgery+adjuvant CT vs. surgery (n=5226 with 936 events):

benefit of adding CT after surgery (HR 0.75; 95% CI 0.66 to 0.94; p< 0.0001)

Surgery+RT+adjuvant CT vs. surgery+RT (n=2247 with 533 events):

benefit of adding CT after surgery (HR 0.79; 95% CI 0.67 to 0.85; p= 0.0008)

Time to distant recurrence

Surgery vs. surgery+adjuvant CT (n=5224 with 1267 events):

benefit of adding CT after surgery (HR 0.80; 95% CI 0.72 to 0.89; p= 0.0007)

Surgery vs. surgery+adjuvant CT (n=2247 with 533 events):

benefit of adding CT after surgery (HR 0.75; 95% CI 0.66 to 0.87; p< 0.0001)

1a

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: “Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy.

These systematic reviews and meta-analyses use individual participant data, which is considered the gold standard of this type of review. We included all eligible trials if possible, no matter what language they were published in or whether they were published or not. The first meta-analysis (surgery versus surgery plus adjuvant chemotherapy) included 92% of all patients in eligible trials and the second meta-analysis (surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy) included 86% of all patients in eligible trials.

We are confident that further research is unlikely to change the findings. The studies were well designed and conducted, address the review question, and the effects are consistent across trials. The impact of any data we have not been able to include in our analyses is small.”

Schlussfolgerung der Begutachterin: Systematische Übersicht, geringfügige Einschränkung der Qualität (keine Untersuchungen zum Publikationsbias, aber Suche in Registern laufender Studien und Konferenzbänden und Kontaktierung von Autoren), basiert auf 47 Vergleichen in Studien unter Einschluss von 11 107 Patienten aller Stadien (geringe Anzahl im Stadium IIIB und IV) mit NSCLC mit einer Auswertung von individuellen Patientendaten und in der Regel geringem Verzerrungspotential (fehlende Verblindung beeinflusst den Hauptendpunkt Gesamtüberleben kaum).   Es wird die Wirksamkeit von adjuvanten Chemotherapien zusätzlich zur Operation oder zu Operation und Strahlentherapie berichtet und es werden Ergebnisse aus Subgruppenanalysen (auch für Stadien ) berichtet. Die Suche erfasste Studien mit einem Publikationsdatum bis Dezember 2013, die Autoren gehen davon aus, dass zukünftige Studien die Behandlungseffekte nicht beeinflussen werden.

Hata 2017

(23)

04/2005 to 01/2012

Japan

RCT

feasibility of the conventional treatment schedule of S-1 and the shorter treatment schedule of S-1 as adjuvant treatment of patients with completely resected NSCLC

Inclusion Criteria:

· histologically confirmed primary lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and adenosquamous carcinoma;

· R0 resection of the primary tumor; pathological stage IB to IIIA disease

· patients aged 20-74 yrs; ECOG 0 or 1;

· adequate organ function able to start within 9 weeks after surgery;

· no prior therapy

Exclusion criteria:

· history of previous CT, RT or surgery for lung cancer;

· pulmonary fibrosis; pleural effusion, ascites, or cardiac effusion that required drainage; concomitant malignancy; significant comorbidity; diarrhea; pregnancy;

· desiring to have children;

· drug allergy to S-1 or any of its components

n=80 randomized, 78 analysed

age: 63±8 yrs

males: 65%

ECOG 0/1: 94/6 %

Adeno/squamous/large cell carcinoma: 64/29/5 %

Stage IB/IIA/IIB/IIIA: 78/1/4/4 %

Lobectomy: 96 %

within 9 wks after surgery:

conventional treatment schedule of S-1 (n=39): administered for 4 weeks followed by a 2-week rest

vs.

shorter treatment schedule of S-1 (n=41): administered for 2 weeks followed by a 1-week rest

over 12 monthsunless there was any evidence of recurrence, other malignancies, or SAEs 

Primary:

rates of completing the planned administration schedule over 12 months

Secondary:

relative total administration dose of S-1

toxicity

3-year disease-free survival (DFS)

Median follow-up: 64 (range 6-113) months

Completion rates (over 12 months):

· higher in IG: 73.7% (95% CI 58.0%–85.0%) vs. 45.0% (95% CI: 30.7%–60.2%) (p=0.001)

· 73.7% vs. 45.0% received S-1 administration according the planned schedule

· S-1 administration was halted because of

-    AEs or refusal for 18% (n = 6 AEs, n= 1 refusal) vs. 38%) (n = 9 AEs, n= 6 refusal).

-    tumor recurrence or other non-S-1-related complications for 8% (n =1 tumor recurrence, n = 2 non-S-1-related complications) vs. 18% (n = 4 tumor recurrence, n =3 non-S1-related complications)

· higher averages of the relative dose intensity over 12 months in IG:  77.2 % vs.  58.4% (p = 0.01)

Adverse events:

· primary adverse events were hematological, gastrointestinal, and cutaneous signs and symptoms

· no difference in AEs: 38 (100%) (grade 1/2 in 89% and grade 3 in 11%) vs. 39 (98%) (grade 1/2 in 93% and grade 3 in 5%; p = 0.42)

· no difference in SAEs grade 3: 4 (11%) (elevated bilirubin, neutropenia, and rash) vs. 2 (5%) (anorexia and nausea, p = 0.43)

· Elevated bilirubin, AST, ALT, and alkaline phosphatase levels were more frequent in IG vs. CG (p = 0.01, <0.01, 0.01, <0.01, respectively).

· Two patients, 1 in each died during drug administration period, although the causes death were unknown and were not considered to be related to S-1 administration

Disease-free survival and recurrance:

· No difference in 3-year DFS rates: 79.0% vs. 79.3% (p=0.94)

· 9 (23.7%) vs. 8 (20.0%) relapsed within 3 years with predominant locoregional recurrence in both arms (6 vs. 5)

2b

Abwertung aufgrund von Studienlimitationen, geringer Präzision und Indirektheit

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „The superiority of feasibility of the shorter schedule was not recognized in the present study. The conventional schedule showed higher completion rates over 12 months (p = 0.01) and relative dose intensity of S-1 (p = 0.01). Toxicity showed no significant difference among the shorter schedule and the conventional schedule, except for grade 1–3 elevation of bilirubin.“

Schlussfolgerung der Begutachterin: Multizentrische, in Japan durchgeführte Machbarkeitsstudie unter Einschluss von 80 NSCLC Patienten (Grad 1B-IIIA, daher Abwertung aufgrund von Indirektheit und fehlender Präzision) zum Vergleich von 2 Regimes zur Verabreichung einer Chemotherapie auf der Grundlage von S-1 mit zentraler Randomisierung, aber ohne Beschreibung der Randomisierungsordnung, ohne Verblindung oder verblindete Endpunkterfassung und Registrierung des Protokolls (daher Abwertung aufgrund von schwerwiegenden Studienlimitationen). Die Studie wurde von JSPS KAKENHI unterstützt (kein Einfluss auf Datensammlung und –analyse, Interpretation der Ergebnisse und Schreiben der Veröffentlichung.

Iwamoto 2015

(24)

Japan

 09/2007 to 12/2009 (Japan)

RCT

Efficacy and safety of S-1 versus cisplatin +S-1 in patients with completely resected stage II and IIIA non–small cell lung cancer

Inclusion criteria:

· adults (20-74 yrs)

· completely resected NSCLC (stage II or IIIA, metastasis to a single mediastinal lymph node only)

· ECOG PS 0 or 1

· Adequate bone marrow and organ function

Exclusion criteria:

· drug allergies, interstitial pneumonia, concomitant malignancies

· heart failure, uncontrolled diabetes mellitus, and active infections.

· Pneumonectomy

n=200

median age: 62 years

males: 76%

IIA/B/III: 23/34/43 %

Adeno/Squamous/other carcinoma: 67/23/10%

Lobectomy: 100%

ND0-1 /ND2 lymph node dissection: 5/95 %

within 8 weeks after surger:

Longterm S-1 (40 mg/m² twice per day) for 2 consecutive weeks repeated every 3 weeks for 1 year (n=100)

vs.

Cisplatin/S-1 (60 mg/m²) d1 plus S-1 (40 mg/m² twice per day) for 2 consecutive weeks repeated every 3 weeks for four cycles (n=100)

Primary:

relapse-free survival (RFS) at 2 years and identification of predictive biomarkers* Secondary:

OS

rate of AEs  (NCI-CTC 3.0)

medical

treatment completion rate

relapse

*Not extracted

Feasibility:

· 52.6 % received 15 cycles of adjuvant CT vs. 74.7% completed four cycles of adjuvant CT as planned

· High median relative dose intensities (85.2 vs. 86.4 and 94.1%

Survival:

· Comparable 2-year RFS rate: 65.6% (95% CI 55.3–74.0%) vs. 58.1% (95% CI 47.7–67.2); HR 0.90 (95%CI 0.59–1.37).

· comparable 5-year OS rates: 72.6% (95% CI, 64.3–82.0) vs. 72.2% (95% CI, 63.8–81.7)

Safety:

· anemia or neutropenia (grade 3 or 4): lower in IG (anemia: 1.0% vs. 8.4% (p=0.018); neutropenia: 13.4% vs. 27.4% (p=0.02)

· nonhematologic toxicities (grade 3 or 4): anorexia (anorexia: 2.1 vs. 9.5%; p=0.032) and nausea (0 vs. 6.3%; p=0.014) were lower in IG

· but: more grade 1 or 2 skin rash with IG (26.8% vs.9.5; p=0.002)

· 17 vs. 18 deaths (not treatment related)

2b

Abwertung aufgrund von geringer Präzision und Indirektheit

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „In conclusion, this study suggests that adjuvant long-term S-1 monotherapy or CDDP+S-1 for completely resected stage II–III

NSCLC is a viable alternative to cisplatin doublet chemotherapy in terms of efficacy and toxicity. UMPS/OPRT expression may be a useful marker for identifying patients who would benefit most from adjuvant long-term S-1, although the fact that we did not adjust for multiple testing may limit the relevance of this finding. „

Schlussfolgerung der Begutachterin: Multizentrische, in Japan durchgeführte Phase II unter Einschluss von 200 Patienten mit NSCLC nach vollständiger Resektion (Grad IIA/B-IIIA) (daher Abwertung aufgrund von Indirektheit) mit adäquater Beschreibung der Randomisationgszuweisung, aber ohne verblindete Messpunkterhebung und ohne Zugriff auf das Protokoll (trotz Angabe der Registrierungsnummer) mit vollständiger Auswertung aller Patienten nach 2 Jahren zeigt Machbarkeit, Wirksamkeit und Sicherheit einer Langzeit-Monotherapie mit S-1 bei geringen Nebenwirkungen. Abwertung aufgrund von fehlender Präzision (geringe Fallzahl) und Indirektheit (43% der Patienten waren im Stadium III, Studie wurde vollständig in Japan durchgeführt).  Die Studie wurde von der West Japan Oncology Group unterstützt, mehrere Autoren berichten Interessenkonflikte (Forschungsförderung und Honorare durch pharmaceutische Firmen).

Kenmotsu 2017

(25)

03/2012-08/2016

Japan

RCT

efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous NSCLC

Inclusion criteria:

·       patients who underwent complete surgical resections by lobectomy or pneumonectomy with resection of any involved N2 lymph nodes within 3-8 weeks before enrollment.

·       patients were age 20-75 years with histologically confirmed pathologic stage II or IIIA nonsquamous NSCLC, proven results of the EGFR gene mutation test, ECOG 0 or 1, and adequate hematologic and organ function.

Exclusion criteria:

·  Severe postoperative complications, interstitial pneumonia on computed tomography of the chest, current pregnancy, and other severe comorbidity.

·  Patients who received neoadjuvant CT or had planned to receive EGFR tyrosine kinase inhibitors

n=804, 784 treated

males: 58.9 %

ECOG 0: 76.7 

IIA/IIB/IIIA: 33.9/13.8/52.3 %

Adenocarcinoma/others: 95.9/4.1 %

EGFR pos: 24.5 %

Lobectomy: 98.5 %

vinorelbine (25 mg/m², days 1 and 8) plus cisplatin (80 mg/m², day 1) (n=402, n=287 (71.4 %) completed treatment)

vs.

pemetrexed (500 mg/m², day 1) plus cisplatin (75 mg/m², day 1) (n=402 randomised, n=342 (85.0 %) completed treatment)

every 3 wks for 4 cycles

Primary: overall survival (changed to recurrence-free survival in an protocol amendment)

Secondary:  recurrence-free survival

rate of treatment completion

toxicity (NCI-CTC)

for up to 30 days beyond the last dose of any protocol treatment.

recurrence-free survival (RFS):

Disease recurrence or death in 53% vs. 51%

Median RFS: no difference: 37.3 months (95% CI 28.8 to 52.5) vs. 38.9 months (95% CI, 28.7 to 55.3 months), HR 0.98 (95% CI, 0.81 to 1.20),

With no differences depending on pathologic stge (stage IIIA:  1.05 (95%CI 0.82 to 1.34)

2-year RFS: 60.7% (95% CI, 55.7% to 65.3%) vs. 58.3% (95% CI, 53.2% to 63.0%)

3-year RFS: 50.2% (95% CI, 45.0% to 55.2%) vs. 51.1% (95% CI, 45.8% to 56.0%)

Overall survival (OS):

75 vs. 71 patients had died at time of analysis

Median OD: not reached, HR 0.98 (95% CI, 0.71 to 1.35)

3-year OS: 83.5% (95% CI, 79.2% to 87.0%) vs. 87.2% (95% CI,

83.8% to 90.2%)

Adverse events:

any grade AE: 100 vs. 99.7 %

grade 3-5 AE: 89.4% vs. 47.4%

Grade 3-4 febrile neutropenia: 11.6% vs. 0.3% (p<0.01)

Grade 3-4 WBC count decrease, neutrophil count decrease,

and anemia: 51.0%, 81.1 % and 9.3 % vs. 5.9%, 22.7% and 2.8% (p<0.01)

grade 4 WBC count decrease and neutrophil count decrease:  9.3% and 56.6% vs. 0.3% and 3.3%

One treatment-related death in each arm by sudden death and pneumonitis

1b-

Abwertung aufgrund von Indirektheit

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: “In conclusion, although the JIPANG study failed to show the superiority of pemetrexed plus cisplatin in terms of recurrence-free survival, toxicity profiles favored this regimen. Therefore, this combination can be an option for postoperative adjuvant chemotherapy in patients with completely resected nonsquamous NSCLC. The results of the JIPANG study indicate that the optimal platinum-based chemotherapy is still unclear in the adjuvant chemotherapy setting for resected nonsquamous NSCLC.”

Schlussfolgerung der Begutachterin: Multizentrische, in Japan durchgeführte Phase III unter Einschluss von 904 Patienten mit NSCLC (Grad II-IIA, >50 % im Grad IIIA) nach vollständiger Resektion mit Ergebnissen zum Grad IIIA für das krankheitsfreie Überleben mit adäquater Beschreibung der Randomisationgszuweisung, aber ohne verblindete Messpunkterhebung und ohne Zugriff auf das Protokoll mit vollständiger Auswertung aller behandelten Patienten (98%) zeigt keinen Unterschied in der Wirksamkeit, aber eine geringere Toxizität in der Gruppe mit Pemetrexed und Cisplatin, keine Abwertung der Evidenz aufgrund von Indirektheit (Studie wurde vollständig in Japan durchgeführt, Ergebnisse entsprechen denen der deutschen Studie).  Die Studie wurde von der West Japan Oncology Group, Pharma-Valley Center und der Japan Agency for Medical Research and Development unterstützt, mehrere Autoren berichten Interessenkonflikte (Forschungsförderung und Honorare durch pharmaceutische Firmen).

Kreuter 2014

(26-28)

(TREAT study)

NCT00349089

10/2006 to 12/2009

Deutschland, Belgien und Luxemburg

RCT

feasibility of a protocol with reduced toxicity might improve feasibility of postoperative delivery of adjuvant chemotherapy drugs in NSCLC, to improve compliance and survival

Inclusion criteria:

· adults (≥18,

·  histo-pathologically confirmed NSCLC (stage IB, IIA, IIB or T3N1) without need for further radiotherapy and R0 resection and removal of mediastinal lymph nodes > 1,5 cm on the preoperative CT sca

· full recovery after surgery

· Karnovsky performance ≥ 80%, ECOG 1

Exclusion criteria:

· Presence of a Pancoast tumor

· Involvement of N2/N3 lymph nodes

· Distant metastases

n=132

age: 59 (38-74) years

26% females

29% smoker

66% ex-smoker

83% lobectomy, 14% pneumenectomy, 3% complex resections

Stage IB/IIA/IIB/T3N1: 38/10/47/5 %

COPD (I/II/III): 23/13/2%

under therapy with bronchodilators: 28%

4-6 weeks postoperative:

Cisplatin(75 mg/m² d1; q d22) and Pemetrexed (500 mg/m² d1)

with vitamin-supplemen-tation

(folic acid, vitamin B 12 ) and dexamethasone (4 mg of oral or

equivalent, twice daily the day before, the day of and the day after each dose of pemetrexed for rash prophylaxis, unless medically

contraindicated)

(n=67)

vs.

Cisplatin (50 mg/m² d1, 8; q d29) and Vinorelbine (25 mg/m² d1, 8, 15, 22; q d29) (n=65)

for 4 cycles

Primary:

feasibility of 4 cycles of adjuvant CT (no death due to cancer, toxicity, or comorbidity; no non-acceptance by the patient leading

to premature withdrawal; and no DLT

Secondary:

drug delivery, time to treatment failure, distant metastases free survival, local RFS, OS, localization of relapse, dose delivery, RFS

safety: NCICTC version 3.0

Feasibility:

90 % vs. 66 % of the planned doses were given

Tumor relapse and relapse-free survival (RFS):

· Relapse in 31 % vs. 36 %

· RFS: medians not reached, very similar 3-year RFS rates (59 vs. 60%), no difference in RFS: HR 0.831 (95% CI: 0.317–2.177); p=0.707)

· More patients with local relapses in IG (18% vs. 5%), with most being mediastinal lymph node metastases in IG

· no differences in  rates of distant relapse (20.9% versus 18.5%).

· More frequent brain metastases in IG (75% vs. 21%)

· no difference in local RFS and distant metastasis–free survival

Deaths and Overall survival:

27% vs. 26% of patients died with comparable between groups, 17% due to tumor relapse (18% vs. 15%), 5% unrelated to therapy or tumor (5% in each arm), and 5% unknown.

no differences in death by resection type: 83% of the patients received a lobectomy, with death rates of 22% in both arms, and 14% of patients received a pneumonectomy, with a death rate of 4% (5 vs. 3%)

no differences on OS, medians not reached vs 59 months; (HR 0.594; 95% CI 0.165–2.131, p=0.424);

Toxicities:

generally mild, no grade 3/4 toxicity

most frequent pulmonary toxicities: grade 1/2 cough (13.4% vs. 7.7%) and dyspnoe (9% vs. 4.6%)

Pneumonia noted in 1 vs. 0 patients, bronchitis in 1 patient in each arm, no COPD exacerbations reported.

2b

Abwertung aufgrund von Studienlimitationen, geringer Präzision und Indirektheit

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: “In conclusion, the present study provides evidence that adjuvant chemotherapy does not have a negative effect on pulmonary function. However, a non-significant difference between D LCO decline in different therapy arms warrants further study.“(28)

“Although adjuvant chemotherapy with CPx is safe and characterized by less toxicity and better dose delivery than CVb, overall survival was not influenced by treatment arm in the context of this phase II trial.”(26)

Schlussfolgerung der Begutachterin: Multizentrische, in Deutschland, Belgien und Luxemburg durchgeführte Phase II unter Einschluss von 132 Patienten mit NSCLC nach vollständiger Resektion (Grad IB-T2N1) ohne adäquater Beschreibung der Randomisation (trotz veröffentlichtem Protokoll) und ohne Verblindung (daher Abwertung aufgrund von Studienlimitationen) zeigt Machbarkeit und Sicherheit einer Therapie mit Cisplatin und Pemetrexed bei geringen Nebenwirkungen. Trotz vollständigerer Therapie konnten keine Unterschiede hinsichtlich des Überleben und Anzahl der Rückfälle zwischen den Interventionsgruppen gezeigt werden.Abwertung aufgrund von fehlender Präzision (geringe Fallzahl) und Indirektheit (5% der Patienten waren im Stadium T3N1, 38% im Stadium IB und 57% im Stadium II).

Okamoto 2018

(29)

2009-2013

Japan

RCT

efficacy

and safety of S-1 versus cisplatin + S-1, followed by S-1 in patients with completely resected stage IB-III NSCLC

Inclusion criteria:

· adults (20-75 yrs)

· completely resected NSCLC (stage IB, II or III)  

· ECOG PS 0 or 1

· No previous CT or RT

· Adequate bone marrow and organ function

Exclusion criteria:

· drug allergies, cardiac infarction

· uncontrolled diabetes mellitus, problematic infections. Interstitial pneumonia, concomitant malignancies

n=141

mean age: 62.7±7.8 years

males: 76%

PS 0/1: 76/24%

Smoking history: 81%

IIA/B/IIIA: 31/26/42 %

Adeno/Squamous/large/other carcinoma: 63/28/3/6 %

Lobectomy: 92%

Pneumonectomy: 8%

within 8 weeks after surger:

Longterm S-1 (80 mg/m² oral) for 2 consecutive weeks repeated every 3 weeks for 1 year (n=100)

vs.

S-1 (80 mg/m² oral) for 3 consecutive weeks +  Cisplatin (60 mg/m²) d8

repeated every 5 weeks for four cycles, followed by  Longterm S-1 (80 mg/m² oral) for 2 consecutive weeks repeated every 3 weeks for 1 year (n=100)

Primary:

disease-free survival (DFS) at 2 years

Secondary:

OS

Safety

feasibility

Survival:

· Comparable 2-year DFS rate: 52 % (95% CI 40-63) vs. 61% (95% CI 48-70); HR 1.37 (95% CI 0.88–2.13).

· comparable OS: HR 0.94 (95% CI 0.48-1.85)

Safety:

· no significant differences in occurance of grade 3-4 AEs

· main grade 3-4 AEs: appetite loss: 4.3 vs. 11.6 %, decreased neutrophil count (5.7 vs. 10.1% and anemia ( 0vs. 5.8 %)

· no treatment related deaths

Feasibility:

· no differences in treatment completion: 45.7 % (95% CI 41.9-66.3) vs. 43.5 % (95%CI 44-69.4)

2b

Abwertung aufgrund von geringer Präzision und Indirektheit

 Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „In conclusion, long-term adjuvant chemotherapy with S-1 was a feasible and promising treatment for patients with completely resected NSCLC, regardless of whether cisplatin was added. We recommend that S-1 monotherapy should be investigated further owing to its low toxicity and practical convenience.“

Schlussfolgerung der Begutachterin: Multizentrische, in Japan durchgeführte Phase II unter Einschluss von 141 Patienten mit NSCLC nach vollständiger Resektion (Grad IIA/B-IIIA) (daher Abwertung aufgrund von Indirektheit) mit adäquater Beschreibung der Randomisationgszuweisung, aber ohne verblindete Messpunkterhebung und Hinweise auf ein veröffentlichtes Protokoll mit vollständiger Auswertung aller Patienten zeigt Machbarkeit, Wirksamkeit und Sicherheit einer Langzeit-Monotherapie mit S-1 bei geringen Nebenwirkungen. Abwertung aufgrund von fehlender Präzision (geringe Fallzahl) und Indirektheit (42 % der Patienten waren im Stadium III, Studie wurde vollständig in Japan durchgeführt).  Die Studie wurde mit öffentlichen Fördergeldern unterstützt, 2 Autoren einer großen Gruppe berichten Interessenkonflikte (Forschungsförderung und Honorare durch pharmaceutische Firmen).

AE: Adverse event; CG: Control group; CI: Confidence interval; CRT: Chemo-radiotherapy; CT: Chemotherapy; CTCAE: Common Terminology Criteria for Adverse Events;  d: Tag; DCR: Disease control rate; DFS: Disease-free survival; DLT: dose-limiting toxicity; ECOG: Eastern Cooperative Oncology Group; FACT-L: Functional Assessment of Cancer Therapy-Lung; GHS: Global health scores; HR: Hazard ratio; IG: Intervention group; LCS: Lung Cancer Symptom Scale; N: Number of studies; n: Number of participants; NCI CTCAE: National Cancer Institute Common Toxicity Criteria; NR: not reached; NSCLC: Non-small cell lung cancer;  OR: Odds Ratio; OS: overall survival; PFS: Progression-free survival; PSI: Pulmonary Symptom Index; QoL: Quality of life; RECIST: Response Evaluation Criteria in Solid Tumors; RCT: Randomized controlled trial; RFS: Relapse-free survival; RoB: Risk of bias; RR: Relative Risk; RT: Radiotherapy; SAE: Serious adverse event;TTF: Time to treatment failure;  wks: weeks; yrs: years