Neoadjuvante Chemotherapie NSCLC Stadium II/III

Anderson 2017

(37)

USA (National Cancer Database)

2006-2011

Retrospective cohort study with Propensity score  adjustment

Impact of induction therapy prior to an operation in patients with cT3 NSCLC  on survival and subsequent surgical resection

Inclusion criteria:

·  Adult patients with a single, primary cancer diagnosis of NSCLC who underwent surgical resection

·  tumour sizes > 7 cm (cT3), no clinically positive lymph nodes (cN0) and no signs of distant metastases (cM0) (7^th edition AJCC)

·  cT2, tumour size >7cm (6^th edition AJCC)

Exclusion criteria:

patients with T4 (invasion into surrounding structures) tumours, N1, N2 or N3 nodal disease status or with distant metastases

n=3819, 1749 matched and analysed

age: 61 (IQR 53-68)

males: 56.9 %

white: 89.3 %

Charlson-Deyo score (0/1/2): 65.1 / 25.2 /9.8 %

Tumor size: 63 (38 -80)

cT stage (2/3): 11.2/88.8 %

pT stage (0/1/2/3/4/X): 3.6/5.2/20.5/58/2.3/7.8 %

pN stage (0/1/2/3/X): 75.1/13.1/4.5/0/7.2 %

days to definitive surgery: 49 (IQR 23-108)

adjuvant RT: 13.4 %

adjuvant CT: 41.5 %

lobectomy: 81.5 %

surgery (VATS/ Converted/Open): 14.3/6.3/79.4 %

Induction CT and. surgical resection (lobectomy or pneumonectomy) (n=583)

vs.

surgical resection alone (n=3236, 1166 matched)

Primary: Overall survival

Secondary:

30- and 90-day mortality rates

30-day readmission rates surgical margin status

number of lymph nodes removed

hospital length of stay

Confounder adjustment (propensity score matching) for age, gender, race, Charlson-Deyo Comorbidity Index score, treatment facility type, education quartile, income quartile, insurance status, tumour size, AJCC pathological T and N stages and use of adjuvant CRT

predictors of induction cCT:

·     older patients (OR 0.67; 95%CI 0.61 to 0.75), with a higher Charlson-Deyo score ( 1 vs. 0: OR 0.61; 95%CI 0.50 to 0.76, ≥ 2 vs. 0: OR 0.70; 95 % CI 0.52 to 0.95) and Medicare/Medicaid insurance ( OR 0.8; 95 % CI 0.65 to 1.0) were less likely to receive induction therapy prior to operative resection

·     with confounder adjustment: patients who underwent induction CT were more likely to have a lower pathological T stage and less likely to have a lower pathological N stage (both p-values < 0.001).

Treatment (with confounder adjustment):

Patients who underwent induction CT

·     had a longer time to surgery (121 (IQR 99-147) vs. 30 (IQR 15-51) days

·     were less likely to receive adjuvant radiation (6.9% vs 16.7%) chemotherapy (13.6% vs 55.5%, both p-values < 0.001).

·     were more likely to undergo an open operative approach (87.3% vs 77.8%, p= 0.005)

Surgical results (with confounder adjustment):

·     Patients with induction therapy were less likely to have positive surgical margins (386 events): 6.7% vs 10.0%, p = 0.04),

·     R0: 90.3 vs. 90 %, R1: 2.7 vs. 5.2 %

·     no differences in removed nodes (9 (IQR 4-17) vs. 10 (IQR 6-17)

Hospital Length of stay: no difference (6 vs. 6 days

Mortality and readmission (with confounder adjustment):

·     Similar short-term outcomes of 30-day mortality (2.6 vs. 1.5%, p = 0.15) and 30-day readmission rates (4.5% vs 4.5%, p = 0.99)

·     Higher 90-day mortality (6.6 vs. 3.4 %, P = 0.003) with induction

·     similar overall 5-year survival: 49.3 vs. 52.5% (p = 0.116) .

2b

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „Despite yielding increased rates of R0 resection, induction chemotherapy for cT3N0M0 NSCLC is not associated with improved survival and should not be considered routinely. Further studies are warranted to elucidate cohorts that may benefit from induction therapy.”

Schlussfolgerung der Begutachterin: Retrospektive Auswertung der in der US-amerikanischen National Cancer Datenbank gespeicherten Daten aller in den Jahren 2006 bis 2011 behandelten Patienten mit NSCLC im Stadium cT3. Es erfolgte ein Propensity-Score Matching mit dem Ziel der Vergleichbarkeit der Gruppe mit und ohne Induktionstherapie für alle vorliegenden und prognostisch als relevant erachteten Variablen (age, gender, race, Charlson-Deyo Comorbidity Index score, treatment facility type, education quartile, income quartile, insurance status, tumour size, AJCC pathological T and N stages and use of adjuvant CRT) und anschließende Auswertung von Daten von 1749 Patienten, von denen 583 mit Induktionschemotherapie behandelt wurden. Die Datenerhebung basiert auf vorliegenden Krankenakten. Auch nach dem Matching wurde ein geringeres pT-Stadium und ein höheres N-Stadium häufiger bei Patienten mit Induktionstherapie festgestellt. Auch wenn Patienten nach Induktionstherapie seltener positive Operationsränder aufwiesen, konnte kein langfristig besseres Überleben nachgewiesen werden. Zu beachten ist, dass das Überleben mit dem Zeitpunkt der Diagnose beginnt und Patienten in der Gruppe mit Induktionstherapie später operiert wurden, so dass die Therapie insgesamt länger dauerte.

Eberhardt 2015 (ESPATUE)

(35)

01/2004 to 01/2013, mainly in Germany

RCT

Efficacy of a definitive concurrent CRT boost in patients after a complex induction protocol

Inclusion criteria:

· pathologically proven NSCLC stage IIIA (N2) or selected IIIB disease withmedical/functional operability

· ECOG 0 or 1,

· Diagnosis, adequate renal, hepatic, and hematologic functions

n=246

72% males

≥ 60 yrs: 47 %

ECOG 0/1/2: 69/30.5/0.5 %

Histology (adeno, squamous cell, large cell/mixed or other carcinoma): 43.5/38.5/9/9 %

Tumour node (T4, N0 or N1/ T1-3, N2/T1-4; N3 or T4, N2): 32.4 / 30.5 / 37 %)

Stage IIIA/IIIB: 30.5/69.5 %

Induction CT (3 cycles cisplatin 50 mg/m² d 1, 8 + paclitaxel 175 mg/m² d1 every 21 days)+ neoadjuvant CRT (to 45 Gy given as 1.5 Gy twice daily, concurrent cisplatin 50

mg/m² d 2, 9 + concurrent vinorelbine 20 mg/m² d 2, 9)

Patients whose tumors were reevaluated and deemed resectable in the last week of RT:

CRT boost (n=80)

(risk adapted between 65 and 71 Gy)

vs.

surgery (n=81)

Primary: OS

Secondary: PFS

over a median follow-up of 78 months

Treatment compliance:

N=246 recruited, 237 induction CT as planned, and 227 CRT according to the protocol, 161 (65.4%) were randomized, 66/80  (82.5 %) received the assigned, planned boost CRT and 70/81 (86.4 %)received surgery with R0 resection in 66/3 and 1 patients

Surgical results (only reported for IG):

70 patients (86.4 %) received surgery,

R0: 94.3 %

R1/R2: 4.3/0.01 %

Overall survival:

· 47 vs. 43 deaths with no differences between groups (p=0.34)

· 5-year-OS:  40% (95% CI, 29% to 52%) vs. 44% (95% CI, 32% to 56%)

Progression-free survival:

· 47 vs. 43 deaths and 6 vs. 12 progressions without death vwith no differences between groups (p=0.75)

5-year-PFS:  35% (95% CI, 25% to 46%) vs. 32% (95% CI, 22% to 43%)

Toxicities:

· All toxicities (grade 3/4) were not unexpected and could be considered acceptable, most common (all grade 3/4):

-    Leukopenia: 44/16 vs. 49/11 %

-    Anemia: 9/0 vs. 12/0  %

-    Thromocytopenia: 8/3 vs. 10/1 %

-    Nausea/vomiting: 9/0 vs. 12/0 %

-    Neuropathy: 6/0 vs. 6/0 %

-    Esophagitis: 26/0 vs. 14/0 %

-    Fatique: 10/0 vs. 6/0 %

-    Pain: 20/0 vs. 23/0 %

· Deaths ((probably therapy-related reasons):

-     2 patients before random assignment

-    7 patients after random assignment:

-    2 in IG (1 from pneumonia after neutropenia, 1 after pneumonia and multiorgan failure) vs.

-    5 in CG (3 as a result of lung bleeds, 2 after pneumonia and empyema, all > 30 days after thoracotomy)

1b-

Abwertung aufgrund geringer Präzision

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „In conclusion, both trimodality treatment that includes surgery and bimodality treatment without surgery but with a definitive chemoradiotherapy boost lead to excellent long-term OS and PFS. In our patients,who included those with resectable stage IIIA(N2) or selected stage IIIB NSCLC, we observed 5-year OS rates greater than 40%, an acceptable toxicity profile, and moderate treatment-induced events when performed in high-level multimodality treatment centers.”

Schlussfolgerung der Begutachterin: Methodisch gute multizentrische deutsche RCT unter Einschluss von 246 potentiell resektabler NSCLC, Stage III-Patienten, von denen 161 randomisiert einer zusätzlichen CRT-Boosttherapie vs. Placebotherapie zugeordnet wurden. Es existiert keine Beschreibung einer verblindeten Endpunkterhebung und der öffentlichen Registrierung eines Studienprotokolls. Die Studie wurde aufgrund der langsamen Rekrutierung vorzeitig beendet (geplant war die Randomisierung von 300 Patienten, daher Abwertung aufgrund geringer Präzision) ohne nachgewiesene Unterschiede für OS und PFS, Finanzierung der Studie durch die Deutsche Krebshilfe, Interessenkonflikte der Autoren können nicht ausgeschlossen werden.

Luo 2017

(32)

Search from 01/1994 to 12/2015

Systematic Review

Effect of induction CT on survival outcomes of patients with NSCLC

Inclusion criteria:

publications that studied survival outcomes in NSCLC patients treated with induction chemotherapy and concurrent CRT  

Exclusion criteria: noninduction CT, articles with no control group, a lack of data sufficient for OR determination, and non-English language studies

Search in 4 databases

N=7 with n=1143 patients: 5 RCTs and 2 retrospeczove cohort studies

Stages:

N=2 with IIA/IIB-IIIB and N=5 with IIIA/IIIB patients

Induction chemotherapy and concurrent CRT (N=7)

vs. concurrent CRT alone (N=2)

or concurrent CRT followed by consolidation CT (N=5)

N=4 trials investigated cisplatin-based CT (taxane, etoposide, gemcitabine, vinorelbine, and docetaxel)

N=2 trials investigated carboplatin combined with paclitaxel CT,

N=1 trial on gemcitabine with docetaxel

Median follow-up : 3.3 years

Survival

Induction CT followed by concurrent CRT versus concurrent CRT alone

Overall survival (N=2, n=596):

·    No differences shown for 1-year OS (OR 2.07; 95 %CI 0.64 to 6.69), 2-year OS (OR 1.42; 95 %CI 0.85 to 2.35), 3-year OS (OR 1.42; 95 %CI 0.98 to 2.08), 4-year OS (OR 1.97; 95 %CI 0.91 to 4.26) with substantial heterogeneity between studies for 1 and 4.year OD (I²= 89 % and 67 %) 

·    Longer OS with induction CT at 5-year OS (OR 1.98; 95 %CI 1.24 to 3.17) with small heterogeneity between studies (I²=0 %)

Induction chemotherapy followed by concurrent CRT versus  concurrent CRT followed by consolidation CT:

Overall survival (N=5, n=547):

·    No differences shown for 1-year OS (OR 1.09; 95 %CI 0.77 to 1.54), 2-year OS (OR 1.05; 95 %CI 0.74 to 1.49) and 3-year OS (OR 0.99; 95 %CI 0.67 to 1.46) with small heterogeneity between studies (I²= 26 %, 0 % and 23 %)

·    No differences shown for 4-year OS (OR 1.12; 95 %CI 0.52 to 2.42) and 5--year OS (OR 0.84; 95 %CI 0.33 to 2.18) with moderate heterogeneity between studies (I²= 48 and 59 %) 

Overall response rate (N=5, n=547):

No differences shown (OR 1.25; 95%CI 0.86 to 1.83) with no heterogeneity (I²=0 %) between studies

Adverse effects (grade III/IV) :

·    No differences shown for esophagitis: 16 vs. 21 % (OR 0.71; 95 %CI 0.46 to 1.11), thrombocytopenia: 6.4 vs. 9.4  (OR 0.66; 95 %CI 0.33 to 1.30) and radiation pneumonitis : 4 vs. 7.7 % (OR 0.49; 95 % CI 0.23 to 1.06)

·    Less leucopenia: 26 vs. 44 %; OR 0.43; 95 %CI 0.30 to 0.62), all with low heterogeneity between studies

·    No significant difference in the number of treatment-related severe pulmonary, neurological, infection, cardiovascular, liver, and renal toxicity was observed between the 2 modalities.

2a-

Abwertung aufgrund von Studien-limitationen, geringer Präzision und Indirektheit

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „In conclusion, published evidence is limited but does support the inclusion of induction chemotherapy for locally advanced NSCLC to achieve long-term survival. Both induction chemotherapy and consolidation chemotherapy are efficient for patients of locally advanced NSCLC who treated by  concurrent CRT, given the potential toxicities of adding consolidation chemotherapy to concurrent CRT, clinicians should consider using this treatment strategy only in the context of a clinical trial to allow better assessment of its effectiveness.”

Schlussfolgerung der Begutachterin: Systematische Übersicht, moderate  Einschränkung der Qualität (kein Protokoll, keine Informationen zum doppelten Screenen, keine Bewertung des Verzerrungspotentials, keine Subgruppenanalysen), basiert auf 7 Studien (5 randomisierten Studien und 2 retrospektiven Studien) mit Daten von 1143 Patientendaten von 2358 Patienten mit resektablen NSCLC (5 Studien schlossen nur Stadium III ein, andere ab Stadium IIA bzw. IIB, alle Studien schließen bis Stadium IIIB ein, so dass Resktabilität nicht klar ist, daher Abwertung aufgrund von Indirektheit), Verzerrungspotential basiert vorrangig auf retrospektivem Design in 2 Studien mit Vergleichsgruppen ohne Konsolidierungstherapie und Einschränkungen der systematischen Übersicht (daher Abwertung aufgrund von Studienlimitationen) und fehlender Präzision der Ergebnisse, aufgrund derer (nahezu) keine Unterschiede zwischen den Gruppen gezeigt werden konnten.

NSCLC 2014

(33)

Search until 05/2013

Systematic Review

Effect of preoperative chemotherapy for patients with resectable NSCLC

Inclusion criteria:

· RCTs comparing CT with subsequent surgery versus surgery alone

· started 12/1964 including CT-naive NSCLC patients, suitable for surgery, without any previous malignancy

· Trials that planned to use postoperative RT in both arms or postoperative CT in the preoperative arm

· Published and unpublished trials with no language restrictions

N=19 RCTs, individual patient data were eligible for 15 RCTs with n=2358 patients with low risk of bias

80% males

median age: 62 (IQR 55-68) yrs

88% with PS 0 or 1

IB-IIB: 70%

IIIA: 23%

IIIB: <1%

IV: <1%

Predominatelly squamous carcinoma: 50% or adenocarcinoma (29%)

Risk of bias: Early stop in 12 RCTs, small trials with

extreme positive and negative estimates seem to strongly aff ect this result

CT and subsequent surgery

(with or without postoperative RT and CT)

vs.

Surgery

(with the same postoperative RT and CT)

N=10 with only pre-operative CT, 5 RCTs with post-operative CR usually to responders

N=7 with cisplatin, N=4 with carboplatin, N=3 with cisplatin or carboplatin, N=1 with docetaxel

N=8 with postoperative RT

Primary:

Overall survival

Secondary:

recurrence-free survival

time to locoregional and distant recurrence (from 6 months after randomization)

cause-specific survival

complete and overall resection rates

postoperative mortality

Overall survival (N=15, 2385 patients, 1427 deaths):

· benefit of preoperative chemotherapy (HR 0.87, 95% CI 0.78–0.96; p=0.007) with an improvement in 5-year survival at 5 years (from 40% to 45%), for stage III from 20 to 25%

· Only small heterogeneity between results (I²=25%) despite a variety of CT regimens, exclusive use of preoperative CT,  use of postoperative RT in both arms, and inclusion of all stages or only a specific stage of patient

· No evidence for significant different effects , but

-    Slightly larger effects for younger patients,

-    patients with better oerformance status,

-    lower clinical stage

-    for males

-    patients with adenocarcinoma

· slightly larger relative effect if postoperative CT is given to  responders (HR 0·78, 95% CI 0·64–0·95) vs. preoperative chemotherapy alone (HR 0·94, 95% CI 0·75–1·18)

· 30-day / 6 months-mortality ( 9/15 RCTs, 1611/2381 patients, 52/254 deaths) after surgery: no difference between groups

Resection (N=11, n=1778):

· 4 RCTs with 100% resection in both arms

· No reliable analysis possible for the remaining trials

· No influence of preoperative CT on complete resection shown

Recurrence-free survival (14 RCTs, 2326 patients, 1524 events):

· benefit of preoperative CT (HR 0·85, 95% CI 0·76–0·94, =0·002) with no substantial heterogeneity

· absolute improvement in RFS of 6% at 5 years (from 30% to 36%).

· greater relative benefit on time to recurrence in trials with postoperative CT (HR 0·53, 95% CI 0·39–0·73, p<0·001) vs. only preoperative CT (HR 0·78, 95% CI 0·63–0·96, p=0·02).

Time to locoregional and distant recurrence (13 RCTs, 1913 patients, 426 and 526 events):

· benefit of preoperative CT on time to distant recurrence (HR 0·69, 95% CI 0·58–0·82) with no substantial heterogeneity between studies and resulting absolute improvement of 10% at 5 years (from 60% to 70%).

· no influence stated on time to locoregional recurrence (HR 0·88, 95% CI 0·73–1·07; p=0·20

1a-

Abwertung aufgrund von Studien-limitationen

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „Findings, which are based on 92% of all patients who were randomised, and mainly stage IB–IIIA, show preoperative chemotherapy signifi cantly improves overall survival, time to distant recurrence, and recurrencefree survival in resectable NSCLC. The fi ndings suggest this is a valid treatment option for most of these patients. Toxic eff ects could not be assessed.“

Schlussfolgerung der Begutachterin: Systematische Übersicht, geringe Einschränkung der Qualität (fehlendes Flussdiagramm), basiert auf 15 randomisierten Studien mit verfügbaren ondividuellen Patientendaten von 2358 Patienten mit resektablen NSCLC (ca. 23% im Stadium III), Verzerrungspotential basiert vorrangig auf ungeplantem Studienabbruch in 12 Studien, es konnte ein Einfluss von extrem kleinen Studien mit extrem positiven und negativen Ergebnissen gezeigt werden (daher Abwertung aufgrund von Studienlimitationen). Es wird die Wirksamkeit von neoadjuvanten Chemotherapien vor der Operation auf das Überleben und die Rekurrenz gezeigt, es fehlen jedoch Ergebnisse zur Sicherheit (Auftreten von Nebenwirkungen der Therapie).

Ma 2019

(36)

05/2013-05/2017

China

RCT

effect of docetaxel plus cisplatin preoperative neoadjuvant CT in stage III NSCLC

Inclusion criteria:

· confirmed stage IIIA NSCLC

· age < 70 years and karnofsky performance status score ≥ 70

· no distant metastasis

Exclusion criteria:

· patients with severe heart, liver, and kidney disease

· those who had undergone CRT

n=82

57 % males

Age: 42-69 (57.04 ±2.63) yrs

Weight:  45-68 (61.57 ±1.86) kg

63.4% squamous cell carcinoma, 29.3 % adenocarcinoma, 7.3 % of adenosquamous carcinoma

neoadjuvant chemotherapy (n=41)

(docetaxel iv,  75 mg/m2 d1 +cisplatin, 25 mg/m2 d2,5

over 3 weeks with a total of 2 courses+ surgery (3 weeks after the end of CT)

vs.

surgery (n=41)

after preoperative examination.

Surgical resection rate

operative time

intraoperative blood loss

1-yr OS

surgical resection rate:

higher with IG: 97.6 vs. 80.5 % (p=0.013)

Operation time:

shorter with IG: 109.4 ±17.4 vs. 148.2± 23.5 min (p<0.001)

intraoperative blood loss:

lower with IG: 498.2±31.6 vs. 602.8±51.6 ml (p<0.001)

Overall survival:

Higher 1-year survival with IG: 95.1 vs. 78 % (p=0.023)

Toxicities:

· No treatment-related death in both groups

· No allergic reaction and peripheral neurotoxicity during the treatment

· Main adverse reactions: radiation esophagitis, radiation pneumonia and leukopenia (all grade I-II)

· no grade III-IV adverse reactions occurred

2b

Abwertung aufgrund geringer Präzision und Indirektheit

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „In conclusion, presurgical treatment with docetaxel and cisplatin can play a synergistic role, and it is feasible to treat stage III NSCLC.“

Schlussfolgerung der Begutachterin:  Monozentrische chinesische RCT (daher Abwertung aufgrund eingeschänkter Übertragbarkeit) unter Einschluss und Randomisierung von 82 NSCLC-Patienten im Stadium III (aufgrund der Anzahl Abwertung wegen fehlender Präzision). Es existiert keine Beschreibung der verblindeten Zuweisung der Behandlung, verblindeten Endpunkterhebung oder Registrierung eines Protokolls mit Nachweis von relevanten Unterschieden in Operationszeit, Resektionsrate, Blutverlust und Gesamtüberleben, ohne exakte Angaben zu Toxizitäten und Finanzierung der Studie, es werden keine Interessenkonflikte der Autoren berichtet

Speicher 2016

(38)

USA (National Cancer Database)

2006-2011

2 publications with slightly differing numbers, but similar results

Retrospective cohort study with Propensity score  adjustment

Impact of induction therapy in patients with cT1-T3 N1 M0 NSCLC  on survival

Inclusion criteria:

·       Patients diagnosed with clinical T1-3 N1 M0 NSCLC

·       treated with lobectomy or pneumonectomy

·       Patients treated with postoperative CT  were included regardless of whether postoperative RT was used

Exclusion criteria:

·       Sublobar resections

·       patients with a previous cancer diagnosis or missing information regarding use of CT or clinical nodal status

·       Patients who received preoperative RT without preoperative CT

n=5364, 1695 matched and analysed, predictors of IT are listed under results

Induction CT and surgical resection (n=565)

vs.

surgical first (n=4799, 1130 matched)

Survival

Confounder adjustment (propensity score matching) for patient age, sex, race, Charlson/Deyo Comorbidity Score, clinical T stage, extent of resection required (pneumonectomy vs lobectomy), and treatment facility type (academic or community hospital)

predictors of induction CT:

·  younger patients (OR 0.77; 95%CI 0.69 to 0.85), with a lower comorbidity burden (Charlson-Deyo score: 1 vs. 0: OR 0.63; 95%CI 0.51 to 0.78, ≥ 2 vs. 0: OR 0.61; 95 % CI 0.44 to 0.85), a private insurance and higher education

·  patients with T2 tumors (vs. T1: OR 1.78; 95 %CI 1.40 to 2.27) and T3 tumors

Treatment (with confounder adjustment):

Patients who underwent induction CT

·    had a longer time to resection (125 (105 to 153) vs. 32 (16 to 50) (38),

·    were less likely to receive adjuvant RT (13.5 vs. 16.6 %), CT (16.1 vs 59.7 %)

Surgical results (with confounder adjustment): no differences in

·    extent of resection: Locectomy: 76.6 vs. 74.5 % and pneumonectomy: 23.5 vs. 25.5 %,

·    surgical approach: VATS: 14.2 vs. 14.3 %, Converted: 7.1 vs. 6.3 %, Open: 78.7 vs. 79.5 %,

·    removed nodes: 11 (6-20) vs. 12 (7 to 19)

·    positive margins: 9.4 vs. 9.5 %

·    Surgical margins: R0: 90.6 vs. 90.5 %

·    R1/R2: 4.7 / 0.4 vs. 4.9/0.4 %

·    Positive not otherwise specified: 4.3 vs. 4.1 %

Hospital Length of stay: 6 (4 to 8) days with no differences between groups

Mortality and readmission (with confounder adjustment):

·     Similar short-term outcomes of 30-day mortality (3.2 vs. 2.5%, p = 0.47) and 30-day readmission rates (5.5 vs 3.7 %, p = 0.11) and 90-day mortality (6.6 vs. 4.0 %, p = 0.19)

similar overall survival (p=0.525):

1-year survival: 86.5 vs. 84.9 %

5.year survival: 45.6 vs. 49.0 %

Median survival: 47.4 vs. 56.1 months

patients with tumors >4 cm (with confounder adjustment):

no differences in survival (p=0.892)

1-year survival: 84.6 vs. 82.3 %

5.year survival: 42.1 vs. 46.1

Median survival: 46.9 vs. 50.9 months

Patients with T3 tumors (with confounder adjustment):

no differences in survival (p=0.323)

1-year survival: 83.1 vs. 80.3 %

5.year survival: 45.0 vs. 43.4 % (p=0.32)

Median survival: 48.2 vs. 51.7 %

2b

Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „Induction chemotherapy for cN1 NSCLC is not associated with improved survival. This finding supports the currently recommended treatment paradigm of surgery first for cN1 NSCLC.”

Schlussfolgerung der Begutachterin: Retrospektive Auswertung der in der US-amerikanischen National Cancer Datenbank gespeicherten Daten aller in den Jahren 2006 bis 2011 behandelten Patienten mit NSCLC im Stadium cT1-T3 N1. Es erfolgte ein Propensity-Score Matching mit dem Ziel der Vergleichbarkeit der Gruppe mit und ohne Induktionstherapie für alle vorliegenden und prognostisch als relevant erachteten Variablen (patient age, sex, race, Charlson/Deyo Comorbidity Score, clinical T stage, extent of resection required and treatment facility type) und eine anschließende Auswertung von Daten von 1695 Patienten, von denen 565 mit einer Induktions-Chemotherapie behandelt wurden. Die Datenerhebung basiert auf vorliegenden Krankenakten. Es konnte weder für die Operationsergebnisse noch für das Überleben ein Vorteil für Patienten nach Induktionstherapie nachgewiesen werden. Dieses Ergebnis gilt sowohl für alle eingeschlossenen Patienten als auch für die in Subgruppen untersuchten Patienten mit großen Tumoren bei Diagnose (>4 cm) und Patienten mit T3 Tumoren.

Zhang 2017

(34)

Search period not named (last included study from 2013)

Systematic Review

Comparision of neoadjuvant CT by surgery with upfront surgery  in efficacy and safety among nonmetastatic NSCLC patients

Inclusion criteria:

· RCTs on pathologically diagnosed non-metastatic NSCLC patients (NCCN)

· comparison of neoadjuvant CT and surgery and surgery alone or

· RCTs comparing neoadjuvant CT with upfront surgery

· Patients with no age, sex and racial limitations, naive for CT and CRT in good condition to receive surgery, regardless of the chemotherapeutic regimen and dose, surgical procedure and tumor stage

Exclusion criteria:

· RCTs with only 1 arm receiving postoperative therapy

· RCTs on patients with other pulmonary diseases (e.g., pneumonia and tuberculosis) unless separate results were reported

· earlier report of data updated in a subsequent publication

N=11 with 3263 patients

Males: 81 %

ECOG 0-1: 91 %

Squamous cell /adenocarcinoma: 48/30 %

N=3 mit ausschließlichem Einschluss im Stadium III,

N=5 nur Stadium I

Risk of bias:

All RCTs had adequate sequence generation, but no blinding of observers and patients,6 RCTs trials did not report allocation concealment, 7 did not address loss of follow-up, and 4 did not report

sample size calculation

Neoadjuvant CT and surgery (n=1624)

vs.

surgery alone (n=1639)

median follow-up: 55 months

Primary:

3- and 5-year survival rates

overall survival  disease-free survival

total and perioperative

mortalities

recurrence

Scondary:

overall and R0 resection

postoperative complications

CT-related response and toxicity

Response (tumour downstaging)

Overall survival:

· 3-year OS (10 RCTs, 2854 patients): no difference: 54.7% vs. 50.0%, RR: 1.08, 95% CI: 0.93–1.27 with substantil differences between studies (I²=75%)

· 5-year OS (all RCTs): benefit with IG: 35.6% vs. 27.9%, RR: 1.35, 95% CI: 0.98–1.85,p = 0.07) with substantil differences between studies (I²=87%)

· Longer pooled OS duration (4 RCTs, 1022 patients): 53.7 vs. 33.7 months, WMD: 13.43, 95% CI: 6.89–19.97 with no heterogeneity between studies (I²=0%)

Disease-free survival:

· 3-year DFS rate: benefit with IG IG (8 RCTs, 2072 patients): 40.4% vs. 35.0%, RR: 1.16, 95% CI: 1.04–1.29, p = 0.01 with moderate heterogeneity between studies (I²=44 %)

· 5-year rate (7 RCTs, 1717 patients): benefit with IG: 23.0% vs.19.4%, RR: 1.19, 95% CI: 1.00–1.41, p = 0.06) with moderate heterogeneity between studies (I²=37 %)

· Median DFS (4 RCTs, 1022 patients): benefit with IG: 29.9 vs. 18.2 months, WMD: 9.53, 95% CI: 4.93–14.12, p < 0.0001; with no heterogeneity between studies (I²=0 %) and HR 0.87 (95% CI: 0.76–1.00, p = 0.04)

Total and perioperative mortality:

· Lower mortality in IG (11 RCTs, 3263 patients): 64.6 vs. 70.7% RR: 0.91, 95% CI: 0.83–0.99, p = 0.03 with substantil differences between studies (I²=82%)

· No difference in perioperative mortality (10 RCTs, 3052 patients): 3.8% vs. 3.7%, RR: 1.03, 95% CI: 0.72–1.48 with no differences between studies (I²=0%)

Recurrance and metastasis:

· Lower overall postsurgical recurrence (6 RCTs, 1601 patients): 46.5% vs. 52.0%, RR: 0.89, 95% CI: 0.80–1.00, p = 0.04 with small differences between studies (I²=10%)

· No differences in local recurrance rates (6 RCTs, 1601 patients): 17.7% vs. 18.2%, RR: 0.96, 95% CI: 0.79–1.18, p = 0.71 with no differences between studies (I²=0%)

· lower incidence of distant metastasis (4 RCTs, 1271 patients): 21.6% vs. 27.5%, RR: 0.78, 95% CI: 0.65–0.95, p = 0.01 with no differences between studies (I²=0%)

Surgery and resection:

· lower surgery in IG: 91.5% vs. 96.5%, RR: 0.96, 95% CI: 0.93–0.99, p=0003 and resection rates: 89.5% vs. 93.1%, RR: 0.97, 95% CI: 0.93–1.00, p = 0.04

· higher R0 resection rate in IG: 89.9% vs. 86.5%, RR: 1.04, 95% CI: 1.00–1.08, p = 0.05

Postoperative adverse events:

· no difference: 17.3% vs. 16.3%, RR: 1.06, 95% CI: 0.88–1.28, p = 0.54

Safety analysis of neoadjuvant CT (only in IG):

· most common NAC-related adverse effects:

· leucopenia (20.8%) and nausea/vomiting (10.6%) (reported in 8 RCTs)

· serious alopecia in 7.3% of patients (reported in 3 RCTs)

2a-

Abwertung aufgrund von Studien-limitationen, Inkonsistenz und Indirektheit

 Zusammenfassende Beurteilung

Schlussfolgerungen der Autoren der Studie: „NAC (neoadjucant CT) may provide better survival, reduced recurrence, and improved R0 resection rates among NSCLC patients who had surgery, especially in occident patients. Further studies are needed to clarify the ethnic differences“

Schlussfolgerung der Begutachterin: Systematische Übersicht, moderate Einschränkung der Qualität (kein Protokoll, Datum der Suche fehlt, missverständliche Beschreibung des Verzerrungspotentials und keine Untersuchung zum Einfluss des Verzerrungspotentials auf die Ergebnisse ), basiert auf 11 randomisierten Studien von 3263 Patienten der Stadien I-III (deshalb Abwertung der Evidenz aufgrund von Indirektheit), Verzerrungspotential basiert vorrangig auf fehlender verblindeter Endpunkterfassung, sowie einer fehlenden Beschreibung der verblindeten Zuteilung und Nachbeobachtung  (daher Abwertung aufgrund von Studienlimitationen). Es wird die Wirksamkeit von neoadjuvanten Chemotherapien vor der Operation auf das Überleben, die Rekurrenz gezeigt, wobei die Ergebnisse häufig eine substantielle Heterogenität aufweisen (z.B. bedingt durch verschiedene CT Regimes, daher Abwertung aufgrund von Inkonsistenz)

AJCC: American Joint Committee on Cancer; 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; ECOG: Eastern Cooperative Oncology Group; HR: Hazard ratio; IG: Intervention group; N: Number of studies; n: Number of participants; NCI CTCAE: National Cancer Institute Common Toxicity Criteria; NSCLC: Non-small cell lung cancer;  OR: Odds Ratio; OS: overall survival; PFS: Progression-free survival; 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