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Background. cis-platin based chemotherapy has already been the standard care for IB-IIIA NSCLC. NCCN: 2007 NSCLC treatment guideline (conclusion section). Situation and issues concerning NSCLC post-operative adjunctive therapy in China.
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cis-platin based chemotherapy has already been the standard care for IB-IIIA NSCLC
Situation and issues concerning NSCLC post-operative adjunctive therapy in China Only 5-year post-operative survival reports are available, while large-scale investigation results for post-operative adjuvant chemotherapy are absent China has the largest population of lung cancer cases, but lacks of corresponding phase III clinical study Clinical trials on lung cancer have already fallen behind neighbouring countries or areas, like Japan, Korea, Taiwan and Hongkong Results from Phase III clinical trials of adjuvante therapy following surgery for NSCLC is needed for chinese edition of guideline
Survival rate of NSCLC patients after surgical excision Surgery outcome for NSCLC in China Yan Sun et. Medical Oncology，People‘s Medical Publishing House 2001，P658
The research of multi-disciplinary treatment for NSCLC has been the important part of China National Science & Technology Infrastructure Program of 11th 5-year Plan, which consists of series of clinical tries according to evidence based medicine principals and basic studies. The research will provide important theoretic support for the guideline for NSCLC, which is suitable for Chinese population.
Limitations of the traditional adjuvant chemotherapy LACE study indicates that post operative platin-containing chemotherapy only increased the 5-year survival rate by 5% Searching for new treatment modality is ergent According to the treatment outcome for late stage tumor, chemo- therapy combined with target treatment (antiangiogenesis therapy) Improves efficacy and is feasible. Such as E4599, Endostar combined chemotherapy, Shenyi combined chemotherapy, etc.
Rationales for adjuvant chemotherapy combined with anti-angiogenesis agents for NSCLC Angiogenesis is a complicated process mediated by vascular endothelial growth factors (VEGF) and their receptors Treatment on angiogenesis will put the tumor cells downstream of vessels into necrosis This therapy will reverse the resistance of tumor cells, effect on existing tumor microvasculature system to atrophy
Combination of Chemotherapy and Anti- angiogenesis agents Enhance the cytotoxicity of chemotherapy agents Chemotherapy increases DNA repairment, thus demands supportion from oxygen and nutrition Initially, it helps with vasculature to facilitate chemotherapy agents reaching tumor site In the later period, it causes the apoptosis of endothelial cells, thus influences the growth of tumor cells
Molecular target treatment in each stage of lung cancer Localized tumor (adjunctive therapy) Late stage or metastasis precancerous lesions(Chemical prevention) Tumor in local progression stage (RT) CT S CT + RT Alone CT Molecule targeted treatment Onn A, et al. Lancet. 2005; 366:1507-1508. Thatchera N, et al. Lancet. 2005; 366:1527-1537.
ECOG1505 StudyPhase III clinical trial of adjuvant chemotherapy± Bevacizumab ） RANDOMIZATION • Eligibility • Resected ⅠB( ≥4cm )–Ⅲ A • ≥ lobectomy • No previous chemo • No planned XRT • No CVA/TIA • No ATE in 12 months • Chemotherapy q 3 wk x 4 • Vinorelbine-cisplatin • Taxotere-cisplatin • Gemcitabine-cisplatin Chemotherapy q 3 wk x 4 +Bevacizumab q 3 wk x 1 year • Target enrollment = 1,500 patients • Primary endpoint = Overall survival Secondary endpoints: Disease-free survival, safety
regimen selection: NVB/DDP • The most widely used regimen in adjuvant • chemotherapy for NSCLC : • IALT，BR.10, ANITA • The most stages are benefited: IIA-IIIA • Cost-effective: follow the rules in therapy • economics
Endostar • Endostar is a recombinant human endostatin. • Preclinical data revealed that Endostar could inhibit tumor angiogenesis and growth. • In a phase III trial, patients with advanced NSCLC were treated with cisplatin/vinorelbine (NP) plus Eendostar or placebo. The addition of Endostar to NP regimen resulted in higher response rate, median time to progression, and clinical benefit rate compared with NP alone in advanced NSCLC patients. (Sun Y, Wang JW, Liu Y et al, Results of phase III trial of rh-endostatin (YH-16) in advanced non-small lung cancer (NSCLC) patients. Proc ASCO 2005; 23:7138a) • Because of the promising results in advanced NSCLC, we investigated adjuvant NP regimen with or without Endostar in early-stage NSCLC, and the preliminary results of the first enrolled 545patients were reported.
Objectives of the Study • Primary Objective • To compare the OS of early- stage NSCLC patients who receive either Navelbine＋ Cis-platin (NP)＋ Endostar or Navelbine＋ Cis-platin (NP) after operation • Secondary objectives • Compare both groups (with or without Endostar): Relapse free survival (RFS) • Safety • Analyze the quality of life • Establish prognosis factors of NSCLC through the analysis on tissue and blood samples • Investigate the relationship between smoking and prognosis
Study design Vinorelbine+Cis-platin+Recombined Human Endostatin Vinorelbine 25mg/m2 IV d1.8 Cis-platin 80mg/m2 IV d1, or divided into d 1-3 RecombinedHuman Endostatin7.5mg/m2 IV d1-14 in 21 days cycle for 4 cycles randomization IB-IIIA NSCLC post-operative patients Vinorelbine+Cis-platin Vinorelbine25mg/m2 IV d1.8 Cis-platin 80mg/m2 IV d1, or divided into d 1-3 in 21 days cycle for 4 cycles
Sample size Main reference：ANITA study and ECOG1505study The median post-operative survival time in the NP group is defined as 55.8 months (ANITA 65.8months) RecombinedHuman Endostatin combined therapy is expected to prolong median survival time by 27% (26.5%,for ECOG1505), that is from 55.8 months to 70.9 months The significance level will be 0.05 (bilateral), statistical power 80%, enrollment time 2 years, sample size for each group will be 503, lost to follow-up 10%, total size 1107.
Inclusion criteria 1. NSCLC patients who are pathologically determined to suffer from adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or mixed type of above. 2. Clinical stage will be classified as IB-IIIA phase with the tumors completely excised (left total lung excision, lobi pulmonis excision, sleeve resection);The scope of clearance includes homonymy hilus pulmonis and mediastinum lymph nodes (including eminence); incisal edge should be trimmed. • Surgery date to adjunctive treatment ≤8 weeks • ； 4. No evidence of tumor relapse from examination performed before adjunctive therapy 5.Aged between 18~70, physical status score ECOG 0～1； 6. Subjects have no major organ dysfunction; blood routine, hepatic, renal, cardio function (examination) all turn out normal; laboratory test indicators must meet following requirements: Hematology: Leukocyte≥4.0×109/L; Neutrophils≥2.0×109/L Platelet count≥100×109/L; Hemoglobin≥95g/L。 Renal function: Serum bilirubin is below 1.5 X upper normal limit; ALT and AST are below 1.5 X upper normal limit. • Patients have no prior chemotherapy or radiotherapy; 8. Patients are compliant with the treatment and follow-ups, and understand the study well, and sign informed consent form.
Exclusion criteria • Classified as a pathology category which does not • meet inclusion criteria; 2. Total or partial resection of the right lung; 3. Enrollment is more than 8 weeks away from the surgery date; • Patients are complicated with any acute or chronic diseases • or mental disorders or laboratory abnormality; those complicated • diseases may Increase the risk of participating this study or taking • this test drug, or have an influence on the study results; it is judged • by investigators that under some circumstance patients are not • suitable to participate this trial： • Uncontrolled hypertension, unstable angina, myocardial infarction • history or symptomatic congestive heart-failure or uncontrolled • Arrhythmia in the past 12 months; • ECG shows there Is ischemia pathology or clinically diagnosed • heart valve disease; • In bacteria, fungi or virus caused disease active phase; • Before enrollment, the patients who suffer from • other progressive malignant tumor than NSCLC will • be excluded; Except for nonmelanoma skin cancer, • in situ cervical carcinoma, and cured early-stage • Prostate cancer; • 5.Patients who are pregnant or breast-feeding； • Have allergic constitution or known to be allergic to • any test drug; • Patients who are poorly compliant to the treatment; 9. Patients who are judged by the investigators not suitable to participate this trial.
Follow up per protocal Within 2years Chest CT or X-ray 3 months Abdominal B ultra inspection 3 months after relapse 3-5years Half year Evaluation time Pulmonary tumor markers Skull MRI and bone scan
Total 43 centers
Comparison of enrollment speed with large, multinational,multi-center clinical trials
There are 43 patients (7.3%) who did not undergo chemotherapy after randomization, thus the data from the rest 545 patients (92.7%) was analyzed for survival and safty. 78.63 % patients in group A and 76.33% patients in group B completed 4 cycles of chemotherpy. Up to analysis, 26.4% patients in group A and 23.6% patients in group B had the relapsed disease.
Results (545 patients) Survival time: because the follow-up for most patients is not up to 5 years, the majority of them survive. Therefore, the comparison on the median survival time of both groups is not available.
