To Evaluate the Role of Postoperative Radiotherapy in Patients With IIIA(N2) Non-Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
Rationale: Completely resected non-small cell lung cancer (NSCLC) patients with histologically confirmed N2 disease are a heterogeneous population, with 5-year survival rates ranging from 10% to 30%. Systemic recurrence following surgery is one of the major problems in stage IIIA(N2) patients, and the use of postoperative chemotherapy (POCT) in stage IIIA disease prolongs survival. The value of postoperative radiotherapy (PORT) for completely resected NSCLC remains controversial, as the effect on survival has been inconclusive. Recently, several large retrospective studies and reviews of the National Cancer Database indicated that modern PORT appears to confer an additional 5% survival advantage beyond that achieved with adjuvant chemotherapy alone. Actually, after complete resection and POCT, 20%-40% of cases have a risk of locoregional recurrence (LRR). Patients with completely resected stage IIIA(N2) disease might hold different postoperative patterns-of-failure and prognosis. It is not yet known for subsets with specific prognostic factors that confer lower LRR risks, whether giving PORT is more effective than no radiation therapy in treating patients with completely resected pathologic stage IIIA(N2) NSCLC. Purpose: This randomized phase II trial is studying the clinical efficacy of PORT administered using three-dimensional conformal radiotherapy (3D-CRT) techniques and the proposed standard PORT clinical target volume (CTV) delineation guideline in treating low risk of LRR patients with completely resected pathologic stage IIIA(N2) NSCLC.

Detailed Description
-----------------
OBJECTIVES: Primary Investigate the value of PORT for completely resected pathologic stage IIIa(N2) NSCLC by comparing the disease-free survival of patients with low risk of LRR treated with PORT vs no PORT. Secondary Determine the overall survival of patients treated with these regimens. Compare the locoregional recurrence-free survival in patients treated with these regimens. Compare the distant metastasis-free survival in patients treated with these regimens. Determine patterns of recurrence in patients treated with these regimens. Determine the treatment-related adverse events of these regimens in these patients. Determine the prediction models for locoregional recurrence and brain metastasis based on the clinical, pathological, radiological, genetic, tumor microenvironmental and immunological data. OUTLINE: This is a multicenter, randomized study. The clinical risk prediction model for LRR has been established based on our large institutional database. On multivariate analysis, heavy cigarette smoking history, cN2 status, and number of involved lymph nodes>4 were independently significant factors predicting high risk of LRR. The PI equation was built including the three categorical variables and coefficients based on their level of significance: PI＝(0.9×smoking history)＋(0.5×clinical N status)＋(0.8×number of involved lymph nodes). Patients with the PI score<3.5 were considered as low risk of LRR. Patients are stratified according to participating center, EGFR mutation status (EGFR 19del or 21L858R mutations vs others), and use of pretreatment positron emission tomography scans (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I (PORT): Participants in the Arm I will receive four cycles of adjuvant chemotherapy and after that, sequential adjuvant thoracic conformal radiotherapy (50.4 Gy, 1.8 Gy once daily over 5.5 weeks) will be administered. PORT begins within 2-6 weeks after chemotherapy. Arm II (no PORT): Participants in the Arm II will receive four cycles of adjuvant chemotherapy and do not undergo adjuvant thoracic conformal radiotherapy. PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.

Official Title
-----------------
Phase II Study to Evaluate the Role of Postoperative Radiotherapy for Low Risk of Locoregional Recurrence Patients With Completely Resected Stage IIIA(N2) Non-Small Cell Lung Cancer

Conditions
-----------------
Non-small Cell Lung Cancer Stage IIIA, Radiotherapy

Intervention / Treatment
-----------------
* Radiation: PORT
* Drug: Platinum-based two drug chemotherapy (cisplatin/carboplatin + vinorelbine or cisplatin/carboplatin + pemetrexed regimen)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, aged 18 years to 75 years Complete resection through a surgical procedure of lobectomy, sleeve lobectomy or bilobectomy with microscopically tumor-free resection margins and margin-negative resection of all gross disease; Has undergone systematic nodal assessment (lymph node dissection or sampling with a minimum of three N2 stations sampled or completely dissected, one of which must be the subcarinal station) Histologically proven lung adenocarcinoma or squamous cell lung carcinoma of stage pT1-3N2M0 (according to the TNM classification in the Union for International Cancer Control (UICC) 7th ed.) Determined as the postoperative low risk of locoregional recurrence No documented metastases (M1) and/or invasion (T4) by the pretreatment examination or at the time of surgery No prior neoadjuvant therapy (chemotherapy and/or RT) No prior adjuvant thoracic RT No severe perioperative complications and expected postoperative lifespan ≥4 months ECOG Performance Status 0-1 Voluntarily participated in this study and signed the informed consent form by himself or his agent. Had good compliance with the study procedures, and can cooperate with the relevant examination, treatment and follow-up Exclusion Criteria: Histologically confirmed large cell carcinoma, adenosquamous carcinoma, sarcomatoid carcinomas, neuroendocrine tumors (small cell carcinoma, large cell neuroendocrine carcinoma, carcinoid tumors, etc.), salivary-gland type tumors, adenomas, papillomas, or other and unclassified carcinomas Patients undergoing pneumonectomy Diagnosed with other prior or concurrent malignancies (neoplasm) except for basal cell carcinoma of the skin or carcinoma in situ of the cervix within the last 5 years Patients with severe postoperative complications; and time to beginning of the adjuvant therapy has been more than 2 months from the date of surgery Patients with any severe or uncontrolled systematic disease including severe cardiovascular, liver, kidney, hematopoietic, metabolic disease, or uncontrolled active infection that would preclude study participation Patients with positive mental disorder that would preclude study participation; Contradictory to chest radiotherapy Pregnant or nursing women Concurrent other anti-cancer treatment Prior preoperative Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) treatment or other targeted therapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (PORT)<br>Participants in the Arm I will receive four cycles of adjuvant chemotherapy and after that, sequential adjuvant thoracic conformal radiotherapy (50.4 Gy, 1.8 Gy once daily over 5.5 weeks) will be administered. PORT begins within 2-4 weeks after chemotherapy. | Radiation: PORT<br>* 3-dimensional conformal or intensity-modulated radiotherapy, total dose of 50.4 Gy, 1.8 Gy once daily over 5.5 weeks, following the standard and consistent PORT CTV delineation guideline<br>Drug: Platinum-based two drug chemotherapy (cisplatin/carboplatin + vinorelbine or cisplatin/carboplatin + pemetrexed regimen)<br>* Cisplatin/ carboplatin + vinorelbine regimen for squamous cell lung carcinoma Cisplatin/carboplatin + pemetrexed regimen for lung adenocarcinoma<br>|
| Placebo Comparator: Arm II (no PORT)<br>Participants in the Arm II will receive four cycles of adjuvant chemotherapy and after that, do not undergo adjuvant thoracic conformal radiotherapy. | Drug: Platinum-based two drug chemotherapy (cisplatin/carboplatin + vinorelbine or cisplatin/carboplatin + pemetrexed regimen)<br>* Cisplatin/ carboplatin + vinorelbine regimen for squamous cell lung carcinoma Cisplatin/carboplatin + pemetrexed regimen for lung adenocarcinoma<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival (DFS) |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | 3 years | 
| Locoregional recurrence-free survival (LRFS) |  | 3 years | 
| Distant metastasis-free survival (DMFS) |  | 3 years | 
| Treatment-related adverse event | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 1 years |