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

 1. 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.

 2. 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.
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