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

• ClinicalTrials.gov Identifier: NCT02977169
• Recruitment Status: Recruiting
• First Posted: November 30, 2016
• Last Update Posted: November 13, 2020
• Sponsor: Shanghai Chest Hospital
• Information provided by (Responsible Party): Xiaolong Fu, Shanghai Chest Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Non-small Cell Lung Cancer Stage IIIA; Radiotherapy	Radiation: PORT; Drug: Platinum-based two drug chemotherapy (cisplatin/carboplatin + vinorelbine or cisplatin/carboplatin + pemetrexed regimen)	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: November 2016
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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 2-4 weeks after chemotherapy.	Radiation: PORT; 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; Drug: Platinum-based two drug chemotherapy (cisplatin/carboplatin + vinorelbine or cisplatin/carboplatin + pemetrexed regimen); Cisplatin/ carboplatin + vinorelbine regimen for squamous cell lung carcinoma Cisplatin/carboplatin + pemetrexed regimen for lung adenocarcinoma
Placebo Comparator: Arm II (no PORT); 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); Cisplatin/ carboplatin + vinorelbine regimen for squamous cell lung carcinoma Cisplatin/carboplatin + pemetrexed regimen for lung adenocarcinoma

Outcome Measures

Primary Outcome Measures :

1. Disease-free survival (DFS) [ Time Frame: 3 years ]

Secondary Outcome Measures :

1. Overall survival (OS) [ Time Frame: 3 years ]
2. Locoregional recurrence-free survival (LRFS) [ Time Frame: 3 years ]
3. Distant metastasis-free survival (DMFS) [ Time Frame: 3 years ]
4. Treatment-related adverse event [ Time Frame: 1 years ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Xiaolong Fu, MD; 862122200000 ext 3609; xlfu1964@126.com

Contact: Wen Feng, MD; 862122200000 ext 3609; fengwen412@126.com

Locations

China, Shanghai

Shanghai Chest Hospital; Recruiting

Shanghai, Shanghai, China

Contact: Xiaolong Fu, PhD +862122200000 ext 3602 xlfu1964@126.com

Sponsors and Collaborators

Shanghai Chest Hospital

Investigators

• Principal Investigator: Xiaolong Fu, MD; Shanghai Chest Hospital

More Information

Publications:

NSCLC Meta-analyses Collaborative Group, Arriagada R, Auperin A, Burdett S, Higgins JP, Johnson DH, Le Chevalier T, Le Pechoux C, Parmar MK, Pignon JP, Souhami RL, Stephens RJ, Stewart LA, Tierney JF, Tribodet H, van Meerbeeck J. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet. 2010 Apr 10;375(9722):1267-77. doi: 10.1016/S0140-6736(10)60059-1. Epub 2010 Mar 24.

Lally BE, Zelterman D, Colasanto JM, Haffty BG, Detterbeck FC, Wilson LD. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol. 2006 Jul 1;24(19):2998-3006. Epub 2006 Jun 12.

Douillard JY, Rosell R, De Lena M, Riggi M, Hurteloup P, Mahe MA; Adjuvant Navelbine International Trialist Association. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys. 2008 Nov 1;72(3):695-701. doi: 10.1016/j.ijrobp.2008.01.044. Epub 2008 Apr 24.

Robinson CG, Patel AP, Bradley JD, DeWees T, Waqar SN, Morgensztern D, Baggstrom MQ, Govindan R, Bell JM, Guthrie TJ, Colditz GA, Crabtree TD, Kreisel D, Krupnick AS, Patterson GA, Meyers BF, Puri V. Postoperative radiotherapy for pathologic N2 non-small-cell lung cancer treated with adjuvant chemotherapy: a review of the National Cancer Data Base. J Clin Oncol. 2015 Mar 10;33(8):870-6. doi: 10.1200/JCO.2014.58.5380. Epub 2015 Feb 9.

Billiet C, Decaluwé H, Peeters S, Vansteenkiste J, Dooms C, Haustermans K, De Leyn P, De Ruysscher D. Modern post-operative radiotherapy for stage III non-small cell lung cancer may improve local control and survival: a meta-analysis. Radiother Oncol. 2014 Jan;110(1):3-8. doi: 10.1016/j.radonc.2013.08.011. Epub 2013 Oct 4. Review. Erratum in: Radiother Oncol. 2014 Nov;113(2):300-1.

Burdett S, Rydzewska L, Tierney J, Fisher D, Parmar MK, Arriagada R, Pignon JP, Le Pechoux C; PORT Meta-analysis Trialists Group. Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev. 2016 Oct 11;10:CD002142. Review.

Feng W, Fu XL, Cai XW, Yang HJ, Wu KL, Fan M, Xiang JQ, Zhang YW, Chen HQ. Patterns of local-regional failure in completely resected stage IIIA(N2) non-small cell lung cancer cases: implications for postoperative radiation therapy clinical target volume design. Int J Radiat Oncol Biol Phys. 2014 Apr 1;88(5):1100-7. doi: 10.1016/j.ijrobp.2013.12.048. Epub 2014 Feb 11.

• Responsible Party: Xiaolong Fu, Director, Department of Radiation Oncology, Shanghai Chest Hospital
• ClinicalTrials.gov Identifier: NCT02977169
• Other Study ID Numbers: SCHLC009
• First Posted: November 30, 2016
• Last Update Posted: November 13, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Cisplatin; Carboplatin; Pemetrexed; Vinorelbine; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Antineoplastic Agents, Phytogenic; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators