Hypofraction Radiotherapy for Locally Advanced Non-small Cell Lung Cancer

Trial title: Hypofraction radiotherapy followed by immune checkpoint inhibitors for locally advanced non-small cell lung cancer: A phase II clinical trial.

Trial objective: To explore the safety and primary efficacy of hypofraction radiotherapy followed by immune checkpoint inhibitors for stage III locally advanced non-small cell lung cancer.

Trial Design: To enroll 36 patients diagnosed with stage III locally advanced non-small cell lung cancer to receive hypofraction radiotherapy (18 patients receiving high dose of 60 (Gray, Gy) /15 (fraction, f) and 18 patients receiving low dose of 48Gy/12f) followed by 1-year maintenance of immune checkpoint inhibitors.

Inclusion Criteria: a. 18-70 years old; b. Eastern Cooperative Oncology Group (ECOG) 0-1; c. non-small cell lung cancer including squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, large-cell carcinoma; d. wild-type of driven genes; e. stage II-III (AJCC 8th Edition) confirmed by cranial MRI, chest CT, abdominal ultrasonograph, bone scan or cranial MRI and Positron Emission Tomography (PET-CT); f. surgically unresectable or deny of surgery; g. signature of inform consent.

Exclusion Criteria: a. younger than 18 years old or older than 70 years old; b. ECOG>1; c. small-cell lung cancer and other neuroendocrine carcinoma including typical or atypical carcinoid, large-cell neuroendocrine carcinoma; d. mutant type of driven genes; e. Stage I and IV (AJCC 8th Edition) confirmed by cranial MRI, chest CT, abdominal ultrasonograph, bone scan or cranial MRI and PET-CT; f. surgically resectable; g. no signature of inform consent.

Staging Examination before Radiotherapy: a. ECOG scoring. b. Cranial contrast MRI and PET-CT, or cranial contrast MRI (preferred), chest contrast CT, abdominal ultrasonography and bone scan. c. Bronchoscopy for centrally-located lung cancer. d. Staging examination is mandatory after inductive chemotherapy \& chemotherapy with immunotherapy. e. Pulmonary function test.

Inductive therapy before radiotherapy: Chemotherapy or chemotherapy combined with immunotherapy is allowed as inductive therapy. Detailed regimen could refer to NCCN guidelines. Tyrosine kinase inhibitors are not allowed as inductive therapy.

Randomization: Patients would be randomly assigned to high dose group and low dose group using random number table method.

Radiotherapy CT simulation: 4-Dimensional CT (4D-CT) with intravenous contrast is recommended for simulation. Scan thickness should be less than 5 mm. Thermal mask or vacuum bag is recommended.

Target Delineation: Considering hypofraction and involved field irradiation (IFI), only Internal Tumor Volume (ITV) should be delineated without the need to delineate Clinical Tumor Volume (CTV).

Delineation of ITV: ITV should include pulmonary gross tumor and metastatic mediastinal lymph nodes. PET-CT registration with simulation CT is recommended for patients with obstructive atelectasis. For patients with suspected mediastinal lymph nodes, Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) is recommended.

Production of Planning Tumor Volume (PTV):

Low-dose Arm (48Gy/12f) PTV: PTV is produced by a margin of 5 mm added to ITV. Modification of PTV is suggested to respect anatomic boundary.

High-dose Arm (60Gy/15f) PTV: Planning Tumor Volume (PTV) is produced by a margin of 5 mm added to ITV. Modification of PTV is suggested to respect anatomic boundary.

Dosimetric Limitation: 95% prescription dose should cover 100% PTV and 95% PTV should receive 100% prescription dose. Total Lung: V20<25%, Dmean<13Gy, V5<50%. Spinal Cord: Dmax<40Gy. Heart: V30<40%, Dmean<15Gy.

Esophagus: V40<2.5 cc in low-dose arm, V45<2.5cc in high-dose arm. The protection of OAR is prioritized to the prescription dose coverage of PTV. Treatment Implementation: Radiotherapy is implemented every day. Cone-beam CT should utilized every day to minimize set-up error.

Concurrent Chemotherapy: If patients have received over 4 cycles of inductive chemotherapy with or without immunotherapy, no concurrent chemotherapy is needed. If patients have received less than 4 cycles of inductive chemotherapy with or without immunotherapy, concurrent chemotherapy is needed to ensure 4 cycles of chemotherapy. Adenocarcinoma: Pemetrexed combined with platinum is recommended. Squamous-cell lung cancer: Etoposide combined with platinum is recommended. One month after completion of radiotherapy, chest CT and abdominal ultrasonography should be undertaken. After exclusion of disease progression and grade 2 or more radiation-induced pneumonitis, consolidative immunotherapy should be started. Durvalumab maintenance for one year is recommended.

Follow-up: Patients should be follow-up every three months right after the completion of radiotherapy to 3 years after radiotherapy. Then follow-up every half year is allowed to 5 years after radiotherapy. After 5 years, follow-up every year is appropriate. In follow-up, chest CT and abdominal ultrasonography should be implemented. Cranial MRI should be performed every half year for patients with adenocarcinoma. Bone scan should be undertaken every year for all patients.

Primary Endpoint: Rate of radiation-induced pneumonitis, esophagitis, central hilar structure injury rate, hematologic toxicity (CTCAE V4.0).

Secondary Endpoint: Median overall survival, 2-year overall survival rate, Median progression-free survival, 2-year progression-free survival, Objective response rate, Complete response rate, Partial response rate (RECIST v1.1).