Radical Resection Vs. Ablative Stereotactic Radiotherapy in Patients With Operable Stage I NSCLC

Phase 2

Active, not recruiting

Conditions: Non-small Cell Lung Cancer

Interventions: Procedure: Surgery
Radiation: Stereotactic Body Radiation Therapy (SBRT)

Registration Number: NCT01753414

Lead Sponsor: Radiation Therapy Oncology Group

Brief Summary: Rationale: Surgery remains the standard of care for stage 1 (T1-2a N0)non-small cell lung cancer. Stereotactic body radiation therapy is a newer radiation treatment that gives fewer but higher and possibly more effective doses of radiation than standard radiation. This technique may be able to send x-rays directly to the tumor and cause less damage to normal tissue. It is not yet known whether stereotactic body radiation therapy is more effective than surgery in treating non-small cell lung cancer.

Purpose: The primary aim of this randomized phase II trial is to determine if the efficacy of SBRT is comparable to that of standard surgical interventions for patients with T1N0 non-small cell lung cancer.

Detailed Description: Not available

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 44

Inclusion Criteria

Pathologically (histologically or cytologically) proven diagnosis of Stage I NSCLC [American Joint Committee on Cancer (AJCC), 7th ed.], T1N0M0; note: T1N0 disease must be confirmed by FDG-PET/CT. (FDG = 18F-fluorodeoxyglucose; PET = positron emission tomography; CT = Computed Tomography)

Biopsy confirmation of diagnosis is strongly recommended but not required. If the biopsy is attempted and non-diagnostic, if the patient refuses biopsy, or if the risk of biopsy is considered too high, patients may be enrolled if the mass is suspicious for NSCLC based on 2 or more of the following criteria:

Positive smoking history;
Absence of benign calcifications within suspicious nodule;
Activity on PET greater than normal tissue;
Evidence of growth compared to previous imaging;
Presence of spiculation.

The following primary cancer types are eligible: squamous cell carcinoma; adenocarcinoma; large cell carcinoma/ large cell neuroendocrine carcinoma; non-small cell carcinoma not otherwise specified.

Patients with hilar or mediastinal lymph nodes ≤ 1 cm and no abnormal hilar or mediastinal uptake on PET and CT will be considered N0. Mediastinal lymph node biopsy is required for patients with visible nodes: patients with > 1 cm hilar or mediastinal lymph nodes on CT or with nodes appearing as abnormal on PET (including suspicious but nondiagnostic uptake). Such patients will not be eligible unless directed biopsies of all abnormal lymph nodes are negative for cancer or these nodes demonstrate a lack of change during the prior 6 months and thus are considered to be non-malignant.
The patient must be considered a reasonable candidate for surgical resection using a lobectomy or pneumonectomy of the primary tumor within 6 weeks prior to registration, according to the following criteria based on the American College of Chest Physicians guidelines [165]:
- A qualified thoracic surgeon should make the determination that there would be a high likelihood of negative surgical margins;
- Baseline forced expiratory volume in 1 second (FEV1) >60% predicted, postoperative predicted FEV1 >40% predicted;
- Diffusion capacity of the lung for carbon monoxide (DLCO) >60% predicted, postoperative predicted DLCO > 40 % predicted;
- No baseline hypoxemia and/or hypercapnia;
- If the estimated postoperative FEV1 or DLCO <40% predicted indicates an increased risk for perioperative complications, including death, from a standard lung cancer resection (lobectomy or greater removal of lung tissue), then cardiopulmonary exercise testing to measure maximal oxygen consumption (VO2max) must be >60%;
- No severe pulmonary hypertension;
- No severe cerebral, acute or chronic cardiac, or peripheral vascular disease;
Pleural effusion, if present, must be deemed too small to tap under CT guidance and must not be evident on chest x-ray. Pleural effusion that appears on chest x-ray will be permitted only if there is no evidence of malignancy after invasive cytologic assessment.
Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup:
- History/physical examination, including documentation of weight within 6 weeks prior to registration;
- Evaluation by an experienced thoracic surgeon within 6 weeks prior to registration;
- FDG-PET/CT scan for staging and RT plan within 4 weeks prior to registration;
- CT scan (preferably with intravenous contrast, unless medically contraindicated) within 4 weeks prior to registration to include the entirety of both lungs, the mediastinum, liver, and adrenal glands; primary tumor dimension will be measured on CT scan.
Zubrod Performance Status 0-1 within 6 weeks prior to registration;
Age ≥ 18;
For women of childbearing potential, a serum or urine pregnancy test must be negative within 72 hours prior to registration;
Women of childbearing potential and male participants who are sexually active must practice adequate contraception during treatment if assigned to treatment with SBRT.
Patients must provide study specific informed consent prior to study entry.

Exclusion Criteria

Direct evidence of regional or distant metastases after PET and surgical staging studies, or synchronous primary malignancy or prior invasive malignancy in the past 3 years, with the following exceptions:
- carcinoma in situ;
- early stage skin cancer that has been definitively treated;
- when an invasive malignancy has been treated definitively and the patient has remained disease free for ≥ 3 years;
Primary tumors >3 cm;
Prior systemic chemotherapy or thoracic surgery involving lobectomy or pneumonectomy;
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;
Pure bronchioloalveolar carcinoma subtype of non-small cell lung cancer;
Active systemic, pulmonary, or pleural pericardial infection;
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Surgery	Surgery	Complete resection, i.e., removal of the primary tumor with at least a 2 cm margin together with nodal dissection/sampling
Stereotactic Body Radiation Therapy (SBRT)	Stereotactic Body Radiation Therapy (SBRT)	Stereotactic Body Radiation Therapy (SBRT) given every other day 11 Gy in 5 fractions to a total dose of 55 Gy in 10-15 days with an inter-fraction interval of 2-3 days

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Alive Without Local-regional Failure at Two Years (Local-regional Tumor Control)	From date of randomization to two years	Local-regional failure (LRF) is defined differently for each arm. LRF after RODS is defined as recurrence, defined by CT, confirmed by PET/CT whenever possible, i.e., development of tumor masses at site of resection, hilum (N1 nodal region), mediastinum (N2-N3 nodes), ipsilateral supraclavicular fossa for upper lobe tumors (N3 nodes), or within 3 cm of the staple line of RODS. LRF after SBRT is defined as tumor progression on CT per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, confirmed by positron PET/CT, within same lobe, hilum (N1 nodes), mediastinum (N2-N3 nodes), or ipsilateral supraclavicular fossa for upper lobe tumors (N3 nodes), or within 3 cm of original planning target volume (PTV). Local-regional control time is defined as time from randomization to the date of first LRF, death, or last known follow-up (censored), whichever occurred first. Rates are estimated using the Kaplan-Meier method.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (Percentage of Participants Alive)	From date of randomization to date of death or last follow-up. Maximum follow-up was 7.0 years.	Overall survival rates are estimated by the Kaplan-Meier method. The distribution of DFS estimates between the two arms is compared using the log rank test. Overall survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Two-year rates are provided.
Percentage of Participants With Local-regional Failure (LRF)	From date of randomization to the date of first local-regional failure, death, or last known follow-up, whichever occurred first. Maximum follow-up is 7.0 years.	LRF rates are estimated using the cumulative incidence method. LRF is defined differently for each arm. LRF after RODS is defined as recurrence, defined by CT, confirmed by PET/CT whenever possible, i.e., development of tumor masses at site of resection, hilum (N1 nodal region), mediastinum (N2-N3 nodes), ipsilateral supraclavicular fossa for upper lobe tumors (N3 nodes), or within 3 cm of the staple line of RODS. LRF after SBRT is defined as tumor progression on CT per Response Evaluation Criteria in Solid Tumors (RECIST) criteria, confirmed by PET/CT, within same lobe, hilum (N1 nodes), mediastinum (N2-N3 nodes), or ipsilateral supraclavicular fossa for upper lobe tumors (N3 nodes), or within 3 cm of original PTV. LRF time is defined as time from randomization to the date of first LRF, last known follow-up (censored), or death without LRF (competing risk), whichever occurred first. Two-year rates are provided.
Percentage of Participants With Distant Failure	From date of randomization to date of first distant failure, death, or last known follow-up, whichever occurred first. Maximum follow-up was 7.0 years.	Distant failure rates are estimated using the cumulative incidence method. Distant failure is defined as appearance of tumor within another ipsilateral (non-primary) lobe ≥ 2 cm from the original planning target volume (PTV) or distant metastasis, including appearance of tumor deposits characteristic of NSCLC metastasis (chest wall other than incision sites, mediastinal structures/diaphragm, malignant pleural/pericardial effusion), contralateral lung and/or other distant sites. Time to distant failure is defined as time from randomization to the date of first failure, last known follow-up (censored), or death without failure (competing risk). Two-year rates are provided.
Percentage of Participants Alive Without Disease [Disease-free Survival (DFS)]	From date of randomization to the date of first failure, death, or last known follow-up, whichever occurred first. Maximum follow-up is 7.0 years.	Failure rates are estimated using the Kaplan-Meier method, where failure is defined as LRF, DF, or death from any cause. LRF is defined differently for each arm. LRF after RODS is defined as recurrence, defined by CT, confirmed by PET/CT whenever possible, i.e., development of tumor masses at the resection site, hilum, mediastinum, or ipsilateral supraclavicular fossa for upper lobe tumors, or within 3 cm of the staple line of RODS. LRF after SBRT is defined as tumor progression on CT per RECIST criteria, confirmed by PET/CT, within same lobe, hilum, mediastinum, or ipsilateral supraclavicular fossa for upper lobe tumors, or within 3 cm of original PTV. DF is defined as tumor within a non-primary lobe ≥ 2 cm from the original planning target volume or distant metastasis. Failure time is defined as time from randomization to the date of first failure or last known follow-up (censored), whichever occurred first. Two-year rates are provided.
Number of Participants by Failure Site	From date of randomization to date of last known follow-up. Maximum follow-up was 7.0 years.	Local-regional failure (LRF) is defined differently for each arm. LRF after RODS is defined as recurrence, defined by CT, confirmed by PET/CT whenever possible, i.e., development of tumor masses at site of resection, hilum, mediastinum, ipsilateral supraclavicular fossa for upper lobe tumors, or within 3 cm of the staple line of RODS. LRF after SBRT is defined as tumor progression on CT per RECIST criteria, confirmed by PET/CT, within same lobe, hilum, mediastinum, or ipsilateral supraclavicular fossa for upper lobe tumors, or within 3 cm of original planning target volume (PTV). Distant failure is defined as tumor within a non-primary lobe ≥ 2 cm from the original planning target volume or distant metastasis, including tumor deposits characteristic NSCLC metastasis (chest wall other than incision sites, mediastinal structures/diaphragm, malignant pleural/pericardial effusion), contralateral lung and/or other distant sites.
Best PET Tumor Response	From date of randomization to date of last known follow-up. Maximum follow-up was 7.0 years.	PET Tumor Response of Irradiated Target Lesions is defined as * Complete Metabolic Response (CMR): Tumor 18F-fluorodeoxyglucose (FDG)-activity decreased to less than mean background of the aortic arch blood pool. * Partial Metabolic Response (PMR): At least a 30% decrease in the maximum of relative tumor FDG-activity of target lesions * Progressive Metabolic Disease (PMD): At least a 20% increase in the maximum of relative tumor FDG-activity of target lesions * Stable Metabolic Disease (SMD): Neither sufficient reduction to qualify for (major pathological response) PMR nor sufficient increase to qualify for PMD The percentage of decrease or increase was globally estimated based on readings of (tumor activity-aorta activity)/aorta activity.
Number of Participants by Highest Grade Adverse Event Reported	From date of randomization to the date of last known follow-up. Maximum follow-up time was 7.0 years.	Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Number of Participants With Surgical and Radiation Treatment Credentialing Completed and Documented Before Enrollment (Trial Feasibility)	baseline
Number of Eligible Participants (Trial Feasibility)	Baseline	Goal: 95% of participants retain eligibility status (meet all eligibility criteria) after central review by headquarters staff.
Number of Participants With Baseline Forms Completed and Provided Within 30 Days of Randomization (Trial Feasibility)	Baseline
Number of Participants Lost to Follow-up (Trial Feasibility)	From date of randomization to date of last known follow-up. Maximum follow-up was 7.0 years.	Goal: \< 3% of participants lost to follow-up.

Trial Locations

Locations (4): Shanghai Cancer Center/Fudan University
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Shanghai, China
Chinese Academy of Medical Science
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Beijing, China
Shandong Cancer Hospital, Jinan
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Shangdong, China
Zhejiang Cancer Hospital, Hangzhou
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Zhejiang, China