Surgery With or Without Internal Radiation Therapy Compared With Stereotactic Body Radiation Therapy in Treating Patients With High-Risk Stage I Non-Small Cell Lung Cancer

A Randomized Phase III Study of Sublobar Resection (+/- Brachytherapy) Versus Stereotactic Body Radiation Therapy in High Risk Patients With Stage I Non-Small Cell Lung Cancer (NSCLC)

RATIONALE: Surgery with or without internal radiation therapy may be an effective treatment for non-small cell lung cancer. Internal radiation uses radioactive material placed directly into or near a tumor to kill tumor cells. Stereotactic body radiation therapy 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 with or without internal radiation therapy in treating non-small cell lung cancer.

PURPOSE: This randomized phase III trial is studying how well surgery with or without internal radiation therapy works compared with stereotactic body radiation therapy in treating patients with high-risk stage IA or stage IB non-small cell lung cancer.

Study Overview

• Status: Terminated
• Conditions: Lung Cancer
• Intervention / Treatment: Procedure: therapeutic conventional surgery; Radiation: stereotactic body radiation therapy; Radiation: iodine I 125

Detailed Description

OBJECTIVES:

Primary

• To ascertain whether patients treated by stereotactic body radiation therapy (SBRT) have a 3-year overall survival (OS) rate that is no more than 10% less than patients treated with sublobar resection (SR).

Secondary

• To compare loco-regional recurrence-free survival between study arms.
• To compare disease-free survival between study arms.
• To compare grade 3 or higher specific adverse event profiles between study arms at 1, 3, 6, and 12 months post-therapy.
• To compare pulmonary function between patients treated with SBRT and patients treated with SR.
• To compare the adverse events and pulmonary function tests (PFTs) in each arm for patients with low or high Charlson comorbidity index scores, including a test interaction between Charlson comorbidity index scores (low vs high) and treatment arm.

Tertiary

• To compare the quality-adjusted survival between the SBRT and SR treatments in terms of time to death (primary) and time until recurrence (secondary).
• To examine whether pre-operative and post-operative clinically significant deficits in previously identified prognostic PRO domains (overall quality of life [QOL], fatigue, anxiety, and dyspnea) are associated with shorter patient survival in this patient population and to compare the relative effectiveness of each treatment (SBRT and SR).
• To contribute to an ACOSOG bank of normative data in order to improve short/long-term outcomes of cancer patients by identifying patients experiencing clinically significant deficits in patient-reported outcomes and the relationship to genetic variables.
• To explore whether blood-based biomarkers, including osteopontins, will be able to predict which patients will be at high risk for recurrence by treatment with either SBRT or SR. (exploratory)
• To explore whether blood-based biomarkers, including TGF-β1, will be able to predict which patients will be at high risk for pulmonary complications by treatment with either SBRT or SR. (exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to planned brachytherapy (yes vs no) and ECOG performance status (0 vs 1 vs 2). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo sublobar resection comprising either a wedge resection or anatomical segmentectomy with or without intraoperative brachytherapy* comprising an iodine I 125 implant at the resection margin.
• Arm II: Patients undergo 3 fractions of stereotactic body radiation therapy at 2-8 days apart.

NOTE: *Patients may receive brachytherapy at the discretion of treating physician.

Patients may undergo blood sample collection at baseline and periodically during study for correlative studies. Tumor tissue samples may also be collected from patients who undergo resection.

Patients complete the Lung Cancer Symptom Scale (LCSS), the Linear Analogue Self-Assessment (LASA), and the UCDS Shortness of Breath quality-of-life questionnaires at baseline and periodically during study and follow-up.

After completion of study treatment, patients are followed up for 30 days, every 3 months for 2 years, every 6 months for 1 year, and then yearly for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program at London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Hospital Regional Cancer Centre - General Campus
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • Hopital Notre-Dame du CHUM
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • UAB Comprehensive Cancer Center
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
    • Scottsdale, Arizona, United States, 85259-5499
      • Mayo Clinic Scottsdale
  • California
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • Stanford, California, United States, 94305-5824
      • Stanford Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Baptist Cancer Institute - Jacksonville
    • Orlando, Florida, United States, 32806
      • M.D. Anderson Cancer Center at Orlando
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
    • Atlanta, Georgia, United States, 30308
      • Emory Crawford Long Hospital
    • Savannah, Georgia, United States, 31403-3089
      • Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Peoria, Illinois, United States, 61637
      • OSF St. Francis Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0093
      • Lucille P. Markey Cancer Center at University of Kentucky
    • Louisville, Kentucky, United States, 40202
      • James Graham Brown Cancer Center at University of Louisville
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • DeCesaris Cancer Institute at Anne Arundel Medical Center
    • Baltimore, Maryland, United States, 21229
      • St. Agnes Hospital Cancer Center
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University Cancer Research Center
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0942
      • University of Michigan Comprehensive Cancer Center
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital - Royal Oak Campus
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • Valley Hospital - Ridgewood
  • New York
    • New York, New York, United States, 10025
      • St. Luke's - Roosevelt Hospital Center - St.Luke's Division
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Stony Brook, New York, United States, 11794-9446
      • Stony Brook University Cancer Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Charles M. Barrett Cancer Center at University Hospital
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Columbus, Ohio, United States, 43210-1240
      • Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97213-2967
      • Providence Cancer Center at Providence Portland Medical Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822-0001
      • Geisinger Cancer Institute at Geisinger Health
    • Philadelphia, Pennsylvania, United States, 19107-5541
      • Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Cancer Center at Allegheny General Hospital
    • York, Pennsylvania, United States, 17405
      • York Cancer Center at Apple Hill Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center - Dallas
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
    • Norfolk, Virginia, United States, 23507
      • Sentara Cancer Institute at Sentara Norfolk General Hospital
  • Washington
    • Everett, Washington, United States, 98201
      • Providence Regional Cancer Partnership
    • Seattle, Washington, United States, 98122-4307
      • Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Center for Cancer and Blood
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin Cancer Center
    • Milwaukee, Wisconsin, United States, 53295
      • Veterans Affairs Medical Center - Milwaukee
    • Waukesha, Wisconsin, United States, 53188
      • Waukesha Memorial Hospital Regional Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Lung nodule suspicious for non-small cell lung cancer (NSCLC)

  • Biopsy confirmation is strongly recommended but not required; if 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 two 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
• Tumor ≤ 4 cm maximum diameter, clinical stage IA or selected IB (i.e., with visceral pleural involvement) by PET/CT scan of the chest and upper abdomen performed within 60 days prior to registration
• All clinically suspicious mediastinal N1, N2, or N3 lymph nodes (> 1 cm short-axis dimension on CT scan and/or positive on PET scan) confirmed negative for involvement with NSCLC by one of the following methods: mediastinoscopy, anterior mediastinotomy, endoscopic and/or endobronchial ultrasonography (EUS/EBUS)-guided needle aspiration, CT-guided, or video-assisted thoracoscopic or open lymph node biopsy
• Tumor verified by a thoracic surgeon to be in a location that will permit sublobar resection

• Tumor located peripherally within the lung, defined as not touching any surface within 2 cm of the proximal bronchial tree in all directions

  • Patients with non-peripheral (central) tumors are NOT eligible
• No evidence of distant metastases

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0, 1, or 2

• Patient at high-risk for surgery by meeting a minimum of one major criteria or two minor criteria as described below:

  • Major criteria

    • FEV1 ≤ 50% predicted
    • DLCO ≤ 50% predicted

  • Minor criteria

    • Age ≥ 75 years
    • FEV1 51-60% predicted
    • DLCO 51-60% predicted
    • Pulmonary hypertension (defined as a pulmonary artery systolic pressure greater than 40 mm Hg) as estimated by echocardiography or right heart catheterization
    • Poor left ventricular function (defined as an ejection fraction of 40% or less)
    • Resting or exercise arterial pO2 ≤ 55 mm Hg or SpO2 ≤ 88%
    • pCO2 > 45 mm Hg
    • Modified Medical Research Council (MMRC) Dyspnea Scale ≥ 3
• Not pregnant or nursing
• Negative urine or serum pregnancy test
• Fertile patients must use effective contraception
• No prior invasive malignancy, unless disease-free for ≥ 3 years prior to registration (except non-melanoma skin cancer, in-situ cancers).

PRIOR CONCURRENT THERAPY:

• No prior intra-thoracic radiotherapy

  • Prior radiotherapy as part of treatment for head and neck, breast, or other non-thoracic cancer is permitted
• Prior chemotherapy or surgical resection for the lung cancer being treated on this protocol is NOT permitted

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm I (SR+Brachytherapy); Patients undergo sublobar resection comprising either a wedge resection or anatomical segmentectomy with or without intraoperative brachytherapy comprising an iodine I 125 implant at the resection margin.	Procedure: therapeutic conventional surgery; Undergo surgery; Radiation: iodine I 125; Undergo seed implant radiotherapy
Experimental: Arm II (SBRT); Patients undergo 3 fractions of stereotactic body radiation therapy at 2-8 days apart.	Radiation: stereotactic body radiation therapy; Undergo radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year Overall Survival (OS) Rate	Overall survival is defined as the time from randomization until death from any cause.	Up to 3 years post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Loco-regional Recurrence-free Survival	Loco-regional recurrence is defined as recurrence within the same lobe or hilum (N1 nodes), or within 2 cm of the staple line or within 2 cm of the PTV after treatment effects such as scarring have subsided.	Up to 5 years post-randomization
Adverse Event Profiles at 1 Month Post-therapy	Adverse events are described and graded using the terminology and grading categories defined in the NCI's Common Toxicity Criteria (CTCAE), Version 4.0. Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death.	1 month post-therapy
Adverse Event Profiles at 3 Months Post-therapy	Adverse events are described and graded using the terminology and grading categories defined in the NCI's Common Toxicity Criteria (CTCAE), Version 4.0. Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death.	3 months post-therapy
Adverse Event Profiles at 12 Months Post-therapy	Adverse events are described and graded using the terminology and grading categories defined in the NCI's Common Toxicity Criteria (CTCAE), Version 4.0. Grading: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening, Grade 5=Death.	12 months post-therapy
Disease-free Survival	Disease free survival is defined as the time from randomization until documented disease recurrence or death, whichever occurs first. Patient who are disease free and alive at the time of analysis will be censored at the time of their last follow up.	Up to 5 years post-randomization
Pulmonary Function Test Values	Pulmonary function test values include forced expiratory volume 1 (FEV1), carbon monoxide diffusion (DLCO) and forced vital capacity (FVC).	Up to 12 months post-therapy

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Hiran C. Fernando, MD, Boston Medical Center

Publications and helpful links

General Publications

• Fernando HC, Timmerman R. American College of Surgeons Oncology Group Z4099/Radiation Therapy Oncology Group 1021: a randomized study of sublobar resection compared with stereotactic body radiotherapy for high-risk stage I non-small cell lung cancer. J Thorac Cardiovasc Surg. 2012 Sep;144(3):S35-8. doi: 10.1016/j.jtcvs.2012.06.003. Epub 2012 Jul 11.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): March 27, 2017

Study Registration Dates

• First Submitted: April 15, 2011
• First Submitted That Met QC Criteria: April 15, 2011
• First Posted (Estimate): April 18, 2011

Study Record Updates

• Last Update Posted (Actual): May 30, 2017
• Last Update Submitted That Met QC Criteria: April 25, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: stage IA non-small cell lung cancer; stage IB non-small cell lung cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: Z4099; U10CA076001 (U.S. NIH Grant/Contract); NCI-2011-02667 (Registry Identifier: NCI Clinical Trials Reporting Office); CDR0000698986 (Registry Identifier: Physician Data Query)