Surgery With or Without Internal Radiation Therapy in Treating Patients With Stage I Non-Small Cell Lung Cancer

A Randomized Phase III Study of Sublobar Resection Versus Sublobar Resection Plus Brachytherapy in High Risk Patients With Non-Small Cell Lung Cancer (NSCLC), 3cm or Smaller

This randomized phase III trial studies surgery and internal radiation therapy to see how well they work compared to surgery alone in treating patients with stage I non-small cell lung cancer. Surgery 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. It is not yet known whether surgery and internal radiation therapy are more effective than surgery alone in treating non-small cell lung cancer.

Study Overview

• Status: Completed
• Conditions: Lung Cancer
• Intervention / Treatment: Procedure: surgery; Radiation: brachytherapy

Detailed Description

PRIMARY OBJECTIVES:

I. To ascertain whether patients treated by sublobar resection (SR) + brachytherhapy (BX) have longer time to local recurrence as compared to the patients treated by SR (local recurrence includes recurrence within the same lobe or hilum [N1 nodes], or progression at the staple line after treatment effects such as scarring have subsided).

SECONDARY OBJECTIVES:

I. To compare procedure specific morbidity and mortality between study arms. II. To compare overall survival and failure-free survival between study arms. III. To assess freedom from regional or distant recurrence. IV. To assess the effect of histological or cytologic positive resection margins on time to local recurrence.

V. To determine the effect of brachytherapy on quality of life (QoL). VI. To determine the effect of brachytherapy on pulmonary function.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo open or thoracoscopic sublobar resection comprising either a wedge resection or anatomical segmentectomy.

ARM II: Patients undergo surgery as in arm I. Patients also undergo intraoperative brachytherapy comprising iodine I 125 implant at the resection margin.

After completion of study treatment, patients are followed at 3, 6, 12, 18, 24, 30, and 36 months and then yearly for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 224
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program at London Health Sciences Centre
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259-5499
      • Mayo Clinic Scottsdale
  • California
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Illinois
    • Evanston, Illinois, United States, 60201-1781
      • Evanston Hospital
    • Springfield, Illinois, United States, 62781-0001
      • Regional Cancer Center at Memorial Medical Center
    • Springfield, Illinois, United States, 62794-9677
      • Simmons Cooper Cancer Institute
    • Springfield, Illinois, United States, 62702
      • Cancer Institute at St. John's Hospital
  • Maryland
    • Towson, Maryland, United States, 21204
      • Cancer Institute at St. Joseph Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University Cancer Research Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0942
      • University of Michigan Comprehensive Cancer Center
  • 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 Hampshire
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • Valley Hospital - Ridgewood
  • New York
    • Oceanside, New York, United States, 11572
      • South Nassau Communities Hospital
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • North Carolina
    • Charlotte, North Carolina, United States, 28233-3549
      • Presbyterian Cancer Center at Presbyterian Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Charles M. Barrett Cancer Center at University Hospital
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Knight Cancer Institute At Oregon Health and Science University
  • Pennsylvania
    • New Castle, Pennsylvania, United States, 16105
      • Jameson Memorial Hospital - North Campus
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center - Philadelphia
    • Philadelphia, Pennsylvania, United States, 19104-4283
      • Abramson Cancer Center of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107-5541
      • Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Centers
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Cancer Center at Allegheny General Hospital
    • Reading, Pennsylvania, United States, 19612-6052
      • McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • Miriam Hospital
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital Comprehensive Cancer Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37920-6999
      • U.T. Medical Center Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030
      • Methodist Hospital
  • Utah
    • Murray, Utah, United States, 84157
      • Jon and Karen Huntsman Cancer Center at Intermountain Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
  • Washington
    • Seattle, Washington, United States, 98122-4307
      • Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
    • Seattle, Washington, United States, 98111
      • Floyd and Delores Jones Cancer Institute at Virginia Mason Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive 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

Inclusion Criteria:

• PART I: PRE-OPERATIVE CRITERIA (PRE-REGISTRATION/RANDOMIZATION)
• Patients must have a suspicious lung nodule for clinical stage I non-small cell lung cancer (NSCLC)
• Patient must have a mass =< 3 cm maximum diameter by computed tomography (CT) size estimate: clinical stage Ia or selected Ib (i.e., with visceral pleural involvement)
• Patient must have a CT scan of the chest with upper abdomen within 60 days prior to date of pre-registration
• Eastern Cooperative Oncology Group (ECOG)/Zubrod performance status 0, 1, or 2

• Patient must meet at least one major criteria or meet a minimum of two minor criteria as described below:

  • Major criteria

    • Forced expiratory volume in 1 second (FEV1) =< 50% predicted
    • Diffusing capacity of the lungs for carbon monoxide (DLCO) =< 50% predicted

  • Minor criteria

    • Age >= 75
    • FEV1 51-60% predicted
    • DLCO 51-60% predicted
    • Pulmonary hypertension (defined as a pulmonary artery systolic pressure greater than 40 mmHg) as estimated by echocardiography or right heart catheterization
    • Poor left ventricular function (defined as an ejection fraction of 40% or less)
    • Resting or exercise partial pressure of oxygen (pO2) =< 55 mm Hg or peripheral capillary oxygen saturation (SpO2) =< 88%
    • Partial pressure of carbon dioxide (pCO2) > 45 mm Hg
    • Modified Medical Research Council (MMRC) Dyspnea Scale >= 3
• Patient must not have had previous intra-thoracic radiation therapy
• Women of child-bearing potential must have negative serum or urine pregnancy test
• No prior invasive malignancy, unless disease-free for >= 5 years prior to pre-registration (exceptions: non-melanoma skin cancer, in-situ cancers)
• PART II: INTRA-OPERATIVE CRITERIA (REGISTRATION)
• Patient must have biopsy-proven NSCLC
• Patient must have all suspicious mediastinal lymph nodes (> 1 cm short-axis dimension on CT scan or positive on positron emission tomography [PET] scan) assessed by one of the following methods to confirm negative involvement with NSCLC (mediastinoscopy, endo-esophageal ultrasound guided needle aspiration, CT-guided, video-assisted thoracoscopic or open lymph node biopsy)

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; Patients undergo open or thoracoscopic sublobar resection comprising either a wedge resection or anatomical segmentectomy.	Procedure: surgery
Experimental: Arm II; Patients undergo surgery as in arm I. Patients also undergo intraoperative brachytherapy comprising an iodine I 125 implant at the resection margin.	Procedure: surgery; Radiation: brachytherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Local Recurrence	Local recurrence included the recurrence within the same lobe or hilum (N1 nodes), or progression at the staple line after treatment effects such as scarring have subsided. Time to local recurrence was censored 1) at the time of a distant recurrence, 2) at the last follow-up time when a patient died within 3 years of randomization without a local recurrence or 3) at 3 years follow-up if the patient remains alive 3 years post-randomization without a local recurrence.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS was defined as the time from randomization to death due to any cause.	Up to 5 years
Number of Participants Reported Local Recurrence at 3 Years	Local recurrence was defined as the recurrence within the same lobe or hilum (N1 nodes), or at the staple line after treatment effects such as scarring have subsided.	3 years
Number of Participants Reported Regional Recurrence at 3 Years	Regional recurrence was defined as the recurrence within another lobe or pleura on the same side as the resection, or the ipsilateral mediastinal (N2) nodes.	3 years
Number of Participants Reported Distant Recurrence at 3 Years	Distant recurrence was defined as the recurrence within contralateral lobe, contralateral mediastinal (N3) nodes or distant> metastatic disease (other organs).	3 years
Mortality Rates at 30- and 90-day After Sublobar Resection		90 days
Number of Participants Reported Grade 3+ Adverse Events Within 90 Days After Sublobar Resection	Adverse Events were assessed via the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.	90 days
Number of Participants Reported Grade 3+ Respiratory Adverse Events Within 90 Days After Sublobar Resection	The respiratory AE included adult respiratory distress syndrome, aspiration, bronchospasm, bronchostenosis, dyspnea, hypoxia, pleural effusion, pneumonitis, chest tube drainage or leak, prolonged intubation, pulmonary-other, and pneumonia as defined by the CTCAE version 3.0.	90 days
Global QOL as Measured Using SF36 at Baseline, Month 3, 12 and 24	Short-form health survey (SF36) consist of 36 items, where scores can be reported as 8 domains of functional health and well-being, or transformed into a physical component summary (PCS) score and a mental component summary (MCS) score. Standardized scores of SF36 PCS and MCS scores were calculated using the mean, SD, and scoring coefficients from the US general population. The standardized scores were then adjusted for age and gender using the mean and SD of the US general population according to age and gender grouping, and employing a linear transformation. Scores <50 indicate below-average health status.	24 months
Dyspnea as Measured Using SOBQ at Baseline, Months 3, Months 12 and 24	Dyspnea was evaluated using the University of California, San Diego Shortness of Breath Questionnaire (SOBQ). It consists of 24-item on a scale of 0 to 5 with 0=not at all and 5=maximal or unable to do because of breathlessness. The total scores was calculated by summation of the 24 items scores and transformed into 0-100, with 0= poor quality of life , and 100= excellent quality of life..	24 months
FEV1% Measured at Baseline and Month 3	Pulmonary function tests included percentage predicted forced expiratory volume in 1 second (FEV1%) at baseline and month 3 were compared between arms	3 months
DLCO% Measured at Baseline and Month 3	Pulmonary function tests included percentage predicted carbon > monoxide diffusing capacity of the lung (DLCO%) at baseline and month 3 were compared between arms.	3 months

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Smith RP, Schuchert M, Komanduri K, Burton S, Heron DE, Luketich JD, d'Amato T, Landreneau R. Dosimetric evaluation of radiation exposure during I-125 vicryl mesh implants: implications for ACOSOG z4032. Ann Surg Oncol. 2007 Dec;14(12):3610-3. doi: 10.1245/s10434-007-9624-0. Epub 2007 Oct 2.
• Fernando HC, Landreneau RJ, Mandrekar SJ, Hillman SL, Nichols FC, Meyers B, DiPetrillo TA, Heron DE, Jones DR, Daly BD, Starnes SL, Tan A, Putnam JB. Thirty- and ninety-day outcomes after sublobar resection with and without brachytherapy for non-small cell lung cancer: results from a multicenter phase III study. J Thorac Cardiovasc Surg. 2011 Nov;142(5):1143-51. doi: 10.1016/j.jtcvs.2011.07.051. Epub 2011 Aug 26.
• Fernando HC, Landreneau RJ, Mandrekar SJ, Hillman SL, Nichols FC, Meyers B, DiPetrillo TA, Heron D, Jones DR, Daly BD, Starnes SL, Hatter JE, Putnam JB. The impact of adjuvant brachytherapy with sublobar resection on pulmonary function and dyspnea in high-risk patients with operable disease: preliminary results from the American College of Surgeons Oncology Group Z4032 trial. J Thorac Cardiovasc Surg. 2011 Sep;142(3):554-62. doi: 10.1016/j.jtcvs.2010.10.061. Epub 2011 Jul 2.
• Fernando HC, Landreneau RJ, Mandrekar SJ, Nichols FC, Hillman SL, Heron DE, Meyers BF, DiPetrillo TA, Jones DR, Starnes SL, Tan AD, Daly BD, Putnam JB Jr. Impact of brachytherapy on local recurrence rates after sublobar resection: results from ACOSOG Z4032 (Alliance), a phase III randomized trial for high-risk operable non-small-cell lung cancer. J Clin Oncol. 2014 Aug 10;32(23):2456-62. doi: 10.1200/JCO.2013.53.4115. Epub 2014 Jun 30.
• Fernando HC, Landreneau RJ, Mandrekar SJ, Nichols FC, DiPetrillo TA, Meyers BF, Heron DE, Hillman SL, Jones DR, Starnes SL, Tan AD, Daly BD, Putnam JB; Alliance for Clinical Trials in Oncology. Analysis of longitudinal quality-of-life data in high-risk operable patients with lung cancer: results from the ACOSOG Z4032 (Alliance) multicenter randomized trial. J Thorac Cardiovasc Surg. 2015 Mar;149(3):718-25; discussion 725-6. doi: 10.1016/j.jtcvs.2014.11.003. Epub 2014 Nov 13.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2005
• Primary Completion (Actual): April 18, 2013
• Study Completion (Actual): February 15, 2019

Study Registration Dates

• First Submitted: April 5, 2005
• First Submitted That Met QC Criteria: April 5, 2005
• First Posted (Estimate): April 6, 2005

Study Record Updates

• Last Update Posted (Actual): October 18, 2019
• Last Update Submitted That Met QC Criteria: October 4, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: stage I 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: ACOSOG-Z4032; CDR0000422346 (Registry Identifier: NCI Physician Data Query)