A Randomized Comparison of Radiation Therapy Techniques in the Management of Node Positive Breast Cancer

Radiotherapy has been shown to reduce breast-cancer specific mortality in patients at high risk for distant dissemination. It has also been shown to increase rates of non-breast cancer deaths and morbidity due to cardiovascular and pulmonary toxicity. Although treatment planning has improved significantly through the years, recent reports still demonstrate treatment-related morbidity even with 3-dimensional planned techniques. Thus, while 3D planning represents the state of the art treatment for loco-regional radiotherapy for breast cancer, further improvement is needed to continue to decrease heart and lung exposure. The ultimate goal of the proposed research is to determine whether treatment planning using intensity-modulated radiotherapy (IMRT), the "next generation" of radiation treatment delivery systems, results in less radiation exposure to the heart and lungs than the best current RT technique in women with node positive breast cancer. This proposal will test the potential clinical value of IMRT compared to the best standard 3D plan (partially wide tangent fields, PWTF) in the treatment of breast cancer. These two treatment techniques will be studied in a Phase II randomized trial using quantitative indicators of potential cardiac and lung toxicity. The preliminary data generated from this trial will be used to ultimately justify a multi-institutional comparison of the two treatment techniques with long-term clinical cardiac and pulmonary toxicity as endpoints.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Radiation: IMRT; Radiation: 3D

Detailed Description

1. Primary Objective 1.1 To compare the extent of new myocardial perfusion defects following breast cancer radiotherapy using the best standard 3-D radiotherapy technique, partially wide tangent fields, versus the best optimized technique.
2. Secondary Objectives 2.1 To compare changes in ejection fraction and alterations in cardiac wall motion with treatment by technique 2.2 To compare changes in lung perfusion defects and pulmonary function tests (DLCO, FEV1, and FVC) by technique 2.3 To compare rates of pericarditis and pneumonitis by technique

Cardiac Endpoints: Myocardial SPECT-CT perfusion defects, ejection fraction, alterations in cardiac wall motion, per SPECT-CT (adenosine stress and rest (if necessary)) scan.

Pulmonary Endpoints: Lung SPECT-CT perfusion defects per SPECT-CT scan, and changes in pulmonary function tests: DLCO, FEV1, FVC Clinical Endpoints: pericarditis and pneumonitis.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5010
      • University of Michigan Health Systems

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:

Eligibility Criteria

• Breast cancer diagnosis: Patients must have histologically confirmed adenocarcinoma of the breast requiring comprehensive loco-regional irradiation that includes treatment to the intact breast/chest wall, supraclavicular (SCV), infraclavicular nodes (ICV), and internal mammary nodes (IMN).
• Patients must have pathologic T 1, 2, 3 or 4, N 1, 2, or 3 Stage II or III disease as defined by the AJCC Staging System, 6th edition. Patients who do not undergo axillary staging but are at risk for nodal involvement may also be treated.
• All patients must have left-sided breast cancer.
• Both men and women are eligible.
• Patients must be adults (18 years of age or older)
• For women of child-bearing age, effective contraception must be used. A written statement must be obtained that the patient is not pregnant. If there is any question of pregnancy at time of therapeutic RT or at time of each SPECT-CT scan, a pregnancy test will be done to confirm the patient is not pregnant.
• Performance status should be 0-2 by ECOG criteria.
• Patients that have received prior RT may be enrolled on the present study if the new breast lesion can be treated with no overlap of RT fields.
• Patients must be aware of the neoplastic nature of her/his disease.
• Patients must be informed of the investigational nature of this study and must sign an informed consent in accordance with the Institutional Review Board (IRB) of the University of Michigan and federal guidelines.
• Patients' blood tests should indicate they are able to tolerate radiotherapy. Tests must be done within 28 days of registration:

CBC with differential and platelet count (Hemoglobin > 8.0 g/dl; wbc > 2000/mm3; absolute neutrophil count > 1000/mm3; platelet count > 75,000/mm3.

Exclusion Criteria:

• Patients who are pregnant or are nursing are excluded.
• Pathologically node negative breast cancer unless treated with neo-adjuvant chemotherapy.
• Performance status > 2 by ECOG criteria
• Patients who are unable to lie on their back and raise their arm above their head in the treatment planning position for radiotherapy
• Patients with a clinically unstable medical condition
• Patients with a life-threatening disease state
• History or suspicion of serious life-threatening allergic reaction to Tc-99m imaging agents.
• Patients that have had breast-conservation surgery with positive margins or any patient with negative margins with a tumor positive for an extensive intraductal component.
• Patients that are not able to use the ABC device.

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
Experimental: 1; Best Delivery-optimized radiotherapy technique (IMRT)	Radiation: IMRT; All patients treated with the optimized plan will be treated to the entire target volume to 52.2 Gy in 1.74 Gy fractions, which is biologically equivalent to 50 Gy in 2 Gy fractions. This fractionation scheme will allow the boost of 10 Gy to be incorporated into the planning directive and to be delivered simultaneously with the treatment to the remaining target volume.
Active Comparator: 2; Best 3-dimensional standard PWTF technique	Radiation: 3D; All patients treated using the best standard technique will receive 50 Gy in 2 Gy fractions or 50.4 Gy in 1.8 Gy fractions to the entire target volume delivering one treatment per day, five fractions per week (excluding holidays). A boost of 10 Gy to the tumor bed of an intact breast will be delivered. Patients treated to the chest wall will receive a 10Gy scar boost if mastectomy margins are positive in a patient with Stage II disease or if the patient was originally diagnosed with T3 or T4 (Stage III) disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants With a Significant Increase in Perfusion Defects (PD)	To compare the extent of new myocardial perfusion defects following breast cancer radiotherapy using the best standard 3-D radiotherapy technique, partially wide tangent fields, versus the best optimized technique. Perfusion defects (PD) were assessed by comparing normalized perfusion distributions against our institution's normal polar map databases for the left anterior descending artery (LAD) using thresholds of 2.5-SD (standard deviation) and 1.5-SD below the normal mean. On the basis of interest variability, a PD increase greater than 5% or 10% was considered significant for 2.5- and 1.5-SD thresholds, respectively.	1 Year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Percent Change in Ejection Fraction (LVEF)	To compare change in ejection fraction between treatment arms.	baseline to approx 1 year
Number of Participants With New Lung Perfusion Defects	To compare changes in lung perfusion defects by treatment arm. Perfusion defects (PD) were assessed by comparing normalized perfusion distributions against our institution's normal polar map databases for the left anterior descending artery (LAD).	baseline to approx 1 year
The Number of Participants That Experience Pericarditis and Pneumonitis	To compare rates of pericarditis and pneumonitis by treatment arm. Pericarditis (inflammation of the pericardium): Grade1: Asymptomatic, ECG or physical exam; changes consistent with pericarditis Grade 2: Symptomatic pericarditis Grade 3: Pericarditis with physiologic consequences Grade 4: Life-threatening Pneumonitis (inflammation of the walls of the alveoli in the lungs) Grade 1: Asymptomatic, radiographic findings only Grade 2: Symptomatic, not interfering with ADL (activities of daily living) Grade 3: Symptomatic, interfering with ADL Grade 4: Life-threatening	approx 1 year

Collaborators and Investigators

• Sponsor: University of Michigan Rogel Cancer Center
• Investigators: Principal Investigator: Lori Pierce, MD, University of Michigan Rogel Cancer Center

Publications and helpful links

General Publications

• Jagsi R, Griffith KA, Moran JM, Ficaro E, Marsh R, Dess RT, Chung E, Liss AL, Hayman JA, Mayo CS, Flaherty K, Corbett J, Pierce L. A Randomized Comparison of Radiation Therapy Techniques in the Management of Node-Positive Breast Cancer: Primary Outcomes Analysis. Int J Radiat Oncol Biol Phys. 2018 Aug 1;101(5):1149-1158. doi: 10.1016/j.ijrobp.2018.04.075. Epub 2018 May 5.

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: December 20, 2007
• First Submitted That Met QC Criteria: December 25, 2007
• First Posted (Estimate): December 27, 2007

Study Record Updates

• Last Update Posted (Actual): October 31, 2017
• Last Update Submitted That Met QC Criteria: September 28, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: left sided
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: UMCC 2004.038; IRB #2002-387 ~ HUM 39607 (Other Identifier: University of Michigan Medical IRB)