NSABP PROTOCOL B-39 RTOG PROTOCOL 0413

Transcription

1 NSABP PROTOCOL B-39 RTOG PROTOCOL 0413 A Randomized Phase III Study of Conventional Whole Breast Irradiation (WBI) Versus Partial Breast Irradiation (PBI) for Women with Stage 0, I, or II Breast Cancer Date Opened for Accrual: March 21, 2005 Number of Patients: Accruing Protocol Chairs: Protocol Officers: Behavioral and Health Outcomes Officer: Protocol Statisticians: Behavioral and Health Outcomes Statistician: Protocol Pathologist: Frank Vicini, MD (NSABP) Julia White, MD (RTOG) Thomas Julian, MD (NSABP) David Parda, MD (NSABP) Michael Scheier, PhD (NSABP) Joseph P. Costantino, DrPH (NSABP) Kathryn Winter, MS (RTOG) Stephanie Land, PhD (NSABP) Soonmyung Paik, MD (NSABP)

2 NSABP PROTOCOL B-39 I. SPECIFIC AIMS The primary aim of this study is to evaluate the effectiveness of partial breast irradiation (PBI) compared to whole breast irradiation (WBI) in providing local tumor control in the breast following lumpectomy for early stage breast cancer. Secondary aims include the comparison of overall survival, recurrence-free survival, and distant disease-free survival between women receiving PBI and WBI, and the comparison of quality of life (QOL) parameters related to cosmesis, fatigue, treatment-related symptoms, and perceived convenience of care. NSABP B-39/RTOG 0413 SCHEMA Patients with Stage 0, I, or II Breast Cancer Resected by Lumpectomy Tumor Size 3.0 cm No More Than 3 Histologically Positive Nodes STRATIFICATION Disease Stage (DCIS only; invasive and node negative; invasive with 1-3 positive nodes) Menopausal Status (premenopausal, postmenopausal) Hormone Receptor Status (ER-positive and/or PgR-positive; ER-negative and PgR-negative) Intention to Receive Chemotherapy (yes or no) RANDOMIZATION GROUP 1 Whole Breast Irradiation (WBI) 50 Gy (2.0 Gy/fraction) or 50.4 Gy (1.8 Gy/fraction) to whole breast, followed by optional boost to Gy GROUP 2 Partial Breast Irradiation (PBI) 34 Gy in 3.4 Gy fractions using multi-catheter brachytherapy or 34 Gy in 3.4 Gy fractions using MammoSite balloon catheter or 38.5 Gy in 3.85 Gy fractions using 3D conformal external beam radiation For all PBI techniques: RT given to tissue surrounding lumpectomy cavity only, BID (with a fraction separation of at least 6 hours), for a total of 10 treatments given on 5 days over a period of 5 to 10 days.

3 II. STUDY DESIGN Patients must have stage 0 (DCIS) or stage I or II invasive adenocarcinoma of the breast with no evidence of metastatic disease. If stage II, tumor size must be three cm or less. Women must have undergone a lumpectomy with the margins of the resected specimen histologically free of cancer including DCIS. For patients with positive axillary nodes, eligibility is restricted to those with three or fewer positive axillary nodes. Patients are stratified according to disease stage, menopausal status, hormone receptor status, and intention to receive chemotherapy. Following stratification, patients are randomized to receive WBI or PBI. WBI for this study will utilize standard techniques delivered over five to seven weeks. PBI will utilize the technologies of high dose-rate multi-catheter brachytherapy, high dose-rate single catheter balloon brachytherapy (mammosite ), and three-dimensional conformal external beam radiation therapy. Ideally, PBI therapy will be given twice a day, at least six hours apart, on five treatment days over a period of five to ten days and the technique selected will depend on technical considerations, radiation oncology facility technique credentialing, as well as patient preference. Patients randomized to WBI will receive chemotherapy, if applicable, before their radiation therapy. Patients randomized to PBI will receive radiation therapy before chemotherapy, if applicable. The protocol was opened for accrual on March 21, This trial was designed to accrue 3,000 patients. On December 30, 2006, the accrual was stopped for two low-risk groups (DCIS patients who are 50 years of age or older regardless of hormone-receptor status; and node-negative, hormone receptor-positive patients who are 50 years of age or older with invasive disease). Because of this, the total accrual to the trial was increased from 3,000 to 4,300 women. A quality of life study will be performed in a subset of 964 protocol participants. The subset will include 482 enrolled patients who have indicated the intention to receive chemotherapy and 482 patients who have indicated the intention not to receive chemotherapy. III. SUMMARY OF DATA A. Patient Entry and Patient Characteristics As of December 31, 2009, a total of 3,636 patients have been randomized (Table 1). This represents about 85% of the total population to be accrued. At the current rate of accrual, it is anticipated that the study sample size of 4,300 patients will be obtained in July of Patient and tumor characteristics of all randomized patients are summarized in Table 2.

4 As of December 31, 2009, follow-up information is available for 3,381 of the 3,636 patients randomized (93%). Of all randomized patients, 59 have been declared ineligible. B. Toxicity As of December 31, 2009, data were available for 3,430 patients (94%). Tables 3a and 3b summarize the distribution of patients by the highest grade experienced within each type of toxicity reported. It should be noted that some patients have had concomitant adverse conditions which may result in these individuals appearing in several toxicity categories. There were 96 patients (6%) in the WBI group and 132 (7%) in the PBI group experiencing a grade 3 adverse event as their highest grade of toxicity. As of December 31, 2009, there were a total of ten grade 4 toxicities reported (four in the WBI group and six in the PBI group). There were two patients who had a grade 5 toxicity (cardiac ischemia and pneumonia), both in the PBI group.

5 NSABP Protocol B-39 Table 1. Summary of Patient Accrual Information Observed Protocol % Protocol Percent Accrual Observed Projected Projected Of Total Since Cumulative Cumulative Cumulative Target Date Last Date Accrual Accrual Accrual Accrual 3/20/ /31/ /30/ /30/ /31/ /31/ /30/ /30/ /31/ /31/ /30/ /30/ /31/ /31/ /30/ /30/ /31/ /31/ /30/ /30/ /31/ Total Target Accrual 4300 Protocol Activation Date March 21, 2005 Protocol Projected Completion Date* October 16, 2010 Needed Accrual 664 Average Monthly Accrual** 21.8 Additional Months Required 30.4 Current Estimated Completion Date July 13, 2012 * Revised according to accrual and sample size adjustment ** Averaged over the last six months

6 NSABP Protocol B-39 Table 2. Patient Characteristics Characteristics WBI PBI Total Number of Patients Entered On Study Ineligible Without Follow-up RANDOMIZED PATIENTS Mean Time on Study (months) Race* White Black/African American Asian Other Unknown Multi-Racial Ethnicity* Non-Hispanic Hispanic or Latino Unknown Disease Stage* DCIS Invasive N Invasive N Menopausal Status* Pre Post Age* <= Hormonal Status* ER or PR ER and PR Intended Chemotherapy* No Yes Intended PBI Technique* MCB MammoSite D Conformal EBR * Values are percent of all patients randomized.

7 31Dec2009 cut-off As of 04Jan2010 TABLE 3a NSABP PROTOCOL B-39 (WHOLE VS PARTIAL IRRADIATION) GREATEST TOXICITY GRADE PER PATIENT ALL PATIENTS ALL REPORTING PERIODS Frequency Report WBI (N= 1659) PBI (N= 1771) WBI Percent Report PBI Toxicity OVERALL TOXICITY < <1 <1 CONSTITUTIONAL SYMPTOMS Fatigue <1 0 DERMATOLOGY/SKIN Dermatitis Chemoradiation < <1 0 0 Dermatitis Radiation Hyperpigmentation Induration < Telangiectasia < <1 0 0 Ulceration < Wound complication, non-infectious <1 < <1 <1 0 0 INFECTION Infection with normal ANC Skin (cellulitis) < <1 0 0 Infection with normal ANC Wound < LYMPHATICS Edema: limb <1 0 0 Edema: trunk/genital < <1 0 0 MUSCULOSKELETAL/SOFT TISSUE Fibrosis-cosmesis < Fibrosis-deep connective tissue < Seroma < <1 0 0 Soft tissue necrosis Thorax <1 < <1 <1 0 0 PAIN Pain Breast <1 0 Pain - Other (Specify) PULMONARY/UPPER RESPIRATORY Cough <1 < Dyspnea <1 <1 0 0 Pneumonitis <1 <1 < <1 <1 0 0 SEXUAL/REPRODUCTIVE FUNCTION Breast < <1 0 0 Nipple/areolar < OTHER TOXICITIES (Not Named on AE Form) Overall Other <1 < <1 <1 <1

8 31Dec2009 cut-off As of 04Jan2010 TABLE 3b NSABP PROTOCOL B-39 (WHOLE VS PARTIAL IRRADIATION) GREATEST TOXICITY GRADE PER PATIENT ALL PATIENTS ALL REPORTING PERIODS OTHER TOXICITIES LISTED ON AE FORM Frequency Report WBI (N= 1659) PBI (N= 1771) WBI Percent Report PBI Toxicity BLOOD/BONE MARROW Hemoglobin < < Leukocytes <1 < <1 0 Lymphopenia <1 0 < CARDIAC ARRHYTHMIA Cardiac Arrhythmia - Other (Specify) < Palpitations <1 < Prolonged QTc < CARDIAC GENERAL Cardiac ischemia/infarction <1 Hypertension < Pericardial effusion <1 0 0 CONSTITUTIONAL SYMPTOMS Constitutional Symptoms - Other (Specify) < Fever < <1 < Insomnia < <1 < Sweating < Weight gain < <1 0 <1 0 0 Weight loss <1 < < DERMATOLOGY/SKIN Alopecia <1 < <1 < Atrophy, skin <1 < < Atrophy, subcutaneous fat < < Bruising Burn < <1 < Chelitis < Decubitus < Dermatology - Other (Specify) <1 < <1 <1 0 0 Dry skin < < Erythema multiforme < Flushing < Hypopigmentation < < Nail changes < < Photosensitivity < <1 < Pruritus < < Rash < Striae < < ENDOCRINE Endocrine - Other (Specify) <

9 31Dec2009 cut-off As of 04Jan2010 TABLE 3b NSABP PROTOCOL B-39 (WHOLE VS PARTIAL IRRADIATION) GREATEST TOXICITY GRADE PER PATIENT ALL PATIENTS ALL REPORTING PERIODS OTHER TOXICITIES LISTED ON AE FORM Frequency Report WBI (N= 1659) PBI (N= 1771) WBI Percent Report PBI Toxicity Hot flashes <1 < <1 0 0 GASTROINTESTINAL Anorexia < < Constipation <1 < < Dehydration <1 <1 0 0 Diarrhea <1 < <1 0 <1 0 0 Dry mouth < Dysphagia < < Esophagitis < Heartburn < < Mucositis (clinical exam) Oral cavity < Mucositis (functional/symptomatic) Oral cavity < Nausea < <1 <1 0 0 Proctitis < Taste alteration < < Vomiting <1 <1 < <1 <1 <1 0 0 HEMORRHAGE/BLEEDING CNS hemorrhage <1 0 Hematoma < < Hemorrhage - Other (Specify) < < Hemorrhage, pulmonary Nose < Petechiae < INFECTION Febrile neutropenia <1 0 0 Infection (documented clinically) Lung (pneumonia) < Infection (documented clinically) Urinary tract 1658 NO < Infection - Other (Specify) <1 < <1 <1 0 0 Infection with normal ANC Lung (pneumonia) < <1 Infection with normal ANC Soft tissue NOS < Infection with unknown ANC Bronchus < Infection with unknown ANC Lymphatic < Infection with unknown ANC Salivary gland < Infection with unknown ANC Skin (cellulitis) < Infection with unknown ANC Wound <1 < < Opportunistic infection < LYMPHATICS Dermal change < Edema: head and neck < Lymphatics - Other (Specify) <

10 31Dec2009 cut-off As of 04Jan2010 TABLE 3b NSABP PROTOCOL B-39 (WHOLE VS PARTIAL IRRADIATION) GREATEST TOXICITY GRADE PER PATIENT ALL PATIENTS ALL REPORTING PERIODS OTHER TOXICITIES LISTED ON AE FORM Frequency Report WBI (N= 1659) PBI (N= 1771) WBI Percent Report PBI Toxicity Lymphedema-related fibrosis < <1 < Phlebolymphatic cording <1 0 <1 0 0 METABOLIC/LABORATORY ALT < < AST < Cholesterol < < Creatinine < Hyperglycemia < Hypertriglyceridemia < Hyperuricemia < MUSCULOSKELETAL/SOFT TISSUE Arthritis < Extremity-upper (function) < Fracture < Joint-function < < Muscle weakness Extremity-lower < Muscle weakness Extremity-upper < < Muscle weakness Whole body/generalized <1 < Musculoskeletal - Other (Specify) <1 < <1 < Myositis < < Osteonecrosis < Osteoporosis < NEUROLOGY Confusion < Dizziness <1 < <1 < Mood alteration Agitation < Mood alteration Anxiety <1 < <1 < Mood alteration Depression <1 < <1 <1 0 <1 0 Neurology - Other (Specify) <1 0 0 Neuropathy - motor < <1 <1 <1 0 0 Neuropathy - sensory < < Tremor < OCULAR/VISUAL Blurred vision <1 < Dry eye < Flashing lights < Keratitis < Uveitis < Watery eye <

11 31Dec2009 cut-off As of 04Jan2010 TABLE 3b NSABP PROTOCOL B-39 (WHOLE VS PARTIAL IRRADIATION) GREATEST TOXICITY GRADE PER PATIENT ALL PATIENTS ALL REPORTING PERIODS OTHER TOXICITIES LISTED ON AE FORM Frequency Report WBI (N= 1659) PBI (N= 1771) WBI Percent Report PBI Toxicity PAIN Pain Abdomen NOS < Pain Back <1 <1 0 0 Pain Bone < <1 < Pain Chest wall < < Pain Chest/thorax NOS < Pain Extremity-limb < < Pain Head/headache < < Pain Joint < Pain Muscle < < Pain Neuralgia/peripheral nerve < Pain Pain NOS < Pain Pelvis < Pain Pleura < PULMONARY/UPPER RESPIRATORY Atelectasis < Bronchospasm < < Hypoxia < <1 0 0 Pleural effusion <1 <1 0 0 Pulmonary - Other (Specify) < < Pulmonary fibrosis <1 < < Voice changes < SECONDARY MALIGNANCY Secondary Malignancy (possibly related to cancer 1658treatment) < SEXUAL/REPRODUCTIVE FUNCTION Breast function < Gynecomastia < Irregular menses <1 < Sexual - Other (Specify) <1 <1 < < Vaginal discharge < Vaginal dryness < < SURGERY/INTRA-OPERATIVE INJURY Intraop Injury - Other (Specify) <1 0 < VASCULAR Phlebitis < Thrombosis/thrombus/embolism < <1 0 Vascular - Other (Specify) < <