The RTOG Cooperative Group celebrated its 40-year anniversary this year. However, the present Working Group is much younger, established in 1994 to focus on local-regional breast cancer issues involving radiation therapy questions. This chapter discusses those initiatives.

The concept of partial breast irradiation (PBI) was brought to the attention of the RTOG by Dr Robert Kuske, at one of the first meetings of the group. The idea was not new; Fentiman and colleagues had published a pilot study exploring the use of a small iridium 192 implant for breast cancer treatment in 1991. The local failure rate was higher than that of standard whole breast radiation, and the cosmetic outcome was inferior.1

However, both Kuske at the Ochsner Clinic and Vicini at William Beaumont Hospital pursued the idea of treating less than the whole breast after lumpectomy, utilizing low-dose-rate (LDR) and then high-dose-rate (HDR) brachytherapy when it became available. Based on their early, positive results,2,3 the RTOG Breast Group began to design the first cooperative group PBI trial, RTOG 95-17. This phase I/II trial specifically targeted small lesions (3 cm or less) with invasive ductal histology (IDC) only. Invasive lobular carcinoma was specifically excluded, as were patients with an extensive intraductal component to their IDC. This decision was made to exclude carcinomas characterized by microscopic extension beyond their clinically or radiographically apparent borders. In addition to the lumpectomy, an axillary node dissection was required, reflecting the surgical standard of the time. Women were eligible for entry in the trial with up to 3 nodes involved, although no extra capsular extension was allowed.

For women with an indication for systemic chemotherapy, the order of treatment was radiation first, followed by chemotherapy, with at least a 2-week interval from the completion of the radiation. The original accrual goal was 46 HDR cases and 46 LDR cases.

RTOG 95-17: Accrual and Results

The study opened in 1997 and completed accrual in 2000; 100 women were accrued, with just 1 excluded from analysis because she underwent a sentinel node biopsy only. Reflecting changing trends in brachytherapy, 66 cases were accrued to the HDR arm and 33 to the LDR arm. Of interest, only 11 RTOG institutions placed cases on this protocol, reflecting the high level of skill required of the oncologist to perform these implants.

This study set a high standard for quality assurance (QA), requiring a credentialing process for each participating center before enrolling cases. In addition, each case was “rapidly reviewed” by the principal investigator within 24 hours of catheter placement. For 8 patients, this led to revisions in their implant dosimetry prior to treatment. The success of the quality assurance program is evidenced by 96% of cases meeting specified requirements and only minor variation in the other 4% on final analysis.4 This plan formed the foundation for quality assurance in the large phase III RTOG 0413/NSABP B-39 trial that was to follow.

The 99 cases in this study included stage I-II breast cancer patients (88% T1 tumors, 20% N1 axilla) and with predominantly estrogen receptor–positive disease (75%). Median age of women in this study was 62 years; 45% were between the ages 50 and 69, 35% were 70 years or above, and just 21% were below 50 years. Tamoxifen was the most commonly used systemic agent, prescribed alone or in combination with chemotherapy in 55% of the patients. Analysis of this study demonstrated acceptable acute toxicity with 4% grade 3 to 4 toxicity occurring during treatment, 10% ≥ grade 3 toxicity at any point during follow-up and 4% ≥ grade 3 toxicity at last follow-up.5 The excellent/good cosmetic rate for 66 HDR patients at 2 years was 78% as reported by radiation oncologists, and 86% as reported by the patients.6 With a median follow-up time of 7 years, there have been 6 in-breast failures for a 5-year rate of 4% and 4 regional nodal failures for a 5-year rate of 3%.7

PBI with Mammosite Brachytherapy

Another brachytherapy technique for PBI was industry developed based on the principles of multicatheter PBI used in RTOG 95-17 with the goal of simplifying the technology to improve utilization. The MammoSite device is a single catheter with an inflatable balloon at the distal end that expands to fill the surgical cavity after placement. There are 2 channels in the catheter: one for balloon inflation with sterile normal saline and the second to carry a small radioactive source into the device after it is in position in the breast following a lumpectomy. An initial multi-institutional phase I-II study evaluating the feasibility and safety of the device treated 43 women with stage I breast cancer with invasive ductal histology only, between 2000 and 2001. The 5-year follow-up of the study has demonstrated excellent local control, and acceptable toxicity and cosmetic outcome.8

MammoSite was approved by the FDA in May 2002, and because of its relative simplicity to use, was met with great popularity across the United States. It is estimated that more than 2500 balloons were placed by late 2003.9 The original manufacturer of the device, Proxima Therapeutics, did initiate a registry for its use, which was taken over by the American Society of Breast Surgeons in late 2003. Its first report documented placement of the device in 1403 women enrolled in the study, from May 2002 through July 2004.10

In 2000, Vicini and colleagues at William Beaumont Hospital initiated a phase I/II study to explore an external beam method of doing PBI. Using 4 or 5 non-coplanar beams, and with additional margin around the planned target volume to accommodate breathing motion, the group reported on results with their first 9 patients in 2003. The initial dose in the study was 34 Gy in 10 fractions, delivered BID. However, in brachytherapy the dose prescribed is generally the minimum dose covering the target; the external beam technique resulted in a very uniform dose throughout the target. Based on radiobiology modelling, to estimate the equivalent dose to most of the target with external beam PBI compared to brachytherapy, the total dose was increased to 38.5 Gy.11

This study was rapidly embraced by the RTOG Breast Group, as a possible means of expanding its role in investigating PBI, but using a technology familiar to all RTOG members, not just those select few with the technical skills required to perform breast brachytherapy. Under Dr Vicini’s leadership, RTOG 0319 was conceived using similar entry criteria as 95-17. The most significant aspect of this trial is that a treatment planning computed tomography (CT) simulation was required, with contouring of both target and normal structures and a QA program for pretreatment documentation of dose delivery to the target and avoidance of normal tissues. This represents the first use of CT-based conformal radiation for breast cancer in a cooperative group clinical trial.

In just 9 months, 31 centers were credentialed for participation in the study, and accrual of 58 women was reached. Analysis of the first 42 patients in the study demonstrated both feasibility and reproducibility of this technique on a large scale across many centers.12 Other endpoints such as local control and cosmetic outcome will require longer follow-up.