Current Status of Radiation in the Treatment of Breast Cancer
Current Status of Radiation in the Treatment of Breast Cancer
ABSTRACT: Radiation therapy in combination with lumpectomy and axillary dissection has remained standard therapy for early-stage disease since the 1970s. Although there has been no definitive trial in patients with ductal carcinoma in situ, the data suggest that excision plus radiation therapy is a viable option. The local management of early-stage breast cancer includes modified radical mastectomy, with or without reconstruction, or breast-conserving therapy. Six prospective randomized trials compared mastectomy with breast-conserving therapy, and all have shown equivalent survival. Despite efforts to identify subgroups of patients with invasive disease who do not require breast irradiation, based on current data, this modality remains standard treatment after conservative surgery in all patients. Ongoing multicenter studies may clarify the role of brachytherapy, which may provide advantages in some patients after breast-conserving therapy. Axillary radiation is a viable option for patients who fail to undergo sampling of the axilla and may be a future option for patients who have a positive sentinel node but no further dissection. The ability of postmastectomy radiation to affect survival has long been controversial. [ONCOLOGY 15(4):469-488, 2001]
Radiation therapy continues to have a major therapeutic role in the treatment of breast cancer. Radiation therapy in combination with lumpectomy and axillary dissection has been standard therapy for early-stage disease since the 1970s. There has been increasing interest recently in the use of postmastectomy radiation. A number of areas of controversy surround which patients will benefit from postmastectomy radiation. In addition to the questions about patient selection, the volumes and techniques of radiation continue to be redefined. This review will discuss the current status of radiation in breast cancer, with emphasis on the areas of controversy.
Before the widespread use of screening mammography, ductal carcinoma in situ (DCIS) was an uncommon diagnosis. Rosner, in an American College of Surgeons survey published in 1980, reported that only 2.1% of patients with ductal histology had noninvasive cancer. The age-adjusted incidence of DCIS increased more than 500% between 1973 and 1992.
Treatment options for DCIS range from mastectomy to excision plus radiation therapy to excision alone. Tamoxifen (Nolvadex) may also play a role in preventing recurrences. Mastectomy is curative in 95% to 100% of patients with DCIS.[3-5] As breast-conserving therapy for early-stage invasive disease became widely accepted, its use began to be investigated in DCIS patients.
Table 1 reviews the results of the treatment of DCIS with excision and radiation therapy.[5-10] The follow-up in these series varies, but recurrence rates ranged from 7% to 19%, and approximately 30% to 50% of recurrences were invasive.
No randomized trial has compared mastectomy vs lumpectomy and radiation in DCIS patients, as has been done for invasive disease. The review by Solin et al included 268 DCIS patients from 10 institutions in Europe and the United States, who were followed for a median of 10.3 years (range: 0.9 to 26.8 yr). In this series, the 15-year actuarial rate of local failure was 19% with a 96% cause-specific survival, despite the inclusion of a large number of patients with an unknown margin status. In summary, although there is no definitive trial, the data suggest that excision and radiation therapy is a viable treatment option for patients with DCIS.
A number of investigators have suggested that excision alone may be the most appropriate therapy in selected patients. Silverstein has been a leading proponent of excision alone. He and others developed the Van Nuyes index, which takes into account the size of the tumor, width of the margin, and pathologic classification. Based on their series, patients with a low score have a small chance of developing a recurrence.
In a follow-up publication, it appeared that margin status was highly predictive of recurrence. There are a number of limitations in attempting to generalize single-institution results. These limitations include the retrospective nonrandomized nature of the studies, the ability to reproduce the mammographic and pathologic elements of the evaluations, and the differences in treatment time between patients who had excision and radiation vs radiation alone. These problems have been discussed in detail by Schnitt et al.
Randomized Trials of Radiation Therapy
The most appropriate method for determining the value of radiation therapy in DCIS is a randomized trial. The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a prospective randomized trial in 818 women comparing excision alone vs excision and 50 Gy of radiation. Negative margins were required. At 90 months of follow-up, the incidence of invasive recurrence decreased from 13.4% to 3.9% with the addition of radiation therapy, and recurrences of DCIS decreased from 13.4% to 8.2%.
Similar results were obtained in a randomized trial conducted by the European Organization for Research and Treatment of Cancer (EORTC), in which 1,010 patients were randomized to either excision alone or excision and 50 Gy of radiation. At 4 years, the local relapse-free survival was 84% in the excision-alone arm and 91% in the radiation arm (P = .005).
In NSABP trial B-24, 1,804 patients with DCIS were randomized to 20 mg of tamoxifen daily for 5 years or placebo, after lumpectomy and radiation therapy. Initial results at 62 months revealed significant reductions in invasive recurrences (4.1% with tamoxifen, 7.2% without) and a nonsignificant reduction in DCIS recurrences (4.2% with tamoxifen, 6.2% without) with the addition of tamoxifen.
The current status of radiation therapy in the treatment of DCIS should continue to be dominated by the results of well-organized prospective randomized trials. The two large randomized trials reported from the NSABP and EORTC clearly demonstrate the need to add radiation therapy to excision in patients with DCIS. A legitimate argument can be made that there are sufficient data supporting the use of excision alone or combined with tamoxifen in subgroups of patients with a low enough risk of recurrence. This question is being explored in the Radiation Therapy Oncology Group (RTOG) randomized trial 98-04, which is comparing tamoxifen alone vs tamoxifen and radiation in good-risk DCIS patients.
The local management of early-stage breast cancer has been the subject of much interest over the last 20 years. Treatment options include modified radical mastectomy, with or without reconstruction, or breast-conserving therapy. Six prospective, randomized trials have compared mastectomy with breast-conservation therapy, and all have shown equivalent survival. The results of these trials are summarized in Table 2 and Table 3.[16-21]
Subgroups Who Do Not Need Radiation
Investigators have attempted to identify a subgroup of patients with invasive disease who do not need breast irradiation. In NSABP B-06, breast recurrences decreased with the addition of radiation in each tumor size group. In the smallest tumors (£ 1.0 cm), breast recurrences decreased from 21% to 11% (P = .06).
The Joint Center for Radiation Therapy at Harvard attempted to identify a subgroup of patients for whom treatment with conservative surgery alone would be appropriate. They performed a prospective single-arm trial. Eligibility for the trial included a tumor size ≤ 2 cm, negative axillary nodes, no lymphatic vessel invasion, no extensive intraductal component, and microscopic margin of at least 1 cm. With a median follow-up of 66 months, the crude local recurrence rate was 20%. Given the available data, breast irradiation continues to be standard treatment after conservative surgery in all subgroups of patients.
Areas of Controversy
There is general agreement about the appropriateness of breast-conserving therapy in stage I and II disease, but some areas of controversy remain regarding the specifics of radiation. These include the need for a tumor bed boost in patients with negative margins and the exact target volume.
Tumor Bed Boost: With the exception of the NSABP trial, all the other randomized trials listed in Table 2 and Table 3 used a boost to the tumor bed. A randomized trial reported by Romestaing et al in 1997 attempted to define the role of a 10-Gy boost after 50-Gy breast irradiation delivered in 20 fractions over 5 weeks. In this trial, 1,024 women were randomized to receive a boost or no boost after whole breast irradiation. At 5 years, the recurrence rate was 4.5% in patients who did not have a boost vs 3.6% rate in those who received a boost (P = .044). There was a higher rate of grade I and II telangiectasia in the boost patients, but no difference in the self-assessment score for the overall cosmetic result. Currently, I incorporate a tumor bed boost in the majority of my breast conservation patients.
Brachytherapy Options: After breast-conserving therapy, most recurrences occur in the same quadrant as the initial tumor.[25,26] This has led a number of investigators to consider brachytherapy alone after excision of the primary tumor. If brachytherapy could be substituted for external-beam radiation, it might give patients who are unable to receive daily radiation for 5 to 7 weeks the option of breast-conserving therapy. In addition to the logistical benefits of brachytherapy, there may be a biological advantage to the high central tumor bed dose of radiation given with brachytherapy and the ability to complete therapy in a short period of time.
Guy’s Hospital in Great Britain conducted a pilot study of low-dose rate iridium (Ir)-192 brachytherapy (ie, a dose of radiation delivered by brachytherapy at a rate of approximately 0.4 to 2 Gy/h) without external-beam radiation. This trial required only grossly negative margins and utilized a radiation dose of 55 Gy delivered over 5½ days. The study found a 15% local recurrence rate, with a 96% rate of excellent/good cosmesis as assessed by patients.
Kuske et al reported the results of a prospective phase I/II trial in 51 patients who received both low- and high-dose rate brachytherapy (where high dose rate referred to a dose of radiation delivered at a rate of approximately 0.2 Gy/min). Low and high dose rates were alternated in groups of 10 patients with histologically negative margins. Low-dose rate patients received 45 Gy in 3.5 to 6 days; high-dose rate patients received 32 Gy in 8 fractions over 4 days. A 5.8% grade 3 complication rate was seen, with no local recurrences and a 73% excellent/good cosmesis rate.
Investigators from William Beaumont Hospital entered 50 patients with tumors ≤ 3 cm and negative margins into a low-dose rate protocol delivering 50 Gy over 96 hours. No patient developed a recurrence, and the good/excellent cosmesis rate was 98%. A study by Polgar and colleagues also noted excellent control and cosmesis with brachytherapy alone after breast-conserving therapy. These results are being confirmed in a multi-institutional RTOG phase I/II trial. Accrual to this trial is complete, and the results are awaited.