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Is Less More? Lessons in Radiation Schedules in Breast Cancer Carolyn I. Sartor, Joel E. Tepper A 1990 National Institutes of Health consensus conference concluded that appropriate conservative therapy for breast cancer includes postexcision breast radiotherapy. However, patterns-of-care studies show that, although more patients are being treated with breast-conserving surgery, the use of radiotherapy in this setting is declining and the likelihood of receiving radiotherapy is related to insurance, race, income, and distance from radiotherapy centers (1–4). To help alleviate the strain on patient and institutional resources that a 5- to 6-week radiotherapy treatment course creates, several Canadian institutions have explored delivery of shorter radiotherapy regimens, demonstrating acceptable cosmesis and local control of breast cancer in prospective nonrandomized and retrospective matched-control series. Although radiobiologic principles dictate that, given enough dose per fraction and total dose, radiation therapy delivered in more rapid treatment schedules can be as effective in controlling tumor recurrence as longer schedules, the issue is whether the toxicity and cosmesis will remain acceptable. In this issue of the Journal, Whelan et al. (5) report the initial results of a randomized comparison of two radiation fractionation schedules—42.5 Gy in 16 fractions over 22 days (2.65 Gy/day) and a standard regimen of 50 Gy in 2-Gy fractions over 35 days—in lymph node-negative, margin-negative breast cancer patients. The shortened course did not result in excess ipsilateral breast tumor recurrence or in worse cosmesis. At a median follow-up of 69 months, the 5 year in-breast recurrence (invasive and in situ) rates were 4% in both treatment arms. This recurrence rate is similar to the recurrence rate seen in a nonrandomized prospective trial in Vancouver (6) of 186 lymph node-negative patients treated with 44 Gy in 16 fractions (2.75 Gy per fraction), which was 6% at a median follow-up of 6.7 years, and to the recurrence rate seen in a retrospective analysis from Ontario of 294 patients treated with 40 Gy in 16 fractions (2.5 Gy per fraction), which was 3.5% at a median follow-up of 5.5 years (7). 1114 EDITORIALS With a larger dose per fraction, poor cosmesis (e.g., fibrosis and edema), cardiotoxicity, and brachial plexopathy are concerns. Neither supraclavicular nor axillary fields were used in the present study of lymph node-negative patients, so brachial plexopathy is not anticipated. The follow-up duration is insufficient to define rates of cardiac injury, which are being followed. Cosmesis, however, was reportable and was not found to be worse in the shorter-course arm, confirming the acceptable rates of excellent or good cosmesis demonstrated in the nonrandomized, single-institution studies (6,7). Does this study set a new standard for adjuvant external beam radiotherapy for early-stage breast cancer? Perhaps, in certain situations. Of 3732 screened patients with early-stage, lymph node-negative breast cancer treated with breast-conserving therapy, more than one third were not deemed appropriate candidates for the trial. One reason for exclusion was the presence of invasive or intraductal carcinoma at the inked margin of excision. Margin status may be particularly important for adequate local control when using shorter radiotherapy regimens that do not include a boost (additional radiotherapy directed to the tumor bed after the course of radiotherapy to the entire breast). In the Ontario study (7), 12 patients with clear margins but with tumor cells within 2 mm of the margin were treated without a boost, and two of the 12 patients developed in-breast recurrence within 5 years. Two other studies (8,9) of shorter radiotherapy courses, in which negative margins were not required, demonstrated a 12%–13% recurrence rate without a tumor bed boost. Because the incidence of recurrence in patients excised with Affiliation of authors: University of North Carolina School of Medicine, Chapel Hill. Correspondence to: Carolyn I. Sartor, M.D., University of North Carolina School of Medicine, Department of Radiation Oncology, Campus Box 7512, Chapel Hill, NC 27599-7512 (e-mail: [email protected]). © Oxford University Press Journal of the National Cancer Institute, Vol. 94, No. 15, August 7, 2002 close margins was not reported in the present randomized trial, caution should be exercised in applying these results to patients with close margins. Another reason for exclusion from the present study was large breast size, because earlier studies demonstrated worse cosmesis with a large dose per fraction in patients with large breasts. Thus, the results do not apply to large-breasted women. Other features associated with at least a 10% risk of ipsilateral breast tumor recurrence within 5 years in nonrandomized studies of shorter fractionation schemas include lobular histology and lack of estrogen receptor expression. Therefore, caution should be exercised when extrapolating the results of Whelan et al. to patients with these features (7). Furthermore, the results of this trial do not apply to patients with ductal carcinoma in situ, because such patients were excluded. Finally, given that only 11% of patients received chemotherapy, the acceptable toxicity and cosmesis seen with this fractionation may not be obtained in patients treated with chemotherapy. Nearly half the patients who met all stated eligibility criteria declined to participate, illustrating the difficulties in accruing patients to randomized clinical trials that offer less versus standard radiotherapy. However, this level of nonparticipation may also reflect physician bias, with unknown selection factors that could affect the ability to generalize these results to standard practice. Even though patients with stage T2 tumors (2–5 cm in greatest dimension) were eligible for the trial, 80% of the patients enrolled had stage T1 tumors (艋2 cm in greatest dimension). Fewer than 20% had high-grade tumors, and fewer than one third had estrogen receptor-negative disease. These favorable tumor characteristics are reflected in the low use of chemotherapy. The success of reduced fractionation may depend on careful selection for patients with a low likelihood of a substantial burden of residual malignant cells in the breast after breastconserving surgery. The Whelan et al. study thus supports the use of a shorter course of radiotherapy for patients with the most favorable infiltrating ductal carcinomas. However, it may be possible to make therapy even shorter, more convenient, and perhaps less expensive. This same subset of patients may be well-treated with partial breast irradiation, which enables delivery of radiotherapy over very short periods by using brachytherapy, intraoperative radiotherapy, or conformal techniques as the sole treatment modality. Single-institution experience with partial breast brachytherapy (32 Gy over 4 days), delivered by experienced clinicians (10), demonstrates excellent local control with preservation of cosmesis and may be technically more generally applicable if devices are used that simplify brachytherapy, such as the MammoSite, an applicator for brachytherapy sources (11). Preliminary results using intraoperative radiotherapy as the sole treatment for this favorable subset of patients (21 Gy in one fraction) are promising, raising the possibility of shortening treatment to a single day for such patients (12). However, all partial breast radiotherapy techniques (as sole therapy) should be considered experimental at this time. The carefully performed and reported study by Whelan et al. demonstrates that, in carefully selected patients, use of shorter, less expensive, and more convenient radiotherapeutic approaches can produce excellent local control of breast cancer with acceptable cosmesis. It is premature to generalize these results beyond the categories of patients actually treated in the trial, but, with further technologic and biologic advances, perhaps we can ultimately do even “less.” REFERENCES (1) Nattinger AB, Hoffmann RG, Kneusel RT, Schapira MM. Relation between appropriateness of primary therapy for early-stage breast carcinoma and increased use of breast-conserving surgery. Lancet 2000;356:1148–53. (2) Morrow M, White J, Moughan J, Owen J, Pajack T, Sylvester J, et al. Factors predicting the use of breast-conserving therapy in stage I and II breast carcinoma. J Clin Oncol 2001;19:2254–62. (3) McGinnis LS, Menck HR, Eyre HJ, Bland KI, Scott-Conner CE, Morrow M, et al. National Cancer Data Base survey of breast cancer management for patients from low income zip codes. Cancer 2000;88:933–45. (4) Athas WF, Adams-Cameron M, Hunt WC, Amir-Fazli A, Key CR. Travel distance to radiation therapy and receipt of radiotherapy following breastconserving surgery. J Natl Cancer Inst 2000;92:269–71. (5) Whelan T, MacKenzie R, Julian J, Levine M, Shelley W, Grimard L, et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst 2002; 94:1143–50. (6) Olivotto IA, Weir LM, Kim-Sing C, Bajdik CD, Trevisan CH, Doll CM, et al. Late cosmetic results of short fractionation for breast conservation. Radiother Oncol 1996;41:7–13. (7) Shelley W, Brundage M, Hayter C, Paszat L, Zhou S, Mackillop W. A shorter fractionation schedule for postlumpectomy breast cancer patients. Int J Radiat Oncol Biol Phys 2000;47:1219–28. (8) Clark RM, Wilkinson RH, Miceli PN, MacDonald WD. Breast cancer. Experiences with conservation therapy. Am J Clin Oncol 1987;10:461–8. (9) Yamada Y, Ackerman I, Franssen E, MacKenzie RG, Thomas G. Does the dose fractionation schedule influence local control of adjuvant radiotherapy for early stage breast cancer? Int J Radiat Oncol Biol Phys 1999;44:99–104. (10) Baglan KL, Martinez AA, Frazier RC, Kini VR, Kestin LL, Chen PY, et al. The use of high-dose-rate brachytherapy alone after lumpectomy in patients with early-stage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys 2001;50:1003–11. (11) Edmundson GK, Vicini FA, Chen PY, Mitchel C, Martinez AA. Dosimetric characteristics of the MammoSite RTS, a new breast brachytherapy applicator. Int J Radiat Oncol Biol Phys 2002;52:1132–9. (12) Veronesi U, Orecchia R, Luini A, Gatti G, Intra M, Zurrida S, et al. A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated. Eur J Cancer 2001;37: 2178–83. Journal of the National Cancer Institute, Vol. 94, No. 15, August 7, 2002 EDITORIALS 1115