Severe complications requiring a mastectomy occurred in three patients (skin necrosis in one and severe breast pain in two). The lack of stringent selection criteria and inclusion of patients with large tumors that required higher radiation doses resulted in toxicity and inferior cosmetic outcomes.

Resch et al[13] reported that when using pulsed–dose-rate brachytherapy alone, prescribing a dose of 40.2 to 50 Gy limited the toxicity to moderate grade 1/2 fibrosis only.

• High Dose Rate—Limited data are available for the use of high–dose-rate brachytherapy for retreatment. A preliminary experience in 10 patients was reported by Trombetta et al[10] using the intracavitary MammoSite balloon technique. With a reirradiation dose of 3.4 Gy × 10 fractions, these investigators’ observations suggest acceptable toxicity and good cosmesis. However, the authors suggest alternative intracavitary techniques might achieve better dosimetry when the tumor bed is in proximity to the skin of the breast or the rib. The authors caution that these preliminary observations warrant additional study, with specific attention to technique and dose fraction schedule.

Protocols using high–dose-rate brachytherapy will need to establish safe dose thresholds for breast, skin, and subcutaneous tissues. The established high–dose-rate brachytherapy dosimetric guidelines used when prescribing PBI as primary treatment for the initial diagnosis of breast cancer may not necessarily be the optimal dose for reirradiation.

External-Beam Radiotherapy
Recht et al[18] reported on a single case of in-breast recurrence treated with wide excision and postoperative external irradiation; the patient was disease free at 72 months postprocedure. Mullen et al[35] published an initial report describing a series of patients retreated with external-beam therapy at a dose of 5,000 cGy (200 cGy/fraction) to the involved quadrant only. All patients had a prior history of receiving 4,500 to 5,040 cGy at 180 to 200 cGy/fraction as part of initial BCT. Deutsch[11] later expanded the series reporting on 39 patients, with in-breast invasive ductal carcinoma in 31 and DCIS in 8 patients. Five patients had positive margins of resection at the time of reirradiation. The 5-year disease-free and overall survival rates were 68.5% and 77.9 %, respectively. The reported cosmetic results were good in 12 patients, fair in 15 patients, and poor in 9 patients (Figures 3A and 3B).

• RTOG Phase II Trial—A proposed Radiation Therapy Oncology Group (RTOG) phase II study will include patients experiencing an in-breast recurrence after lumpectomy and whole-breast irradiation for primary early-stage breast carcinoma (personal communication, D. Arthur, 2009). Patients with biopsy-proven recurrent tumors ≤ 3 cm in greatest dimension, and with mammographic or magnetic resonance imaging (MRI) documenting no evidence of multicentric disease are eligible. Patients with ≤ 1 year between whole-breast radiation therapy and recurrence will be ineligible.

The retreatment will consist of a second lumpectomy followed by a hyperfractionated regimen of 1.5 Gy twice daily for a total dose of 45 Gy delivered in 30 treatments over 15 days using the 3D-conformal PBI technique. The protocol will include only one PBI technique, to gain meaningful and interpretable results without adding the confounding variable of varying dosimetry within the target. The 3D conformal technique was also selected because its reproducibility has been established in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B39/RTOG 0413 phase III trial, and it is the most common PBI technique used by the participating institutions. Concerns about clinical safety and toxicity of reirradiating normal tissues weighed on the choice of the dose fractionation schedule (personal communication, D. Arthur, 2009).

It is anticipated that approximately 69 patients are needed to answer the primary goal of the trial and, with the participation of multiple centers, that enrollment will be completed in a 2-year period. The endpoints of the study will include incidence of acute and late toxicity, cosmetic results, local control rate, and freedom-from-mastectomy rate. In addition, a translational study is incorporated in the protocol as a secondary endpoint to evaluate the rate of circulating tumor cells in this patient population as well as their significance and predictive ability with regard to outcome. With a prospective national study, we will gain additional clinical experience in this controversial treatment approach.

Conclusions

In an era of individualized care, the treatment options for second cancer events in a previously irradiated breast need to be redefined. Due to the accepted bias that a second lumpectomy and reirradiation is associated with unacceptable soft-tissue toxicity and cosmesis, the alternative to mastectomy has never been primarily studied in a large clinical trial. In light of recent advances on many fronts—including improved understanding of the biology of breast disease, imaging modalities, and advances in targeted radiation therapy techniques—there is a renewed interest in studying the alternative of breast conservation for patients presenting with a small recurrence in the previously irradiated breast.

Better selection using biologic markers may be forthcoming. Studies suggest that new primary tumors in a breast previously treated for cancer have a more favorable outcome than true local recurrences. Further research in the area of genetic fingerprinting will provide more accurate means of distinguishing between true recurrence and a new primary by identifying a true clonogenic recurrence from de novo cancer.

With careful selection criteria, there may be opportunities to individualize treatment options and to offer women a second chance at breast conservation. Early data on a second chance at breast conservation, as published in the literature, suggest that mastectomy may not be the only treatment option for women who have a small second cancer in a previously irradiated breast. Finally, as proposed by the RTOG, a prospective multi-institutional trial would be the appropriate means of addressing this controversial clinical issue.

Case Report: A Woman With a Local Breast Recurrence Who Refuses Mastectomy
A 54-year-old female diagnosed in 1988 with stage T1, cN0 infiltrating duct cell cancer at the 12 o’clock axis of the right breast was treated with lumpectomy and axillary dissection followed by external-beam radiation therapy, receiving a total dose of 60 Gy. She also received adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy followed by tamoxifen for a period of 3 years.

In February 2003, on self-exam the woman palpated an approximately 1-cm freely mobile mass in the lower outer quadrant of the right breast. Pathology confirmed a 1.5-cm poorly differentiated infiltrating duct cell cancer. The workup included a bilateral MRI that reported no additional lesions.

The patient refused the recommended mastectomy and signed an informed consent to participate in an IRB-approved reirradiation protocol to have a second lumpectomy and partial breast brachytherapy. In April 2003, following lumpectomy and pathologically documented negative margins, a multicatheter interstitial implant was performed. The patient received 45 Gy at 9 Gy per day low–dose-rate brachytherapy using Ir-192 ribbons. With the exception of breast asymmetry secondary to volume loss from the second lumpectomy, the cosmetic result achieved was good and has remained stable. At last follow-up (6/17/09) the patient was alive and well with an intact breast and no evidence of disease (see Figure).