• Low Dose Rate—The selection of low–dose-rate brachytherapy for retreatment is mostly based on the fact that practitioners have had the longest clinical experience with this technique. Moreover, the low–dose-rate approach may be radiobiologically safer in the retreatment setting, by limiting the risk of late effects while potentially delivering higher radiation doses in the tumor cavity. This technique, however, requires that the physician be experienced in brachytherapy.
The feasibility and safety of brachytherapy to reirradiate a recurrent tumor bed in the breast using a dose of 30 Gy was studied at Beth Israel Medical Center. The target volume was identified as the lumpectomy cavity plus 1- to 2-cm margin, and the prescription isodose was defined as the dose encompassing the target volume. In cases where the skin proximity was of concern, the calculated skin dose was maintained at ≤ 20 Gy.
After administering a dose of 30 Gy, no major toxicity was observed over a follow-up period of 1 year, so the prescribed dose for all subsequent patients on the study was increased to 45 Gy.
The combined experience from Allegheny General Hospital and Beth Israel Medical Center includes 38 patients treated with second lumpectomy and partial-breast reirradiation with interstitial low–dose-rate brachytherapy to a dose of 45–55 Gy (Figure 1). The investigators reported the following median results: Time from initial primary to in-breast recurrence was 11.5 years; age at diagnosis of the in-breast cancer was 61 years; tumor size was 1 cm; and follow-up after salvage brachytherapy was 45.5 months. The 5-year actuarial overall survival rate after salvage brachytherapy was 87.9% (95% confidence interval [CI] = 77.4%–99.8%; Figure 2A). The 5-year mastectomy-free survival rate was 94.4% (95% CI = 95.5–100; Figure 2B).
Most patients had some degree of baseline asymmetry due to the deficit in breast volume from the second lumpectomy. With breast asymmetry as a given, the postbrachytherapy cosmetic result observed in 35 patients has been good to excellent. Three patients have grade 3 (or fair) cosmesis as per the Harvard scoring criteria. On further analysis, the negative contributing factor among all three of these patients was the minimal residual breast tissue at the implant site after the second lumpectomy. This observation illustrates that patient selection criteria should include focused evaluation of the anatomic site. Further, prescription dose constraints should be clearly defined when the dosimetry is less than ideal. In summary, among properly selected patients, we observed good cosmetic results, high levels of local control, and freedom from mastectomy.
Experience using low–dose-rate brachytherapy as a reirradiation modality has been reported in a combined experience from Hannoun-Levi at the Marseille and Nice Cancer Institute including 69 patients (Table 2). In this study, patients treated with second lumpectomy and low–dose-rate interstitial brachytherapy represented only a select 14.6% of all local failures. Patients treated at Nice received 30 Gy, whereas 45 to 50 Gy was delivered to all patients treated at Marseille. The investigators observed an association between brachytherapy dose and toxicity. The incidence of grade 2/3 complications was 0%, 28%, and 32% with brachytherapy doses of 30 Gy, 45 to 46 Gy, and 50 Gy, respectively (P = .01). The 5-year overall survival rate was 91.8%, and the 5-year freedom from second local recurrence and disease-free-survival rates were 77.4% and 68.9%, respectively. On multivariate analysis, factors associated with a higher overall survival included absence of axillary lymph node metastases at initial presentation, time interval between initial and in-breast cancer, and the site of relapse in a quadrant other than that of the initial primary cancer. Also, patients treated with a fewer number of interstitial catheters and who received lower brachytherapy doses were at a higher risk for local failure.
The report by Maulard et al included 38 patients with isolated local relapses who underwent salvage treatment with perioperative or split-course low–dose-rate interstitial brachytherapy. With a mean follow up of 40 months (range = 16–64 months), 21% (8 patients) experienced a local relapse after salvage treatment. The overall 5-year survival rate was 55%.
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 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 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.
Recht et al 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 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 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.
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.
Acknowledgements: The authors would like to thank Dr. Doug Arthur for his contribution on the details about the proposed RTOG trial mentioned in this paper.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Osborne MP, Simmons RM: Salvage surgery for recurrence after breast conservation. World J Surg 18:93-97, 1994.
2. Huston TL, Simmons RM: Locally recurrent breast cancer after conservation therapy. Am J Surg 189:229-235, 2005.
3. Stotter AS, Kroll S, McNeese M, et al: Salvage treatment for loco-regional recurrence following breast conservation therapy for early stage breast cancer. Eur J Surg Oncol 17:231-236, 1991.
4. Kennedy MJ, Abeloff MD: Management of locally recurrent breast cancer. Cancer 71:2395-2409, 1993.
5. Salvadori B, Marubini E, Miceli R, et al: Reoperation for locally recurrent breast cancer in patients previously treated with conservative surgery. Br J Surg 86:84-87, 1999.
6. Voogd AC, Tienhoven G, Peterse HL, et al: Local recurrence after breast conservation therapy for early stage breast carcinoma. Cancer 85:437-446, 1999.
7. Dalberg K, Mattson A, Kerstin S, et al: Outcome of treatment for ipsilateral breast tumor recurrence in early-stage breast cancer. Br Cancer Res Treat 49:69-78, 1998.
8. Komoike Y, Motomura K, Inaji H, et al: Repeat lumpectomy for patients with ipsilateral breast tumor recurrence after breast-conserving surgery. Oncology 64:1-6, 2003.
9. Chadha M, Feldman S, Boolbol S, et al: The feasibility of a second lumpectomy and breast brachytherapy for localized cancer in a breast previously treated with lumpectomy and radiation therapy for breast cancer. Brachytherapy 7:22-28, 2008.
10. Trombetta M, Julian TB, Miften M, et al: The use of the MammoSite® balloon applicator in re-irradiation of the breast. Brachytherapy 7:316-319, 2008.
11. Deutsch M: Repeat high-dose external beam irradiation for in-breast tumor recurrence after previous lumpectomy and whole breast irradiation. Int J Radiat Oncol Biol Phys 53:687-691, 2002.
12. Hannoun-Levi J, Houvenaeghel G, Ellis S, et al Partial breast irradiation as second conservative treatment for local breast cancer recurrence Int J Radiat Oncol Biol Phys 60:1385-1392, 2004.
13. Resch A, Fellner C, Mock U, et al: Locally recurrent breast cancer: Pulse dose rate brachytherapy for repeat irradiation following lumpectomy—a second chance to preserve the breast. Radiology 225:713-718, 2002.
14. Kurtz JM, Jacquemier J, Amalric R, et al: Is breast conservation after local recurrence feasible? Eur J Cancer 27:24-244, 1991.
15. Abner AL, Recht A, Eberlein T, et al: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11:44-48, 1993.
16. Solin LJ, Fourquet A, Vicini F, et al: Salvage treatment for local recurrence after breast conserving surgery and radiation as initial treatment for mammographically detected ductal carcinoma in situ of the breast. Cancer 91:1090-1097, 2001.
17. Fortin A, Larochelle M, Laverdiere J, et al: Local failure is responsible for the decrease in survival of patients with breast cancer treated with conservative surgery and postoperative radiotherapy. J Clin Oncol 17:101-109, 1999.
18. Recht A, Schnitt SJ, Connolly JL, et al: Prognosis following local or regional recurrence after conservative surgery and radiotherapy for early stage breast carcinoma. Int J Radiat Oncol Biol Phys 16:3-9, 1989.
19. Kurtz J, Spitalier J, Amalric R, et al: The prognostic significance of late local recurrence after breast-conserving therapy. Int J Radiat Oncol Biol Phys 18:87-93, 1990.
20. Smith TE, Lee D, Turner BC, et al: True recurrence vs. new ipsilateral breast tumor relapse: An analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys 48:1281-1289, 2000.
21. Haffty BG, Fischer D, Beinfield M, et al: Prognosis following local recurrence in the conservatively treated breast cancer patient. Int J Radiat Oncol Biol Phys 21:293-298, 1991.
22. Huang E, Buchholtz TA, Meric F, et al: Classifying local disease recurrences after breast conservation therapy based on location and histology: New primary tumors have more favorable outcomes than true local disease recurrences. Cancer 95:2059-2067, 2002.
23. Kurtz JM, Amalric R, Brandone H, et al: Results of salvage surgery for mammary recurrence following breast-conserving therapy. Ann Surg 207:347-351, 1988.
24. Ries LAG, Miller BA, Hankey BF, et al (eds): SEER Cancer Statistics Review, 1973-1991. NIH pub no. 94-2789. Bethesda, Md; US Dept of Health and Human Services, National Cancer Institute; 1994.
25. Cajucom CC, Tsangaris TN, Nemoto T, et al: Results of salvage mastectomy for local recurrence after breast-conserving surgery without radiation therapy. Cancer 57:1174-1779, 1993.
26. Ganz PA, Schag AC, Lee JJ, at al: Breast conservation versus mastectomy. Is there a difference in psychological adjustment or quality of life in the year after surgery? Cancer 69:1729-1738, 1992.
27. Rowland JH, Desmond KA, Meyerowtiz BE, et al: Role of breast reconstructive surgery in physical and emotional outcomes among breast cancer survivors. J Natl Cancer Inst 92:1422-1429, 2000.
28. Maunsell E, Brisson J, Deschenes L: Psychological distress after initial treatment for breast cancer: A comparison of partial and total mastectomy. J Clin Epidemiol 42:765-771, 1989.
29. Chen SL, Martinez SR: The survival impact of the choice of surgical procedure after ipsilateral breast cancer recurrence. Am J Surg 196:495-499, 2008.
30. Kuske RR, Bolton JS, Wilenzick RM, et al: Brachtherapy as the sole method of breast irradiation in Tis, T1, T2, N0-1 breast cancer (abstract). Int J Radiat Oncol Biol Phys 30(suppl 1):245, 1994.
31. Vicini FA, Chen PY, Fraile M, et al: Low-dose-rate brachytherapy as the sole radiation modality in the management of patients with early-stage breast cancer treated with breast conserving therapy: Preliminary results of a pilot trial. Int J Radiat Oncol Biol Phys 38:301-310, 1997.
32. Polgar C, Major T, Fodor J, et al: High-dose rate brachytherapy alone versus whole breast radiotherapy with or without tumor bed boost after breast-conserving surgery: Seven-year results of a comparative study. Int J Radiat Oncol Biol Phys 60:1173-1181, 2004.
33. Wallner P, Arthur D, Bartelink H, et al: Workshop on partial breast irradiation: State of the art and the science; Bethesda, Md; Dec 8–10, 2002. J Natl Cancer Inst 96:175-184, 2004.
34. Maulard C., Housset M., Brunel P, et al: Use of perioperative or split-course interstitial brachytherapy techniques for salvage irradiation of isolated local recurrences after conservative management of breast cancer. Am J Clin Oncol 18:348-352 1995.
35. Mullen EE, Deutsch M, Bloomer WD, et al: Salvage radiotherapy for local failures of lumpectomy and breast irradiation. Radiother Oncol 42:25-29, 1997.