Mastectomy has long been regarded as the standard of care for local relapse after breast-conserving surgery and radiation therapy. Because of the perceived heightened risk of toxicity, a similar rationale and approach is often employed for patients that develop a new breast cancer after being treated with mantle field irradiation for lymphoma. Patients are increasingly requesting additional breast conserving treatment following an initial excellent cosmetic outcome prior to recurrence. After receiving whole breast external beam radiation therapy, most recurrences occur within or close to the quadrant of the index lesion.1 Partial breast irradiation (PBI) can target the areas at greatest risk for residual microscopic disease while minimizing the volume of healthy breast tissue reirradiated. Studies with short follow-up suggest that catheter-based interstitial brachytherapy or limited-field external beam radiotherapy can be safely delivered to the breast after an initial course of external bream radiotherapy with acceptable outcomes.2–7
In addition to concern of a more diffuse or multicentric recurrence pattern, the presumption by many oncologists is that subjecting the breast tissue to a second course of high-dose breast radiation would lead to significant toxicity; however, data are limited for repeat breast conserving surgery with or without postoperative reirradiation. One challenge in the metachronous ipsilateral breast cancer setting is that patients must have adequate quantity of breast tissue after the first lumpectomy to be a candidate for a cosmetically acceptable second breast conserving surgery. Contrary to popular belief, breast reirradiation has been performed with limited late sequelae.2,3,5–7 Since PBI treats only the region at highest risk of harboring residual microscopic disease, and it limits the volume of reirradiated breast tissue over a truncated treatment course. Whether this will result in comparable local control rates with no significant increase in toxicity requires further clinical investigation.
Our report describes the use of accelerated partial breast irradiation (APBI) with high-dose rate brachytherapy as a component of salvage breast conserving treatment. In selected patients with negative microscopic resection margins, with neither multicentric disease nor lymph node recurrence, repeat breast conservation therapy appears to be feasible.
Eleven patients who were treated with prior external beam radiotherapy to the breast were included in our analysis. Six patients had received prior mantle radiation for Hodgkin disease, 4 received prior whole breast radiation following lumpectomy for invasive or in situ breast cancer, and 1 received prior external beam radiation for soft tissue sarcoma. The index lesion was determined to lie within the prior treatment portals upon review by the treating physician. All patients underwent lumpectomy before APBI with pathology revealing tumor size ≤2 cm and negative surgical margins. Patients had clinically negative lymph nodes, and no nodes were detectable on treatment planning computed tomography (CT) scan following interstitial catheter placement.
Ultrasound allowed visualization of the seroma cavity, and most of the fluid within the cavity was aspirated with subsequent injection of nonionic contrast using sterile technique. Preimplantation mammography confirmed the location of the seroma, and a rigid template system was applied in the prone position such that the contrast-enhanced cavity was centered on the template coordinate system with the surgical scar between the 2 templates. The target volume was defined as expansion of 2 cm around the seroma unless restricted by skin or pectoralis muscle. The breast was numbed with local anesthetic and needles were placed parallel to each other via the guidance of the thick guiding template. Occasional free-hand needles were placed in areas to ensure optimal target-volume coverage when regions were not accessible via the template.
CT-based simulation was performed in the supine position within 24 hours of implantation. Contrast injected into the lumpectomy cavity before the CT or during catheter placement enhanced target visualization, and the seroma was contoured on each axial CT slice. The target volume was defined as the lumpectomy cavity with a 2-cm margin to treat the region at risk for microscopic disease, modified to allow for 5-mm depth from skin surface or along the pectoral muscle.
High-dose-rate brachytherapy was delivered in the outpatient setting using an iridium-192 source through a high-dose-rate computer-controlled afterloader. Patients were treated twice per day with a 6-hour interval between treatments. A total dose of 34 Gy was delivered over 10 fractions of 3.4 Gy per fraction. Prior to each treatment, the medical physicist connected transfer cables to the high-dose-rate afterloader, and the treatment was delivered with the computer-optimized dwell-times. Routine nursing care was done during each treatment, with treatments lasting 10 to 15 minutes. A surgical bra was provided to each patient to discreetly hide the catheters and allow for activity during the 1-week treatment interval.
Collection and analysis of data were performed under an institutional review board approved protocol of the University of Wisconsin Hospital. The purpose of the analysis was to determine local control rates and toxicities of treatment. Patient satisfaction following treatment was also assessed (Tables 1–3).
At a median follow-up of 53.7 months, 10 patients were alive without evidence of disease recurrence following treatment, and 1 patient was lost to follow-up. The median interval from prior radiation therapy to APBI was 19.1 years (range: 5.1–34.7). The median prior radiation dose was 45 gray (Gy) (range: 40–50.4 Gy) as detailed in Table 1.
One patient developed mastitis under treatment which failed oral antibiotics and required a 2-day hospital admission with intravenous antibiotics followed by 1 week of oral antibiotics. Another was treated with oral antibiotics for 6 weeks after formation of a sinus tract with serous drainage. This led to marked field contracture and painless subcutaneous fibrosis.
One patient with prior whole breast radiation developed soft tissue necrosis and required mastectomy 9.4 months after retreatment. She was initially treated with hyperbaric oxygen for duration of 2.5 months beginning 5 months after completion of reirradiation. She had subsequent courses of antibiotic therapy and supportive care with narcotics for pain control. The pathology specimen from her mastectomy revealed no evidence for neoplasia and was signed out as a chronic breast abscess with granulation tissue. She recovered well after mastectomy with no further complications.
Marked fibrosis occurred only in the patient with sinus tract formation following infection. Three other women reported only slight to moderate firmness. Four patients had mild hyperpigmentation or redness, and no patient developed telangiectasia.
Nine patients tolerated the treatment well with tolerable acute toxicity and successful breast conservation. The patient with sinus tract formation following infection was displeased with the cosmetic outcome, scored as poor because of fibrosis and contracture formation. All the other women with successful breast conservation reported satisfaction with the decision to pursue breast conservation rather than mastectomy, with patient scored cosmesis excellent in 5 patients and good in 3 patients.
A major transition in locoregional management of breast cancer in the last 2 to 3 decades has been the acceptance of breast conservation therapy (lumpectomy and whole breast irradiation) as a viable alternative to mastectomy. The objective is to minimize morbidity, optimize cosmesis, and maintain treatment outcomes. The National Surgical Adjuvant Breast and Bowel Project (NSABP B-06) reported 20-year findings for women treated with lumpectomy followed by fractionated whole breast radiotherapy and cited a 14.3% cumulative incidence of ipsilateral breast tumor recurrence.8 Although mastectomy has been traditional treatment for breast cancer following prior radiotherapy, patients are increasingly requesting additional breast conservation.
Several reports have suggested that the risk of local recurrence following a second conservative surgical approach is higher than clinically acceptable. For example, the European Institute of Oncology in Milan, Italy, reported a second in-breast local recurrence rate of 19% for patients treated with local re-excision only compared with a 4% chest wall recurrence rate in patients salvaged with mastectomy. However, no difference was noted in disease-free survival between patients treated with local re-excision versus mastectomy at a median follow-up of 73 months.9 Voogd et al reported a higher, albeit nonsignificant, rate of second recurrence after local excision versus mastectomy (38% vs. 25%, P = 0.27).10 The higher local failure rate in these studies suggests that additional radiation therapy after repeat breast-conserving surgery seems as important for local control as the role for radiation after initial treatment with breast conserving surgery.
In the retreatment setting, partial breast irradiation has been studied mainly using external beam radiotherapy and interstitial brachytherapy. Repeat high-dose partial breast irradiation with electrons of appropriate energy to treat the entire operative quadrant following salvage lumpectomy has been safely delivered to a retreatment dose of 50 Gy in 25 fractions to 38 women at University of Pittsburg Medical Center.3 All women had received whole breast radiation after initial lumpectomy, with a minimal dose of 50 Gy to at least a portion of the breast, similar to other studies of repeat breast conservation therapy. At a median follow-up of 51.5 months, 76.9% of women had an intact breast free of tumor at death or at last follow-up after reirradiation. Reresection margins were positive in 15% of patients, and 1 of 8 women with a second ipsilateral breast tumor recurrence had positive margins. The initial tumor was ductal carcinoma in situ for 21% of patients and invasive carcinoma for 79%. Interestingly, the incidence of contralateral breast cancer (21%) was equal to the incidence of ipsilateral breast tumor recurrence. The overall and disease-free 5-year survival rates were 77.9% and 68.5%, respectively. Although 1 patient discontinued treatment at 32 Gy for nonmedical reasons, 38 women successfully completed therapy, with portions of the breast receiving at least 100 Gy. Physician-scored cosmesis was reported as excellent or very good in 31%, good in 38%, and fair to poor in 23%. Poor cosmesis using electron therapy was mostly attributed to marked deformity, size differences, or excessive skin pigmentation in this retrospective series. This study demonstrated the feasibility of repeat full-dose partial breast irradiation after a second breast conserving surgery.
The combination of brachytherapy with or without external beam whole breast radiation therapy was studied in a prospective study from Vienna University, which examined 17 patients treated with repeat irradiation following local tumor excision for ipsilateral breast tumor recurrences.7 Treatment for initial breast cancer included lumpectomy or quadrantectomy followed by external-beam radiation therapy to 50 Gy. Eight of the 17 patients had a tumor bed boost dose of 10 Gy using either external-beam radiation or interstitial high dose-rate brachytherapy. All patients had infiltrating ductal carcinomas, with pathology at re-excision revealing negative margins and tumors of 0.5 to 2.5 cm in maximum tumor dimension. Eight patients during the pilot phase of the study were treated with external beam radiation to the whole breast followed by an additional pulse dose rate (PDR) brachytherapy boost. The starting doses were 30 Gy for external beam radiation and 12.5 Gy for the PDR brachytherapy boost. With accrual of additional patients, the external beam dose was decreased as the brachytherapy dose was increased. The final 9 patients studied were treated with PDR brachytherapy alone without external beam to doses of 40.2 to 50 Gy. PDR brachytherapy was delivered at radiation doses of 0.6 to 1.0 Gy per pulse, with a 1 hour interval between the pulses. As in most other partial breast irradiation studies, clinical target volume was defined as the former tumor bed with a 2-cm margin. At median follow-up of 59 months, 4 patients (24%) developed a second local tumor recurrence, and all recurrences were treated during the pilot phase with a combination of whole breast irradiation and PDR brachytherapy. All second recurrences were located close to the area of the first recurrence with a median time to recurrence of 8 months. Two of the 4 patients with local recurrences died of distant metastases, and 1 had 2 other local recurrences after undergoing mastectomy and plastic surgery without distal metastases. None of the patients treated with PDR brachytherapy alone had evidence of local recurrence. Cosmetic results were good to excellent in 29%, moderate in 47%, acceptable in 24%, and unacceptable in no patient. Even following whole breast irradiation, side effects were limited to NCI CTC Grade 1 or 2 fibrosis, skin hyperpigmentation, and minimal telangiectasia at the endpoints of the needle.
Retreatment with interstitial brachytherapy with or without surgical resection was investigated in a French study reported by Maulard et al, who treated 38 patients with local tumor recurrence using brachytherapy.6 In this study, 15 patients underwent local resection of invasive tumors with a mean tumor size of 2.4 cm followed by perioperative interstitial brachytherapy to a dose of 30 Gy (the dose rate was not specified). At a mean follow-up of 48 months, 26% presented with a second relapse. Metastatic disease was detected in 75% of patients with local recurrence. Five-year overall- and disease-free survival were 61% and 31%, respectively. Another 23 patients were treated with exclusive split course brachytherapy without repeat surgical resection with a mean follow-up of 36 months. The mean gross tumor size was 3.9 cm, and 60 to 70 Gy was delivered by 2 implants at a 1-month interval. Unexpectedly, the 17% local recurrence rate for patients with unresected gross disease treated with split course brachytherapy was lower than patients treated with repeat surgical resection and lower dose brachytherapy (26%). Five-year overall- and disease-free survival were 50% and 41%, respectively. Cosmetic outcomes were reported for 8 of the patients treated with postoperative brachytherapy, with no sequelae in 1 patient, minor sequelae in 1 patient, and major sequelae in 3 patients. One patient had mastectomy for breast erythema concerning for a Pagetoid reaction, but the pathologic specimen was free of malignancy. Another patient had local necrosis treated with local wound care without surgical intervention. Cosmetic outcomes were reported for 18 patients undergoing split-course salvage brachytherapy alone with no sequelae in 3 patients, minor sequelae in 8 patients, and major sequelae in 6 patients. Two patients underwent mastectomy for persistent breast pain and late necrosis in the submammary groove, with no pathologic evidence of residual tumor. This study established a relationship between radiation dose and local control, with higher doses demonstrating superior local control rates, even when gross tumor remained unresected.
Marseille and Nice Cancer Institutes reported on 69 patients over a 21-year period treated with a second lumpectomy followed by interstitial brachytherapy catheter placement intraoperatively.5 Nice Cancer Institute delivered 30 Gy whereas Marseille delivered 45 to 50 Gy using 192Ir wires in 1 or 2 planes. Second local recurrences occurred in the group treated with 30 Gy in 43.8% of patients compared with only 5.3% in patients treated with 50 Gy, although univariate analysis did not identify a statistically significant difference for patients treated to 50 Gy or more. The only 2 factors to achieve statistical significance for 5-year freedom from second local recurrence using Cox multivariate analysis were total number of iridium wires ≥5 and interval between initial treatment and first local recurrence >36 months. Second local control benefit did not translate into an overall survival difference, with 5-year overall survival of 91.8%. At median follow-up of 50.2 months after second treatment, grade 2 to 3 complication rates were lower for patients who received brachytherapy doses of less than 46 Gy compared with those who received 46 Gy or more (13.6% vs. 36%, P = 0.007). Complications occurred in 10.2% of patients requiring surgical intervention, with necrosis noted in 2 patients requiring surgery. The authors recommended delivering interstitial brachytherapy doses of at least 46 Gy in 2 planes when initial radiotherapy delivered 50 Gy, citing the statistically significant difference (P = 0.05) between interstitial brachytherapy doses of 30 to 45 Gy versus 46 to 60 Gy from univariate analysis. However, the absolute differences in local control rates between these 2 groups with patients were not reported. Although a dose response effect seems apparent, the optimal dose must balance local control and toxicity.
Beth Israel Medical Center in New York enrolled 15 patients on a phase I/II study administering low dose rate multicatheter interstitial iridium brachytherapy after repeat lumpectomy for patients who refused mastectomy. The first 6 patients were treated to a dose of 30 Gy, and subsequent patients were treated to 45 Gy after no unacceptable toxicities were observed. Only 1 patient developed a local recurrence, which was salvaged effectively with mastectomy at 27 months after completion of brachytherapy, yielding a local disease-free survival of 89%. No grade 3 or 4 fibrosis, necrosis, ulcer, or telangiectasia was observed. Although breast asymmetry occurred because of additional volume deficit in relation to the second lumpectomy, the cosmetic result was good to excellent in all patients.2 Prophylactic antibiotics were administered in all cases while brachytherapy was administered. There was no reportable infection in relation to therapy, unlike in our study in which 2 patients developed clinical infections and 1 patient developed a chronic abscess in the presence of necrosis.
Breast conservation therapy for secondary breast cancer developed after treatment of Hodgkin lymphoma has also met resistance since many physicians are equally reluctant to deliver radiotherapy to previously treated portions inside the mantle field. Mantle irradiation is an established risk factor for secondary breast cancers; analysis of 3 studies revealed that breast cancer was in the field or at the margin in 54 of 59 cases.11–13 Deutsch reported on breast conservation therapy for 11 women with Hodgkin lymphoma and 1 woman with non-Hodgkin lymphoma.4 Women developed breast cancer 10 to 29 years after radiotherapy for lymphoma. Tumors were located in the upper outer quadrants in 5 patients and in inner quadrants of the breast in 6 patients. Deutsch reported that definitive radiotherapy following breast conserving surgery resulted in no severe late sequelae, and all women had good to excellent cosmetic result at a median follow-up of 46 months following completion of breast irradiation. Doses were 50 to 51 Gy to the entire breast followed by a 9 to 10 Gy boost to the operative area. Two women died of distant metastases without local recurrence. One patient developed an opposite breast cancer and opted for bilateral mastectomies, which revealed no evidence of residual tumor in the ipsilateral irradiated breast. In contrast, Stanford's published experience with breast conservation following radiotherapy for Hodgkin lymphoma was limited to 2 patients, one of whom developed tissue necrosis in the region of overlap with her prior mantle field along the lateral breast and chest wall.14 Our series treated prior lymphoma patients with interstitial brachytherapy with similar outcomes to Deutsch's experience.
The toxicity profile in our small series was influenced strongly by infection rates. The patient who required mastectomy because of necrosis also had a chronic breast abscess, and the patient with sinus tract formation following infection had the only ultimate poor cosmetic outcome. The cosmetic outcomes from our study appear favorable compared with the University of Pittsburg experience with partial breast electrons, and the European low-dose rate experiences5,6 demonstrate similar cosmesis and toxicity profiles to our series. The Beth Israel Medical Center2 prescribed prophylactic antibiotics to all patients retreated with low-dose rate brachytherapy and had no unacceptable cosmetic outcomes. Pulsed dose rate brachytherapy similarly reported no unacceptable cosmetic outcomes.7 Normal tissue repair in low dose or pulsed dose rate experiences may have contributed to decreased toxicity. However, in our series, prevention of infection would have likely improved cosmesis, particularly for the patient with sinus tract formation and potentially for the patient with necrosis requiring mastectomy.
Reirradiation requires careful patient selection to achieve disease control with acceptable toxicity. Our institution currently restricts repeat breast conservation with APBI to patients with at least a 5-year interval from the first course of radiotherapy. The time to initial recurrence may impact subsequent control rates as 1 series reported that patients who recurred after 5 years had reduced second local recurrence (49%) compared with patients who recurred sooner (92%) when treated with repeat lumpectomy alone.15 Future upcoming trials should likely focus on node-negative patients with tumor size ≤2 cm and negative surgical margins. Prophylactic antibiotic treatment should be strongly considered surrounding the duration of catheter placement given the potential detriment to cosmesis in the reirradiation setting.
APBI using multicatheter based HDR interstitial brachytherapy can be safely delivered to the breast following an initial course of external beam radiotherapy with acceptable early outcomes. This potentially provides an alternative to mastectomy in appropriately selected patients with a favorable in breast recurrence. A prospective, randomized phase II multicenter trial to evaluate repeat lumpectomy followed by APBI for in-breast tumor recurrence is warranted to establish the role of repeat breast conservation.
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