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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 (2008) 22e28
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 Manjeet Chadha*, Sheldon Feldman2, Susan Boolbol2, Lin Wang1, Louis B. Harrison1 1
Department of Radiation Oncology, Beth Israel Medical Center, New York, NY 2 Department of Surgery, Beth Israel Medical Center, New York, NY
ABSTRACT
PURPOSE: With accumulating evidence supporting partial-breast irradiation, we conducted a Phase I/II study to evaluate the role of a second conservative surgery and brachytherapy for patients presenting with a local recurrence/new primary in a breast who has previously undergone a lumpectomy and external radiation therapy for breast cancer. METHODS AND MATERIALS: Fifteen patients with a localized lesion in the breast have undergone a second lumpectomy and received low-dose-rate brachytherapy on protocol. The first 6 patients received a dose of 30 Gy. With no unacceptable acute toxicity observed, the brachytherapy dose was increased to 45 Gy. Three patients received adjuvant chemotherapy and 8 patients are on antiestrogen therapy. RESULTS: The median time interval between the primary breast cancer diagnosis and the second cancer event in the ipsilateral breast is 94 months (range, 28e211). With a median followup of 36 months after brachytherapy, the 3-year KaplaneMeier overall survival, local disease-free survival and mastectomy-free survival are 100% and 89%, respectively. There was no Grade 3/4 fibrosis or necrosis observed. All patients had baseline asymmetry due to the breast volume deficit from the second lumpectomy. With breast asymmetry as a given, the cosmetic result observed in all patients has been good to excellent. CONCLUSIONS: Early results suggest low-complication rates, high rate of local control and freedom from mastectomy. Additional studies are needed to establish whether a second lumpectomy and breast brachytherapy are an acceptable alternative to mastectomy for patients presenting with a localized cancer in a previously irradiated breast. Ó 2008 American Brachytherapy Society. All rights reserved.
Keywords:
Recurrent breast cancer; Second lumpectomy; Partial-breast brachytherapy; Accelerated irradiation; Breastconserving therapy
Introduction Most women presenting with a local recurrence after breast cancer treated with lumpectomy and external radiation therapy (ERT) are advised mastectomy. Among patients with a local recurrence who do not consent for
Received 19 June 2007; accepted 12 October 2007. Presented in part at the 48th Annual Meeting of the American Society of Radiology and Oncology, Philadelphia 2006. The authors of this article have no conflict of interest with the material presented in this manuscript. * Corresponding author. Department of Radiation Oncology, Beth Israel Medical Center, 10 Union Square East, New York, NY 10003. Tel.: þ1-212-844-8022; fax: þ1-212-844-6556. E-mail address: [email protected] (M. Chadha).
mastectomy, the relapse rate with surgical excision alone is in the range of 19e50% (1e5). Since the late 1990s, there is accumulating evidence that partial-breast brachytherapy (PBB) is safe and effective after lumpectomy for selected early-stage breast cancer (6e11). There is, however, very little clinical experience regarding the feasibility of administering PBB in previously irradiated breast. In this article, we report the initial results of a second breast conservative treatment in patients who develop a localized relapse or a new primary cancer in the breast previously treated for breast cancer with lumpectomy and ERT. The objectives of the study were to assess the technical feasibility, cosmetic results, complication rates, local control rate, and freedom from mastectomy when treating a localized cancer in the breast with a second lumpectomy and PBB.
1538-4721/08/$ e see front matter Ó 2008 American Brachytherapy Society. All rights reserved. doi:10.1016/j.brachy.2007.10.006
M. Chadha et al. / Brachytherapy 7 (2008) 22e28
Methods and materials We conducted an institutional review board approved, Phase I/II study to evaluate the role of a second conservative surgery and PBB among patients presenting with a local recurrence/new primary in a breast who had previously received a therapeutic dose of ERT for breast cancer. Patient eligibility required a localized lesion in the breast and included all histologic subtypes. After multidisciplinary evaluation, patients must have signed an informed consent refusing the recommended mastectomy. The protocol design included a dose-escalation regimen: the first 6 patients received 30 Gy. After a minimum followup period of 12 months, which confirmed that there was no unacceptable acute toxicity in the treated breast, the total brachytherapy dose was increased to 45 Gy. Systemic therapy, when recommended started after a minimum of 2 weeks after removal of brachytherapy catheters. In consideration of the prior history of radiation therapy (RT), and the lack of established safety of retreatment, the protocol only permitted 192Ir multicatheter interstitial lowdose-rate (LDR) brachytherapy. This technique was selected for the protocol because it has the longest clinical track record. Other breast brachytherapy techniques, that
a
23
is, high-dose-rate (HDR) and Mammosite brachytherapy were introduced during the course of this study; however, the brachytherapy technique in the protocol was not changed so as to avoid confounding variables in assessing the safety of this treatment approach. All patients underwent a lumpectomy lymphadenectomy. The surgical margins were microscopically assessed to be negative before performing the brachytherapy procedure. All patients were noted to have a breast volume deficit as a result of the second lumpectomy performed before brachytherapy. This factor influenced the number of catheters placed at the lumpectomy site. For catheter placement, standard free-hand insertion technique with image guidance was used. In cases where catheters were placed during the lumpectomy procedure, the catheter placement was guided by direct vision. Orthogonal (Fig. 1a), ultrasound (Fig. 1b), and/or CT scans (Fig. 1c) were used to further define the adequacy of catheter placement in relation to the target volume (TV). The TV was the lumpectomy cavity identified by clips plus 1 to 2 cm margin. Orthogonal X-rays were used for dosimetry. The prescription isodose was the dose encompassing the TV. In addition, point-dose calculations at the clips within
b
Skin distance
e Lumpectomy cavity
c
Needle Clips
Catheters
C Clips
Fig. 1. Evaluation of appropriateness of catheter placement by (a) intraoperative ultrasound; (b) orthogonal X-rays; and (c) computed axial tomography scan.
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M. Chadha et al. / Brachytherapy 7 (2008) 22e28
the lumpectomy cavity were recorded to establish that these points of interest within the TV received a dose greater than or equal to the prescribed dose. In cases where the skin proximity was a concern, the dose-to-skin points were calculated using fiducial markers on the skin. The skin dose was maintained at <20 Gy. Additional measures to spare skin toxicity included special attention during catheter insertion such that the entry and exit points of the catheters were beyond the TV and the 192Ir seeds at the ends of the ribbon were positioned well within the breast tissue, creating a 1e2 cm dead space between the 192Ir seed and the skin. Prophylactic antibiotics were administered in all cases for the duration of the brachytherapy. Catheter sites were cleaned and dressed with bacitracin ointment twice a day. The catheter site was covered with abdominal pads that were held in place by a surgical bra. Tape was not applied to the site. After administering the prescribed dose, the catheters were removed at the bedside. Pain medication was prescribed approximately 1 h before catheter removal. After removing the 192Ir ribbons, care was given to the technique of catheter removal so as to minimize risk for infection. One end of the catheter was cut just below the skin surface by maneuvering it gently to get the right exposure. In this manner, when the catheter was pulled from the other side only the in vivo segment of the catheter traversed the breast tissue. In most instances, no discharge or oozing was noted at the brachytherapy site. However, when discharge was observed its drainage was facilitated with gentle pressure so as to decrease formation of a seroma and to prevent subsequent infection. After catheter removal, patients were instructed to cleanse the catheter site twice a day and apply topical bacitracin until the catheter sites were completely closed. Patients were seen in followup 1 week, 4 weeks, and 3 months after the completion of brachytherapy and then every 6 months. Followup was conducted by the multidisciplinary team with imaging and physical examination at regular intervals or as clinically indicated.
Results From 1999 to present, 15 patients have been treated on this study (Table 1). The initial breast cancer stage included Stage 0 to Stage IIb disease. The median ERT dose from the prior RT was 60 Gy. The time interval between the first and second breast cancer event was 94 months ranging from 28 to 211 months. The median age at the time of the second cancer event was 54 years (46e81), 12 patients had an infiltrating cancer and 3 patients had ductal carcinoma in situ (DCIS). The median tumor size was 0.9 cm (0.4e2.0). With respect to the location of the second breast cancer, 9 patients had cancer in the same quadrant as the previous cancer, and 6 patients had the cancer in a location other than the quadrant of the initial cancer. The median number of interstitial catheters inserted was 11. Three
Table 1 Patient characteristics Median age (range) Histology Median tumor size (range) Site of cancer recurrence Adjuvant systemic therapy
54 yr (46e81) Invasive, 12 DCIS, 3 0.9 cm (0.4e2.0) Nine, same quadrant as initial tumor Six, another quadrant Chemotherapy, 3 patients Antiestrogens, 8 patients
patients had a single-plane implant, and in 12 patients a two-plane implant was performed. Brachytherapy was delivered at dose rates of 900e 1100 cGy/d, with a median dose homogeneity index of 0.80 (range, 0.75e0.85). In the Phase I (n 5 6), 5 patients received the planned 30 Gy, and the treatment was discontinued at 10 Gy in 1 patient due to unrelated medical problems. In the second phase of the study (n 5 9), the planned total dose of 45 Gy was administered in all but 1 patient. In this patient, the prescription dose was decreased to 41.8 Gy to maintain the skin dose within the 20 Gy threshold established for the study. Three patients have received systemic chemotherapy and 8 patients are on antiestrogen therapy. At a median followup of 36 months, the overall survival is 100%, the local disease-free and effectively the mastectomy-free survival is 89%. One patient developed a local recurrence at 27 months after breast brachytherapy and underwent a salvage mastectomy and remains free of disease. She was among the group of patients who received a dose 30 Gy, had a less than 4-year time interval between the first and second cancer event and the local relapse was located in the same quadrant as the primary tumor. Acute side effects and complications of treatment were recorded on the CTC Toxicity Criteria (12). There was no incidence of infection. Three patients had a permanent change in skin pigmentation at the catheter entry and exit site (Fig. 2a and b). We observed no Grade 3 or 4 fibrosis, telangiectasia, ulcer, or necrosis. Breast symmetry was assessed before brachytherapy and at followup intervals. Because our study population was undergoing conservative surgery for the second time, asymmetry from the surgicalinduced breast volume deficit was a baseline observation among all patients before brachytherapy. In followup, after PBB the baseline breast contour and symmetry remained stable in all patients. We did not observe a negative impact of the brachytherapy on the eventual cosmetic result (Fig. 3).
Discussion The incidence of local regional failure after breastconserving therapy (BCT) for early-stage disease is in the range of 5e20% (13e15). Although mastectomy is the widely accepted recommendation for women relapsing after lumpectomy and ERT for the primary breast cancer (16e19), the incidence for secondary locoregional
M. Chadha et al. / Brachytherapy 7 (2008) 22e28
25
a Prior cancer
Prior cancer
New cancer site following PBB
New cancer site following PBB
Follow up: 39 months Dose: 45Gy
Follow up: 24 months Dose: 45Gy
b
20-mo after PBB catheter site. Fig. 2. Cosmetic result with respect to skin. (a) Grade 0 skin effects; and (b) Grade 2 skin effects secondary to track site hypo-pigmentation.
recurrence after salvage mastectomy is in the range of 4e37% (20, 21). Among patients who do not consent for mastectomy, the relapse rates with surgical excision alone are in the range of 19e50% (1e5) (Table 2). With the
prevalence of routine screening, there is a higher likelihood of detecting smaller and localized cancers in the breast. MRI has become an increasingly useful screening tool for detection of a recurrent cancer in the breast that has
Cosmetic Results
Asymmetry prior to PBB
12-mo after PBB, baseline asymmetry unchanged
Fig. 3. Cosmetic result with respect to asymmetry.
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M. Chadha et al. / Brachytherapy 7 (2008) 22e28
Table 2 Outcome of patients treated with conservative surgery alone after an in-breast failure Author
No. of patients
Median followup (mo)
Local recurrence (%)
Salvadori (1999) Kurtz (1991) Abner (1993) Voogd (1999) Dalberg (1998)
57 55 16 16 14
73 51 39 52 156
19 27 31 38 50
previously received breast-conserving treatments. Drew et al. (22) reported 100% sensitivity and 93% specificity in detecting a local relapse in the ipsilateral breast after breast conservation. Alternatives to a mastectomy for the biologically favorable screen-detected cancers in a previously irradiated breast should be explored. The application of ERT as a treatment for recurrence is often cited as an absolute contraindication due to the risk of reirradiating the breast tissue. But the option of partial breast irradiation for treating a localized second cancer event in a previously irradiated breast is appealing in that it delivers a highly conformal dose to the TV while sparing adjacent critical structures, such as lung, heart, chest wall, and breast tissue remote from the lumpectomy cavity. However, what is unknown is whether limiting the treatment volume would allow an opportunity to safely administer higher than the traditionally accepted radiation dose. There are published data that suggest that by reducing the treatment volume the tolerance threshold for a given radiation dose is higher (23). Also, higher therapeutic RT dose can be safely delivered to target tissues when sparing adjoining normal structures (24, 25). With this line of thought, one might postulate the potential opportunity to apply a second breast conservative treatment using breast brachytherapy for treating patients with small localized tumors who find the therapeutic option of mastectomy unacceptable. The role of brachytherapy as primary treatment for localized breast cancer has been studied (6e11, 26e28). The Radiation Oncology Therapy Group (RTOG) recently reported a Phase II trial examining the safety and efficacy of interstitial brachytherapy (29). One hundred patients were enrolled with primary invasive nonlobular tumors measuring up to 3 cm with zero to three positive nodes without extracapsular extension. The brachytherapy was delivered by either LDR (33%) or HDR (66%). After median followup of more than 6 years, the authors noted a 5-year mastectomy-free survival of 88% in both groups. They concluded that patients treated with multicatheter brachytherapy experienced excellent in-breast control rates and overall outcome. There is currently an ongoing Phase III NSABP B-39/RTOG 0413 cooperative group trial for early-stage breast cancer that randomizes patients to receive either whole-breast irradiation or partial-breast treatment (30). There are several factors that may influence the outcome of patients who experience a local recurrence after
conservative treatment (3, 31e37). The various prognostic factors include tumor size, histologic subtype of recurrent disease (invasive and noninvasive), involvement of the skin and lymph nodes at the time of recurrence, location of tumor in the breast in relation to the initially treated breast cancer, and the time interval between the first and second cancer diagnosis in the ipsilateral breast. Patients who have a longer time interval between the two cancer events have a better outcome. Kurtz et al. (2) reported 5-year local control of 92% for recurrences occurring after 5 years versus 49% for shorter intervals. Review of the patterns of failure (35, 38) after lumpectomy and ERT illustrates that the most common site of relapse is within the same quadrant, and the 10e15% incidence of failure in a quadrant other than the primary tumor site may most likely represent a new primary breast cancer. Studies suggest that new primary tumors in a breast previously treated for cancer with a conservative approach have a more favorable outcome than true local recurrences (38e40). The clinical classification that is often used to distinguish true recurrence from a new primary is less precise than molecular methods. In our study, we did not attempt to classify and distinguish between true local recurrences from new primary tumors but defined the time to relapse and the location of the relapse in the breast. The patients were eligible for the study on the basis of the unicentric nature of the ipsilateral recurrence that could be removed at the time of lumpectomy achieving negative margins. The tumor size and histology characteristics of the second breast cancer events treated on our study using multicatheter interstitial PBB are very similar to the new primary breast cancers (median tumor size of 1.0 cm, and included 86% invasive cancer and 14% DCIS lesions) that were treated with Mammosite catheter brachytherapy (41). To date, our experience compares quite favorably to published experience using LDR brachytherapy in a previously irradiated breast (Table 3). A combined series from Marseille and Nice Cancer Institute (42) reported outcome of second lumpectomy and interstitial brachytherapy on 69 patients that represented a select 14.6% of all local failures. 192 Ir was used to deliver LDR brachytherapy through a 1- or 2-plane implant. Patients treated at Nice received 30 Gy, and 45e50 Gy was delivered to all patients treated at Marseille. A relationship of the brachytherapy dose with risk of developing complications noted that the incidence of Grade 2 and 3 complications was 0%, 28%, and 32% with a brachytherapy dose of 30, 45e46, and 50 Gy, respectively ( p 5 0.01). They reported a 5-year overall survival of 91.8%. The KaplaneMeier 5-year freedom from second local recurrence and disease-free survival was 77.4% and 68.9%, respectively. On multivariate analysis, absence of axillary lymph-node metastases at initial presentation and the site of relapse in a quadrant other than the initial primary cancer was more likely to result in a higher overall survival. Further, similar to our results they also observed that the risk of local failure after second conservative
M. Chadha et al. / Brachytherapy 7 (2008) 22e28
27
Table 3 Brachytherapy alone after second lumpectomy for breast cancer Author
No. of patients
Brachytherapy technique
Median followup (mo)
Mastectomy-free survival (%)
Maingon et al. Hannoun-Levi et al. Resch et al. Chadha
32 69 17 15
LDR LDR PDR brachytherapy ERT LDR
55 50.2 59 36
73 77.4 76 89
LDR 5 low dose rate; PDR 5 pulsed dose rate; ERT 5 external radiation therapy.
treatment was more likely to occur among patients with a shorter time interval between the primary breast-cancer treatment and the local recurrence. Also, patients treated with a fewer number of interstitial catheters and receiving lower brachytherapy dose were at a significantly higher risk for local failure. Among patients who refused mastectomy and were treated with a second lumpectomy and interstitial brachytherapy, Maingon et al. (43) observed 5-year overall survival, local relapse, and distant failure to be 80%, 27%, and 5%, respectively. Cosmetic outcome was good/acceptable in 75% of patients with a 5-year breast conservation rate of 73%. Maulard et al. (44) reported their observation on 38 patients with isolated local relapses after radiation therapy who underwent salvage treatment with perioperative or split-course interstitial brachytherapy. The patients with smaller tumors (mean, 2.4 cm; range, 0.5e4.0 cm) were treated with a lumpectomy and a perioperative brachytherapy dose of 30 Gy. Whereas patients with larger mean tumor size (3.9 cm; range, 1.5e7.0 cm) were treated with a brachytherapy dose of 60e70 Gy via two interstitial implants performed 1 month apart. All patients achieved a clinical complete response after treatment. With a mean followup of 40 months (range, 16e64), 21% (8 patients) experienced a local relapse. In 7 patients, the second local recurrence was associated with metastatic disease and the local recurrence was an isolated event in 1 patient. The overall 5-year survival was 55%. Severe complications requiring a mastectomy were noted in 3 patients (skin necrosis in 1 and severe breast pain in 2 patients). The toxicity and inferior cosmetic outcome were influenced by the inclusion of patients with large tumors that required higher radiation dose. Other small series have reported the use of ERT in the retreatment for small recurrent breast cancers in previously irradiated breast. Resch et al. (45) applied pulsed dose rate (PDR) þ ERT in 8 patients. In the combination treatment, the PDR brachytherapy dose ranged from 12.5 to 28 Gy and the ERT dose ranged from 12 to 30 Gy. Four of the 8 patients had a second local recurrence requiring a mastectomy. A later experience using PDR brachytherapy only and a dose of 40.2e50 Gy resulted in low-complication rates with side effects limited to moderate Grade 1e2 fibrosis. Deutsch et al. (46) reported that 5-year disease-free and overall survival were 68.5% and 77.9%, respectively, after
a local recurrence treated with a second lumpectomy and 50 Gy ERT to the lumpectomy site using electrons. The clinical experience being reported in this article specifically notes the safety and feasibility of LDR interstitial brachytherapy in breast previously treated with a fractionated course of ERT using standard fractionation schedule (180e200 cGy). This clinical experience cannot be translated to the management of a local recurrence after accelerated treatment schedules that use larger than the conventional RT dose per fraction, HDR Mammosite catheter, or multicatheter brachytherapy techniques. Among patients who recur after accelerated treatment schedules, the feasibility of second conservative treatment using PBB requires investigation. It may seem plausible if the second lumpectomy removes the breast tissue that was within the high-dose gradient of the initial accelerated treatment.
Conclusions Our observations suggest that repeat lumpectomy and LDR interstitial breast brachytherapy are well tolerated with acceptable toxicity. With careful selection criteria, there may be an opportunity to offer women a second chance at breast conservation. Clearly, larger studies and longer followup are needed. Nonetheless, encouraging early results may suggest that mastectomy may not be the only treatment option for women who have history of previous ERT.
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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 Manjeet Chadha*, Sheldon Feldman2, Susan Boolbol2, Lin Wang1, Louis B. Harrison1 1
Department of Radiation Oncology, Beth Israel Medical Center, New York, NY 2 Department of Surgery, Beth Israel Medical Center, New York, NY
ABSTRACT
PURPOSE: With accumulating evidence supporting partial-breast irradiation, we conducted a Phase I/II study to evaluate the role of a second conservative surgery and brachytherapy for patients presenting with a local recurrence/new primary in a breast who has previously undergone a lumpectomy and external radiation therapy for breast cancer. METHODS AND MATERIALS: Fifteen patients with a localized lesion in the breast have undergone a second lumpectomy and received low-dose-rate brachytherapy on protocol. The first 6 patients received a dose of 30 Gy. With no unacceptable acute toxicity observed, the brachytherapy dose was increased to 45 Gy. Three patients received adjuvant chemotherapy and 8 patients are on antiestrogen therapy. RESULTS: The median time interval between the primary breast cancer diagnosis and the second cancer event in the ipsilateral breast is 94 months (range, 28e211). With a median followup of 36 months after brachytherapy, the 3-year KaplaneMeier overall survival, local disease-free survival and mastectomy-free survival are 100% and 89%, respectively. There was no Grade 3/4 fibrosis or necrosis observed. All patients had baseline asymmetry due to the breast volume deficit from the second lumpectomy. With breast asymmetry as a given, the cosmetic result observed in all patients has been good to excellent. CONCLUSIONS: Early results suggest low-complication rates, high rate of local control and freedom from mastectomy. Additional studies are needed to establish whether a second lumpectomy and breast brachytherapy are an acceptable alternative to mastectomy for patients presenting with a localized cancer in a previously irradiated breast. Ó 2008 American Brachytherapy Society. All rights reserved.
Keywords:
Recurrent breast cancer; Second lumpectomy; Partial-breast brachytherapy; Accelerated irradiation; Breastconserving therapy
Introduction Most women presenting with a local recurrence after breast cancer treated with lumpectomy and external radiation therapy (ERT) are advised mastectomy. Among patients with a local recurrence who do not consent for
Received 19 June 2007; accepted 12 October 2007. Presented in part at the 48th Annual Meeting of the American Society of Radiology and Oncology, Philadelphia 2006. The authors of this article have no conflict of interest with the material presented in this manuscript. * Corresponding author. Department of Radiation Oncology, Beth Israel Medical Center, 10 Union Square East, New York, NY 10003. Tel.: þ1-212-844-8022; fax: þ1-212-844-6556. E-mail address: [email protected] (M. Chadha).
mastectomy, the relapse rate with surgical excision alone is in the range of 19e50% (1e5). Since the late 1990s, there is accumulating evidence that partial-breast brachytherapy (PBB) is safe and effective after lumpectomy for selected early-stage breast cancer (6e11). There is, however, very little clinical experience regarding the feasibility of administering PBB in previously irradiated breast. In this article, we report the initial results of a second breast conservative treatment in patients who develop a localized relapse or a new primary cancer in the breast previously treated for breast cancer with lumpectomy and ERT. The objectives of the study were to assess the technical feasibility, cosmetic results, complication rates, local control rate, and freedom from mastectomy when treating a localized cancer in the breast with a second lumpectomy and PBB.
1538-4721/08/$ e see front matter Ó 2008 American Brachytherapy Society. All rights reserved. doi:10.1016/j.brachy.2007.10.006
M. Chadha et al. / Brachytherapy 7 (2008) 22e28
Methods and materials We conducted an institutional review board approved, Phase I/II study to evaluate the role of a second conservative surgery and PBB among patients presenting with a local recurrence/new primary in a breast who had previously received a therapeutic dose of ERT for breast cancer. Patient eligibility required a localized lesion in the breast and included all histologic subtypes. After multidisciplinary evaluation, patients must have signed an informed consent refusing the recommended mastectomy. The protocol design included a dose-escalation regimen: the first 6 patients received 30 Gy. After a minimum followup period of 12 months, which confirmed that there was no unacceptable acute toxicity in the treated breast, the total brachytherapy dose was increased to 45 Gy. Systemic therapy, when recommended started after a minimum of 2 weeks after removal of brachytherapy catheters. In consideration of the prior history of radiation therapy (RT), and the lack of established safety of retreatment, the protocol only permitted 192Ir multicatheter interstitial lowdose-rate (LDR) brachytherapy. This technique was selected for the protocol because it has the longest clinical track record. Other breast brachytherapy techniques, that
a
23
is, high-dose-rate (HDR) and Mammosite brachytherapy were introduced during the course of this study; however, the brachytherapy technique in the protocol was not changed so as to avoid confounding variables in assessing the safety of this treatment approach. All patients underwent a lumpectomy lymphadenectomy. The surgical margins were microscopically assessed to be negative before performing the brachytherapy procedure. All patients were noted to have a breast volume deficit as a result of the second lumpectomy performed before brachytherapy. This factor influenced the number of catheters placed at the lumpectomy site. For catheter placement, standard free-hand insertion technique with image guidance was used. In cases where catheters were placed during the lumpectomy procedure, the catheter placement was guided by direct vision. Orthogonal (Fig. 1a), ultrasound (Fig. 1b), and/or CT scans (Fig. 1c) were used to further define the adequacy of catheter placement in relation to the target volume (TV). The TV was the lumpectomy cavity identified by clips plus 1 to 2 cm margin. Orthogonal X-rays were used for dosimetry. The prescription isodose was the dose encompassing the TV. In addition, point-dose calculations at the clips within
b
Skin distance
e Lumpectomy cavity
c
Needle Clips
Catheters
C Clips
Fig. 1. Evaluation of appropriateness of catheter placement by (a) intraoperative ultrasound; (b) orthogonal X-rays; and (c) computed axial tomography scan.
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M. Chadha et al. / Brachytherapy 7 (2008) 22e28
the lumpectomy cavity were recorded to establish that these points of interest within the TV received a dose greater than or equal to the prescribed dose. In cases where the skin proximity was a concern, the dose-to-skin points were calculated using fiducial markers on the skin. The skin dose was maintained at <20 Gy. Additional measures to spare skin toxicity included special attention during catheter insertion such that the entry and exit points of the catheters were beyond the TV and the 192Ir seeds at the ends of the ribbon were positioned well within the breast tissue, creating a 1e2 cm dead space between the 192Ir seed and the skin. Prophylactic antibiotics were administered in all cases for the duration of the brachytherapy. Catheter sites were cleaned and dressed with bacitracin ointment twice a day. The catheter site was covered with abdominal pads that were held in place by a surgical bra. Tape was not applied to the site. After administering the prescribed dose, the catheters were removed at the bedside. Pain medication was prescribed approximately 1 h before catheter removal. After removing the 192Ir ribbons, care was given to the technique of catheter removal so as to minimize risk for infection. One end of the catheter was cut just below the skin surface by maneuvering it gently to get the right exposure. In this manner, when the catheter was pulled from the other side only the in vivo segment of the catheter traversed the breast tissue. In most instances, no discharge or oozing was noted at the brachytherapy site. However, when discharge was observed its drainage was facilitated with gentle pressure so as to decrease formation of a seroma and to prevent subsequent infection. After catheter removal, patients were instructed to cleanse the catheter site twice a day and apply topical bacitracin until the catheter sites were completely closed. Patients were seen in followup 1 week, 4 weeks, and 3 months after the completion of brachytherapy and then every 6 months. Followup was conducted by the multidisciplinary team with imaging and physical examination at regular intervals or as clinically indicated.
Results From 1999 to present, 15 patients have been treated on this study (Table 1). The initial breast cancer stage included Stage 0 to Stage IIb disease. The median ERT dose from the prior RT was 60 Gy. The time interval between the first and second breast cancer event was 94 months ranging from 28 to 211 months. The median age at the time of the second cancer event was 54 years (46e81), 12 patients had an infiltrating cancer and 3 patients had ductal carcinoma in situ (DCIS). The median tumor size was 0.9 cm (0.4e2.0). With respect to the location of the second breast cancer, 9 patients had cancer in the same quadrant as the previous cancer, and 6 patients had the cancer in a location other than the quadrant of the initial cancer. The median number of interstitial catheters inserted was 11. Three
Table 1 Patient characteristics Median age (range) Histology Median tumor size (range) Site of cancer recurrence Adjuvant systemic therapy
54 yr (46e81) Invasive, 12 DCIS, 3 0.9 cm (0.4e2.0) Nine, same quadrant as initial tumor Six, another quadrant Chemotherapy, 3 patients Antiestrogens, 8 patients
patients had a single-plane implant, and in 12 patients a two-plane implant was performed. Brachytherapy was delivered at dose rates of 900e 1100 cGy/d, with a median dose homogeneity index of 0.80 (range, 0.75e0.85). In the Phase I (n 5 6), 5 patients received the planned 30 Gy, and the treatment was discontinued at 10 Gy in 1 patient due to unrelated medical problems. In the second phase of the study (n 5 9), the planned total dose of 45 Gy was administered in all but 1 patient. In this patient, the prescription dose was decreased to 41.8 Gy to maintain the skin dose within the 20 Gy threshold established for the study. Three patients have received systemic chemotherapy and 8 patients are on antiestrogen therapy. At a median followup of 36 months, the overall survival is 100%, the local disease-free and effectively the mastectomy-free survival is 89%. One patient developed a local recurrence at 27 months after breast brachytherapy and underwent a salvage mastectomy and remains free of disease. She was among the group of patients who received a dose 30 Gy, had a less than 4-year time interval between the first and second cancer event and the local relapse was located in the same quadrant as the primary tumor. Acute side effects and complications of treatment were recorded on the CTC Toxicity Criteria (12). There was no incidence of infection. Three patients had a permanent change in skin pigmentation at the catheter entry and exit site (Fig. 2a and b). We observed no Grade 3 or 4 fibrosis, telangiectasia, ulcer, or necrosis. Breast symmetry was assessed before brachytherapy and at followup intervals. Because our study population was undergoing conservative surgery for the second time, asymmetry from the surgicalinduced breast volume deficit was a baseline observation among all patients before brachytherapy. In followup, after PBB the baseline breast contour and symmetry remained stable in all patients. We did not observe a negative impact of the brachytherapy on the eventual cosmetic result (Fig. 3).
Discussion The incidence of local regional failure after breastconserving therapy (BCT) for early-stage disease is in the range of 5e20% (13e15). Although mastectomy is the widely accepted recommendation for women relapsing after lumpectomy and ERT for the primary breast cancer (16e19), the incidence for secondary locoregional
M. Chadha et al. / Brachytherapy 7 (2008) 22e28
25
a Prior cancer
Prior cancer
New cancer site following PBB
New cancer site following PBB
Follow up: 39 months Dose: 45Gy
Follow up: 24 months Dose: 45Gy
b
20-mo after PBB catheter site. Fig. 2. Cosmetic result with respect to skin. (a) Grade 0 skin effects; and (b) Grade 2 skin effects secondary to track site hypo-pigmentation.
recurrence after salvage mastectomy is in the range of 4e37% (20, 21). Among patients who do not consent for mastectomy, the relapse rates with surgical excision alone are in the range of 19e50% (1e5) (Table 2). With the
prevalence of routine screening, there is a higher likelihood of detecting smaller and localized cancers in the breast. MRI has become an increasingly useful screening tool for detection of a recurrent cancer in the breast that has
Cosmetic Results
Asymmetry prior to PBB
12-mo after PBB, baseline asymmetry unchanged
Fig. 3. Cosmetic result with respect to asymmetry.
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M. Chadha et al. / Brachytherapy 7 (2008) 22e28
Table 2 Outcome of patients treated with conservative surgery alone after an in-breast failure Author
No. of patients
Median followup (mo)
Local recurrence (%)
Salvadori (1999) Kurtz (1991) Abner (1993) Voogd (1999) Dalberg (1998)
57 55 16 16 14
73 51 39 52 156
19 27 31 38 50
previously received breast-conserving treatments. Drew et al. (22) reported 100% sensitivity and 93% specificity in detecting a local relapse in the ipsilateral breast after breast conservation. Alternatives to a mastectomy for the biologically favorable screen-detected cancers in a previously irradiated breast should be explored. The application of ERT as a treatment for recurrence is often cited as an absolute contraindication due to the risk of reirradiating the breast tissue. But the option of partial breast irradiation for treating a localized second cancer event in a previously irradiated breast is appealing in that it delivers a highly conformal dose to the TV while sparing adjacent critical structures, such as lung, heart, chest wall, and breast tissue remote from the lumpectomy cavity. However, what is unknown is whether limiting the treatment volume would allow an opportunity to safely administer higher than the traditionally accepted radiation dose. There are published data that suggest that by reducing the treatment volume the tolerance threshold for a given radiation dose is higher (23). Also, higher therapeutic RT dose can be safely delivered to target tissues when sparing adjoining normal structures (24, 25). With this line of thought, one might postulate the potential opportunity to apply a second breast conservative treatment using breast brachytherapy for treating patients with small localized tumors who find the therapeutic option of mastectomy unacceptable. The role of brachytherapy as primary treatment for localized breast cancer has been studied (6e11, 26e28). The Radiation Oncology Therapy Group (RTOG) recently reported a Phase II trial examining the safety and efficacy of interstitial brachytherapy (29). One hundred patients were enrolled with primary invasive nonlobular tumors measuring up to 3 cm with zero to three positive nodes without extracapsular extension. The brachytherapy was delivered by either LDR (33%) or HDR (66%). After median followup of more than 6 years, the authors noted a 5-year mastectomy-free survival of 88% in both groups. They concluded that patients treated with multicatheter brachytherapy experienced excellent in-breast control rates and overall outcome. There is currently an ongoing Phase III NSABP B-39/RTOG 0413 cooperative group trial for early-stage breast cancer that randomizes patients to receive either whole-breast irradiation or partial-breast treatment (30). There are several factors that may influence the outcome of patients who experience a local recurrence after
conservative treatment (3, 31e37). The various prognostic factors include tumor size, histologic subtype of recurrent disease (invasive and noninvasive), involvement of the skin and lymph nodes at the time of recurrence, location of tumor in the breast in relation to the initially treated breast cancer, and the time interval between the first and second cancer diagnosis in the ipsilateral breast. Patients who have a longer time interval between the two cancer events have a better outcome. Kurtz et al. (2) reported 5-year local control of 92% for recurrences occurring after 5 years versus 49% for shorter intervals. Review of the patterns of failure (35, 38) after lumpectomy and ERT illustrates that the most common site of relapse is within the same quadrant, and the 10e15% incidence of failure in a quadrant other than the primary tumor site may most likely represent a new primary breast cancer. Studies suggest that new primary tumors in a breast previously treated for cancer with a conservative approach have a more favorable outcome than true local recurrences (38e40). The clinical classification that is often used to distinguish true recurrence from a new primary is less precise than molecular methods. In our study, we did not attempt to classify and distinguish between true local recurrences from new primary tumors but defined the time to relapse and the location of the relapse in the breast. The patients were eligible for the study on the basis of the unicentric nature of the ipsilateral recurrence that could be removed at the time of lumpectomy achieving negative margins. The tumor size and histology characteristics of the second breast cancer events treated on our study using multicatheter interstitial PBB are very similar to the new primary breast cancers (median tumor size of 1.0 cm, and included 86% invasive cancer and 14% DCIS lesions) that were treated with Mammosite catheter brachytherapy (41). To date, our experience compares quite favorably to published experience using LDR brachytherapy in a previously irradiated breast (Table 3). A combined series from Marseille and Nice Cancer Institute (42) reported outcome of second lumpectomy and interstitial brachytherapy on 69 patients that represented a select 14.6% of all local failures. 192 Ir was used to deliver LDR brachytherapy through a 1- or 2-plane implant. Patients treated at Nice received 30 Gy, and 45e50 Gy was delivered to all patients treated at Marseille. A relationship of the brachytherapy dose with risk of developing complications noted that the incidence of Grade 2 and 3 complications was 0%, 28%, and 32% with a brachytherapy dose of 30, 45e46, and 50 Gy, respectively ( p 5 0.01). They reported a 5-year overall survival of 91.8%. The KaplaneMeier 5-year freedom from second local recurrence and disease-free survival was 77.4% and 68.9%, respectively. On multivariate analysis, absence of axillary lymph-node metastases at initial presentation and the site of relapse in a quadrant other than the initial primary cancer was more likely to result in a higher overall survival. Further, similar to our results they also observed that the risk of local failure after second conservative
M. Chadha et al. / Brachytherapy 7 (2008) 22e28
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Table 3 Brachytherapy alone after second lumpectomy for breast cancer Author
No. of patients
Brachytherapy technique
Median followup (mo)
Mastectomy-free survival (%)
Maingon et al. Hannoun-Levi et al. Resch et al. Chadha
32 69 17 15
LDR LDR PDR brachytherapy ERT LDR
55 50.2 59 36
73 77.4 76 89
LDR 5 low dose rate; PDR 5 pulsed dose rate; ERT 5 external radiation therapy.
treatment was more likely to occur among patients with a shorter time interval between the primary breast-cancer treatment and the local recurrence. Also, patients treated with a fewer number of interstitial catheters and receiving lower brachytherapy dose were at a significantly higher risk for local failure. Among patients who refused mastectomy and were treated with a second lumpectomy and interstitial brachytherapy, Maingon et al. (43) observed 5-year overall survival, local relapse, and distant failure to be 80%, 27%, and 5%, respectively. Cosmetic outcome was good/acceptable in 75% of patients with a 5-year breast conservation rate of 73%. Maulard et al. (44) reported their observation on 38 patients with isolated local relapses after radiation therapy who underwent salvage treatment with perioperative or split-course interstitial brachytherapy. The patients with smaller tumors (mean, 2.4 cm; range, 0.5e4.0 cm) were treated with a lumpectomy and a perioperative brachytherapy dose of 30 Gy. Whereas patients with larger mean tumor size (3.9 cm; range, 1.5e7.0 cm) were treated with a brachytherapy dose of 60e70 Gy via two interstitial implants performed 1 month apart. All patients achieved a clinical complete response after treatment. With a mean followup of 40 months (range, 16e64), 21% (8 patients) experienced a local relapse. In 7 patients, the second local recurrence was associated with metastatic disease and the local recurrence was an isolated event in 1 patient. The overall 5-year survival was 55%. Severe complications requiring a mastectomy were noted in 3 patients (skin necrosis in 1 and severe breast pain in 2 patients). The toxicity and inferior cosmetic outcome were influenced by the inclusion of patients with large tumors that required higher radiation dose. Other small series have reported the use of ERT in the retreatment for small recurrent breast cancers in previously irradiated breast. Resch et al. (45) applied pulsed dose rate (PDR) þ ERT in 8 patients. In the combination treatment, the PDR brachytherapy dose ranged from 12.5 to 28 Gy and the ERT dose ranged from 12 to 30 Gy. Four of the 8 patients had a second local recurrence requiring a mastectomy. A later experience using PDR brachytherapy only and a dose of 40.2e50 Gy resulted in low-complication rates with side effects limited to moderate Grade 1e2 fibrosis. Deutsch et al. (46) reported that 5-year disease-free and overall survival were 68.5% and 77.9%, respectively, after
a local recurrence treated with a second lumpectomy and 50 Gy ERT to the lumpectomy site using electrons. The clinical experience being reported in this article specifically notes the safety and feasibility of LDR interstitial brachytherapy in breast previously treated with a fractionated course of ERT using standard fractionation schedule (180e200 cGy). This clinical experience cannot be translated to the management of a local recurrence after accelerated treatment schedules that use larger than the conventional RT dose per fraction, HDR Mammosite catheter, or multicatheter brachytherapy techniques. Among patients who recur after accelerated treatment schedules, the feasibility of second conservative treatment using PBB requires investigation. It may seem plausible if the second lumpectomy removes the breast tissue that was within the high-dose gradient of the initial accelerated treatment.
Conclusions Our observations suggest that repeat lumpectomy and LDR interstitial breast brachytherapy are well tolerated with acceptable toxicity. With careful selection criteria, there may be an opportunity to offer women a second chance at breast conservation. Clearly, larger studies and longer followup are needed. Nonetheless, encouraging early results may suggest that mastectomy may not be the only treatment option for women who have history of previous ERT.
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