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Report on the Clinical Outcomes of Permanent Breast Seed Implant for Early-Stage Breast Cancers
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Report on the Clinical Outcomes of Permanent Breast Seed Implant for Early-Stage Breast Cancers Jean-Philippe Pignol, MD, PhD,*,y Jean-Michel Caudrelier, MD,z Juanita Crook, MD,x Claire McCann, PhD,* Pauline Truong, MD, MSc,jj and Helena A. Verkooijen, MD, PhD{ *Radiation Oncology Department, University of Toronto at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; yRadiation Oncology Department, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands; zDepartment of Radiation Medicine, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; xDepartment of Radiation Oncology, BC Cancer Agency Center for the Southern Interior, Kelowna, British Columbia, Canada; jjRadiation Oncology Department, BC Cancer Agency Vancouver Island Centre, Victoria, British Columbia, Canada; and { Imaging Division, University Medical Centre Utrecht, Utrecht, The Netherlands Received Apr 21, 2015, and in revised form Jun 28, 2015. Accepted for publication Jul 13, 2015.
Summary Permanent breast seed implant is an accelerated partial breast irradiation technique using permanent insertion of 103Pd seeds into the seroma after breastconserving surgery. We report the 5-year outcomes of 3 consecutive trials. The local control and tolerance are similar to those of whole breast irradiation and other forms of accelerated partial breast irradiation.
Purpose: Permanent breast seed implant is an accelerated partial breast irradiation technique realizing the insertion of 103Pd seeds in the seroma after lumpectomy. We report the 5-year efficacy and tolerance for a cohort, pooling patients from 3 clinical trials. Methods and Materials: The trials accrued postmenopausal patients with infiltrating ductal carcinoma or ductal carcinoma in situ 3 cm and clear surgical margins, who were node negative, and had a planning target volume <120 cm3. The outcomes included overall and disease-free survival and local and contralateral recurrence at 5 years. The true local recurrence rate was compared using 2-tailed paired t tests for estimates calculated using the Tufts University ipsilateral breast tumor recurrence and Memorial Sloan Kettering ductal carcinoma in situ nomograms. Results: The cohort included 134 patients, and the observed local recurrence rate at a median follow-up period of 63 months was 1.2% 1.2%, similar to the estimate for whole breast irradiation (PZ.23), significantly better than for surgery alone (relative risk 0.27; P<.001), and significantly lower than contralateral recurrence (relative risk 0.33; P<.001). The 5-year overall survival rate was 97.4% 1.9%, and the diseasefree survival rate was 96.4% 2.1%. At 2 months, 42% of the patients had erythema, 20% induration, and 16% moist desquamation. The rate of mainly grade 1
Reprint requests to: Jean-Philippe Pignol, MD, PhD, Radiation Oncology Department, Erasmus Medical Center Cancer Institute, Daniel Den Hoed, Groene Hilledijk 301, Rotterdam 3075 EA, The Netherlands. Tel: (10) 704-1366; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 93, No. 3, pp. 614e621, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.07.2266
Conflict of interest: none. AcknowledgmentsdThis research was supported by the Canadian Breast Cancer Foundation, Ontario Chapter.
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telangiectasia was 22.4% at 2 years and 24% at 5 years. The rate of asymptomatic induration was 23% at 2 years and 40% at 5 years. Conclusions: The 5-year data suggest that permanent breast seed implantation is a safe accelerated partial breast irradiation option after lumpectomy for early-stage breast cancer with a tolerance profile similar to that of whole breast irradiation. Ó 2015 Elsevier Inc. All rights reserved.
Introduction Most breast cancers are diagnosed at an early stage (1, 2), and the current standard of care includes breast-conserving surgery with limited node sampling, followed by whole breast irradiation (WBI) delivered 5 days per week for 3 to 7 weeks (3-5). For appropriately selected patients, limiting radiation to the postoperative cavity with a margin can suffice to prevent local recurrence (6-9). Also, because a smaller volume of normal tissue is treated, the radiation therapy can be delivered within a shorter period (8, 9). The concept of accelerated partial breast irradiation (APBI) has been tested in multiple studies, including phase 3 trials (10-13), and diverse techniques have been proposed, including brachytherapy, external beam 3-dimensional conformal radiation therapy, and intraoperative radiation therapy (11-13). The American Society for Radiation Oncology and several other societies have published recommendations for the careful use of APBI (14-17). In 2006, our team reported the first use of permanent breast seed implant (PBSI) as a technique for APBI (18). Patients have been enrolled in 3 consecutive pilot or registry trials. Thus, in the present study, we performed a post hoc analysis of the 5-year efficacy and tolerance for a cohort of patients accrued in those trials. The results were compared with the calculated probability of local control using the Tuft University ipsilateral breast tumor recurrence (IBTR) invasive carcinoma nomogram and the Memorial Sloan Kettering Cancer Center ductal carcinoma in situ (DCIS) recurrence nomogram (19, 20).
Methods and Materials Patients The first phase 1/2 study included patients aged 40 years who had undergone lumpectomy for unifocal infiltrating ductal carcinoma, grade 1 or 2, <3 cm in diameter, with surgical margins of 5 mm, no lymphovascular invasion, and <25% DCIS. Lobular histologic features were excluded. Initially, patients with 1 to 3 positive nodes were included; however, after the publication of the American Society for Radiation Oncology guidelines (14), such patients were also excluded. The endpoints were local control and the rate of serious adverse events. The second phase 2 multicenter study included patients aged 50 years after lumpectomy for a unifocal DCIS,
<3 cm in diameter, with 3 mm surgical margins. Patients with diabetes, autoimmune disorder, or postlumpectomy infection were excluded. The endpoint was local control. The third multicenter registry study included patients aged 50 years with inclusion criteria similar to those of the first infiltrating ductal carcinoma study. The endpoint was the serious adverse event rate. The second and third studies were conducted concurrently. For all 3 studies, patients with a postoperative seroma >2.5 cm or planning target volume (PTV) >120 cm3 were excluded. The institutional research ethic boards approved each trial, and all patients provided written informed consent.
Planning Details of the planning and dosimetry optimization have been previously reported. In brief, a computed tomography simulation was performed to position the patient the same as for external beam breast radiation therapy. The clinical target volume was defined as the seroma plus an additional 1-cm margin, cropped at the fascia pectoralis and at 5 mm below the skin surface. The PTV was defined as an additional 0.5-cm margin around the clinical target volume with the same skin and chest wall limits (21). The optimal entry position and angle of a fiducial needle were determined; these were generally tangential to the chest wall to minimize the risk of lung puncture. The fiducial needle is a sturdy localizing needle placed in the center of the PTV and through the brachytherapy template to guide the insertion of the seed-bearing needles. The images were resliced perpendicular to the fiducial needle and spaced evenly every 5 mm using the MIM Symphony software (MIM Software Inc, Cleveland, OH). Next, brachytherapy needles bearing stranded 103Pd seeds with a 2.5 U activity were placed in a triangular or square fashion inside the PTV, whichever better fit the PTV shape. To improve the dose homogeneity, the peripheral needles were loaded alternating 1 seed and 1 spacer. The seeds of the central needles were separated by 2 spacers, staggering the seeds in the adjacent strands. At that stage, a lengthy manual optimization was performed, removing or adding seeds as necessary to ensure that the PTV receiving 100% of the dose (V100) would be >95% and the V200 remained at <20%. Eventually, the activity of the seeds was adjusted to deliver a dose of 90 Gy to the minimal peripheral dose isodose line enclosing the PTV (22) (Fig. 1). The palladium
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(Fig. 2). At the end of the implant procedure, a dry dressing was applied for 24 hours.
Data collection and study endpoints The patients were seen 2 months after implantation for clinical assessment, and a quality assurance postimplant computed tomography scan was performed. The subsequent examinations were at 6 months and then annually for clinical assessment and mammography. The endpoints of the present cohort study included overall and disease-free survival; local, regional, and metastatic recurrence; and the occurrence and severity of side effects. The severity of late toxicity was graded according to the effect on the activity of daily life using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, 4-point scale for desquamation, skin pigmentation, or induration (23, 24) and the Bentzen 4-point scale for telangiectasia (none, <1, 1-4, and >4 cm2) (25).
Statistical analysis
Fig. 1. Permanent breast seed implant setup. The fiducial needle is placed first and centered on the template. This enables the precise insertion of the needles loaded with the stranded seeds. sources have a half-life of 16.8 days; thus, a 5 half-life therapeutic dose would be delivered in 84 days.
Treatment The patients were instructed to consume a fluid diet the day before the implant. The anesthesia protocol included ketoprofen twice daily for 48 hours, intravenous neurolept anesthesia, and local freezing using bupivacaine. For the implant procedure, the patients were positioned on a breast board, with the arm abducted the same as for computed tomography simulation. The breast skin was cleansed with chlorhexidine 0.5%, and the projected PTV was outlined on the skin surface and verified using ultrasonography. The fiducial needle was then inserted in the surgical cavity under ultrasound guidance, and its position and direction were verified using the skin marks. A PBSI template was attached to the fiducial needle and immobilized using a modified medical articulated arm (Fisso; Baitella Alt, Zurich, Switzerland). The preloaded needles containing 103 Pd strands were inserted under ultrasound guidance, starting with the deepest row closest to the chest wall
The patient characteristics are presented as proportions or median values and their ranges. Overall survival, disease-free survival, and local or contralateral breast recurrence at 5 years were calculated using Kaplan-Meier statistics. The theoretical risk of local recurrence was calculated for each patient using the Tufts University IBTR nomogram for infiltrating ductal carcinoma (19) and the Memorial Sloan Kettering Cancer Center nomogram for DCIS recurrence (20), for both categories of having received or not received adjuvant radiation therapy. For the IBTR nomogram, patient age, tumor size, tumor grade, margin status, presence of lymphovascular invasion, and the delivery of chemotherapy or endocrine therapy were extracted from the medical records, and the individual local recurrence risk was calculated. For the Memorial Sloan Kettering Cancer Center nomogram, patent age, familial history, tumor presentation, use of endocrine therapy, tumor grade, presence of necrosis, surgical margin status, and number and year of surgery were extracted from the medical records, and the individual risk of DCIS recurrence was calculated. Because the Tufts University IBTR nomogram calculated the recurrence risk at 10 years, the 5-year values were estimated to be one half of the 10-year values. The average observed rate of local recurrence was compared with the theoretical one for the entire cohort using 2-tailed paired t tests.
Results Patients, date, and census From April 2004 to May 2014, 134 patients were treated in the 3 studies and in 3 centers by 4 radiation oncologists. The initial phase 1/2 study accrued 67 patients from April 2004 to April 2007. A 2-year gap separated the first and the
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Fig. 2. Preimplant planning optimization. The red contour indicates the planning target volume and the green isodose, the planning target volume receiving 100% of the dose. A color version of this figure is available at www.redjournal.org. second 2 subsequent studies to collect the efficacy, tolerance, and safety PBSI data. The 2 subsequent multicenter studies also accrued 67 patients from April 2009 to May 2014. Only patients with a minimum 6-month follow-up period were selected for the present analysis. The final cohort included a total of 128 patients. The patient characteristics of the study cohort are summarized in Table 1. The median age was 61.9 years, and 116 patients (91%) had invasive carcinoma found on pathology review. One was found to have lobular histologic features and one had node-positive disease. Only 12 patients had DCIS; 11 had been accrued to the multicenter phase 2 study, and 1 was found to have DCIS after the pathology review. That study accrued poorly, and the study investigators decided to close the study and pool the DCIS patients into the present cohort. The vast majority of patients had very favorable pathologic features. The median tumor size was 1.1 cm, the median margin size was 6 mm, 46% had low-grade tumors, 99% had node-negative disease, 96% did not had lymphovascular invasion, and 96% had hormone receptorepositive disease. Only 3 patients had HER2 positivity, and one had triplenegative breast cancer. Thus, very few (11%) received chemotherapy, and most (84%) received endocrine therapy. The median interval between surgery and PBSI was 16 weeks, mainly owing to a median 10-week delay between surgery and the radiation referral. Most patients had undergone their surgery in community hospitals, and the
referral was often sent only when the final pathology result was available and the patient had been examined by a medical oncologist.
Five-year survival outcomes The median follow-up time was 63 months (range 6-122). Also, at the data analysis, 113 of 128 patients (89%) were alive without evidence of disease. Of the 15 patients with evidence of disease, 5 developed ipsilateral cancer recurrence after stopping endocrine treatment, and 6 patients developed contralateral breast cancer. The 1 patient with a positive lymph node developed regional recurrence at 69 months and remained disease free 4 years after additional surgery, regional radiation therapy, and endocrine therapy. Also, 1 patient developed a metastatic adenocarcinoma to the lung and liver presumed to be from the breast primary cancer but without any locoregional recurrence. Finally, 2 patients died of heart failure at 9 and 58 months after PBSI. Both patients had significant cardiac comorbidities at implantation. Accounting for individual risk factors, the theoretical estimate of 5-year local recurrence-free survival for the whole cohort was 98.5% 0.98% with adjuvant radiation therapy and 95.4% 2.4% with surgery alone. The observed rate of local recurrence-free survival at 5 years was 98.8% 1.20%, not significantly different statistically from the theoretical rate for patients receiving adjuvant
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Table 1
Patient clinical, tumor, and treatment characteristics Characteristic
Age (y) Median Range Tumor size (cm) Median Range Pathologic type Infiltrating ductal carcinoma Infiltrating lobular carcinoma Ductal carcinoma in situ Tumor grade 1 2 3 Lymphovascular infiltration Nodal involvement Margin (mm) Median Range Surgically revised Molecular characteristic Estrogen receptor positive Progesterone receptor positive HER2 overexpression Triple-negative breast cancer Adjuvant medical treatment Chemotherapy Hormonal therapy
Value 61.9 41-84.5 1.1 0.2-3.0 115/128 (90) 1/128 (1) 12/128 (9) 59/128 67/128 2/128 5/116 1/116
(46) (52) (2) (4) (1)
6.0 1.0-40 12/128 (9) 121/126 120/125 3/87 1/87
(96) (96) (3) (1)
11/104 (11) 98/117 (84)
Data presented as median and range or n (%); proportions excluded patients without data available.
radiation therapy (PZ.235) but significantly better than that for patients treated with surgery alone (relative risk 0.27, P<.001). Similarly, the rate of ipsilateral recurrence was significantly lower than the rate of contralateral recurrence (relative risk 0.33, P<.001). The 5-year overall survival rate was 97.4% 1.91%, and the disease-free survival rate was 96.4% 2.07% (Table 2).
Side effects The side effects at 6 to 8 weeks and 2 and 5 years after PBSI are summarized in Table 3. The most frequent acute Table 2
side effect was skin erythema just above the implant, occurring in 42% of the patients, and with an impact on the activity of daily life in only 4.7%. Moist desquamation was seen in 16%, affecting the activities of daily life in 6%. One patient with severe visual and cardiac complications of type 1 diabetes developed a skin ulceration above the implant site that required 4 months to heal. Regarding delayed side effects, few patients had skin erythema, desquamation, or skin discoloration at 2 years, because these side effects usually disappear with longer follow-up. Asymptomatic skin induration was found in 23% at 2 years and had doubled to 39% at 5 years but remained constant thereafter. A total of 22% patients experienced telangiectasia at 2 years. The vast majority of telangiectasia corresponded to a small number of visible vessels on a surface <1 cm2 or grade 1 (19%), and few patients presented with telangiectasia grade 2 (3%; Fig. 3). These rates remained stable at 5 years, and 4 patients with a longer follow-up period showed progressive full disappearance of the telangiectasia.
Discussion The present study reports on the 5-year outcomes of patients with early-stage breast cancer treated with PBSI as the sole form of adjuvant radiation therapy. The efficacy appeared similar to that of WBI, with a 5-year local recurrence rate similar to that predicted by nomograms, 1.2% versus 1.4% (PZNS). This rate of local recurrence is one quarter of that estimated for patients treated with lumpectomy without radiation therapy (4.6%; P<.001) and one third of that calculated for contralateral breast cancer occurrence (3.6%; P<.001). Although the Tufts University IBTR nomogram provides local recurrence estimates at 10 years (19), we assumed the risk of recurrence to be linear for that time to calculate the 5-year risk. This can be considered a “conservative” approach, because several reports, including the Early Breast Cancer Trialists’ Collaborative Group meta-analysis, have shown that most recurrences develop within the first 5 years (3). Concern has arisen regarding the accuracy of the IBTR nomogram, but it has been reported to be accurate for patients with a low to moderate risk of in-breast recurrence and might overestimate the risk for patients with higher risk features.
Five-year outcomes observed for PBSI and calculated using nomograms
Survival endpoint
Method used
5-y Rate (%)
RR
P value
1 0.8 0.26 0.33
.092 <.001 <.001
Ipsilateral recurrence free
Contralateral recurrence free Disease-free survival Overall survival
PBSI observed WBI nomograms Surgery alone Observed Observed Observed
98.8% 98.5% 95.4% 96.4% 96.4% 97.4%
1.20% 0.98% 2.09% 2.09% 2.07% 1.91%
Abbreviations: PBSI Z permanent breast seed implant; RR Z relative risk; WBI Z whole breast irradiation. Data presented as mean standard deviation.
Volume 93 Number 3 2015 Table 3
Long-term results of PBSI
PBSI acute and long-term side effects Follow-up point
Symptom Redness None No effect on ADL Effect on ADL Induration None No effect on ADL Effect on ADL Desquamation None No effect on ADL Effect on ADL NA Telangiectasia None <1 cm2 1-4 cm2 4 cm2
2 mo (nZ122)
2y (nZ112)
5y (nZ74)
71 (58) 45 (37) 6 (5)
112 (100) 0 0
74 (100) 0 0
98 (80) 23 (19) 1 (1)
86 (77) 26 (23) 0
45 (61) 29 (40) 0
112 (100) 0 0
74 (100) 0 0
87 (78) 21 (19) 4 (3) 0
56 (76) 16 (21) 2 (3) 0
101 12 8 1
(83) (10) (6) (1)
122 (100) 0 0 0
Abbreviations: ADL Z activity of daily life; NA Z not available; PBSI Z permanent breast seed implant. Side effects were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (24).
We did not perform a sensitivity analysis, because the standard deviation for the theoretical risk of recurrence for the whole cohort was small at 0.98%, despite very different patient presentations in term of age, tumor size, margins, and hormone receptor status (19). Compared with other modern series of adjuvant radiation therapy for early-stage breast cancer, the PBSI local control rates appear similar to those reported by Fyles et al (26) and Hughes et al (27) in randomized studies evaluating
Fig. 3. Typical grade 1 telangiectasia seen at 2 to 5 years after seed implantation.
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the benefit of adjuvant radiation therapy after lumpectomy for patients receiving 5 years of tamoxifen. The local recurrence rate for patients undergoing WBI in addition to taking tamoxifen was 0.6% and 1% in the Fyles et al and Hughes et al studies, respectively, and was 7.7% and 4% without tamoxifen, respectively. Of note, the patients were older in the studies by Fyles et al (26) and Hughes et al (27), with a median age of 68 and >75 years, respectively. Also, all the patients received tamoxifen for 5 years. In the present series, the median age was 61.9 years, with 10% of the patients <50 years. In addition, 84% received antihormonal treatment. The PBSI cohort had better overall survival (97.4%) than that (92.8% and 87%, respectively) reported by Fyles et al (26) and Hughes et al (27). Also, the PBSI local control results compared favorably with the intraoperative radiation results of the targeted intraoperative radiotherapy (TARGIT) trial (12), which reported a 5-year risk of ipsilateral local recurrence of 3.3% for the intraoperative APBI arm versus 1.3% for the WBI arm (PZ.042). Similarly, the electron intraoperative radiation therapy (ELIOT) study achieved a local recurrence rate of 4.4% at 5.8 years (28). Finally, the present results compare favorably to the MammoSite registry, which reported an ipsilateral recurrence rate of 3.8%, disease-free recurrence of 86.1%, and overall survival of 92.4% at 5 years (29). The efficacy results of the various external beam radiation APBI trials are still pending. Regarding acute side effects, the rate of 16% moist desquamation was high compared with other APBI techniques using high-dose-rate (HDR) brachytherapy, with which moist desquamation is rarely observed. However, those techniques deliver lower physical doses. In contrast, the present rate compared favorably to that after WBI, with a moist desquamation rate of 31% using breast intensity modulated radiation therapy and 48% using a standard wedge technique in the Canadian breast intensity modulated radiation therapy study (29). We have previously reported the PBSI cosmetic outcomes and patient satisfaction, with 97% excellent (83%) or good (14%) cosmetic results at 3 years. Also, 92% of the patients declared they were “very satisfied” at 6 months after the implant (22). The telangiectasia rates at 2 and 5 years (22% and 25%, respectively) were comparable to those after external beam radiation therapy. An unpublished analysis of the Canadian breast intensity modulated radiation therapy study (30) found that at 8 years, the rate of telangiectasia was 19%, with 6% of the patients presenting with telangiectasia grade 2. This rate is also comparable to that reported by Ott et al (31) for HDR brachytherapy (19% at 5 years) but better than that reported by Chen et al (32) using low-dose-rate or HDR catheter brachytherapy (34% at 5 years). As reported by Chen et al (32), the vast majority of telangiectasia is grade 1 and barely visible (Fig. 3). The induration rate of 39% at 5 years was halfway between the rate reported by Chen et al (32) (46% at 5 years) and that reported by Ott et al (31) (31%). As stressed by Chen et al (32), it is important that any degree of scar induration
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should be scored as fibrosis, regardless of whether postoperative changes might have contributed. However, the rate of induration has clearly been higher for PBSI than for WBI, with a 7% rate reported by Rosenkranz et al (33), and the occurrence of induration might be the price to pay for a more convenient technique. PBSI shares with intraoperative radiation therapy the advantage of being delivered in a single session. In contrast to intraoperative radiation therapy, PBSI is delivered after the final pathology report is available and the seroma has stabilized, because the dose distribution can be optimized. It is a 1-hour procedure performed with the patient under light sedation; thus, the patient is released home the same day. The disadvantage compared with IORT is that PBSI requires additional operating room time and specific brachytherapy skills. Also, the cost of the seeds could be a factor in the decision to use PBSI. We have previously reported the need for an average of 75 seeds per patient, which represented in 2015 a cost of Canadian $4200 per patient. Compared with HDR brachytherapy, PBSI delivers a lower total body dose, although the significance is unknown. HDR enables dose distribution optimization after catheter or balloon implantation, but PBSI does not allow for postimplant corrections. Also, the real dose distribution is unknown because the breast can move significantly during implantation. We previously reported significant differences between the pre- and post-implant quality assurance for the first 95 PBSI patients (21). A “good” implant was defined, similar to prostate brachytherapy, to have a V100 of >90%. A learning curve was present, with the first 50% of patients having a mean postimplant V100 of 82% compared with a V100 of 89% for the second 50%. Correspondingly, the mean V200 was cooler at 31.1% for the first 50% and 41.2% for the second. We did not find higher rates of acute or late side effects in the earlier treated patients compared with the later ones; however, those treated earlier had very small volume implanted. We also reported a large variation in the skin dose received, with a median dose of 62% (range 11%-186%) (21).
Conclusions The role of APBI is still pending the final results of several multicenter randomized controlled trials in Europe, the United States, and Canada (11). The purpose of the present study was to assess the value of seed brachytherapy as a form of APBI. The results we have reported suggest that the technique is safe and the tolerance is equivalent to that of other APBI brachytherapy techniques.
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Volume 93 Number 3 2015 23. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-181. 24. U.S. Department of Health and Human Services, National Institute of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events, Version 4.03. Published June 14, 2010. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed July 2014. 25. Bentzen SM, Overgaard M. Relationship between early and late normal-tissue injury after postmastectomy radiotherapy. Radiother Oncol 2001;20:159-165. 26. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 2004;351:963-970. 27. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med 2004;351:971-977. 28. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): A randomised controlled equivalence trial. Lancet Oncol 2013;14: 1269-1277.
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Clinical Investigation
Report on the Clinical Outcomes of Permanent Breast Seed Implant for Early-Stage Breast Cancers Jean-Philippe Pignol, MD, PhD,*,y Jean-Michel Caudrelier, MD,z Juanita Crook, MD,x Claire McCann, PhD,* Pauline Truong, MD, MSc,jj and Helena A. Verkooijen, MD, PhD{ *Radiation Oncology Department, University of Toronto at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; yRadiation Oncology Department, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands; zDepartment of Radiation Medicine, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; xDepartment of Radiation Oncology, BC Cancer Agency Center for the Southern Interior, Kelowna, British Columbia, Canada; jjRadiation Oncology Department, BC Cancer Agency Vancouver Island Centre, Victoria, British Columbia, Canada; and { Imaging Division, University Medical Centre Utrecht, Utrecht, The Netherlands Received Apr 21, 2015, and in revised form Jun 28, 2015. Accepted for publication Jul 13, 2015.
Summary Permanent breast seed implant is an accelerated partial breast irradiation technique using permanent insertion of 103Pd seeds into the seroma after breastconserving surgery. We report the 5-year outcomes of 3 consecutive trials. The local control and tolerance are similar to those of whole breast irradiation and other forms of accelerated partial breast irradiation.
Purpose: Permanent breast seed implant is an accelerated partial breast irradiation technique realizing the insertion of 103Pd seeds in the seroma after lumpectomy. We report the 5-year efficacy and tolerance for a cohort, pooling patients from 3 clinical trials. Methods and Materials: The trials accrued postmenopausal patients with infiltrating ductal carcinoma or ductal carcinoma in situ 3 cm and clear surgical margins, who were node negative, and had a planning target volume <120 cm3. The outcomes included overall and disease-free survival and local and contralateral recurrence at 5 years. The true local recurrence rate was compared using 2-tailed paired t tests for estimates calculated using the Tufts University ipsilateral breast tumor recurrence and Memorial Sloan Kettering ductal carcinoma in situ nomograms. Results: The cohort included 134 patients, and the observed local recurrence rate at a median follow-up period of 63 months was 1.2% 1.2%, similar to the estimate for whole breast irradiation (PZ.23), significantly better than for surgery alone (relative risk 0.27; P<.001), and significantly lower than contralateral recurrence (relative risk 0.33; P<.001). The 5-year overall survival rate was 97.4% 1.9%, and the diseasefree survival rate was 96.4% 2.1%. At 2 months, 42% of the patients had erythema, 20% induration, and 16% moist desquamation. The rate of mainly grade 1
Reprint requests to: Jean-Philippe Pignol, MD, PhD, Radiation Oncology Department, Erasmus Medical Center Cancer Institute, Daniel Den Hoed, Groene Hilledijk 301, Rotterdam 3075 EA, The Netherlands. Tel: (10) 704-1366; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 93, No. 3, pp. 614e621, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.07.2266
Conflict of interest: none. AcknowledgmentsdThis research was supported by the Canadian Breast Cancer Foundation, Ontario Chapter.
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telangiectasia was 22.4% at 2 years and 24% at 5 years. The rate of asymptomatic induration was 23% at 2 years and 40% at 5 years. Conclusions: The 5-year data suggest that permanent breast seed implantation is a safe accelerated partial breast irradiation option after lumpectomy for early-stage breast cancer with a tolerance profile similar to that of whole breast irradiation. Ó 2015 Elsevier Inc. All rights reserved.
Introduction Most breast cancers are diagnosed at an early stage (1, 2), and the current standard of care includes breast-conserving surgery with limited node sampling, followed by whole breast irradiation (WBI) delivered 5 days per week for 3 to 7 weeks (3-5). For appropriately selected patients, limiting radiation to the postoperative cavity with a margin can suffice to prevent local recurrence (6-9). Also, because a smaller volume of normal tissue is treated, the radiation therapy can be delivered within a shorter period (8, 9). The concept of accelerated partial breast irradiation (APBI) has been tested in multiple studies, including phase 3 trials (10-13), and diverse techniques have been proposed, including brachytherapy, external beam 3-dimensional conformal radiation therapy, and intraoperative radiation therapy (11-13). The American Society for Radiation Oncology and several other societies have published recommendations for the careful use of APBI (14-17). In 2006, our team reported the first use of permanent breast seed implant (PBSI) as a technique for APBI (18). Patients have been enrolled in 3 consecutive pilot or registry trials. Thus, in the present study, we performed a post hoc analysis of the 5-year efficacy and tolerance for a cohort of patients accrued in those trials. The results were compared with the calculated probability of local control using the Tuft University ipsilateral breast tumor recurrence (IBTR) invasive carcinoma nomogram and the Memorial Sloan Kettering Cancer Center ductal carcinoma in situ (DCIS) recurrence nomogram (19, 20).
Methods and Materials Patients The first phase 1/2 study included patients aged 40 years who had undergone lumpectomy for unifocal infiltrating ductal carcinoma, grade 1 or 2, <3 cm in diameter, with surgical margins of 5 mm, no lymphovascular invasion, and <25% DCIS. Lobular histologic features were excluded. Initially, patients with 1 to 3 positive nodes were included; however, after the publication of the American Society for Radiation Oncology guidelines (14), such patients were also excluded. The endpoints were local control and the rate of serious adverse events. The second phase 2 multicenter study included patients aged 50 years after lumpectomy for a unifocal DCIS,
<3 cm in diameter, with 3 mm surgical margins. Patients with diabetes, autoimmune disorder, or postlumpectomy infection were excluded. The endpoint was local control. The third multicenter registry study included patients aged 50 years with inclusion criteria similar to those of the first infiltrating ductal carcinoma study. The endpoint was the serious adverse event rate. The second and third studies were conducted concurrently. For all 3 studies, patients with a postoperative seroma >2.5 cm or planning target volume (PTV) >120 cm3 were excluded. The institutional research ethic boards approved each trial, and all patients provided written informed consent.
Planning Details of the planning and dosimetry optimization have been previously reported. In brief, a computed tomography simulation was performed to position the patient the same as for external beam breast radiation therapy. The clinical target volume was defined as the seroma plus an additional 1-cm margin, cropped at the fascia pectoralis and at 5 mm below the skin surface. The PTV was defined as an additional 0.5-cm margin around the clinical target volume with the same skin and chest wall limits (21). The optimal entry position and angle of a fiducial needle were determined; these were generally tangential to the chest wall to minimize the risk of lung puncture. The fiducial needle is a sturdy localizing needle placed in the center of the PTV and through the brachytherapy template to guide the insertion of the seed-bearing needles. The images were resliced perpendicular to the fiducial needle and spaced evenly every 5 mm using the MIM Symphony software (MIM Software Inc, Cleveland, OH). Next, brachytherapy needles bearing stranded 103Pd seeds with a 2.5 U activity were placed in a triangular or square fashion inside the PTV, whichever better fit the PTV shape. To improve the dose homogeneity, the peripheral needles were loaded alternating 1 seed and 1 spacer. The seeds of the central needles were separated by 2 spacers, staggering the seeds in the adjacent strands. At that stage, a lengthy manual optimization was performed, removing or adding seeds as necessary to ensure that the PTV receiving 100% of the dose (V100) would be >95% and the V200 remained at <20%. Eventually, the activity of the seeds was adjusted to deliver a dose of 90 Gy to the minimal peripheral dose isodose line enclosing the PTV (22) (Fig. 1). The palladium
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(Fig. 2). At the end of the implant procedure, a dry dressing was applied for 24 hours.
Data collection and study endpoints The patients were seen 2 months after implantation for clinical assessment, and a quality assurance postimplant computed tomography scan was performed. The subsequent examinations were at 6 months and then annually for clinical assessment and mammography. The endpoints of the present cohort study included overall and disease-free survival; local, regional, and metastatic recurrence; and the occurrence and severity of side effects. The severity of late toxicity was graded according to the effect on the activity of daily life using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, 4-point scale for desquamation, skin pigmentation, or induration (23, 24) and the Bentzen 4-point scale for telangiectasia (none, <1, 1-4, and >4 cm2) (25).
Statistical analysis
Fig. 1. Permanent breast seed implant setup. The fiducial needle is placed first and centered on the template. This enables the precise insertion of the needles loaded with the stranded seeds. sources have a half-life of 16.8 days; thus, a 5 half-life therapeutic dose would be delivered in 84 days.
Treatment The patients were instructed to consume a fluid diet the day before the implant. The anesthesia protocol included ketoprofen twice daily for 48 hours, intravenous neurolept anesthesia, and local freezing using bupivacaine. For the implant procedure, the patients were positioned on a breast board, with the arm abducted the same as for computed tomography simulation. The breast skin was cleansed with chlorhexidine 0.5%, and the projected PTV was outlined on the skin surface and verified using ultrasonography. The fiducial needle was then inserted in the surgical cavity under ultrasound guidance, and its position and direction were verified using the skin marks. A PBSI template was attached to the fiducial needle and immobilized using a modified medical articulated arm (Fisso; Baitella Alt, Zurich, Switzerland). The preloaded needles containing 103 Pd strands were inserted under ultrasound guidance, starting with the deepest row closest to the chest wall
The patient characteristics are presented as proportions or median values and their ranges. Overall survival, disease-free survival, and local or contralateral breast recurrence at 5 years were calculated using Kaplan-Meier statistics. The theoretical risk of local recurrence was calculated for each patient using the Tufts University IBTR nomogram for infiltrating ductal carcinoma (19) and the Memorial Sloan Kettering Cancer Center nomogram for DCIS recurrence (20), for both categories of having received or not received adjuvant radiation therapy. For the IBTR nomogram, patient age, tumor size, tumor grade, margin status, presence of lymphovascular invasion, and the delivery of chemotherapy or endocrine therapy were extracted from the medical records, and the individual local recurrence risk was calculated. For the Memorial Sloan Kettering Cancer Center nomogram, patent age, familial history, tumor presentation, use of endocrine therapy, tumor grade, presence of necrosis, surgical margin status, and number and year of surgery were extracted from the medical records, and the individual risk of DCIS recurrence was calculated. Because the Tufts University IBTR nomogram calculated the recurrence risk at 10 years, the 5-year values were estimated to be one half of the 10-year values. The average observed rate of local recurrence was compared with the theoretical one for the entire cohort using 2-tailed paired t tests.
Results Patients, date, and census From April 2004 to May 2014, 134 patients were treated in the 3 studies and in 3 centers by 4 radiation oncologists. The initial phase 1/2 study accrued 67 patients from April 2004 to April 2007. A 2-year gap separated the first and the
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Fig. 2. Preimplant planning optimization. The red contour indicates the planning target volume and the green isodose, the planning target volume receiving 100% of the dose. A color version of this figure is available at www.redjournal.org. second 2 subsequent studies to collect the efficacy, tolerance, and safety PBSI data. The 2 subsequent multicenter studies also accrued 67 patients from April 2009 to May 2014. Only patients with a minimum 6-month follow-up period were selected for the present analysis. The final cohort included a total of 128 patients. The patient characteristics of the study cohort are summarized in Table 1. The median age was 61.9 years, and 116 patients (91%) had invasive carcinoma found on pathology review. One was found to have lobular histologic features and one had node-positive disease. Only 12 patients had DCIS; 11 had been accrued to the multicenter phase 2 study, and 1 was found to have DCIS after the pathology review. That study accrued poorly, and the study investigators decided to close the study and pool the DCIS patients into the present cohort. The vast majority of patients had very favorable pathologic features. The median tumor size was 1.1 cm, the median margin size was 6 mm, 46% had low-grade tumors, 99% had node-negative disease, 96% did not had lymphovascular invasion, and 96% had hormone receptorepositive disease. Only 3 patients had HER2 positivity, and one had triplenegative breast cancer. Thus, very few (11%) received chemotherapy, and most (84%) received endocrine therapy. The median interval between surgery and PBSI was 16 weeks, mainly owing to a median 10-week delay between surgery and the radiation referral. Most patients had undergone their surgery in community hospitals, and the
referral was often sent only when the final pathology result was available and the patient had been examined by a medical oncologist.
Five-year survival outcomes The median follow-up time was 63 months (range 6-122). Also, at the data analysis, 113 of 128 patients (89%) were alive without evidence of disease. Of the 15 patients with evidence of disease, 5 developed ipsilateral cancer recurrence after stopping endocrine treatment, and 6 patients developed contralateral breast cancer. The 1 patient with a positive lymph node developed regional recurrence at 69 months and remained disease free 4 years after additional surgery, regional radiation therapy, and endocrine therapy. Also, 1 patient developed a metastatic adenocarcinoma to the lung and liver presumed to be from the breast primary cancer but without any locoregional recurrence. Finally, 2 patients died of heart failure at 9 and 58 months after PBSI. Both patients had significant cardiac comorbidities at implantation. Accounting for individual risk factors, the theoretical estimate of 5-year local recurrence-free survival for the whole cohort was 98.5% 0.98% with adjuvant radiation therapy and 95.4% 2.4% with surgery alone. The observed rate of local recurrence-free survival at 5 years was 98.8% 1.20%, not significantly different statistically from the theoretical rate for patients receiving adjuvant
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Table 1
Patient clinical, tumor, and treatment characteristics Characteristic
Age (y) Median Range Tumor size (cm) Median Range Pathologic type Infiltrating ductal carcinoma Infiltrating lobular carcinoma Ductal carcinoma in situ Tumor grade 1 2 3 Lymphovascular infiltration Nodal involvement Margin (mm) Median Range Surgically revised Molecular characteristic Estrogen receptor positive Progesterone receptor positive HER2 overexpression Triple-negative breast cancer Adjuvant medical treatment Chemotherapy Hormonal therapy
Value 61.9 41-84.5 1.1 0.2-3.0 115/128 (90) 1/128 (1) 12/128 (9) 59/128 67/128 2/128 5/116 1/116
(46) (52) (2) (4) (1)
6.0 1.0-40 12/128 (9) 121/126 120/125 3/87 1/87
(96) (96) (3) (1)
11/104 (11) 98/117 (84)
Data presented as median and range or n (%); proportions excluded patients without data available.
radiation therapy (PZ.235) but significantly better than that for patients treated with surgery alone (relative risk 0.27, P<.001). Similarly, the rate of ipsilateral recurrence was significantly lower than the rate of contralateral recurrence (relative risk 0.33, P<.001). The 5-year overall survival rate was 97.4% 1.91%, and the disease-free survival rate was 96.4% 2.07% (Table 2).
Side effects The side effects at 6 to 8 weeks and 2 and 5 years after PBSI are summarized in Table 3. The most frequent acute Table 2
side effect was skin erythema just above the implant, occurring in 42% of the patients, and with an impact on the activity of daily life in only 4.7%. Moist desquamation was seen in 16%, affecting the activities of daily life in 6%. One patient with severe visual and cardiac complications of type 1 diabetes developed a skin ulceration above the implant site that required 4 months to heal. Regarding delayed side effects, few patients had skin erythema, desquamation, or skin discoloration at 2 years, because these side effects usually disappear with longer follow-up. Asymptomatic skin induration was found in 23% at 2 years and had doubled to 39% at 5 years but remained constant thereafter. A total of 22% patients experienced telangiectasia at 2 years. The vast majority of telangiectasia corresponded to a small number of visible vessels on a surface <1 cm2 or grade 1 (19%), and few patients presented with telangiectasia grade 2 (3%; Fig. 3). These rates remained stable at 5 years, and 4 patients with a longer follow-up period showed progressive full disappearance of the telangiectasia.
Discussion The present study reports on the 5-year outcomes of patients with early-stage breast cancer treated with PBSI as the sole form of adjuvant radiation therapy. The efficacy appeared similar to that of WBI, with a 5-year local recurrence rate similar to that predicted by nomograms, 1.2% versus 1.4% (PZNS). This rate of local recurrence is one quarter of that estimated for patients treated with lumpectomy without radiation therapy (4.6%; P<.001) and one third of that calculated for contralateral breast cancer occurrence (3.6%; P<.001). Although the Tufts University IBTR nomogram provides local recurrence estimates at 10 years (19), we assumed the risk of recurrence to be linear for that time to calculate the 5-year risk. This can be considered a “conservative” approach, because several reports, including the Early Breast Cancer Trialists’ Collaborative Group meta-analysis, have shown that most recurrences develop within the first 5 years (3). Concern has arisen regarding the accuracy of the IBTR nomogram, but it has been reported to be accurate for patients with a low to moderate risk of in-breast recurrence and might overestimate the risk for patients with higher risk features.
Five-year outcomes observed for PBSI and calculated using nomograms
Survival endpoint
Method used
5-y Rate (%)
RR
P value
1 0.8 0.26 0.33
.092 <.001 <.001
Ipsilateral recurrence free
Contralateral recurrence free Disease-free survival Overall survival
PBSI observed WBI nomograms Surgery alone Observed Observed Observed
98.8% 98.5% 95.4% 96.4% 96.4% 97.4%
1.20% 0.98% 2.09% 2.09% 2.07% 1.91%
Abbreviations: PBSI Z permanent breast seed implant; RR Z relative risk; WBI Z whole breast irradiation. Data presented as mean standard deviation.
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PBSI acute and long-term side effects Follow-up point
Symptom Redness None No effect on ADL Effect on ADL Induration None No effect on ADL Effect on ADL Desquamation None No effect on ADL Effect on ADL NA Telangiectasia None <1 cm2 1-4 cm2 4 cm2
2 mo (nZ122)
2y (nZ112)
5y (nZ74)
71 (58) 45 (37) 6 (5)
112 (100) 0 0
74 (100) 0 0
98 (80) 23 (19) 1 (1)
86 (77) 26 (23) 0
45 (61) 29 (40) 0
112 (100) 0 0
74 (100) 0 0
87 (78) 21 (19) 4 (3) 0
56 (76) 16 (21) 2 (3) 0
101 12 8 1
(83) (10) (6) (1)
122 (100) 0 0 0
Abbreviations: ADL Z activity of daily life; NA Z not available; PBSI Z permanent breast seed implant. Side effects were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (24).
We did not perform a sensitivity analysis, because the standard deviation for the theoretical risk of recurrence for the whole cohort was small at 0.98%, despite very different patient presentations in term of age, tumor size, margins, and hormone receptor status (19). Compared with other modern series of adjuvant radiation therapy for early-stage breast cancer, the PBSI local control rates appear similar to those reported by Fyles et al (26) and Hughes et al (27) in randomized studies evaluating
Fig. 3. Typical grade 1 telangiectasia seen at 2 to 5 years after seed implantation.
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the benefit of adjuvant radiation therapy after lumpectomy for patients receiving 5 years of tamoxifen. The local recurrence rate for patients undergoing WBI in addition to taking tamoxifen was 0.6% and 1% in the Fyles et al and Hughes et al studies, respectively, and was 7.7% and 4% without tamoxifen, respectively. Of note, the patients were older in the studies by Fyles et al (26) and Hughes et al (27), with a median age of 68 and >75 years, respectively. Also, all the patients received tamoxifen for 5 years. In the present series, the median age was 61.9 years, with 10% of the patients <50 years. In addition, 84% received antihormonal treatment. The PBSI cohort had better overall survival (97.4%) than that (92.8% and 87%, respectively) reported by Fyles et al (26) and Hughes et al (27). Also, the PBSI local control results compared favorably with the intraoperative radiation results of the targeted intraoperative radiotherapy (TARGIT) trial (12), which reported a 5-year risk of ipsilateral local recurrence of 3.3% for the intraoperative APBI arm versus 1.3% for the WBI arm (PZ.042). Similarly, the electron intraoperative radiation therapy (ELIOT) study achieved a local recurrence rate of 4.4% at 5.8 years (28). Finally, the present results compare favorably to the MammoSite registry, which reported an ipsilateral recurrence rate of 3.8%, disease-free recurrence of 86.1%, and overall survival of 92.4% at 5 years (29). The efficacy results of the various external beam radiation APBI trials are still pending. Regarding acute side effects, the rate of 16% moist desquamation was high compared with other APBI techniques using high-dose-rate (HDR) brachytherapy, with which moist desquamation is rarely observed. However, those techniques deliver lower physical doses. In contrast, the present rate compared favorably to that after WBI, with a moist desquamation rate of 31% using breast intensity modulated radiation therapy and 48% using a standard wedge technique in the Canadian breast intensity modulated radiation therapy study (29). We have previously reported the PBSI cosmetic outcomes and patient satisfaction, with 97% excellent (83%) or good (14%) cosmetic results at 3 years. Also, 92% of the patients declared they were “very satisfied” at 6 months after the implant (22). The telangiectasia rates at 2 and 5 years (22% and 25%, respectively) were comparable to those after external beam radiation therapy. An unpublished analysis of the Canadian breast intensity modulated radiation therapy study (30) found that at 8 years, the rate of telangiectasia was 19%, with 6% of the patients presenting with telangiectasia grade 2. This rate is also comparable to that reported by Ott et al (31) for HDR brachytherapy (19% at 5 years) but better than that reported by Chen et al (32) using low-dose-rate or HDR catheter brachytherapy (34% at 5 years). As reported by Chen et al (32), the vast majority of telangiectasia is grade 1 and barely visible (Fig. 3). The induration rate of 39% at 5 years was halfway between the rate reported by Chen et al (32) (46% at 5 years) and that reported by Ott et al (31) (31%). As stressed by Chen et al (32), it is important that any degree of scar induration
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should be scored as fibrosis, regardless of whether postoperative changes might have contributed. However, the rate of induration has clearly been higher for PBSI than for WBI, with a 7% rate reported by Rosenkranz et al (33), and the occurrence of induration might be the price to pay for a more convenient technique. PBSI shares with intraoperative radiation therapy the advantage of being delivered in a single session. In contrast to intraoperative radiation therapy, PBSI is delivered after the final pathology report is available and the seroma has stabilized, because the dose distribution can be optimized. It is a 1-hour procedure performed with the patient under light sedation; thus, the patient is released home the same day. The disadvantage compared with IORT is that PBSI requires additional operating room time and specific brachytherapy skills. Also, the cost of the seeds could be a factor in the decision to use PBSI. We have previously reported the need for an average of 75 seeds per patient, which represented in 2015 a cost of Canadian $4200 per patient. Compared with HDR brachytherapy, PBSI delivers a lower total body dose, although the significance is unknown. HDR enables dose distribution optimization after catheter or balloon implantation, but PBSI does not allow for postimplant corrections. Also, the real dose distribution is unknown because the breast can move significantly during implantation. We previously reported significant differences between the pre- and post-implant quality assurance for the first 95 PBSI patients (21). A “good” implant was defined, similar to prostate brachytherapy, to have a V100 of >90%. A learning curve was present, with the first 50% of patients having a mean postimplant V100 of 82% compared with a V100 of 89% for the second 50%. Correspondingly, the mean V200 was cooler at 31.1% for the first 50% and 41.2% for the second. We did not find higher rates of acute or late side effects in the earlier treated patients compared with the later ones; however, those treated earlier had very small volume implanted. We also reported a large variation in the skin dose received, with a median dose of 62% (range 11%-186%) (21).
Conclusions The role of APBI is still pending the final results of several multicenter randomized controlled trials in Europe, the United States, and Canada (11). The purpose of the present study was to assess the value of seed brachytherapy as a form of APBI. The results we have reported suggest that the technique is safe and the tolerance is equivalent to that of other APBI brachytherapy techniques.
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