Breast Conservation Therapy with Tumor Bed Brachytherapy Alone in Stage I Breast Cancer : Results of a Phase II Trial

Background. Radiotherapy after breast conserving surgery increases local control. Standard radiotherapy includes whole breast irradiation delivered in a daily fashion over 5 or 51⁄2 weeks. All patients may not require entire breast treatment. We tested the feasibility of limited surgery with limited irradiation using interstitial brachytherapy to the tumor bed in a selected group of patients with stage I breast cancer in a phase II trial. Methods. Women aged 55 years or older with low or intermediate grade stage I tumors were treated with placement of interstitial catheters at the time of lumpectomy and axillary node dissection. The tumor bed was treated peri-operatively, using either low-dose-rate or high-doserate brachytherapy with Iridium-192 to deliver 16 to 25 Gy to the tumor bed over one to two days. Results. Ninety-five breasts (94 women) were treated on the protocol. There were four (4%) local recurrences in the breast at a median follow-up interval of 66 months (range, 2.8 152). Cosmetic appearance ranged between good to excellent. There were no long-term radiation related complications. Conclusions. In a selected group of patients, lumpectomy and immediate peri-operative lowdose interstitial brachytherapy to the tumor bed yielded local control equivalent, without significant morbidity, to that observed in a historical series of whole breast irradiation. KJM 2009; 2(2):33-40. Introduction Several randomized trials clearly have established that breast conservation therapy with irradiation and mastectomy have equivalent survival results for early stage breast cancer. 1-6 The standard of care for breast conservation therapy includes whole breast irradiation. Over the last decade, there has been increasing interest in the feasibility of doing partial breast irradiation in selected cases with interstitial brachytherapy 7-13 , external beam therapy 14,15 , or intra-operative radiotherapy. 16,17 The rationale for reducing the volume of breast irradiated includes improved cosmesis, improved function, greater convenience for patients, reduced radiation dose, and decreased risk of second malignancy. At our institution, we initiated a single arm Phase II trial in June 1993 to assess the efficacy of a low dose of tumor bed brachytherapy immediately following lumpectomy in a selected subset of patients with invasive breast cancer. 18 This report represents an update of our continued accrual into this Kansas Journal of Medicine 2009 Breast Conservation Therapy 34 trial including a larger number of patients and a longer period of follow-up. Methods Study procedures, including obtaining informed consent, were conducted in accord with the ethical standards of the institution’s Human Subjects Committee. The trial was initiated in June 1993. For enrollment in the study, prospective subjects were required to meet all four of the following criteria: patient age > 60 years, tumor size < 2 cm, low or intermediate histologic grade, and pathologically negative axillary nodes. Subsequently, the study was modified to include patients > 55 years of age based on the finding that local recurrence rate in women over 55 years with quadrantectomy was not significantly different from those who received immediate breast irradiation. 19 The requirement for pathologically negative axillary lymph nodes was modified to include clinically negative nodes in tumors < 1 cm, if an axillary lymph node dissection was deemed medically inappropriate by the treating surgeon. However, with the advent of sentinel lymph nodal sampling, this procedure replaced axillary lymph node dissection. Tumors with the following histologic types made a patient ineligible for the protocol: infiltrating ductal carcinoma with extensive intraductal component, pleomorphic type of infiltrating lobular carcinoma, ductal carcinoma in situ, or lobular carcinoma in situ. The primary outcome of the trial was to assess the rate of local recurrence with limited radiotherapy. The stopping rule specified that the study would be stopped if the local recurrence rate was higher than the local recurrence rate obtained at our institution in operable breast cancer treated with the conventional approach of breast conservation therapy plus brachytherapy to the tumor site and entire breast irradiation. The recurrence rate at a median follow-up of 69 months in our series was 14 of 250 breasts or 5.6%. 20 Pathologic diagnoses were established by either excisional, incisional, mammotest core biopsies, or fine needle aspiration biopsies. Patient eligibility was determined based upon the previously outlined criteria. Eligible patients were advised about the option of partial breast irradiation following lumpectomy utilizing peri-operative brachytherapy and informed consent was obtained. Margin status of the wide excision specimens was evaluated by frozen section examination. Patients with clear margins of invasive or intraductal carcinoma underwent placement of interstitial catheters into the tumor bed by the technique described in our previous papers. 21,22 Patients were treated with low-dose-rate brachytherapy (LDRB) between December 1993 and June 1999, when the new technique of high-dose-rate brachytherapy (HDRB) became routinely available. Subsequently, all patients were treated using HDRB. Prior to July 1999, axillary node dissections were performed and a final pathologic evaluation was obtained within 24 hours from the time of surgery. Subsequently, when sentinel lymph node sampling became the standard, a frozen section examination of the nodes was performed and node negative patients were treated according to the protocol. If the final pathology report revealed positive nodes, the patient was deemed ineligible for the protocol of brachytherapy alone and in addition received whole breast irradiation. After the operation, simulation films were performed for localization of the catheters in the tumor bed and computation of isodose curves was carried out in the Department of Radiation Oncology. In those treated with LDRB, the catheters were after-loaded with low-dose-rate Iridium-192, varying in strength between 0.33 and 0.44 mg radium equivalent. A 20 to 25 Gy dose Kansas Journal of Medicine 2009 Breast Conservation Therapy 35 was delivered to an isodose line that encompassed all the iridium ribbons and was at least one cm deep to the tumor bed over 24 to 48 hours. In HDRB cases, a biological equivalent dose (BED) of 16 to 22 Gy was delivered in four fractions. Not all the patients received adjuvant systemic therapy; some patients were not recommended treatment and others refused treatment. Forty-eight patients received hormonal treatment, either tamoxifen or anastrozole. Three patients received adjuvant chemotherapy. The patients were followed on a regular basis and regular mammograms were obtained. Results A total of 94 post-menopausal patients enrolled in the protocol between December 1993 and November 2005. One AfricanAmerican patient in her 60’s had bilateral breast cancer with diagnoses one year apart and each breast was treated to the tumor bed with brachytherapy. Patient demographics are outlined in Table 1. Tumor characteristics are outlined in Table 2. Tumors ranged in size from a largest dimension of 0.3 cm to 2.0 cm, with a median of 1.0 cm. Sixty-five of 95 tumors were as expected, of the invasive ductal carcinoma type, not otherwise specified (Table 3). The treatment details are provided in Table 4. Median time of follow-up was 69 months with a range of three to 152 months. Eighty of the 94 patients (85%) were alive in 2008, 78 (83%) with no evidence of disease and two (2%) with evidence of distant disease. Of the 14 deaths, there was evidence of breast cancer (distant disease but no local recurrence) at time of death for 10 of the women. Of the 95 breasts treated, a local recurrence occurred in only four women (4%; Figure 1) who were subsequently treated with mastectomy or whole breast Table 1. Demographics of 94 women treated on the protocol. Table 2. Characteristics of 95 tumors at diagnosis. irradiation (Table 5). With only four events, it would not be possible to identify potential prognostic factors for recurrence with any statistical power. All four patients were alive Demographics Number


Breast Conservation Therapy with Tumor Bed Brachytherapy Alone in Stage I Breast Cancer: Results of a Phase II Trial Introduction
2][3][4][5][6] The standard of care for breast conservation therapy includes whole breast irradiation.Over the last decade, there has been increasing interest in the feasibility of doing partial breast irradiation in selected cases with interstitial brachytherapy [7][8][9][10][11][12][13] , external beam therapy 14,15 , or intra-operative radiotherapy. 16,17The rationale for reducing the volume of breast irradiated includes improved cosmesis, improved function, greater convenience for patients, reduced radiation dose, and decreased risk of second malignancy.
At our institution, we initiated a single arm Phase II trial in June 1993 to assess the efficacy of a low dose of tumor bed brachytherapy immediately following lumpectomy in a selected subset of patients with invasive breast cancer. 18This report represents an update of our continued accrual into this trial including a larger number of patients and a longer period of follow-up.

Methods
Study procedures, including obtaining informed consent, were conducted in accord with the ethical standards of the institution's Human Subjects Committee.The trial was initiated in June 1993.For enrollment in the study, prospective subjects were required to meet all four of the following criteria: patient age > 60 years, tumor size < 2 cm, low or intermediate histologic grade, and pathologically negative axillary nodes.Subsequently, the study was modified to include patients > 55 years of age based on the finding that local recurrence rate in women over 55 years with quadrantectomy was not significantly different from those who received immediate breast irradiation. 19he requirement for pathologically negative axillary lymph nodes was modified to include clinically negative nodes in tumors < 1 cm, if an axillary lymph node dissection was deemed medically inappropriate by the treating surgeon.However, with the advent of sentinel lymph nodal sampling, this procedure replaced axillary lymph node dissection.Tumors with the following histologic types made a patient ineligible for the protocol: infiltrating ductal carcinoma with extensive intraductal component, pleomorphic type of infiltrating lobular carcinoma, ductal carcinoma in situ, or lobular carcinoma in situ.
The primary outcome of the trial was to assess the rate of local recurrence with limited radiotherapy.The stopping rule specified that the study would be stopped if the local recurrence rate was higher than the local recurrence rate obtained at our institution in operable breast cancer treated with the conventional approach of breast conservation therapy plus brachytherapy to the tumor site and entire breast irradiation.
The recurrence rate at a median follow-up of 69 months in our series was 14 of 250 breasts or 5.6%. 20athologic diagnoses were established by either excisional, incisional, mammotest core biopsies, or fine needle aspiration biopsies.Patient eligibility was determined based upon the previously outlined criteria.Eligible patients were advised about the option of partial breast irradiation following lumpectomy utilizing peri-operative brachytherapy and informed consent was obtained.
Margin status of the wide excision specimens was evaluated by frozen section examination.Patients with clear margins of invasive or intraductal carcinoma underwent placement of interstitial catheters into the tumor bed by the technique described in our previous papers. 21,22Patients were treated with low-dose-rate brachytherapy (LDRB) between December 1993 and June 1999, when the new technique of high-dose-rate brachytherapy (HDRB) became routinely available.Subsequently, all patients were treated using HDRB.
Prior to July 1999, axillary node dissections were performed and a final pathologic evaluation was obtained within 24 hours from the time of surgery.Subsequently, when sentinel lymph node sampling became the standard, a frozen section examination of the nodes was performed and node negative patients were treated according to the protocol.If the final pathology report revealed positive nodes, the patient was deemed ineligible for the protocol of brachytherapy alone and in addition received whole breast irradiation.
After the operation, simulation films were performed for localization of the catheters in the tumor bed and computation of isodose curves was carried out in the Department of Radiation Oncology.In those treated with LDRB, the catheters were after-loaded with low-dose-rate Iridium-192, varying in strength between 0.33 and 0.44 mg radium equivalent.A 20 to 25 Gy dose was delivered to an isodose line that encompassed all the iridium ribbons and was at least one cm deep to the tumor bed over 24 to 48 hours.
In HDRB cases, a biological equivalent dose (BED) of 16 to 22 Gy was delivered in four fractions.Not all the patients received adjuvant systemic therapy; some patients were not recommended treatment and others refused treatment.Forty-eight patients received hormonal treatment, either tamoxifen or anastrozole.Three patients received adjuvant chemotherapy.The patients were followed on a regular basis and regular mammograms were obtained.

Results
A total of 94 post-menopausal patients enrolled in the protocol between December 1993 and November 2005.One African-American patient in her 60's had bilateral breast cancer with diagnoses one year apart and each breast was treated to the tumor bed with brachytherapy.Patient demographics are outlined in Table 1.Tumor characteristics are outlined in Table 2. Tumors ranged in size from a largest dimension of 0.3 cm to 2.0 cm, with a median of 1.0 cm.Sixty-five of 95 tumors were as expected, of the invasive ductal carcinoma type, not otherwise specified (Table 3).
The treatment details are provided in Table 4.
Median time of follow-up was 69 months with a range of three to 152 months.Eighty of the 94 patients (85%) were alive in 2008, 78 (83%) with no evidence of disease and two (2%) with evidence of distant disease.Of the 14 deaths, there was evidence of breast cancer (distant disease but no local recurrence) at time of death for 10 of the women.Of the 95 breasts treated, a local recurrence occurred in only four women (4%; Figure 1) who were subsequently treated with mastectomy or whole breast at last follow-up, ranging from 13 to 57 months after time of recurrence.Cosmetic appearance of the breast, judged according to our criteria, 23 was deemed to be good to excellent in all patients.Radiation-related complications were evaluated during followup and no long-term sequelae were observed.

Discussion
2][3][4][5][6] The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 clearly demonstrated that omission of radiotherapy leads to an unacceptably high local recurrence rate. 56][27] In each such trial, the local recurrence rate without irradiation was significantly higher than with irradiation.
Pathological analysis of local breast recurrences following lumpectomy in the NSABP B-06 trial determined 86% of local recurrences to be in the same quadrant as the initial primary. 28Gump et al. 29 noted 90% of multicentric foci in 657 mastectomy specimens to be in close proximity to the primary.
Similarly, Holland et al. 30 determined that in 43% of 282 invasive cancers tumor foci were present within two cm from the reference tumor.
A viable compromise between full-scale radiation and no radiation would be radiation restricted to the tumor bed.There are several such trials published in this respect.The doses of radiation to the tumor bed have varied among the different investigators from 30 to 55 Gy.The results of the current on-going NSABP protocol which randomized patients with tumors less than three cm to tumor bed irradiation versus whole breast irradiation would probably standardize radiotherapy in particular subsets of women who desire breast conservation therapy.
When we initiated our phase II trial, we decided on a dose of 20 to 25 Gy to the tumor bed with LDRB on a very conservative principle.31,32 The dose was prescribed to the periphery of tumor bed.The center of the tumor bed would receive at least 150% of the dose (i.e., 30 to 37.5 Gy) which yielded a radiobiological equivalent of approximately 40 to 45 Gy of external beam radiation given at 1.8 Gy per fraction. 33,34hen we replaced LDRB with HDRB, equivalent doses were calculated and delivered in four fractions to facilitate delivery within two days of surgical excision.Further, if any of our patients suffered a recurrence in the breast, at that point, wide excision with external beam radiotherapy to the entire breast could still be offered as an option versus a mastectomy, without risk of tissue necrosis or rib fractures.If the recurrence happened to be in another quadrant, an interstitial boost to the tumor bed in addition could be offered.
In summary, the results presented in this study supported our original preliminary review. 18][9][10][11][12][13] In addition, this rate was lower than the 5.6% obtained in our series with standard radiotherapy. 20The doses used in our trial were lower than those used by other investigators. 7-13However, our trial was in a selected group of patients, who were 55 or older, with stage I tumors with low or intermediate grade.
Our results may be due to the close collaboration between the surgeon and radiation oncologist, meticulous attention to margins, placement of interstitial catheters into the open surgical bed under direct visualization, generous coverage of the tumor cavity, and the biological advantage of immediate (within 24 to 48 hours of surgery) brachytherapy to the tumor bed.

Table 1 .
Demographics of 94 women treated on the protocol.
*Tumor grade is based on the Elston and Ellis modification of the Bloom and Richardson's grading system. 24** Estrogen receptor status is determined by immunohistochemical analysis with expression of >10% nuclear staining considered positive.

Table 4 .
Treatment characteristics of 95 tumors.Figure 1. Freedom from local recurrence of the affected breast (n=95) as a function of time after diagnosis.

Table 5 .
Local tumor recurrence in four patients.
* NED: No evidence of disease.
Polgár C, Sulyok Z, Fodor J, et al.Sole brachytherapy of the tumor bed after conservative surgery for T1 breast cancer: Five-year results of a Phase I-II study and initial findings of a randomized phase III trial.J Surg Oncol 2002; 80:121-128. 14Ribeiro GG, Magee B, Swindell R, Harris M, Banerjee SS.The Christie Hospital breast conservation trial: An update at 8 years from inception.Clin Oncol (R Coll Radiol) 1993; 5:278-283. 13