Local Recurrence After Breast-Conserving Therapy in Patients With Multiple Ipsilateral Breast Cancer: Results From ACOSOG Z11102 (Alliance).

PURPOSE: Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC. PATIENTS AND METHODS: Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%. RESULTS: Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy-proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002). CONCLUSION: The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.

The Feasibility of Radiation Therapy after Breast-Conserving Surgery for Multiple Ipsilateral Breast Cancer: An Initial Report from ACOSOG Z11102 (Alliance) Trial.

PURPOSE: Historically, multiple ipsilateral breast cancer (MIBC) has been a contraindication to breast-conserving therapy. We report the feasibility of radiation therapy (RT) after breast-conserving therapy in MIBC from the Alliance Z11102 trial. METHODS AND MATERIALS: Delineation of targets and organs at risk was performed according to the Radiation Therapy Oncology Group contouring consensus definitions. RT was delivered to the whole breast to 45 to 50 Gy in standard daily fractions of 1.8 to 2.0 Gy. A boost of 10 to 16 Gy in 2.0-Gy daily fractions to each tumor bed was mandatory. RESULTS: A total of 236 eligible patients were enrolled in the study between July 23, 2012 and August 19, 2016. Of those, 195 (83%) completed RT. No patient underwent mastectomy for failure to meet the RT dose constraints. Higher absolute boost volume was associated with increased incidence of grade 2 or higher dermatitis (odds ratio, 1.21; 95% confidence interval, 1.04-1.41; P = .014). Higher relative boost volume as a percentage of the overall breast volume was not associated with increased dermatitis. Neither absolute nor relative boost volume appeared to significantly influence overall cosmesis. CONCLUSIONS: Breast conservation followed by whole breast RT plus boost to each tumor bed was feasible in the majority of patients with MIBC. Increasing radiation boost volume was associated with increased incidence of acute dermatitis, but was not associated with worse overall cosmesis.

NRG Oncology-Radiation Therapy Oncology Group Study 1014: 1-Year Toxicity Report From a Phase 2 Study of Repeat Breast-Preserving Surgery and 3-Dimensional Conformal Partial-Breast Reirradiation for In-Breast Recurrence.

PURPOSE: To determine the associated toxicity, tolerance, and safety of partial-breast reirradiation. METHODS AND MATERIALS: Eligibility criteria included in-breast recurrence occurring >1 year after whole-breast irradiation, <3 cm, unifocal, and resected with negative margins. Partial-breast reirradiation was targeted to the surgical cavity plus 1.5 cm; a prescription dose of 45 Gy in 1.5 Gy twice daily for 30 treatments was used. The primary objective was to evaluate the rate of grade ≥3 treatment-related skin, fibrosis, and/or breast pain adverse events (AEs), occurring ≤1 year from re-treatment completion. A rate of ≥13% for these AEs in a cohort of 55 patients was determined to be unacceptable (86% power, 1-sided α = 0.07). RESULTS: Between 2010 and 2013, 65 patients were accrued, and the first 55 eligible and with 1 year follow-up were analyzed. Median age was 68 years. Twenty-two patients had ductal carcinoma in situ, and 33 had invasive disease: 19 ≤1 cm, 13 >1 to ≤2 cm, and 1 >2 cm. All patients were clinically node negative. Systemic therapy was delivered in 51%. All treatment plans underwent quality review for contouring accuracy and dosimetric compliance. All treatment plans scored acceptable for tumor volume contouring and tumor volume dose-volume analysis. Only 4 (7%) scored unacceptable for organs at risk contouring and organs at risk dose-volume analysis. Treatment-related skin, fibrosis, and/or breast pain AEs were recorded as grade 1 in 64% and grade 2 in 7%, with only 1 (<2%) grade ≥3 and identified as grade 3 fibrosis of deep connective tissue. CONCLUSION: Partial-breast reirradiation with 3-dimensional conformal radiation therapy after second lumpectomy for patients experiencing in-breast failures after whole-breast irradiation is safe and feasible, with acceptable treatment quality achieved. Skin, fibrosis, and breast pain toxicity was acceptable, and grade 3 toxicity was rare.

Long-term results from the Contura multilumen balloon breast brachytherapy catheter phase 4 registry trial.

PURPOSE: To describe the long-term outcomes from a completed, multi-institutional phase 4 registry trial using the Contura multilumen balloon (CMLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer. METHODS AND MATERIALS: Three hundred forty-two evaluable patients were enrolled by 23 institutions between January 2008 and February 2011. All patients received 34 Gy in 10 fractions, delivered twice daily. Rigorous target coverage and normal tissue dose constraints were observed. RESULTS: The median follow-up time was 36 months (range, 1-54 months). For the entire patient cohort of 342 patients, 10 patients experienced an ipsilateral breast tumor recurrence (IBTR). Eight of these IBTR were classified as true recurrences/marginal miss (TRMM), and 2 were elsewhere failures (EF). Local recurrence-free survival was 97.8% at 3 years. For the entire cohort, 88% of patients had good to excellent overall cosmesis. The overall incidence of infection was 8.5%. Symptomatic seroma was reported in only 4.4% of patients. A separate analysis was performed to determine whether improved outcomes would be observed for patients treated at high-volume centers with extensive brachytherapy experience. Three IBTR were observed in this cohort, only 1 of which was classified as a TRMM. Local recurrence-free survival at high-volume centers was 98.1% at 3 years. Overall cosmetic outcome and toxicity were superior in patients treated at high-volume centers. In these patients, 95% had good to excellent overall cosmesis. Infection was observed in only 2.9% of patients, and symptomatic seroma was reported in only 1.9%. CONCLUSION: Use of the CMLB for APBI delivery is associated with acceptable long-term local control and toxicity. Local recurrence-free survival was 97.8% at 3 years. Significant (grade 3) toxicity was uncommon, and no grade 4 toxicity was observed. Treatment at high-volume centers was associated with decreased late toxicity.

Shortened radiation therapy schedules for early-stage breast cancer: a review of hypofractionated whole-breast irradiation and accelerated partial breast irradiation.

Breast-conserving therapy consisting of segmental mastectomy followed by whole-breast irradiation (WBI) has become widely accepted as an alternative to mastectomy as a treatment for women with early-stage breast cancer. WBI is typically delivered over the course of 5-6 weeks to the whole breast. Hypofractionated whole-breast irradiation and accelerated partial breast irradiation have developed as alternative radiation techniques for select patients with favorable early-stage breast cancer. These radiation regimens allow for greater patient convenience and the potential for decreased health care costs. We review here the scientific rationale behind delivering a shorter course of radiation therapy using these distinct treatment regimens in this setting as well as an overview of the published data and pending trials comparing these alternative treatment regimens to WBI.

Contura Multi-Lumen Balloon breast brachytherapy catheter: comparative dosimetric findings of a phase 4 trial.

PURPOSE: Final dosimetric findings of a completed, multi-institutional phase 4 registry trial using the Contura Multi-Lumen Balloon (MLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer are presented. METHODS AND MATERIALS: Three dosimetric plans with identical target coverage were generated for each patient for comparison: multilumen multidwell (MLMD); central-lumen multidwell (CLMD); and central-lumen single-dwell (CLSD) loading of the Contura catheter. For this study, a successful treatment plan achieved ideal dosimetric goals and included the following: ≥ 95% of the prescribed dose (PD) covering ≥ 95% of the target volume (TV); maximum skin dose ≤ 125% of the PD; maximum rib dose ≤ 145% of the PD; and V150 ≤50 cc and V200 ≤ 10 cc. RESULTS: Between January 2008 and February 2011, 23 institutions participated. A total of 318 patients were available for dosimetric review. Using the Contura MLB, all dosimetric criteria were met in 78.93% of cases planned with MLMD versus 55.38% with the CLMD versus 37.66% with the CLSD (P ≤.0001). Evaluating all patients with the full range of skin to balloon distance represented, median maximum skin dose was reduced by 12% and median maximum rib dose by 13.9% when using MLMD-based dosimetric plans compared to CLSD. The dosimetric benefit of MLMD was further demonstrated in the subgroup of patients where skin thickness was <5 mm, where MLMD use allowed a 38% reduction in median maximum skin dose over CLSD. For patients with rib distance <5 mm, the median maximum rib dose reduction was 27%. CONCLUSIONS: Use of the Contura MLB catheter produced statistically significant improvements in dosimetric capabilities between CLSD and CLMD treatments. This device approach demonstrates the ability not only to overcome the barriers of limited skin thickness and close rib proximity, but to consistently achieve a higher standard of dosimetric planning goals.

Early outcomes data for accelerated partial breast irradiation using balloon brachytherapy.

Accelerated partial breast irradiation has been investigated in selected patients with early-stage breast cancer. Accelerated partial breast irradiation limits the radiation target to the volume of tissue immediately surrounding the lumpectomy cavity and reduces the overall treatment time from approximately 6 weeks to 5 days. Balloon brachytherapy was introduced in 2000. Since that time, several clinical experiences have demonstrated excellent outcomes in carefully selected patients. Modern intracavitary brachytherapy offers patients with early-stage breast cancer a promising new option for radiation therapy. This treatment appears to offer high rates of local control with minimal toxicity. Newer multilumen devices allow optimal target coverage while minimizing the dose delivered to the skin and chest wall.

Association between maximal skin dose and breast brachytherapy outcome: a proposal for more rigorous dosimetric constraints.

PURPOSE: Multiple investigations have used the skin distance as a surrogate for the skin dose and have shown that distances <6 mm have been associated with late toxicity after MammoSite brachytherapy. No publications have yet described the relationship between the actual maximal skin dose and the outcome. The present study analyzed the maximal skin dose delivered and the occurrence of late toxicity in a large cohort of patients with prolonged follow-up. METHODS: A total of 96 patients treated with breast brachytherapy between 2000 and 2007 for whom complete planning and follow-up data were available were included in the present analysis. The median follow-up was 48 months (range, 24-111). Of the 96 patients, 40 were treated with multicatheter interstitial brachytherapy and 56 with MammoSite. A multivariate statistical analysis was performed to determine the relationship between several dosimetric parameters and patient outcome. RESULTS: The treatment was well tolerated, with 98% of patients experiencing good to excellent cosmesis. Significant late toxicity was uncommon. The maximal dose delivered to the skin was significantly associated with the incidence of any degree of telangiectasia (p = .009) and moderate to severe fibrosis (p = .010). The incidence of late toxicity was significantly increased when the dose to the skin was >4.05 Gy/fraction. CONCLUSION: The initial skin dose recommendations have been based on safe use and the avoidance of significant toxicity. The results from the present study have suggested that patients might further benefit if more rigorous constraints were applied and if the skin dose were limited to 120% of the prescription dose.

Optimal application of the Contura multilumen balloon breast brachytherapy catheter vacuum port to deliver accelerated partial breast irradiation.

PURPOSE: The impact of using the Contura multilumen balloon (MLB) (SenoRx, Inc., Irvine, CA) breast brachytherapy catheter's vacuum port in patients treated with accelerated partial breast irradiation (APBI) was analyzed. METHODS AND MATERIALS: Data from 32 patients at two sites were reviewed. Variables analyzed included the seroma fluid (SF):air volume around the MLB before and after vacuum port use and on its ability to improve (1) the eligibility of patients for APBI and (2) dose coverage of the planning target volume for evaluation (PTV_EVAL) in eligible patients. RESULTS: The median SF/air volume before vacuum removal was 6.8 cc vs. 0.8 cc after vacuum removal (median reduction in SF/air volume was 90.5%). Before vacuum port use, the median SF/air volume expressed as percentage of the PTV_EVAL was 7.8% (range, 1.9-26.6) in all patients. After application of the vacuum, this was reduced to 1.2%. Before vacuum port use, 10 (31.3%) patients were not considered acceptable candidates for APBI because the SF/air volume:PTV_EVAL ratio (SF:PTV) was greater than 10% (range, 10.1-26.6%; median, 15.2%). After vacuum port use, the median SF:PTV ratio was 1.6% for a median reduction of 91.5%. In addition, the percentage of the prescribed dose covering greater than or equal to 90% of the PTV_EVAL proportionally increased a median of 8% (range, 3-10%) in eligible patients. CONCLUSION: Use of the Contura MLB vacuum port significantly improved the conformity of the target tissue to the balloon surface, leading to reproducible dose delivery and increased target volume coverage. In addition, application of the vacuum allowed the safe treatment of unacceptable patients with APBI.

A comparison of skin and chest wall dose delivered with multicatheter, Contura multilumen balloon, and MammoSite breast brachytherapy.

PURPOSE: Skin and chest wall doses have been correlated with toxicity in patients treated with breast brachytherapy . This investigation compared the ability to control skin and chest wall doses between patients treated with multicatheter (MC), Contura multilumen balloon (CMLB), and MammoSite (MS) brachytherapy. METHODS AND MATERIALS: 43 patients treated with the MC technique, 45 patients treated with the CMLB, and 83 patients treated with the MS were reviewed. The maximum doses delivered to the skin and chest wall were calculated for all patients. RESULTS: The mean maximum skin doses for the MC, CMLB, and MS were 2.3 Gy (67% of prescription dose), 2.8 Gy (82% of prescription dose), and 3.2 Gy per fraction (94% of prescription dose), respectively. Although the skin distances were similar (p = 0.23) for the two balloon techniques, the mean skin dose with the CMLB was significantly lower than with the MS (p = 0.05). The mean maximum rib doses for the MC, CMLB, and MS were 2.3 Gy (67% of prescription dose), 2.8 Gy (82% of prescription dose), and 3.6 Gy per fraction (105% of prescription dose), respectively. Again, the mean rib dose with the CMLB was significantly lower than with the MS (p = 0.002). CONCLUSION: The MC and CMLB techniques are associated with significantly lower mean skin and rib doses than is the MS. Treatment with the MS was associated with significantly more patients receiving doses to the skin or rib in excess of 125% of the prescription. Treatment with the CMLB may prove to yield less normal tissue toxicity than treatment with the MS.

Skin and chest wall dose with multi-catheter and MammoSite breast brachytherapy: Implications for late toxicity.

PURPOSE: Accelerated partial breast irradiation (APBI) continues to increase in popularity. Up to 14% of patients treated with the MammoSite (MS) report some degree of chronic pain, which may be related to chest wall toxicity. Reports from several institutions using the multicatheter (MC) technique have not shown associated elevated chest wall toxicity. Additionally, a recent investigation has suggested that increased toxicity may occur with the MS when the dose to the chest wall exceeds 125% of the prescribed dose. This investigation compares the skin and chest wall doses of a cohort of patients treated with the MC technique to a group treated with the MS. METHODS AND MATERIALS: The dosimetric data for 43 patients treated with the MC technique and 83 patients treated with the MS at Virginia Commonwealth University were reviewed. This cohort represents consecutively treated patients from our most recent experience to minimize any learning curve effect on dosimetry. Plans were generated using 3D software (Brachyvision, Varian Medical Systems, Inc., Palo Alto, CA). Multiple dwell positions were used for all MS patients to optimize dose delivery. The minimum distances from the planning target volume to the skin and chest wall were calculated, as well as the maximum doses delivered to the skin and chest wall. RESULTS: The mean skin distances for patients treated with the MC technique and the MS were 0.5 and 0.9cm, respectively (p<0.002). Despite the significantly smaller mean skin distance, the mean skin dose for the MC technique was only 2.3Gy per fraction (67% of prescription dose). The mean skin dose for the MS was 3.2Gy per fraction (94% of prescription dose, p<0.001). The mean chest wall distance was 0.9cm for the MC technique and 1.0cm for the MS (p=0.55). Again, the mean chest wall dose for the MC technique was only 2.3Gy per fraction (67% of prescription dose). The mean skin dose for the MS was 3.6Gy per fraction (105% of prescription dose, p<0.001). The percentage of patients receiving skin doses in excess of 125% for the MC and MS were 0% and 9.6%, respectively. The percentage of patients receiving chest wall doses in excess of 125% for the MC and MS were 0% and 38.6%, respectively. CONCLUSION: The MC technique results in more conformal dose delivery, with significantly lower mean skin and chest wall doses. Treatment with the MS was associated with significantly more patients receiving doses to the skin or chest wall in excess of 125% of the prescription. Given the limited followup available for the MS, and the significant dose delivered to the chest wall, the use of this device may be associated with a higher incidence of late chest wall toxicity than previously expected.

Multi-institutional experience using the MammoSite radiation therapy system in the treatment of early-stage breast cancer: 2-year results.

PURPOSE: To present a retrospective multi-institutional experience of patients treated with the MammoSite radiation therapy system (RTS). METHODS AND MATERIALS: Nine institutions participated in a pooled analysis of data evaluating the clinical experience of the MammoSite RTS for delivering accelerated partial breast irradiation. Between 2000 and 2004, 483 patients were treated with the MammoSite RTS to 34 Gy delivered in 10 fractions. Treatment parameters were analyzed to identify factors affecting outcome. RESULTS: Median follow-up was 24 months (minimum of 1 year). Overall, infection was documented in 9% of patients, but the rate was only 4.8% if the catheter was placed after lumpectomy. Six patients (1.2%) experienced an in-breast failure; four failures occurred remote from the lumpectomy site (elsewhere failure). Cosmetic results were good/excellent in 91% of patients. Treatment parameters identified as significant on univariate analysis were tested in multivariate regression analysis. The closed-cavity placement technique significantly reduced the risk of infection (p = 0.0267). A skin spacing of <6 mm increased the risk of severe acute skin reaction (p = 0.0178) and telangiectasia (p = 0.0280). The use of prophylactic antibiotics reduced the risk of severe acute skin reaction (p < 0.0001). The use of multiple dwell positions reduced the risk of severe hyperpigmentation (p = 0.0278). Infection was associated with an increased risk of fair or poor overall cosmesis (p = 0.0009). CONCLUSIONS: In this series of patients, the MammoSite RTS seems to have acceptable toxicity rates and cosmetic outcomes, comparable to those with whole-breast radiotherapy. On the basis of these data, the closed-cavity placement technique, use of prophylactic antibiotics, use of multiple dwell positions, and a minimum skin spacing of 6 mm seem to improve patient outcome.

Neural stem cell-preserving external-beam radiotherapy of central nervous system malignancies.

PURPOSE: Recent discoveries have implicated neural stem cells (NSC) as the source of plasticity and repair in the mature mammalian brain. Treatment-induced NSC dysfunction may lead to observed toxicity. This study evaluates the feasibility of NSC-preserving external beam radiotherapy. METHODS AND MATERIALS: A single computed tomography (CT) dataset depicting a right periventricular lesion was used in this study as this location reflects the most problematic geometric arrangement with respect to NSC preservation. Conventional and NSC preserving radiotherapy (RT) plans were generated for the same lesion using two clinical scenarios: cerebral metastatic disease and primary high-grade glioma. Disease-specific target volumes were used. Metastatic disease was conventionally treated with whole-brain radiotherapy (WBRT) to 3,750 cGy (15 fractions) followed by a single stereotactic radiosurgery (SRS) boost of 1,800 cGy to gross disease only. High-grade glioma was treated with conventional opposed lateral and anterior superior oblique beams to 4,600 cGy (23 fractions) followed by a 1,400 cGy (7 fractions) boost. NSC preservation was achieved in both scenarios with inverse-planned intensity modulated radiotherapy (IMRT). RESULTS: Cumulative dose reductions of 65% (metastatic disease) and 25% (high-grade glioma) to the total volume of the intracranial NSC compartments were achieved with NSC-preserving IMRT plans. The reduction of entry and exit dose to NSC niches located contralateral to the target contributed most to NSC preservation. CONCLUSIONS: Neural stem cells preservation with current external beam radiotherapy techniques is achievable in context of both metastatic brain disease and high-grade glioma, even when the target is located adjacent to a stem cell compartment. Further investigation with clinical trials is warranted to evaluate whether NSC preservation will result in reduced toxicity.

Three-dimensional conformal external beam radiotherapy (3D-CRT) for accelerated partial breast irradiation (APBI): what is the correct prescription dose?

OBJECTIVE: This study is an evaluation of the biologic equivalence of the dose prescriptions for brachytherapy and 3-dimensional conformal external beam radiotherapy (3D-CRT) accelerated partial breast irradiation (APBI), using actual patient dose matrix data, and is based on the concept of equivalent uniform biologically effective dose (EUBED). This formalism allows a nonuniform dose distribution to be reduced to an equivalent uniform dose, while also accounting for fraction size. MATERIALS AND METHODS: Five computed tomography scans were selected from a group of patients treated with multicatheter interstitial APBI. Dose matrices for the brachytherapy plans were computed and analyzed with in-house software. For each patient, the EUBED for the brachytherapy dose matrix was generated based on calculations performed at the voxel-level. These EUBED values were then used to calculate the biologically equivalent fraction size for 3D-CRT (eud). RESULTS: The mean equivalent fraction size (eudmean) and maximum equivalent fraction size (eudmax) were calculated for each patient using 100 different values of the alpha/beta ratio. The eudmean ranged from 3.67 to 3.69 Gy, while the eudmax ranged from 3.79 to 3.82 Gy. For all values of the alpha/beta ratio, the maximum fraction size calculated to deliver a biologically equivalent dose with 3D-CRT was 3.82 Gy, with an equivalent total prescription dose of 38.2 Gy. CONCLUSION: Utilizing a wide range of established radiobiological parameters, this study suggests that the maximum fraction size needed to deliver a biologically equivalent dose using 3D-CRT is 3.82 Gy, supporting the continued use of 3.85Gy BID in the current national cooperative trial.

Tumor bed boost omission after negative re-excision in breast-conservation treatment.

BACKGROUND: We evaluated the necessity of a tumor bed boost after whole-breast radiotherapy for early-stage breast cancer after breast-conserving surgery and negative re-excision. METHODS: Of patients treated at the Virginia Commonwealth and Tufts Universities with breast-conservation therapy for early-stage breast cancer between 1983 and 1999, 205 required re-excision of the tumor cavity to obtain clear margins and were found to be without residual disease. Adjuvant conventionally fractionated whole-breast radiotherapy was given to a total dose of 50 Gy in 25 fractions. The tumor bed boost was omitted. RESULTS: The median follow-up was 98 months (range, 6-229 months). The tumor histological diagnosis was primarily infiltrating ductal carcinoma (183 cases; 89%). Nodal involvement was documented in 49 cases (24%). There were four documented recurrences at the tumor bed site. Five in-breast recurrences were documented to be in a location removed from the tumor bed. The overall Kaplan-Meier 15-year in-breast control rate was 92.4%, and the freedom from true recurrence rate was 97.6%. CONCLUSIONS: The findings support the concept that postlumpectomy radiotherapy can be tailored according to the degree of surgical resection. There is an easily identifiable subgroup of patients who can avoid a tumor bed boost, thus resulting in a reduced treatment time and improved cosmesis, while maintaining local control rates that approach 100%. The data suggest that in patients who undergo a negative re-excision, treatment with whole-breast radiotherapy to 50 Gy is a sufficient dose to maximally reduce the risk of local recurrence.