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Our purpose was to examine current practice patterns in non-English-speaking patients with breast cancer undergoing deep inspiratory breath hold (DIBH).An anonymous, voluntary REDCap survey was distributed to 60 residency program coordinators of US radiation oncology departments to survey their faculty and recent graduates. Eligibility was limited to board-certified radiation oncologists who had treated breast cancer within the prior 6 months.There were 69 respondents, 53 of whom were eligible. Forty-two percent (n = 22) of eligible respondents were from the main site at an academic center, with 28% (n = 15) representing a satellite site and 30% (n = 16) from private practice. Fifty-three percent reported at least 10% of their patients were non-English speaking. Ninety percent offered DIBH at their institution; of those, 74% used DIBH for at least one-fourth of their patients with breast cancer. Ninety-eight percent of those who use DIBH performed coaching at simulation, with 32% answering they would be "less likely" to use DIBH for non-English speakers. When used, 94% take into consideration potential language barriers for proper execution of DIBH. However, 51% had an interpreter present 76% to 100% of the time at computed tomography simulation, which decreased to 31% at first fraction and 11% at subsequent treatments. For non-English-speaking patients undergoing DIBH coaching without a certified interpreter, 55% of respondents indicated that they provided verbal coaching in English, 32% indicated "not applicable" because they always use a certified interpreter, 11% used visual aids, and 32% indicated "other." Of those who answered "other," the most commonly cited response was using therapists or staff who spoke the patient's native language.Disparities in the application of DIBH exist despite its established utility in reducing cardiac dose. This study provides evidence that language barriers may affect physician treatment practices from initial consideration of DIBH to subsequent delivery. These data suggest that breast cancer treatment considerations and subsequent execution are negatively affected in non-English-speaking patients.

Because of its rarity, there are no randomized trials investigating postmastectomy radiation therapy (PMRT) in male breast cancer. This study retrospectively examines the impact of PMRT in male breast cancer patients in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database.The SEER database 8.3.2 was queried for men ages 20+ with a diagnosis of localized or regional nonmetastatic invasive ductal/lobular carcinoma from 1998 to 2013. Included patients were treated by modified radical mastectomy (MRM), with or without adjuvant external beam radiation. Univariate and multivariate analyses evaluated predictors for PMRT use after MRM. Kaplan-Meier overall survival (OS) curves of the entire cohort and a case-matched cohort were calculated and compared by the log-rank test. Cox regression was used for multivariate survival analyses.A total of 1933 patients were included in the unmatched cohort. There was no difference in 5-year OS between those who received PMRT and those who did not (78% vs 77%, respectively, P=.371); however, in the case-matched analysis, PMRT was associated with improved OS at 5 years (83% vs 54%, P.001). On subset analysis of the unmatched cohort, PMRT was associated with improved OS in men with 1 to 3 positive nodes (5-year OS 79% vs 72% P=.05) and those with 4+ positive nodes (5-year OS 73% vs 53% P.001). On multivariate analysis of the unmatched cohort, independent predictors for improved OS were use of PMRT: HR=0.551 (0.412-0.737) and estrogen receptor-positive disease: HR=0.577 (0.339-0.983). Predictors for a survival detriment were higher grade 3/4: HR=1.825 (1.105-3.015), larger tumor T2: HR=1.783 (1.357-2.342), T3/T4: HR=2.683 (1.809-3.978), higher N-stage: N1 HR=1.574 (1.184-2.091), N2/N3: HR=2.328 (1.684-3.218), black race: HR=1.689 (1.222-2.336), and older age 81+: HR=4.164 (1.497-11.582).There may be a survival benefit with the addition of PMRT for male breast cancer with node-positive disease.

Purpose Optimal patient selection for stereotactic radiosurgery (SRS) as the initial treatment for brain metastases is complicated and controversial. This study aimed to develop a nomogram that predicts survival without salvage whole brain radiation therapy (WBRT) after upfront SRS. Methods and Materials Multi-institutional data were analyzed from 895 patients with 2095 lesions treated with SRS without prior or planned WBRT. Cox proportional hazards regression model was used to identify independent pre-SRS predictors of WBRT-free survival, which were integrated to build a nomogram that was subjected to bootstrap validation. Results Median WBRT-free survival was 8 months (range, 0.1-139 months). Significant independent predictors for inferior WBRT-free survival were age (hazard ratio [HR] 1.1 for each 10-year increase), HER2(−) breast cancer (HR 1.6 relative to other histologic features), colorectal cancer (HR 1.4 relative to other histologic features), increasing number of brain metastases (HR 1.09, 1.32, 1.37, and 1.87 for 2, 3, 4, and 5+ lesions, respectively), presence of neurologic symptoms (HR 1.26), progressive systemic disease (HR 1.35), and increasing extracranial disease burden (HR 1.31 for oligometastatic and HR 1.56 for widespread). Additionally, HER2(+) breast cancer (HR 0.81) and melanoma (HR 1.11) trended toward significance. The independently weighted hazard ratios were used to create a nomogram to display estimated probabilities of 6-month and 12-month WBRT-free survival with a corrected Harrell's C concordance statistic of 0.62. Conclusions Our nomogram can be used at initial evaluation to help select patients best suited for upfront SRS for brain metastases while reducing expense and morbidity in patients who derive minimal or no benefit.

Targeted intraoperative radiation therapy (TARGIT) puts forward the tantalizing prospect of marked simplification of breast radiation therapy to a single treatment delivered with an easily shielded low-energy (50-kV) x-ray device at the time of breast surgery. Based upon the results of the TARGIT-A trial, on July 25, 2014, the National Institute of Health and Care Excellence (NICE) in the United Kingdom gave preliminary recommendation for the use of TARGIT within the UK National Health Service (1). This endorsement and the growth in the use of this modality appear to be occurring without the full knowledge and recognition of the methodologic flaws of the TARGIT-A trial. These flaws are sufficiently profound as to undermine confidence in both the efficacy and the safety of TARGIT and should provide pause to any clinician considering its application. The prospective TARGIT-A trial used a noninferiority design to randomly assign patients to TARGITorwhole breast external beam radiation therapy (EBRT). For 67%of the study participants, the randomization and treatment occurred at the lumpectomy (classified as “pre-pathology”). The patientswith high-risk features went on to receive EBRT after TARGIT. These features were defined as margin

Purpose To determine whether the American Society for Radiation Oncology (ASTRO) Consensus Statement (CS) recommendations for accelerated partial breast irradiation (APBI) are associated with significantly different outcomes in a pooled analysis from William Beaumont Hospital (WBH) and the American Society of Breast Surgeons (ASBrS) MammoSite® Registry Trial. Methods and Materials APBI was used to treat 2127 cases of early-stage breast cancer (WBH, n=678; ASBrS, n=1449). Three forms of APBI were used at WBH (interstitial, n=221; balloon-based, n=255; or 3-dimensional conformal radiation therapy, n=206), whereas all Registry Trial patients received balloon-based brachytherapy. Patients were divided according to the ASTRO CS into suitable (n=661, 36.5%), cautionary (n=850, 46.9%), and unsuitable (n=302, 16.7%) categories. Tumor characteristics and clinical outcomes were analyzed according to CS group. Results The median age was 65 years (range, 32-94 years), and the median tumor size was 10.0 mm (range, 0-45 mm). The median follow-up time was 60.6 months. The WBH cohort had more node-positive disease (6.9% vs 2.6%, P P =.06). The 5-year actuarial ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), and distant metastasis (DM) for the whole cohort were 2.8%, 0.6%, 1.6%. The rate of IBTR was not statistically higher between suitable (2.5%), cautionary (3.3%), or unsuitable (4.6%) patients ( P =.20). The nonsignificant increase in IBTR for the cautionary and unsuitable categories was due to increased elsewhere failures and new primaries ( P =.04), not tumor bed recurrence ( P =.93). Conclusions Excellent outcomes after breast-conserving surgery and APBI were seen in our pooled analysis. The current ASTRO CS guidelines did not adequately differentiate patients at an increased risk of IBTR or tumor bed failure in this large patient cohort.

Accelerated Partial-Breast Irradiation: Trial by Media or by Science? Laurie W. Cuttino, M.D.,* Julia R. White, M.D.,y Rachel Rabinovitch, M.D.,z David A. Gewirtz, Ph.D.,* Mitchell S. Anscher, M.D.,* David E. Wazer, M.D.,x,k Frank A. Vicini, M.D.,{ Thomas B. Julian, M.D., and Douglas W. Arthur, M.D.* *Virginia Commonwealth University, Richmond, Virginia; yOhio State University, Columbus, Ohio; zUniversity of Colorado, Denver, Colorado; xTufts University, Boston, Massachusetts; kBrown University, Providence, Rhode Island; {Michigan Healthcare Professionals/21st Century Oncology, Royal Oak, Michigan; and Drexel University College of Medicine/ Allegheny General Hospital, Pittsburgh, Pennsylvania

Purpose To evaluate the feasibility, implementation, and early results of noninvasive breast brachytherapy (NIBB) for tumor bed boost with whole breast radiation therapy (WBRT). Methods and Materials NIBB is a commercially available (AccuBoost, Billerica, MA) mammography-based, brachytherapy system in which the treatment applicators are centered on the planning target volume (PTV) to direct 192 Ir emissions along orthogonal axes. A privacy-encrypted online data registry collected information from 8 independent academic and community-based institutions. Data were from 146 consecutive women with early-stage breast cancer after lumpectomy and WBRT receiving boost with NIBB between July 2007 and March 2010. Toxicity and cosmesis were graded according to the Common Toxicity Criteria (v. 3.0) and the Harvard scale. Median follow-up was 6 months (1–39 months). Results Grade 1–2 skin toxicity was observed in 64%, 48%, and 21% during the acute (1–3 weeks), intermediate (4–26 weeks), and late-intermediate (>26 weeks) periods. There was no Grade 4 toxicity. At 6 months, for the entire cohort, cosmesis was excellent/good in 62%/38%. The subset receiving NIBB before WBRT had cosmetic scores of 32% and 63%, whereas during WBRT, 58% and 37% were rated as excellent and good, respectively. Breast compression was scored as "uncomfortable" in 12%, 29%, and 59% when NIBB was delivered before, during, or after WBRT. For each patient, the fraction-to-fraction variability in PTV was low. Skin flash was associated with a higher proportion of excellent cosmesis (58% vs. 42%) relative to having the applicator all within breast tissue. Conclusions These data indicate that NIBB is feasible and can be consistently implemented in a broad array of practice settings. Preliminary evaluation suggests that NIBB is associated with acceptably mild normal tissue toxicity and favorable early cosmesis. The application of NIBB before WBRT may be associated with better patient tolerance at the expense of less favorable cosmetic outcome.

Purpose To perform dose modeling of a noninvasive image-guided breast brachytherapy (NIIGBB) for comparison to electrons and 3DCRT. Methods and Materials The novel technology used in this study is a mammography-based, noninvasive breast brachytherapy system whereby the treatment applicators are centered on the planning target volume (PTV) to direct 192 Ir emissions along orthogonal axes. To date, three-dimensional dose modeling of NIIGBB has not been possible because of the limitations of conventional treatment planning systems (TPS) to model variable tissue deformation associated with breast compression. In this study, the TPS was adapted such that the NIIGBB dose distributions were modeled as a virtual point source. This dose calculation technique was applied to CT data from 8 patients imaged with the breast compressed between parallel plates in the cranial–caudal and medial–lateral axes. A dose–volume comparison was performed to simulated electron boost and 3DCRT APBI. Results The NIIGBB PTV was significantly reduced as compared with both electrons and 3DCRT. Electron boost plans had a lower D min than the NIIGBB technique but higher V 100 , D 90 , and D 50 . With regard to PTV coverage for APBI, the only significant differences were minimally higher D 90 , D 100 , V 80 , and V 90 , with 3DCRT and D max with NIIGBB. The NIIGBB technique, as compared with electrons and 3D-CRT, achieved a lower maximum dose to skin (60% and 10%, respectively) and chest wall/lung (70–90%). Conclusions NIIGBB achieves a PTV that is smaller than electron beam and 3DCRT techniques. This results in significant normal tissue sparing while maintaining dosimetric benchmarks to the target tissue.

Purpose: To evaluate the accuracy of two clinical techniques for electron boost planning compared with computed tomography (CT)-based planning. Additionally, we evaluated the tumor bed characteristics at whole breast planning and boost planning. Methods and Materials: A total of 30 women underwent tumor bed boost planning within 2 weeks of completing whole breast radiotherapy using three planning techniques: scar-based planning, palpation/clinical-based planning, and CT-based planning. The plans were analyzed for dosimetric coverage of the CT-delineated tumor bed. The cavity visualization score was used to define the CT-delineated tumor bed as well or poorly defined. Results: Scar-based planning resulted in inferior tumor bed coverage compared with CT-based planning, with the minimal dose received by 90% of the target volume >90% in 53% and a geographic miss in 53%. The results of palpation/clinical-based planning were significantly better: 87% and 10% for the minimal dose received by 90% of the target volume >90% and geographic miss, respectively. Of the 30 tumor beds, 16 were poorly defined by the cavity visualization score. Of these 16, 8 were well demarcated by the surgical clips. The evaluation of the 22 well-defined tumor beds revealed similar results. A comparison of the tumor bed volume from the initial planning CT scan to the boost planning CT scan revealed a decrease in size in 77% of cases. The mean decrease in volume was 52%. Conclusion: The results of our study have shown that CT-based planning allows for optimal tumor bed coverage comparedwithclinicalandscar-basedapproaches.However,inthesettingofapoorlyvisualizedcavityonCTwithout surgical clips, palpation/clinical-based planning can help delineate the appropriate target volumes and is superior to scar-based planning. CT simulation at boost planning could allow for a reduction in the boost volumes. 2009 Elsevier Inc. Breast cancer, Radiotherapy, Electron boost.

The aim of this study was to select patients with heart anatomy that is specifically unfavorable for tangential irradiation in whole-breast radiotherapy (WBRT), to be used as an experimental cohort to compare cardiac dosimetric and radiobiological parameters of three-dimensional conformal external beam accelerated partial breast irradiation (3D-CRT APBI) to WBRT with techniques as defined by the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 clinical trial.A dosimetric modeling study that compared WBRT and 3D-CRT APBI was performed on CT planning data from 8 patients with left-sided breast cancer. Highly unfavorable cardiac anatomy was defined by the measured contact of the myocardium with the anterior chest wall in the axial and para-sagittal planes. Treatment plans of WBRT and 3D-CRT APBI were generated for each patient in accordance with NSABP B-39/RTOG 0413 protocol. Dose-volume relationships of the heart, including the V5min (minimum dose delivered to 5% of the cardiac volume), biological effective dose (BED) of the V5min, and normal tissue complication probability (NTCP) were analyzed and compared.Despite expected anatomic variation, significantly large differences were found favoring 3D-CRT APBI in cumulative dose-volume histograms (p0.01), dose to the entire heart (mean difference 3.85 Gy, p0.01), NTCP (median difference, 1.00 Gy; p0.01), V5min (mean difference, 24.53 Gy; p0.01), and proportional reduction in radiobiological effect on the V5min (85%, p0.01).Use of 3D-CRT APBI can demonstrate improved sparing of the heart in select patients with highly unfavorable cardiac anatomy for WBRT, and may result in reduced risk of cardiac morbidity and mortality.

Purpose: To investigate the incidence of, and possible factors associated with, seroma formation after intraoperative placement of the MammoSite catheter for accelerated partial breast irradiation. Methods and Materials: This study evaluated 38 patients who had undergone intraoperative MammoSite catheter placement at lumpectomy or reexcision followed by accelerated partial breast irradiation with 34 Gy in 10 fractions. Data were collected regarding dosimetric parameters, including the volume of tissue enclosed by the 100%, 150%, and 200% isodose shells, dose homogeneity index, and maximal dose at the surface of the applicator. Clinical and treatment-related factors were analyzed, including patient age, patient weight, history of diabetes and smoking, use of reexcision, interval between surgery and radiotherapy, total duration of catheter placement, total excised specimen volume, and presence or absence of postprocedural infection. Seroma was verified by clinical examination, mammography, and/or ultrasonography. Persistent seroma was defined as seroma that was clinically detectable >6 months after radiotherapy completion. Results: After a median follow-up of 17 months, the overall rate of any detectable seroma was 76.3%. Persistent seroma (>6 months) occurred in 26 (68.4%) of 38 patients, of whom 46% experienced at least modest discomfort at some point during follow-up. Of these symptomatic patients, 3 required biopsy or complete cavity excision, revealing squamous metaplasia, foreign body giant cell reaction, fibroblasts, and active collagen deposition. Of the analyzed dosimetric, clinical, and treatment-related variables, only body weight correlated positively with the risk of seroma formation (p 0.04). Postprocedural infection correlated significantly (p 0.05) with a reduced risk of seroma formation. Seroma was associated with a suboptimal cosmetic outcome, because excellent scores were achieved in 61.5% of women with seroma compared with 83% without seroma. Conclusion: Intraoperative placement of the MammoSite catheter for accelerated partial breast irradiation is associated with a high rate of clinically detectable seroma that adversely affects the cosmetic outcome. The seroma risk was positively associated with body weight and negatively associated with postprocedural infection. © 2006 Elsevier Inc. Accelerated partial breast irradiation, MammoSite, Seroma, Radiotherapy, Breast cancer.

Purpose: To perform a detailed analysis of variables associated with late tissue effects of high-dose-rate (HDR) interstitial brachytherapy accelerated partial breast irradiation (APBI) in a large cohort of patients with prolonged follow-up. Methods and Materials: Beginning in 1995, 75 women with Stage I/II breast cancer were enrolled in identical institutional trials evaluating APBI as monotherapy after lumpectomy. Patients eligible included those with T1–2, N0–1 (≤3 nodes positive), M0 tumors of nonlobular histology with negative surgical margins, no extracapsular nodal extension, and negative results on postexcision mammogram. All patients underwent surgical excision and postoperative irradiation with HDR interstitial brachytherapy. The planning target volume was defined as the excision cavity plus a 2-cm margin. Treatment was delivered with a high-activity Ir-192 source at 3.4 Gy per fraction twice daily for 5 days to a total dose of 34 Gy. Dosimetric analyses were performed with three-dimensional postimplant dose and volume reconstructions. All patients were evaluated at 3–6-month intervals and assessed with a standardized cosmetic rating scale and according to Radiation Therapy Oncology Group late normal tissue toxicity scoring criteria. Clinical and therapy-related features were analyzed for their relationship to cosmetic outcome and toxicity rating. Clinical features analyzed included age, volume of resection, history of diabetes or hypertension, extent of axillary surgery, and systemic therapies. Therapy-related features analyzed included volume of tissue encompassed by the 100%, 150%, and 200% isodose lines (V100, V150, and V200, respectively), the dose homogeneity index (DHI), number of source dwell positions, and planar separation. Results: The median follow-up of all patients was 73 months (range, 43–118 months). The cosmetic outcome at last follow-up was rated as excellent, good, and fair/poor in 67%, 24%, and 9% of patients, respectively. Suboptimal cosmetic outcome was significantly associated with the number of source dwell positions, V150, and V200 and inversely associated with DHI (0.77 vs. 0.73; p = 0.05). Late skin toxicity was rated as Grade 0, 1, or 2 in 77%, 19%, and 4% of patients, respectively. The risk of Grade 1/2 skin toxicity was significantly associated with V150 and V200 and inversely associated with DHI (0.77 vs. 0.71; p = 0.009). Late subcutaneous toxicity was rated as Grade 0, 1, 2, 3, or 4 in 55%, 15%, 12%, 5%, and 13% of patients, respectively. The risk of Grade 0/1 vs. Grade 2–4 subcutaneous toxicity was significantly associated only with a lower value of DHI (0.77 vs. 0.73; p = 0.02). To further explore factors that might contribute to the risk of fat necrosis (symptomatic or asymptomatic), a separate analysis showed that only dose hotspots as reflected in V150 and V200 were significantly associated with elevated risk. The use of adriamycin-based chemotherapy after APBI was found to be associated with a significant increase in the incidence of higher-grade skin toxicity and a higher risk of fat necrosis and suboptimal cosmetic outcome. Patient age, volume of resection, extent of axillary surgery, a history of diabetes or hypertension, and the use of tamoxifen were not found to be significantly associated with cosmetic outcome or late normal tissue complications. Conclusions: Long-term cosmetic results and the risk of late skin and subcutaneous toxicity after APBI with interstitial HDR brachytherapy can be correlated with specific treatment-related variables. These data provide dosimetric parameters that might be used to minimize the risk of normal tissue injury after APBI interstitial brachytherapy.

Purpose: To investigate the feasibility, toxicity, cosmetic outcome, and local control of high-dose-rate (HDR) brachytherapy alone without whole breast external beam irradiation for early-stage breast carcinoma. Methods and Materials: Between June 1997 and August 1999, 32 women diagnosed with a total of 33 AJCC Stage I/II breast carcinomas underwent surgical breast excision and postoperative irradiation using HDR brachytherapy interstitial implantation as part of a multi-institutional clinical Phase I/II protocol. Eligible patients included those with T1, T2, N0, N1 (≤3 nodes positive), and M0 tumors of nonlobular histologic features with negative surgical margins, no extracapsular lymph node extension, and a negative postexcision mammogram. Brachytherapy catheters were placed at the initial excision, reexcision, or either sentinel or full-axillary sampling. Direct visualization, surgical clips, and ultrasound and/or CT scan assisted in the delineation of the target volume, defined as the excision cavity plus a 2-cm margin. High-activity 192 Ir (3–10 Ci) was used to deliver 340 cGy/fraction, 2 fractions/d, for 5 consecutive days, to a total dose of 34 Gy to the target volume. Source position and dwell times were calculated using standard volume optimization techniques. Results: The median follow-up of all patients was 33 months, and the mean patient age was 63 years. The mean tumor size was 1.3 cm, and 55% had an extensive intraductal component. Three patients had positive axillary nodes. Two patients experienced moderate perioperative pain that required narcotic analgesics. No peri- or postoperative infections occurred. No wound healing problems and no significant skin reactions related to the implant developed. The Radiation Therapy Oncology Group late radiation morbidity scoring scheme was applied to the entire 33-case cohort. In the assessment of the skin, 30 cases were Grade 0–1 and 3 cases were Grade 2. Subcutaneous toxicity was scored as 11 patients with Grade 0, 3 with Grade 1, 8 with Grade 2, 3 with Grade 3, and 8 with Grade 4. Clinically evident fat necrosis occurred in 8 patients at a median of 7.5 months after HDR brachytherapy completion. The only variables significantly associated with Grade 3–4 toxicity were the number of source dwell positions and the volume of tissue encompassed by the prescription isodose shell. The global cosmetic scores after a minimum of 18 months' follow-up were 0 cases with poor, 4 with fair, 5 with good, and 24 with excellent scores. One case of ipsilateral breast tumor recurrence was diagnosed 23 months after HDR brachytherapy, for a 4-year actuarial recurrence rate of 3%. This failure appeared to be a new primary tumor, because it was histologically distinct from the initial tumor and was located 9 cm from the initial tumor bed and 3 cm from the edge of the implant volume. Conclusion: Radiotherapy of the tumor bed alone with HDR interstitial brachytherapy is associated with a 33% incidence of Grade 3–4 s.c. toxicity, but with generally favorable overall cosmetic results. The risk of toxicity appears to be primarily related to the implant volume. With limited follow-up, the incidence of ipsilateral breast tumor recurrence was low.

Purpose: RTOG protocol 90-05 determined the maximum acutely tolerated dose of single-fraction radiosurgery in patients receiving prior fractionated large volume cranial irradiation. Data from 90-05 have suggested that patients treated with a gamma unit, compared to linac-based therapy, have a tumor control advantage and lower rates of severe complications. This study was performed to investigate the radiobiologic effect of using one vs. two isocenters in single-fraction radiosurgery of ellipsoidal targets. Methods and Materials: For a series of ellipsoidal targets that varied by volume and radiosensitivity, single and two-isocenter treatment plans were generated to approximate those typically employed for gamma unit and linac radiosurgery. Tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP) were generated automatically by the treatment planning system based on established parameter values. Results: The modeling data showed that multiple-isocenter plans resulted in improved TCP with equivalent or lesser NTCP, particularly for larger, radioresistant targets. Multiple-isocenter plans reduce the amount of normal tissue that receives high dose. Also, areas within the tumor receive significantly higher doses than the prescription dose, which contributes to increased tumor cell inactivation. Conclusion: For ellipsoidal targets, radiobiologic modeling data are consistent with the clinical findings of the RTOG 90-05 trial, as they predict improved outcome with a multiple-isocenter plan relative to a single-isocenter plan. The benefit is most apparent with increasing target volume and decreasing tumor radiosensitivity.

Purpose: To assess the effect of local-regional radiotherapy (RT) on the outcome of breast cancer patients with ≥ 10 positive axillary lymph nodes who have received modern conventional or high-dose systemic therapy. Methods and Materials: A total of 55 women with local-regionally confined breast cancer involving 10 or more axillary nodes were treated between October 1983 and January 1996. Local-regional therapy consisted of modified radical mastectomy in 39 and breast-conserving surgery in 16. Postoperative radiotherapy was given to 44 of the 55 patients. Radiotherapy consisted of tangential fields to the chest wall or intact breast to a median dose of 50.40 Gy. A total of 86% (38 of 44) received regional nodal irradiation as follows: 35 patients received RT to the supraclavicular (SC) region and axillary midplane to a median dose of 50.40 Gy and 46.20 Gy, respectively; 3 patients received RT to the SC region without inclusion of the axilla to a median dose of 50.40 Gy. All patients received adjuvant standard-dose systemic chemotherapy, 9 of whom received additional intensification chemotherapy followed by autologous bone-marrow transplant (ABMT) or peripheral blood stem-cell transplant (PBSC). Twenty-five patients received adjuvant tamoxifen. Results: With a median follow-up of 30 months, the crude overall survival (OS) and disease-free survival (DFS) for the entire group were 67% and 53%, respectively. On univariate analysis of various clinical, pathological, and therapy-related features, radiotherapy emerged as the most important factor influencing the relapse rate. The addition of RT was significantly associated with an improved DFS ( p = 0.003), specifically by prolonging the time to disease progression. The median time to failure was 61 months and 12.5 months with and without RT, respectively. Patients receiving RT also appeared to survive longer; however, the groups were not statistically different ( p = 0.10). Analysis of the patterns of failure showed local-regional recurrence (LRR) as the first site of failure in 12 (22%) of 55 and distant failure in 20 (36%) of 55. Univariate results revealed both radiotherapy and tamoxifen to be significantly associated with decreased LRR rates ( p = 0.0001 and p = 0.03, respectively); only RT remained independently significant on multivariate analysis. Conclusion: Local-regional radiotherapy is an essential component of the management of breast cancer patients with extensive nodal involvement, despite the use of contemporary adjuvant chemotherapy including high-dose regimens with autologous rescue. In addition to the expected improvement in LRR, radiotherapy is also associated with significantly prolonged DFS and a trend for improvement in OS.

Purpose: Young age and extensive intraductal component (EIC) histology have been shown to be associated with increased local recurrence in women treated with breast conservation therapy. This study was conducted to determine if the status of the lumpectomy specimen margin consistently predicted for residual tumor burden risk irrespective of these variables. Methods and Materials: As part of an institutional prospective approach for breast conservation therapy (BCT), 265 cases with AJCC Stage I/II carcinoma with an initial excision margin that was ≤2 mm or indeterminate were subjected to reexcision. The probability of residual tumor (+RE) was evaluated with respect to tumor size, histopathologic subtype (invasive ductal carcinoma, invasive ductal carcinoma with an EIC, and invasive lobular carcinoma), relative closeness of the measured margin, and the extent of margin positivity graded as focal, minimal, moderate, or extensive. The amount of residual tumor was graded as microscopic, small, medium, or large. All variables were analyzed for patient age ≤45 or >45 years. Results: There was no significant difference in the incidence of a +RE according to age ≤45 versus >45 years when the margin was >0 ≤2 mm. Of the patients aged ≤45 years, the incidence of a +RE with a margin that was positive as compared to >0 ≤2 mm was 71% vs. 23%, respectively ( p = 0.002). For women >45 years old, the difference in the incidence of +RE comparing margins that were positive or >0 ≤2 mm was not significant at 50% vs. 40%, respectively ( p = 0.23). For all cases in aggregate, age ≤45 years was associated with a greater incidence of +RE as compared to patients aged >45 years with the discrepant incidence of a +RE by age strata most pronounced for focally positive margins (60% vs. 18%; p ≤ 0.05). In a logistic regression analysis, age (per year, as a continuous variable) and an EIC histology were significantly associated with the probability of a +RE (odds ratio [OR] = 0.80, p = 0.05 and OR=1.9, p = 0.01, respectively). Tumor size was not significant ( p = 0.23). In patients with an EIC histology, margin status is generally less predictive for differences in the incidence of a +RE. Further, the overall magnitude of difference in the incidence of a +RE related to age appears to be minimized when an EIC histology is present. In contrast, for cases classified as having non-EIC histology, there is a near-linear relationship for both age strata with respect to margin status and the incidence of a +RE. When histology is classified as non-EIC, age ≤45 years is consistently associated with a greater risk of residual tumor for all margin status categories. When the extent of margin positivity was graded as focal or minimal, residual tumor was semiquantitatively estimated as a medium/large amount in 33% versus 26% of cases aged ≤45 or >45 years, respectively ( p = 0.62). Conclusion: For positive lumpectomy specimen margins, younger age is associated with an increased residual tumor risk. An EIC histology appears to be associated with an elevated risk of residual tumor irrespective of age and may undermine the predictive utility of margin status. Therefore, age and an EIC histology should be factored into risk assessments for residual tumor that rely upon margin assessment.

Purpose: A prospectively applied treatment policy for breast-conserving therapy used margin assessment as the exclusive guide to the intensity of therapy directed at the tumor-bearing quadrant. Methods and Materials: From 1982–1994, there were 509 treated Stage I and II breast carcinomas with a median follow-up of 72 months. For operational purposes, tumor excision margins were prospectively defined as: > 5 mm, 2.1–5 mm, > 0 ≤ 2 mm, and positive. If a margin was assessed as ≤2 mm or indeterminate, and it was deemed cosmetically feasible, a reexcision of the tumor bed would be performed. All patients received whole breast irradiation to 50–50.4 Gy. The following scheme for tumor bed boost irradiation as a function of final margin status (FMS) was observed: (a) Minimal risk = no tumor found on reexcision, no boost performed; (b) low risk = FMS > 5 mm, boost of 10 Gy; intermediate risk = FMS 2.1–5 mm, boost to 14 Gy; high risk = FMS ≤ 2 mm or positive, boost to 20 Gy. Cases were analyzed for local failure (LF) with respect to histology (invasive ductal (IDC), IDC with associated DCIS (IDC/DCIS), invasive lobular (ILC)), age, tumor size, total excision volume, reexcision, total dose, tamoxifen therapy, and chemotherapy. Results: There were 19 breast recurrences for a Kaplan–Meier local failure rate for all cases at 5 and 10 years of 2.7% and 7.1%, respectively. Local failure in the first 4 years of follow-up was rare, with a mean annual incidence rate of 0.25% that rose to a mean of 1.1% in subsequent years. Univariate results of Cox proportional hazards regression survival models found positive FMS (p = 0.02), IDC/DCIS (p = 0.04) and age (0.0006) as significantly associated with local failure. In a multivariable model of FMS and IDC/DCIS, FMS retained significance (p = 0.01) but IDC/DCIS was borderline (p = 0.06). When FMS and age were included in a multivariable model, there was a significant interaction (p = 0.01) between the two variables. There was a significant increase in the relative risk of LF for age ≤ 45 years (range 11.1–17.4), irrespective of FMS category. Although excellent overall control rates were achieved for patients > 45 years, for younger patients LF rates appeared to remain proportional to the relative closeness of the FMS, despite rigorous dose escalation. Conclusions: Graded tumor-bed dose escalation in response to FMS results in an exceptionally low risk of “early” local recurrence within the first 5 years of follow-up. However, this strategy is unable to completely overcome the longer term adverse influence of young age and positive FMS.

Purpose: Margin assessment is commonly used as a guide to the relative aggressiveness of therapy for breast conserving treatment (BCT), though its value as a predictor of the presence, type, or extent of residual tumor has not been conclusively studied. Controversy continues to exist as to what constitutes a margin that is "positive," "close,", or "negative." We attempt to address these issues through an analysis of re-excision specimens. Methods and Materials: As part of an institutional prospective practice approach for BCT, 265 cases with AJCC Stage III carcinoma with an initial excision margin that was ≤2 mmor indetermine were subjected to re-excision. The probability of residual tumor (+RE) was evaluated with respect to tumor size, histopathologic subtype, relative closeness of the measured margin, the extent of margin positivity graded as focal, minimal, moderate, or extensive, and the extent of specimen processing as reflected in the number of cut sections per specimen volume (S:V ratio). Teh amount of residual tumor was graded as microscopic, small, medium, or large. The histopathologic subtype of tumor in the re-excision specimen was classified as having an invasive component (ICa) or pure DCIS (DCIS). Results: The primary excision margin was positive, >0≤1 mm, 1.2–2 mm, and indeterminate in 60%, 18%, 5%, and 17%, respectively. The predominant histopathologies in the initial excision specimens were invasvie ductal (IDC) (50%) and tumors with an extensive intraductal component (EIC) 43%). The histopathology of the initial excision specimen was highly predictive of the histopathology of tumor found on re-excision, as residual DCIS was found in 60% of +RE specimens with initial histopathology of EIC compared to 26% for IDC ( p = 0.001). Neither the extent of margin positivity nor the extent of tumor in the re-excision were significantly related to the initial histopathologic subtype; however, a +RE was seen in 59% of EIC, 43% of IDC, and 32% of invasive lobular ILC case ( p = 0.01). The extent of margin positivity was siginificantly related to the size of the tumor such that tumor size ≤ 20 mm was associated with a greater probability of focal or minimal margin involvement. Positive margins graded as focal, minimal, moderate/extensive were associated with a +RE in 26%, 58%, and 84%, respectively ( p = 0.001). Further, the extent of positivity was significantly correlated with the extent of residual tumor such that focal/minimal positivity was more commonly associated with micro/small +RE, whereas moderate/extensive positivity was associated with medium/large +RE. When the closest margin of the initial excision specimen was positive, >0≤1 mm, or 1.1–2 mm, a +RE was foudn in 56%, 41%, and 17%, respectively ( p = 0.01) but did not correlate with the amount of residual tumor. The extent of specimen processing as reflected in the S:V ratio did not correlate with the probability of defining a measured margin as positive nor the probability of a +RE. IN a univariate model, the extent of tumor in the re-excision and the histologic type of tumor in the re-excision were significantly association with margin status adn initial histopathology, respectively. The probability of finding a +RE, based on a multivariate model, was associated with the closeness and extent of margin involvement and initial histopathology of an EIC. Conclusion: The relative closeness of tumor to the specimen and the of margin positivity are predictive for residual tumor, though with an error consistent with its limitations as a sampling procedure. The histopathology of tumor in the initial excision is predictive of the type of residual tumor and the extent of margin positivity was correlated with the amount of residual tumor.

Purpose: Current methods to clinically define head and neck tumor bulk are qualitative and imprecise. Although the American Joint Committee on Cancer (AJCC) staging system is important for this purpose, limitations exist. This study will investigate the prognostic value of computed tomography (CT) derived tumor volume measurements in comparison to AJCC stage and other significant variables. Materials and Methods: Seventy-six patients with advanced head and neck squamous cell carcinoma were treated with concomitant boost accelerated sunerfractionated irradiation. Doses ranged from 68.4-73.8 Gv (median 70.2 Gy). Good quality pretherapy CT scans were available in 51 patie&. Total tumor volumk (TTV) estimates were derived from these scans using digital integration of primary tumor and metastatic lymphadenopathy. Actuarial and multivariate statistical techniques were applied to analyze local control. Results: Thirty-six-month local control was 63%. TTV ranged from 5-l% cm3 (median 35 cm3) for all cases, 5-142 cm3 (median 17 cm3) for those controlled, and 16-l% cm3 (median 47 cm3) for local failures. There was a significant increase in failures above 35 cm’. Univariate analysis found that ‘PI’V, T-stage, Nstage, and primary site were each significant prognostic variables. Local control for TTV 535 cm3 was 92% at 36 months vs. 34% for ‘M’V >35 cm3 (p = 0.0001). Multivariate analysis, however, found that TTV, primary site, and sex were important as independent variables; T and N stage were not independently significant unless TTV was removed from the model. Conclusions: This study demonstrates the prognostic significance of TTV in advanced carcinoma of the head and neck. This variable appears to be a more predictive than AJCC clinical stage. Quantitative tumor volume measurements may prove to be a useful parameter in future analyses of head and neck cancer. Tumor volume, Head and neck neoplasms, Radiotherapy, Prognosis, Local control, Altered fractionation, Staging, Concomitant boost, Radiation dosage.

Purpose : Experience with the University of Wisconsin's stereotactic radiotherapy (SRT) accessory system was applied to build a new system, facilitate alignment of linac photon beams with a Brown-Roberts-Wells (BRW) stereotaxy, and increase the versatility and stability of the stereotaxy. Methods and Materials : High tensile strength stainless steel was used in the floor stand to increase the range of gantry rotation relative to ranges allowed by truss-mounted stands. The collimator assembly and floor stand were each fitted with two-axis gimbal and translation adjustments in addition to the floor stand's three-axis adjustments. The head ring positioning assembly was fitted with two braces to prevent the head ring from deforming with patient motion. Six MV linac photon beam characteristics were measured with a computer-controlled scanning system and a diode in water, at source to surface distances (SSD) of 80 and 100 cm, and for 13 divergent collimators ranging in diameter from 1–4 cm at 100 cm SSD. Quality assurance software was applied to screen data for questionable consistency or symmetry. Integrity of the stereotaxy was evaluated with target simulation films and repeated measurements which were part of the quality assurance of clinical treatments. A method was developed using a glass etched contact reticle to obtain average simulated target to beam center distances (δav) from target simulation films. Results and Conclusion : New aspects of the current system have improved the ability to fine tune and analyze stereotactic alignment. Beam characteristics met stringent output criteria and penumbral widths were the same or narrower than penumbral widths reported elsewhere. The precision of measuring δav was 0.1 mm, and δav averaged over 50 target simulation films was 0.7 ± 0.1 mm. Results suggest that it may be useful to determine δav from target simulation films with the method described here.

Purpose: Between 1982 and 1988 233 American Joint Committee on Cancer Stage I and II invasive breast carcinomas were prospectively treated in 225 women with conservative tumor excision, careful assessment of histopathological margins, and dose-adjusted irradiation to maximum doses of 70 Gy to the tumor bearing quadrant of the breast. Methods and Materials: The pathological stages at presentation were T1 N0 and TINT in 57% and 13% and T2N0 and T2N1 in 19% and 10% of the patients, respectively. All patients were irradiated according to a policy that, beyond the 50 Gy to the whole breast and draining lymphatics, the tumor-bearing quadrant was boosted in adjustment to the histopathological margin. Normal tissue margins of 5 mm negative and were boosted with 20, 15, and 10 Gy, respectively. Patients in whom the margin could not be assessed were re-excised or boosted to 20 Gy. Re-excisions with no residual carcinoma were not boosted. Most patients boosted to 20 Gy to the tumor-bearing quadrant received interstitial 192-Ir implantations. Results: The actuarial local control rates in the treated breast were 97.5% at 10 years with three recurrences having occurred at a median of 4.5 years after completion of radiotherapy. An additional two patients failed regionally outside the irradiation portals. The overall and disease-free survival of the whole group is 87.5% and 77%, respectively. Conclusion: The approach to breast conservation therapy followed in this study has resulted in outstanding local control rates and suggests that there may be a subset of patients that could be irradiated to the tumor bearing quadrant only.

Purpose : To investigate growth regulation and radiosensitivity in surviving clonogens after fractionated irradiation. Methods and Materials : Four breast carcinoma cell lines isolated from the primary tumor (21NT, 21PT) and metastases (21MT-1, 21MT-2) of a single patient were exposed to cumulative radiation doses of 30 Gy yielding cell lines designated -IR with respect to their parent. The irradiated lines were then compared to their parent for serum- and growth factor-requirements under defined media conditions, ability to proliferate in soft agar, concentration of TGF-alpha in conditioned medium, and radiosensitivity. Results : The irradiated lines showed no change in proliferative doubling times under serum- and growth factor supplemented media conditions. A single line, 21MT-1-IR, acquired a limited ability to proliferate in serum- and growth factor-deplete medium with a day 2–4 doubling time of 44.5 hr. Three lines, 21MT-1-IR, 21MT-2-IR, and 21NT-IR, formed colonies in soft agar in contrast to none of the unirradiated parent lines. There were significant 6–8 fold increases in conditioned media TGF-alpha concentrations for 21MT-2-IR and 21NT-IR cells. The 21MTl-IR and 21NT-IR cells were significantly less radiosensitive than their respective parent lines. This decrease in radiosensitivity appeared to be at least partially mediated by a released factor as the radiosensitivity of 21MT-1 cells was significantly decreased by pre-incubation with conditioned medium from 21MT-1-IR cells. Conclusion : Radiation-induced changes in growth phenotype vary with respect to clonal origin of the cell line and may influence the radiosensitivity of surviving clonogens after fractionated treatment.

Between 1980 and 1988, 94 patients with AJCC Stage III and IV squamous cell carcinoma of all sites of the upper aero-digestive tract were treated with radiotherapy. We report here on 62 patients who are followed for a minimum of 2 years. Of these, 30 patients were treated with conventional once-a-day radiotherapy and 32 patients were irradiated using an accelerated superfractionation regimen during part of the treatment course. The altered fractionation schedule employed a concomitant boost technique with clinically demonstrable disease being irradiated twice-a-day during the first or second half of the treatment course. Daily radiation fractions were 1.8 Gy and the boost field was treated with 1.6 Gy after a 4- to 6-hr interval. No significant differences in acute treatment toxicity were observed in the two treatment groups. Patients treated with conventional and accelerated fractionation regimens experienced 36 months actuarial local tumor control rates of 40% and 67% (p = 0.03), respectively, which translated into an actuarial disease-free survival of 40% and 64% (p = 0.04). The increased locoregional control rates in patients treated with accelerated fractionation were associated with an adjusted and overall survival advantage at the p = 0.05 level. We conclude that our regimen of accelerated superfractionated irradiation with shortening of the treatment course resulted in improved control and survival rates at conventional doses of 68.4 to 73.8 Gy.