Jaroslaw T. Hepel

Toxicity of Three-Dimensional Conformal Radiotherapy for Accelerated Partial Breast Irradiation

PURPOSE To assess the incidence and severity of late normal tissue toxicity using three-dimensional conformal radiotherapy to deliver accelerated partial breast irradiation. METHODS AND MATERIALS A total of 60 patients were treated with three-dimensional conformal radiotherapy for accelerated partial breast irradiation. Treatment planning and delivery were in strict accordance with the technique and specified dose-volume constraints of the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology Group 0413 protocol. Late toxicity was evaluated according to the Radiation Therapy Oncology Group grading schema. The cosmetic outcome was scored using the Harvard criteria. Univariate logistic regression analysis was performed to evaluate the correlation of dosimetric variables with outcome. RESULTS At a median follow-up of 15 months, moderate-to-severe late toxicity developed in 10% of patients. The most pronounced late toxicity was subcutaneous fibrosis: 25% Grade 2-4 and 8.3% Grade 3-4. The modified planning tumor volume/whole breast volume ratio, ratio of the volume of breast tissue receiving 5%, 20%, 50%, and 80% of the prescription dose to the whole breast volume, and maximal dose within the breast correlated with the development of fibrosis (p = .10, p = .03, p = .04, p = .06, p = .09, and p = .046, respectively). The overall cosmetic outcome was good to excellent in 81.7%, fair in 11.7%, and poor in 6.7%. The presence of subcutaneous fibrosis, modified planning tumor volume/whole breast volume ratio, ratio of the volume of breast tissue receiving 5% and 20% of the prescription dose to the whole breast volume, and pathologic specimen volume correlated with the risk of a fair/poor cosmetic outcome (p < .001, p = .02, p = .05, p = .04, p = .01, respectively). CONCLUSION The three-dimensional conformal radiotherapy technique for accelerated partial breast irradiation as specified in the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology Group 0413 protocol resulted in a remarkably high rate of moderate-to-severe late normal tissue effects, despite the relatively brief follow-up period. The toxic events correlated clearly with several dose-volume parameters.

An attempt to independently verify the utility of the Van Nuys Prognostic Index for ductal carcinoma in situ

The Van Nuys Prognostic Index (VNPI) purports to predict the risk of ipsilateral breast tumor recurrence (IBTR) after excision of ductal carcinoma in situ (DCIS). It is a simple scoring scheme based on a retrospective evaluation of data from a single group of investigators. Various versions of VNPI have been proposed using clinical and pathologic features including tumor size, tumor grade, margin width, and patient age. Despite common use of VNPI in the clinical management of patients with DCIS, independent validation is lacking.

The Effect of Dose-Volume Parameters and Interfraction Interval on Cosmetic Outcome and Toxicity After 3-Dimensional Conformal Accelerated Partial Breast Irradiation

PURPOSE To evaluate dose-volume parameters and the interfraction interval (IFI) as they relate to cosmetic outcome and normal tissue effects of 3-dimensional conformal radiation therapy (3D-CRT) for accelerated partial breast irradiation (APBI). METHODS AND MATERIALS Eighty patients were treated by the use of 3D-CRT to deliver APBI at our institutions from 2003-2010 in strict accordance with the specified dose-volume constraints outlined in the National Surgical Adjuvant Breast and Bowel Project B39/Radiation Therapy Oncology Group 0413 (NSABP-B39/RTOG 0413) protocol. The prescribed dose was 38.5 Gy in 10 fractions delivered twice daily. Patients underwent follow-up with assessment for recurrence, late toxicity, and overall cosmetic outcome. Tests for association between toxicity endpoints and dosimetric parameters were performed with the chi-square test. Univariate logistic regression was used to evaluate the association of interfraction interval (IFI) with these outcomes. RESULTS At a median follow-up time of 32 months, grade 2-4 and grade 3-4 subcutaneous fibrosis occurred in 31% and 7.5% of patients, respectively. Subcutaneous fibrosis improved in 5 patients (6%) with extended follow-up. Fat necrosis developed in 11% of women, and cosmetic outcome was fair/poor in 19%. The relative volume of breast tissue receiving 5%, 20%, 50%, 80%, and 100% (V5-V100) of the prescribed dose was associated with risk of subcutaneous fibrosis, and the volume receiving 50%, 80%, and 100% (V50-V100) was associated with fair/poor cosmesis. The mean IFI was 6.9 hours, and the minimum IFI was 6.2 hours. The mean and minimum IFI values were not significantly associated with late toxicity. CONCLUSIONS The incidence of moderate to severe late toxicity, particularly subcutaneous fibrosis and fat necrosis and resulting fair/poor cosmesis, remains high with continued follow-up. These toxicity endpoints are associated with several dose-volume parameters. Minimum and mean IFI values were not associated with late toxicity.

Planning the breast boost: comparison of three techniques and evolution of tumor bed during treatment.

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 compared with clinical and scar-based approaches. However, in the setting of a poorly visualized cavity on CT without 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.

A comparison of brachytherapy techniques for partial breast irradiation.

Accelerated partial breast irradiation has emerged as an important treatment option for select patients with early-stage breast cancer. Numerous techniques for the delivery of accelerated partial breast irradiation have been developed involving both external beam and brachytherapy techniques. Brachytherapy techniques in general have the advantage of directly targeting the tumor bed and are not hampered by the requirement for large planning target volume margins needed with external beam techniques to account for uncertainties in targeting a very mobile organ, easily affected by patient and respiratory motion. We review established brachytherapy techniques and new emerging approaches. Technical considerations, available clinical data, advantages and shortcomings of each technique are reviewed.

A flawed study should not define a new standard of care.

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 <1 mm, extensive ductal carcinoma in situ, invasive lobular carcinoma, or “individual centers could specify more than these core factors” (2) at their discretion. For 33% of the study participants, the definitive pathology was already available from a prior lumpectomy. This “post-pathology” stratum of patients was predetermined as being at low risk and, if randomized to

Survival among patients with 10 or more brain metastases treated with stereotactic radiosurgery

OBJECT The goal of this study was to evaluate outcomes in patients with ≥ 10 CNS metastases treated with Gamma Knife stereotactic radiosurgery (GK-SRS). METHODS Patients with ≥ 10 brain metastases treated using GK-SRS during the period between 2004 and 2010 were identified. Overall survival and local and regional control as well as necrosis rates were determined. The influence of age, sex, histological type, extracranial metastases, whole-brain radiation therapy, and number of brain metastases was analyzed using the Kaplan-Meier method. Univariate (log-rank) analyses were performed, with a p value of < 0.05 considered significant. RESULTS Fifty-three patients with ≥ 10 brain metastases were treated between 2004 and 2010. All had a Karnofsky Performance Status score of ≥ 70. Seventy-two percent had either non-small cell lung cancer (38%) or breast cancer (34%); melanoma, small cell lung cancer, renal cell carcinoma, and testicular, colon, and ovarian cancer contributed the remaining 28%. On average, 10.9 lesions were treated in a single session. Sixty-four percent of patients received prior whole-brain radiation therapy. The median survival was 6.5 months. One-year overall survival was 42% versus 14% when comparing breast cancer and other histological types, respectively (p = 0.074). Age, extracranial metastases, number of brain metastases, and previous CNS radiation therapy were not significant prognostic factors. Although the median time to local failure was not reached, the median time to regional failure was 3 months. Female sex was associated with longer time to regional failure (p = 0.004), as was breast cancer histological type (p = 0.089). No patient experienced symptomatic necrosis. CONCLUSIONS Patients with ≥ 10 brain metastases who received prior CNS radiation can safely undergo repeat treatment with GK-SRS. With median survival exceeding 6 months, aggressive local treatment remains an option; however, rapid CNS failure is to be expected. Although numbers are limited, patients with breast cancer represent one group of individuals who would benefit most, with prolonged survival and extended time to CNS recurrence.

Predictors for long-term survival free from whole brain radiation therapy in patients treated with radiosurgery for limited brain metastases

Purpose To identify predictors for prolonged survival free from salvage whole brain radiation therapy (WBRT) in patients with brain metastases treated with stereotactic radiosurgery (SRS) as their initial radiotherapy approach. Materials and methods Patients with brain metastases treated with SRS from 2001 to 2013 at our institution were identified. SRS without WBRT was typically offered to patients with 1–4 brain metastases, Karnofsky performance status ≥70, and life expectancy ≥3 months. Three hundred and eight patients met inclusion criteria for analysis. Medical records were reviewed for patient, disease, and treatment information. Two comparison groups were identified: those with ≥1-year WBRT-free survival (N = 104), and those who died or required salvage WBRT within 3 months of SRS (N = 56). Differences between these groups were assessed by univariate and multivariate analyses. Results Median survival for all patients was 11 months. Among patients with ≥1-year WBRT-free survival, median survival was 33 months (12–107 months) with only 21% requiring salvage WBRT. Factors significantly associated with prolonged WBRT-free survival on univariate analysis (p < 0.05) included younger age, asymptomatic presentation, RTOG RPA class I, fewer brain metastases, surgical resection, breast primary, new or controlled primary, absence of extracranial metastatic disease, and oligometastatic disease burden (≤5 metastatic lesions). After controlling for covariates, asymptomatic presentation, breast primary, single brain metastasis, absence of extracranial metastases, and oligometastatic disease burden remained independent predictors for favorable WBRT-free survival. Conclusion A subset of patients with brain metastases can achieve long-term survival after upfront SRS without the need for salvage WBRT. Predictors identified in this study can help select patients that might benefit most from a treatment strategy of SRS alone.

Perineural tumor spread of bladder cancer causing lumbosacral plexopathy: an anatomic explanation

We present two cases of biopsy-proven neoplastic lumbosacral plexopathy from perineural spread of bladder cancer: one patient presented with predominantly sciatic nerve involvement and the second predominantly with obturator nerve involvement. These two patterns of perineural spread from bladder cancer were supported by imaging in our cases and solidified by review of the literature. Based on the innervation of the bladder, we provide an anatomic explanation for this observation. To our best knowledge, such an anatomic, mechanistic basis for perineural tumor spread in bladder cancer has not yet been described.

Stereotactic radiosurgery for large brain metastases

We evaluated patient outcomes following stereotactic radiosurgery (SRS)-treatment of large brain metastasis (⩾3 cm) at our institution. SRS is an established treatment for limited brain metastases. However, large tumors pose a challenge for this approach. For this study, 343 patients with 754 total brain metastases were treated with SRS, of which 93 had large tumors. The tumor size was 3-3.5, 3.5-4, and ⩾4 cm in 29%, 32%, and 39% of these patients. Surgical resection was performed prior to SRS in 68% of patients, and 53% achieved a gross total resection. The local control of large metastases was inferior compared to smaller tumors, with 1 year local control of 68 versus 86%, respectively (p<0.001). Among the patients with large metastases, no correlation between local control and surgical resection (p=0.747), or extent of surgery (gross total versus subtotal resection; p=0.120), was identified. Histology (p=0.939), tumor size (3-4 versus >4 cm; p=0.551), and SRS dose (⩽16 versus >16 Gy; p=0.539) also showed no correlation with local failure. The overall survival at 1, 2, and 5 years was 46%, 29% and 5%, respectively. Prolonged survival was seen in patients with age <65 years (p=0.009), primary treatment compared with salvage (p=0.077), and controlled primary tumors (p=0.022). Radiation necrosis developed in 10 patients (11.8%). For patients with large brain metastases, SRS is well tolerated and can achieve local central nervous system disease control in the majority of patients, and extended survival in some, though the local control rate is suboptimal. Further strategies to improve the outcomes in this subgroup of patients are needed.