A Phase 1 Dose-Escalation Trial of Radiation Therapy and Concurrent Cisplatin for Stage II and III Triple-Negative Breast Cancer.

PURPOSE: Patients with triple-negative breast cancer (TNBC) experience higher local-regional recurrence rates than those with luminal or HER2-positive tumors. This prospective, phase 1B trial was designed to assess the safety and to establish the maximum tolerated dose (MTD) of cisplatin with radiation therapy for women with early-stage TNBC. METHODS AND MATERIALS: Eligible patients had stage II or III TNBC. Cisplatin was initiated at 10 mg/m2 intravenously once weekly during radiation and then escalated in a 3 + 3 design by 10 mg/m2 at each dose level until 40 mg/m2, or the MTD, was reached. Patients undergoing breast-conserving therapy (BCT) or mastectomy were accrued in separate parallel cohorts during dose escalation, followed by a 10-patient expansion at the MTD. RESULTS: During 2013 to 2018, 55 patients were accrued. Four patients developed dose-limiting toxicity. In the BCT cohort, 1 patient receiving 40 mg/m2 developed tinnitus resulting in a cisplatin delay; therefore, this was the BCT cohort MTD. In the mastectomy cohort, 1 patient receiving 20 mg/m2 developed a grade 3 urinary infection, and 2 additional patients had dose-limiting toxicities at 40 mg/m2 (grade 3 neutropenia and grade 2 tinnitus), both resulting in cisplatin delay. Thus, 30 mg/m2 was the mastectomy cohort MTD. Median follow-up was 48.5 months. Three-year disease-free survival was 74.7% for the BCT cohort and 64.4% for the mastectomy cohort. CONCLUSIONS: Adjuvant radiation therapy with concurrent cisplatin is feasible with a recommended phase 2 dose of 30 mg/m2 and 40 mg/m2 intravenously weekly in mastectomy and BCT cohorts, respectively.

A comparison of the biological effective dose of 50-kV electronic brachytherapy with (192)Ir high-dose-rate brachytherapy for vaginal cuff irradiation.

PURPOSE: Advantages for electronic brachytherapy (EBT) of the vaginal cuff include decreased physical dose to the bladder and rectum. Here we compare (192)Ir with EBT using biological effective dose (BED) to account for the different radiobiological effectiveness (RBE) predicted for low-energy x-rays. METHODS AND MATERIALS: Fifteen data sets from five consecutive postoperative endometrial cancer patients treated with EBT were analyzed. Treatment planning was performed using PLATO software. The dose was prescribed as 21Gy in three fractions to a depth of 0.5cm. Physical dose, BED(3), and BED(10) were evaluated for the mucosa, bladder, and rectum. An RBE value of 1.5 was used for BED calculations. RESULTS: Mucosal physical dose is 28.4% greater with EBT (36.6 vs. 28.5Gy, p<0.05). However, the BED(10) is increased by 79.1% (55.6 vs. 99.6Gy, p<0.05) and the BED(3) by 71.5% (118.8 vs. 203.7Gy, p<0.05). The physical dose (dose to 50% volume of the organ) to the bladder (9.3 vs. 6.6Gy, p<0.05) and rectum (7.2 vs. 4.2Gy, p<0.05) are reduced with EBT. BED(3) to the rectum and bladder are also reduced but to a lesser extent (13 vs. 8.3Gy, p<0.05; 18.9 vs. 14.7Gy, p=0.06, respectively). CONCLUSIONS: BED takes into account the higher RBE of low-energy photons generated with EBT and provides a more accurate estimate of the biological effect. When using EBT, physical dose may underestimate the biological effect on the vaginal mucosa and overestimate the benefit for the bladder and rectum. Dose adjustment for EBT based on BED should be considered.

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.

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.

Intensity-modulated radiotherapy of the prostate after cryotherapy: initial experience.

OBJECTIVES: To analyze results of intensity-modulated radiotherapy after cryotherapy ablation for adenocarcinoma of the prostate. METHODS: Patients were either treated adjuvantly after targeted cryotherapy or treated for salvage after local failure of standard whole-prostate cryotherapy. Patients were treated with intensity-modulated radiotherapy to a minimum dose of 73 Gy (mean dose, >75Gy). Prostate-specific antigen (PSA) failure was defined according to the Radiation Therapy Oncology Group-American Society for Therapeutic Radiology and Oncology 2006 consensus definition. Late gastrointestinal and genitourinary toxicity were graded according to the Radiation Therapy Oncology Group late toxicity scale and the Late Effects of Normal Tissue-Subjective, Objective, Management, and Analytic scale. RESULTS: A total of 16 patients were treated from 1997 to 2007. Three patients were treated adjuvantly, and 13 patients were treated for local failure. The mean pre-cryotherapy PSA value was 8.7 ng/mL. The mean PSA value before irradiation was 6.0 ng/mL. Most patients were intermediate to high risk (8 intermediate risk, 7 high risk). Median follow-up was 33 months. No grade 3 or greater toxicity was seen. Biochemical (PSA) control was achieved in 12 of the 16 patients at last follow-up. CONCLUSIONS: Full-dose intensity-modulated radiotherapy after cryotherapy is well tolerated, without excess late morbidity. This study supports the use of radiation for cryotherapy failure salvage. Furthermore, the combination of cryotherapy and irradiation may be considered in a phase II trial.

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

BACKGROUND: 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. METHODS: A total of 222 patients were retrospectively analyzed with mammographically detected DCIS who were treated with surgical excision alone. Wire-localized excisional biopsy was performed and surgical specimens were measured and inked to assist in margin assessment. Multiple sections of each specimen were evaluated for histopathologic subtype, histologic and nuclear grade, presence of necrosis, maximum dimension of the lesion, and margin width. Each patient was prospectively evaluated by a multidisciplinary management team and presented with adjuvant treatment options including whole breast radiotherapy and/or tamoxifen. All patients in this cohort declined radiotherapy. Thirty-one percent of patients received tamoxifen. Patients were followed clinically every 3 to 6 months, and mammographically every 6 to 12 months. IBTR was confirmed by biopsy. Wilcoxon regression analysis was used to evaluate risk groups according to 3 proposed VNPI classification schemes: VNPI Group 1 (margin, grade, and size), VNPI Group 2 (margin, grade, size, and patient age), and VNPI Group 3 (margin only). RESULTS: With a median follow-up of 4.6 years, the crude rate of IBTR was 8.6% for the entire cohort. Of the patients who developed an IBTR, 73.7% had a lesion with a maximum dimension of < or =15 mm, 47.4% had a margin > or =10 mm, and 36.8% had grade 1 histology. At 5 years, IBTR was statistically indistinguishable for the 3 VNPI models. The 5-year freedom from IBTR for low-risk, intermediate-risk, and high-risk groups according to VNPI Group 1 was 96%, 84%, and 100%, respectively (P = .20). Similarly, the 5-year freedom from IBTR for low-risk, intermediate-risk, and high-risk groups according to VNPI Group 2 was 95%, 83%, and 100%, respectively (P = .19). Taking into account margin status only (VNPI Group 3) the 5-year freedom from IBTR for low-risk, intermediate-risk, and high-risk groups was 92%, 91%, and 91%, respectively (P = .98). Tamoxifen use did not appear to affect the 5-year rate of IBTR (95% vs 94%; P = 1.0). CONCLUSIONS: The results of the current study suggest that VNPI or margin width alone is not a valid tool with which to assist in the stratification of patients after excision alone for their risk of IBTR at 5 years. Further follow-up may strengthen the predictive utility of the various VNPI classification schemes.