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Purpose: To evaluate the feasibility and toxicity of a single-fraction 8-Gy stereotactic boost after whole-breast irradiation in early breast cancer. The primary aim of this phase 2 study was to evaluate cutaneous breast toxicity using National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) 3 months after the boost. Secondary objectives were local control, survival, and patient-reported quality of life using the European Organisation for Research and Treatment of Cancer QLQ-C30 and breast-specific European Organisation for Research and Treatment of Cancer QLQ-BR 23 questionnaires., Methods and Materials: Patients with invasive ductal or lobular pT1-2 breast cancer treated with lumpectomy with clear margins and pN0 were included. Patients requiring chemotherapy were excluded., Results: Twenty-eight eligible patients received the planned boost, and 26 had hormonal therapy. The procedure was technically successful without procedural complications. A median of 3 fiducials were tracked, and 115 beams were used. There were 22 acute grade 1 breast skin toxicities, including fibrosis, pain, erythema, or pigmentation. There were 2 acute grade 2 erythemas. Median skin boost dose was inversely correlated with acute skin toxicity (P = .028). QLQ-C30 scores revealed acute dyspnea and arm symptoms without correlation to the boost dose. Breast symptom QLQ-BR23 scores did not deteriorate, although upset with hair loss and systemic side effects of hormonal therapy were observed. After a median follow-up of 38 months, 1 patient had in-boost-field relapse, and there were 5 late grade 1 and 1 grade 2 skin toxicities., Conclusions: Single-fraction stereotactic boost after conventional whole-breast irradiation in early breast cancer is feasible with minor toxicities. Quality of life and specific breast items showed excellent patient acceptance., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) allows stereotactic irradiation of thoracic tumors. It may have a real impact on patients who may not otherwise qualify for breast-conserving surgery. We conducted a phase 1 trial that tested 5 dose levels of SBRT concomitant with neoadjuvant chemotherapy (NACT) before to surgery. The purpose of the current dose escalation study was to determine the maximum tolerable dose of SBRT in the treatment of breast cancer., Methods and Materials: To define toxicity, we performed dermatologic examinations that included clinical examinations by 2 separate physicians and technical evaluations using colorimetry, dermoscopy, and skin ultrasonography. Dermatologic examinations were performed before NACT, 36 and 56 days after the beginning of NACT, and before surgery. Surgery was performed 4 to 8 weeks after the last chemotherapy session. Efficacy, the primary endpoint, was determined by the pathologic complete response (pCR) rate., Results: Maximum tolerable dose was not reached. Only 1 case of dose-limiting toxicity was reported (grade 3 dermatologic toxicity), and SBRT was overall well tolerated. The pCR rate was 36%, with none being observed at the first 2 dose levels, and the highest rate being obtained at dose level 3 (25.5 Gy delivered in 3 fractions). Furthermore, the breast-conserving surgery rate was up to 92% compared with an 8% total mastectomy rate. No surgical complications were reported., Conclusions: This study demonstrates that SBRT can be safely combined with NACT. Regarding the efficacy endpoints, this trial showed promising results in terms of pCR rate (36%) and breast-conserving rate (92%). The findings provide a strong rationale for extending the study into a phase 2 trial. In view of the absence of correlation between dose and pCR, and given that the data from dose level 3 met the statistical requirements, a dose of 25.5 Gy in 3 fractions should be used for the phase 2 trial., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Robotic stereotactic radioablation (RSR) allows stereotactic irradiation of thoracic tumors; however, it has never been used for breast tumors and may have a real potential. We conducted a Phase I study, including neoadjuvant chemotherapy (NACT), a two-level dose-escalation study (6.5 Gy x 3 fractions and 7.5 Gy x 3 fractions) using RSR and breast-conserving surgery followed by conventional radiotherapy., Materials and Methods: To define toxicity, we performed a dermatologic exam (DE) including clinical examination by two independent observers and technical examination by colorimetry, dermoscopy, and skin ultrasound. DE was performed before NACT (DE0), at 36 days (DE1), at 56 days (DE2), after the NACT treatment onset, and before surgery (DE3). Surgery was performed 4-8 weeks after the last chemotherapy session. A pathologic examination was also performed., Results: There were two clinical complete responses and four clinical partial responses at D56 and D85. Maximum tolerable dose was not reached. All patients tolerated RSR with no fatigue; 2 patients presented with mild pain after the third fraction of the treatment. There was no significant toxicity measured with ultrasound and dermoscopy tests. Postoperative irradiation (50 Gy) has been delivered without toxicity., Conclusion: The study showed the feasibility of irradiation with RSR combined with chemotherapy and surgery for breast tumors. There was no skin toxicity at a dose of 19.5 Gy or 22.5 Gy delivered in three fractions combined with chemotherapy. Lack of toxicity suggested that the dose could be increased further. Pathologic response was acceptable.

Purpose: Brain tumor radiotherapy requires the volume measurements and the localization of several individual brain structures. Any tool that can assist the physician to perform the delineation would then be of great help. Among segmentation methods, those that are atlas-based are appealing because they are able to segment several structures simultaneously, while preserving the anatomy topology. This study aims to evaluate such a method in a clinical context., Methods and Materials: The brain atlas is made of two three-dimensional (3D) volumes: the first is an artificial 3D magnetic resonance imaging (MRI); the second consists of the segmented structures in this artificial MRI. The elastic registration of the artificial 3D MRI against a patient 3D MRI dataset yields an elastic transformation that can be applied to the labeled image. The elastic transformation is obtained by minimizing the sum of the square differences of the image intensities and derived from the optical flow principle. This automatic delineation (AD) enables the mapping of the segmented structures onto the patient MRI. Parameters of the AD have been optimized on a set of 20 patients. Results are obtained on a series of 6 patients' MRI. A comprehensive validation of the AD has been conducted on performance of atlas-based segmentation in a clinical context with volume, position, sensitivity, and specificity that are compared by a panel of seven experimented physicians for the brain tumor treatments., Results: Expert interobserver volume variability ranged from 16.70 cm(3) to 41.26 cm(3). For patients, the ratio of minimal to maximal volume ranged from 48% to 70%. Median volume varied from 19.47 cm(3) to 27.66 cm(3) and volume of the brainstem calculated by AD varied from 17.75 cm(3) to 24.54 cm(3). Medians of experts ranged, respectively, for sensitivity and specificity, from 0.75 to 0.98 and from 0.85 to 0.99. Median of AD were, respectively, 0.77 and 0.97. Mean of experts ranged, respectively, from 0.78 to 0.97 and from 0.86 to 0.99. Mean of AD were, respectively, 0.76 and 0.97., Conclusions: Results demonstrate that the method is repeatable, provides a good trade-off between accuracy and robustness, and leads to reproducible segmentation and labeling. These results can be improved by enriching the atlas with the rough information of tumor or by using different laws of deformation for the different structures. Qualitative results also suggest that this method can be used for automatic segmentation of other organs such as neck, thorax, abdomen, pelvis, and limbs.

Purpose: To evaluate early and late reactions, local control, disease-free survival, cause-specific survival, and overall survival of elderly breast cancer patients treated with adjuvant once-weekly hypofractionated radiotherapy (RT)., Methods and Materials: Between 1987 and 1999, 150 patients (median age, 78 years) who presented with 151 nonmetastatic breast tumors were treated with surgery and then adjuvant hypofractionated RT. The clinical stage distribution was as follows: T1 in 47.7%, T2 in 43.2%, T3 in 6.1%, and T4 in 3.0%. Axillary lymph nodes were positive in 33.8% of cases. Estrogen receptors were present in 89.9%, and progesterone receptors in 77.3%. Conservative breast surgery was performed in 71.5% and total mastectomy in 28.5%. RT was delivered once weekly in five fractions of 6.5 Gy to a total dose of 32.5 Gy. A boost was delivered to the tumor bed in 33.1%. Adjuvant hormonal therapy was given in 76.2% of patients. The median follow-up was 65 months., Results: The Kaplan-Meier rate of all grades of early skin reactions was 26.5%, and the rate of all late reactions was 45.5%, mainly Grades 1 and 2. Early and late reactions were greater in those who underwent boost RT. The long-term local recurrence rate was 2.3%. The 5-year and 10-year disease-free survival rate was 80% and 71.5%, respectively. The corresponding rates for cause-specific survival were 89.1% and 77.6%. The 5-year and 10-year overall survival rate was 71.6% and 46.5%, respectively. These endpoints were influenced by tumor size, lymph node status, and hormone receptor status to varying degrees; however, tumor size appeared to be a major determinant on multivariate analysis., Conclusions: This hypofractionated RT scheme resulted in mild early reactions and acceptable late toxicity, in addition to providing excellent long-term local control. It can be proposed to patients who would have difficulties sustaining daily treatment because of old age or disabling associated disease.

Purpose: To present the first results of uveal melanomas treated with the Medicyc Cyclotron 65 MeV proton beam facility in Nice, analyzing the factors that affect the cause-specific survival (CSS), metastatic rate, and reporting the visual outcome., Methods and Materials: This study concerns 538 patients referred by French institutions between June 1991 and December 1996. The eye and tumor parameters were measured using ultrasonography and angiography. Since 1994, CT scans were performed in most patients to help determine the axial length and the shape of the ocular globe. Tantalum clips were inserted around the tumor by the referring ophthalmologist. There were 349 posterior pole tumors (64.9%), 130 equatorial tumors (24.1%), and 59 ciliary body tumors (11%). Two hundred four patients (37.9%) had T1 or T2 tumors, and 334 patients (62.1%) had T3 or T4 tumors. The median tumor diameter was 14.6 mm, and the median tumor height was 5.1 mm. All patients received 52 Gy (57.20 Gy Co-equivalent dose) on 4 consecutive days. The data were analyzed by December 1997., Results: The CSS was 77.4% at 78 months, the overall survival was 73.8% and the local control was 89.0%. The CSS was not influenced by the patient age or the site of the tumor. It was 81.5% for T1 and T2 tumors, versus 75% for T3 and T4 tumors (P = 0.035). It was found that the tumor diameter, rather than the height, was the most important parameter affecting outcome. The metastatic rate was 8%. It depended on the T stage, tumor diameter and thickness, but not the tumor site. Thirty-eight enucleations were performed, most of them due to tumor progression and/or glaucoma. One-third of the patients in whom visual acuity was adequately scored before and after treatment had a stable, if not improved vision, and half the patients retained useful vision after treatment., Conclusion: The outcome of patients suffering from uveal melanoma and treated with high-energy protons compares favorably with other techniques of treatment. The tumor dimensions affected CSS and metastatic rate. Even though two-thirds of patients had posterior pole tumors, half of them retained useful vision.

Purpose: The aim of this phase II study conducted on unresectable squamous cell carcinoma (USCC) of the oro- and hypopharynx was to associate twice-a-day (b.i.d.) continuous nonaccelerated radiotherapy with concomitant cisplatin (CP)-5-fluorouracil (5-FU) chemotherapy, both given at full dose. Feasibility, efficacy, survival, and pharmacokinetic-pharmacodynamic relationships were analyzed., Methods and Materials: Fifty-four consecutive patients with strictly USCC of oro- and/or hypopharynx received continuous b.i.d. radiotherapy (RT) (2 daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total RT dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Three chemotherapy (CT) courses of CP-5-FU were given during RT at 21-day intervals (third not delivered after the end of RT). CP dose was 100 mg/m2 (day 1) and 5-FU was given as 5-day continuous infusion (day 2-day 6: 750 mg/m2/day cycle 1, 750 mg total dose/day cycle 2 and 3). Pharmacokinetics was performed for 5-FU (105 h follow-up) and CP (single sample at 16 h). Special attention was paid to supportive care., Results: Good feasibility of RT was observed (85.2% of patients with total dose > 75 Gy). Five patients received 1 CT cycle, 34: 2 cycles, and 15: 3 cycles. The most frequent and severe acute toxicities were mucositis with grade 3-4 occurring in 28% at cycle 1 and 86% at cycle 2, as well as neutropenia (43% at cycle 2). Locoregional control at 6 months was observed in 66.7% of patients. No late toxicity above grade 2 RTOG was noticed. CP dose and 5-FU AUC(0-105h) were significantly linked to grade 3-4 neutropenia (cycle 2). Cumulative total platinum (Pt) concentration and Karnofsky index were the only independent predictors of locoregional control at 6 months. Finally, total RT dose and total Pt concentration were the only independent predictors of specific survival., Conclusion: This protocol showed good locoregional response with an acceptable toxicity profile. Pharmacokinetic survey is probably an effective approach to further reduce toxicity and improve efficacy. A multicentric randomized phase III study, now underway, should confirm these encouraging results.

Although most institutions treat all fields each day, some radiotherapists continue to adopt an alternate day schedule. The resulting daily variations of the dose per fraction in laterally located targets have been analyzed using the linear-quadratic model. Patients with breast carcinoma treated with definitive radiotherapy in 1974-1975 with one field a day were studied. An effective dose per fraction was derived, with a value higher than the average dose per fraction received by the reference point. The greater the fluctuations between the doses per fraction on successive days, the higher the effective dose per fraction. The corresponding cell survival due to alternate treatment as compared to survival with daily treatment depends on the alpha/beta ratio. For a late effect with low alpha/beta ratio, an alternate treatment may lead to almost 10-fold increase in cell kill in these lateral targets such as those responsible for subcutaneous sclerosis as compared to daily treatment of all fields with the same total dose. Taking the average effective dose per fraction in our series, the increase in cell kill was 4-fold. Acute effects would suffer less damage due to alternate treatment because of a high alpha/beta ratio. Treatment on an alternate schedule should be restricted to palliative radiotherapy.