Long term update on toxicity and survival of a phase II trial of linac-based stereotactic body radiation therapy for low-intermediate risk prostate cancer.

BACKGROUND: In 2016 we published a phase II study exploring safety and efficacy of Stereotactic Body Radiation Therapy (SBRT) delivered with Volumetric Modulated Arc Therapy (VMAT) and Flattening Filter Free (FFF) beams techniques in prostate cancer (PC) patients. We present herein the updated results on late toxicity and long-term survival. METHODS: Patients enrolled in the study had a biopsy-confirmed localized PC and the features of a low- or intermediate-risk disease (National Comprehensive Network Criteria). The radiotherapy (RT) schedule consisted of 35 Gy delivered in five fractions every other day. Toxicities were registered according to the common toxicity adverse events v4.0. Biochemical recurrence was defined as an increase of prostate specific antigen after nadir, confirmed at least once. Local recurrence (LR) and distant metastases were detected either with Choline- or PSMA-PET/CT scans. Kaplan-Meier curves for Biochemical Recurrence-Free Survival (BFS), Local Control (LC), Distant Metastasis Free Survival (DMFS) and Cancer Specific Survival, were calculated by using MedCalc. RESULTS: Ninety patients were submitted to SBRT between February 2012 and March 2015. Fifty-eight patients (64.5%) had a Gleason Score of 6, while 32 (35.5%) had a Gleason Score of 7. A late grade 1 Genito-Urinary toxicity was observed in 54.5% of patients while a grade 2 in 3.3%. A late Gastro-intestinal grade 1 toxicity was reported in 18.9% of patients, while a grade 2 in 2.2%. Erectile dysfunction was reported by 13% of patients No heavier toxicities were observed. At a median follow-up of 102 months, 5- and 8-year BFS were 93.0% and 84.4% respectively, 5- and 8-year LC were 95.2% and 87.0% respectively, 5- and 8-year DMFS were 95.3% and 88.4%, respectively. CONCLUSIONS: This long-term update confirms that SBRT is a valid therapeutic strategy for low-intermediate risk PC. RT with VMAT and FFF warrants optimal results in terms of toxicity and disease control.

Efficacy of stereotactic body radiotherapy and response prediction using artificial intelligence in oligometastatic gynaecologic cancer.

PURPOSE: We present a large real-world multicentric dataset of ovarian, uterine and cervical oligometastatic lesions treated with SBRT exploring efficacy and clinical outcomes. In addition, an exploratory machine learning analysis was performed. METHODS: A pooled analysis of gynecological oligometastases in terms of efficacy and clinical outcomes as well an exploratory machine learning model to predict the CR to SBRT were carried out. The CR rate following radiotherapy (RT) was the study main endpoint. The secondary endpoints included the 2-year actuarial LC, DMFS, PFS, and OS. RESULTS: 501 patients from 21 radiation oncology institutions with 846 gynecological metastases were analyzed, mainly ovarian (53.1%) and uterine metastases(32.1%).Multiple fraction radiotherapy was used in 762 metastases(90.1%).The most frequent schedule was 24 Gy in 3 fractions(13.4%). CR was observed in 538(63.7%) lesions. The Machine learning analysis showed a poor ability to find covariates strong enough to predict CR in the whole series. Analyzing them separately, in uterine cancer, if RT dose≥78.3Gy, the CR probability was 75.4%; if volume was <13.7 cc, the CR probability became 85.1%. In ovarian cancer, if the lesion was a lymph node, the CR probability was 71.4%; if volume was <17 cc, the CR probability rose to 78.4%. No covariate predicted the CR for cervical lesions. The overall 2-year actuarial LC was 79.2%, however it was 91.5% for CR and 52.5% for not CR lesions(p < 0.001). The overall 2-year DMFS, PFS and OS rate were 27.3%, 24.8% and 71.0%, with significant differences between CR and not CR. CONCLUSIONS: CR was substantially associated to patient outcomes in our series of gynecological cancer oligometastatic lesions. The ability to predict a CR through artificial intelligence could also drive treatment choices in the context of personalized oncology.

Oligoscore: a clinical score to predict overall survival in patients with oligometastatic disease treated with stereotactic body radiotherapy.

BACKGROUND: to find clinical features that can predict prognosis in patients with oligometastatic disease treated with stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: Patients with less than 5 metastases in less than 3 different body sites were included in the analysis. Various clinical and treatment parameters were analyzed to create a Cox proportional hazard model for Overall Survival (OS). Subsequently, significant variables were used to create a score. RESULTS: 997 patients were analyzed. Median OS was 2.61 years, 1 and 3 years OS was respectively 85% and 43%. Location of the primary tumor, performance status, site of irradiated metastases, presence of extratarget non irradiated lesions and RT dose were significant prognostic factors for OS. These parameters were used to create a score and to distinguish three different classes, with median OS of 5.67 years in low risk, 2.47 years in intermediate risk and 1.82 years in high risk group. CONCLUSION: moving from easily accessible clinical parameters, a score was created to help the physician's decision about the better treatment or combination of treatments for the individual patient.

Stereotactic Body Radiation Therapy for Intermediate-risk Prostate Cancer With VMAT and Real-time Electromagnetic Tracking: A Phase II Study.

OBJECTIVES: Stereotactic body radiation treatment represents an intriguing therapeutic option for patients with early-stage prostate cancer. In this phase II study, stereotactic body radiation treatment was delivered by volumetric modulated arc therapy with flattening filter free beams and was gated using real-time electromagnetic transponder system to maximize precision of radiotherapy and, potentially, to reduce toxicities. MATERIALS AND METHODS: Patients affected by histologically proven prostate adenocarcinoma and National Comprehensive Cancer Network (NCCN) intermediate class of risk were enrolled in this phase II study. Beacon transponders were positioned transrectally within the prostate parenchyma 7 to 10 days before simulation computed tomography scan. The radiotherapy schedule was 38 Gy in 4 fractions delivered every other day. Toxicity assessment was performed according to Common Terminology Criteria for Adverse Events (CTCAE), v4.0. RESULTS: Thirty-six patients were enrolled in this study. Median initial prostate-specific antigen was 7.0 ng/mL (range: 2.3 to 14.0 ng/mL). Median nadir-prostate-specific antigen after treatment was 0.2 ng/mL (range: 0.006 to 4.8 ng/mL). A genitourinary acute toxicity was observed in 21 patients (dysuria grade [G] 1: 41.7%, G2: 16.7%). Gastrointestinal acute toxicity was found in 9 patients (proctitis G1: 19.4%, G2: 5.6%). Late toxicity was mild (genitourinary toxicity G1: 30.6%; G2: 8.3%; gastrointestinal toxicity G1: 13.9%; G2: 19.4%). At a median follow-up time of 41 months, 3 biochemical recurrences were observed (2 local recurrences, 1 distant metastasis). Three-year biochemical recurrence-free survival was 89.8% (International Society of Urologic Pathology Grade Group 2: 100%, Grade Group 3: 77.1%, P=0.042). CONCLUSION: Ultrahypofractionated radiotherapy, delivered with flattening filter free-volumetric modulated arc therapy and gated by electromagnetic transponders, is a valid option for intermediate-risk prostate cancer.

Volumetric Modulated Arc Therapy After Lung Sparing Surgery for Malignant Pleural Mesothelioma: A Single Institution Experience.

INTRODUCTION: We investigated the possible role of volumetric modulated arc therapy (VMAT) in the setting of adjuvant treatment of malignant pleural mesothelioma (MPM) after lung-sparing surgery with pleurectomy and decortication. MATERIALS AND METHODS: Patients affected by MPM who had undergone pleurectomy and decortication and adjuvant radiotherapy with VMAT were included. The endpoints of the present analysis were local control, progression-free survival, and overall survival. Assessment of the variables affecting survival was performed using univariate and multivariate Cox proportional hazard models. RESULTS: A total of 49 patients were included in the present study. Of the 49 patients, 96% had been treated with a trimodality approach. Radiotherapy was delivered to a median dose of 44 Gy in 22 fractions (range, 22-59.4 Gy). The treatment was well tolerated, with just 2 grade 3 acute toxicities, 1 grade 5, and 2 grade 4 toxicities recorded during the follow-up period. The median follow-up period was 27.4 months. The local control rate at 12, 24, and 36 months was 75.2%, 67.4%, and 56.5%, respectively. The median progression-free survival was 14.9 months (95% confidence interval [CI], 7.5-25.2). The median overall survival was 21.5 months (95% CI, 15.3-37.1). On multivariate analysis, the administration of carboplatin- instead of cisplatin-based chemotherapy (hazard ratio, 2.97; 95% CI, 1.22-7.26; P = .017) and R2 resection (hazard ratio, 1.95; 95% CI, 1.27-2.99; P = .002) showed a negative correlation with overall survival. On univariate analysis, the percentage of the heart receiving >20 Gy and >30 was associated with the occurrence of late pneumonitis (P = .018 and P = .077). CONCLUSION: VMAT is feasible in the setting of MPM after lung-sparing surgery. The toxicity rates were reduced with this technique compared with historical data of older techniques. Local and distant failure remain a major issue to be addressed in future trials.

Hypofractionated Whole Breast Irradiation and Simultaneous Integrated Boost in Large-breasted Patients: Long-term Toxicity and Cosmesis.

INTRODUCTION: The purpose of this study was to evaluate the impact of breast size on long-term toxicity and cosmesis in patients with breast cancer treated with hypofractionated simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT). PATIENTS AND METHODS: Patients with early stage breast cancer were treated with 3-week hypofractionated SIB-VMAT to the whole breast (40.5 Gy) and tumor bed (48 Gy). Two cohorts were identified: small/medium- (< 1000 cm3) and large- (> 1000 cm3) breasted patients. Acute and late (at 2 and 5 years) skin toxicity and cosmetic data were analyzed. Univariate and multivariate analysis evaluated associations between toxicity and dosimetric/anatomical variables. RESULTS: From August 2010 to March 2017, a total of 1160 patients were treated; 831 had at least 2 years of follow-up and were analyzed. Treated skin area (TSA) receiving at least 20 Gy > 400 cm2 and V105% of Boost > 5 cm3 were significant predictors for acute skin toxicity. Multivariate analysis at 2 years was significant for boost volume > 70 cm3, TSA > 400 cm2, and breast size > 1500 cm3. At 5 year analysis (352 patients), none of the analyzed variables was significant. For cosmetic outcome, only the breast size (> 1000 cm3) and the boost size > 70 cm3 at 2 and 5 years, respectively, confirmed significance. CONCLUSIONS: The TSA > 400 cm2 resulted as a significant predictor of both acute and late skin toxicity at 2 years; however, at 5 years, no breast size or dosimetric parameter suggested indications for increased toxicity. A worse cosmetic outcome was recorded at the 2-year follow up for large breasts, but was not confirmed at the 5-year follow-up. These long-term data suggest that hypofractionated SIB-VMAT is a viable modality also in large-breasted patients.

Intra-operative radiotherapy (IORT) in pancreatic cancer: joint analysis of the ISIORT-Europe experience.

PURPOSE: A joint analysis of data from five contributing centers within the ISIORT-Europe program was performed to investigate the main contributions of intra-operative radiotherapy (IORT) to the multidisciplinary treatment of pancreatic cancer. MATERIALS AND METHODS: Patients with a histologic diagnosis of carcinoma of the pancreas, with an absence of distant metastases, undergoing surgery with radical intent and IORT were considered eligible for participation in this study. RESULTS: From 1985 to 2006, a total of 270 patients were enrolled in the study from five European institutions. Surgery was performed in 91.5% of cases and complicated by adverse events in 59 cases. External radiotherapy (ERT) preceded surgery in 23.9% of cases. One-hundred and six patients received further ERT. After surgery + IORT, median follow-up was 96 months (range 3-180). Median local control was 15 months, 5-year local control was 23.3%. Median overall survival was 19 months, while 5-year survival was 17.7%. A significantly greater local control and survival were observed in patients undergoing preoperative radiotherapy (LC: median not reached; OS: median 30 months) compared to patients treated with postoperative ERT alone (LC: median 28 months; OS: median 22 months), and to patients submitted to IORT exclusively (LC: median 8 months; OS: median 13 months) (p < 0.0001). CONCLUSION: From this joint analysis emerges the fact that preoperative radiotherapy increases the effects of IORT in terms of local control and overall survival. The 5-year local control of 23.3% confirms the beneficial "sterilizing" effect of IORT on the tumor bed.

Role of 11C-choline PET/CT in radiation therapy planning of patients with prostate cancer.

BACKGROUND: In the era of image-guided radiotherapy, PET has become an important tool for tumor delineation in several types of cancer. The aim of this study was to evaluate the effect of this imaging modality in treatment planning of a cohort of patients with prostate cancer eligible for radiotherapy. METHODS: From September 2011 to January 2016, 135 consecutive patients (median age 69 years, range: 53-89) were referred to our department for radiation therapy with radical intent (n=28), for postoperative adjuvant (n=13) or salvage treatment (n=50), for re-irradiation (n=19), or for radiotherapy on oligometastases (n=25). Before planning the radiotherapy course, patients were submitted to carbon-11-choline PET (Cho-PET) to confirm the indication to radiotherapy and the irradiation volumes. RESULTS: Among the 135 patients subjected to Cho-PET, the indication to radiotherapy was modified in 66 (48.8%) cases based on the Cho-PET result. In particular, Cho-PET helped to better define the radiotherapy programme in 12 out of 28 (42.8%) patients who were candidates for primary radiation therapy, 33 (52.4%) of 63 patients undergoing adjuvant/salvage radiotherapy, and 21 out of 44 (47.7%) patients with relapsed/metastatic disease. Overall biochemical response is documented by mean and median prostate specific antigen values, which changed from 15.29 to 4.00 ng/ml, respectively, before to mean 4.74 ng/ml and median 0.81 ng/ml after therapy (P=0.05). CONCLUSION: In our series, Cho-PET had a significant effect on radiotherapy planning of patients affected by prostate cancer, determining a change in management in 48.8% of cases, considering all therapeutic indications.

Role of extra cranial stereotactic body radiation therapy in the management of Stage IV melanoma.

OBJECTIVE: To investigate the role of extracranial stereotactic body radiation therapy (SBRT) in the management of oligometastatic melanoma. METHODS: Patients affected by Stage IV melanoma, with less than three extracranial metastatic lesions, who received SBRT were included in this analysis. Acute and late toxicity, local control (LC), overall survival (OS) and progression-free survival (PFS) were analysed. RESULTS: 31 patients were included in the study. 16 patients (51.6%) were treated for lung meta-stases, 8 patients for liver metastases (25.8%) and 7 (22.6%) for nodal metastases. 38 lesions were irradiated. With a median follow-up time of 13 months, 11 patients (35.4%) were still alive, in four cases (12.9%) with no evidence of disease. Median OS was 10.6 months, and OS at 6, 12 and 24 months was 77, 41 and 21% respectively. LC at 12 and 24 months was 96.6 and 82.8%. 23 patients (74.2%) developed distant metastases. Median PFS was 5.8 months, and PFS at 6, 12 and 24 months was 48.2, 18.5 and 13.9% respectively. Number of irradiated lesions showed a statistically significant correlation only with LC (p = 0.03). Response of the irradiated lesion was related to OS (p = 0.019). Local response showed also a borderline correlation with PFS (p = 0.07). CONCLUSION: SBRT for extracranial metastases from melanoma is feasible and well tolerated. Response of the irradiated lesions is predictive of OS. Advances in knowledge: SBRT for melanoma extracranial metastases is feasible and the response of the irradiated lesions is predictive of OS.

Stereotactic/hypofractionated body radiation therapy as an effective treatment for lymph node metastases from colorectal cancer: an institutional retrospective analysis.

OBJECTIVE: The colorectal cancer (CRC) might present loco-regional recurrence, including lymph-node metastasis. Stereotactic body radiotherapy (SBRT) is a non-invasive and well-tolerated ablative treatment. Aim of the present study is to evaluate efficacy and toxicity of SBRT with volumetric modulated arc therapy (VMAT) in this setting. METHODS: 35 patients presenting a total of 47 nodal recurrences from CRC, treated with VMAT-SBRT from 2008 to 2015, were selected. About three fourth of the treatments delivered 45 Gy in 6 daily fractions. End-points were the detection of toxicities, overall survival (OS), local control (LC), disease progression free incidence (DPFI) and disease free survival (DFS). Tumour response was assessed according to the RECIST criteria. RESULTS: Only Grade 1 and 2 toxicities were recorded. Median follow-up was 15 months (range 2-68). Local relapse was reported in 6 patients, regional relapse in 10 patients. Complete remission was reported in 20 cases (53%), partial remission in 14 (37%). Rates of LC at 1, 2 and 3 years were 85.3, 75.0 and 75.0%, respectively. At 1 year the actuarial OS was 100%, at 2 and 3 years was 81.4%. Median DFS was estimated in 16 months, with an incidence of 69.4, 33.3 and 19.4% at 1, 2 and 3 years, respectively. CONCLUSION: The use of the VMAT-SBRT in lymph-node recurrence of CRC could prevent severe complications and achieve satisfying rates of disease control. Advances in knowledge: The use of VMAT-SBRT is a viable approach for lymph-node recurrence of CRC.

Reducing heart dose during left breast cancer radiotherapy: comparison among 3 radiation techniques.

PURPOSE: Breast cancer survivors have a high risk of cardiac death as a consequence of heart irradiation during left breast tangential radiotherapy (RT). This study compares the cardiac dose delivered by standard 3D conformal tangential RT (CRT) to that delivered by prospective-gating RT (PGRT) or 5-field intensity-modulated RT (IMRT). METHODS: Patients with early left breast cancer, referred for adjuvant RT to our institution, were enrolled in this study. For each patient, 2 simulation computed tomography scans were acquired: the first during free breathing, and the second on prospective gating during deep inspiration breath-hold. The scans were monitored by the Varian RPM™ respiratory gating system. For each patient, 3 treatment plans were performed: a 3D-CRT and an IMRT plan, each based on the free-breathing scan, and a PGRT plan, based on the deep inspiration breath-hold scan. Dose-volume histograms were compared by means of the Friedman test. RESULTS: The median mean heart dose was 3 Gy (range 0.9-7.3 Gy) in the CRT plans, 1.9 Gy (range 0.5-3.6 Gy) in the PGRT plans, and 4.5 Gy (range 1.1-10.5 Gy) in the IMRT plans (p = 0.001). The mean heart V25 was 1.2% (range 0%-9.7%), 0% (range 0%-2.0%), and 0.2% (range 0%-7.3%) for CRT, PGRT, and IMRT plans, respectively (p<0.001). CONCLUSIONS: Prospective-gating RT to the left breast offered the best protection of heart and lung, as well as a lower irradiation of the contralateral breast, compared to CRT or IMRT.

Neoadjuvant Chemoradiotherapy with Volumetric-modulated Arc Therapy for Medium-distal Oesophageal and Gastro-oesophageal Junction Carcinoma.

AIM: to appraise the role of volumetric-modulated arc therapy (VMAT) in the neoadjuvant chemoradiotherapy management of advanced medium and distal oesophageal cancer in terms of toxicity and response to treatment. PATIENTS AND METHODS: Thirty patients were treated according to the neoadjuvant chemoradiation followed by surgery versus surgery-alone trial scheme with VMAT radiation therapy. Patients presented mainly T3-T4 stage (80%) and N1-2 (96.6%) disease. The chemotherapy scheme consisted of 3-5 cycles, while a radiotherapy course of 41.4 Gy in 23 fractions was administered to all patients. RESULTS: The median age of patients was 65 years, and there was a predominance of males (80%), smokers or ex-smokers (90%) and modest alcohol habit (80% negative). Primary tumor localisation was in the medium and distal third of the oesophagus in 57% of the cases, the rest being in the gastro-oesophageal junction. Modest toxicity profiles were observed, with limited incidence of grade 2-3 events. Partial or complete response was observed in more than 90% of the cases (radiological/metabolic) and was confirmed after surgical intervention (67% partial or complete and 27% stable response). Tumor down-staging was recorded in 67% of patients and nodal down-staging in 50%. CONCLUSION: VMAT was applied in the context of neoadjuvant chemoradiotherapy for the treatment of medium and distal oesophageal carcinoma with satisfactory results in terms of tolerance and toxicity.

External beam radiotherapy plus 24-hour continuous infusion of gemcitabine in unresectable pancreatic carcinoma: long-term results of a phase II study.

PURPOSE: To evaluate the efficacy of gemcitabine-based chemoradiation (CT-RT) in treating patients (pts) affected by locally advanced pancreatic cancers (LAPC). METHODS AND MATERIALS: Weekly gemcitabine (100 mg/m(2)) was given as a 24-hour infusion during the course of three-dimensional radiotherapy (50.4 Gy to the tumor, 39.6 Gy to the nodes). After CT-RT, pts received five cycles of sequential chemotherapy with gemcitabine (1000 mg/m(2); 1, 8, q21). Response rate was assessed according to World Health Organization criteria 6 weeks after the end of CT-RT. Local control (LC), time to progression (TTP), metastases-free survival (MFS), and overall survival (OS) were analyzed by the Kaplan Meier method. RESULTS: Forty pts (male/female 22/18; median age 62 years, range, 36-76) were treated from 2000 to 2005. The majority had T4 tumour (n = 34, 85%), six pts (15%) had T3 tumour. Sixteen pts (40%) were node positive at diagnosis. Grade 3-4 acute toxicity was observed in 21 pts (52.5%). Thirty pts (75%) completed the treatment schedule. A clinical response was achieved in 12 pts (30%). With a median follow-up of 76 months (range, 32-98), 2-year LC was 39.6% (median, 12 months), 2-year TTP was 18.4% (median, 10 months), and 2-year MFS was 29.7% (median, 10 months). Two-year OS (25%; median, 15.5 months) compared with our previous study on 5-fluorouracil-based CT-RT (2.8%) was significantly improved (p <0.001). CONCLUSIONS: Gemcitabine CT-RT seems correlated with improved outcomes. Healthier patients who are likely to complete the treatment schedule may benefit most from this therapy.