Cosmetic Results and Side Effects of Accelerated Partial-Breast Irradiation Versus Whole-Breast Irradiation for Low-Risk Invasive Carcinoma of the Breast: The Randomized Phase III IRMA Trial.

PURPOSE: The results in terms of side effects vary among the published accelerated partial-breast irradiation (APBI) studies. Here, we report the 5-year results for cosmetic outcomes and toxicity of the IRMA trial. METHODS: We ran this randomized phase III trial in 35 centers. Women with stage I-IIA breast cancer treated with breast-conserving surgery, age ≥ 49 years, were randomly assigned 1:1 to receive either whole-breast irradiation (WBI) or external beam radiation therapy APBI (38.5 Gy/10 fraction twice daily). Patients and investigators were not masked to treatment allocation. The primary end point was ipsilateral breast tumor recurrence. We hereby present the analysis of the secondary outcomes, cosmesis, and normal tissue toxicity. All side effects were graded with the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Radiation Morbidity Scoring Schema. Analysis was performed with both intention-to-treat and as-treated approaches. RESULTS: Between March 2007 and March 2019, 3,309 patients were randomly assigned to 1,657 WBI and 1,652 APBI; 3,225 patients comprised the intention-to-treat population (1,623 WBI and 1,602 APBI). At a median follow-up of 5.6 (interquartile range, 4.0-8.4) years, adverse cosmesis in the APBI patients was higher than that in the WBI patients at 3 years (12.7% v 9.2%; P = .009) and at 5 years (14% v 9.8%; P = .012). Late soft tissue toxicity (grade ≥ 3: 2.8% APBI v 1% WBI, P < .0001) and late bone toxicity (grade ≥ 3: 1.1% APBI v 0% WBI, P < .0001) were significantly higher in the APBI arm. There were no significant differences in late skin and lung toxicities. CONCLUSION: External beam radiation therapy-APBI with a twice-daily IRMA schedule was associated with increased rates of late moderate soft tissue and bone toxicities, with a slight decrease in patient-reported cosmetic outcomes at 5 years when compared with WBI, although overall toxicity was in an acceptable range.

Comparing hypofractionated and conventionally fractionated whole breast irradiation for patients with ductal carcinoma in situ after breast conservation: a propensity score-matched analysis from a national multicenter cohort (COBCG-02 study).

BACKGROUND AND PURPOSE: Randomized trials confirmed the efficacy and the safety of hypofractionated whole breast irradiation (HF-WBI) in patients with early-stage breast cancer. However, the role of HF-WBI in patients with DCIS after breast conserving surgery has not yet been clearly established in prospective randomized trials. The aim of this study was to evaluate if HF-WBI can be considered comparable to conventionally fractionated (CF)-WBI in DCIS patients. MATERIALS AND METHODS: The analysis included DCIS patients from four Italian centers treated with CF-WBI 50 Gy/25 fractions or HFRT 40.5 Gy/15 fractions, without tumor bed boost. A propensity score matching (PSM) analysis was performed using a logistic regression that considered age, grading, presence of necrosis, resection margin status and adjuvant endocrine therapy. RESULTS: Five hundred twenty-seven patients was included (367 in the CF-WBI-group and 160 in the HR-WBI group). After 1:1 matching, 101 patients were allocated to the CF-WBI-group and 104 to the HF-WBI group. No correlation was observed between the type of RT schedule and LRFS (HR 1.68, 95% CI 0.82-3.45; p = 0.152). After PSM, no statistical difference was observed between the two RT group (HR 1.11, 95% CI 0.40-3.04; p = 0.833), with 3- and 5-years LRFS rates of 100% and 97.9% for CF-WBI and 95.6% and 94% for HF-WBI. CONCLUSION: A short course of radiation therapy seems to be comparable to CF-WBI in terms of clinical outcomes. These data support the use of hypofractionated schedules in DCIS patients, but considering the remaining uncertainties.

Evaluation of the effectiveness of novel single-intervention adaptive radiotherapy strategies based on daily dose accumulation.

Parotid gland (PG) shrinkage and neck volume reduction during radiotherapy of head and neck (H&N) cancer patients is a clinical issue that has prompted interest in adaptive radiotherapy (ART). This study focuses on the difference between planned dose and delivered dose and the possible effects of an efficient replanning strategy during the course of treatment. Six patients with H&N cancer treated by tomotherapy were retrospectively enrolled. Thirty daily dose distributions (DMVCT) were calculated on pretreatment megavoltage computed tomography (MVCT) scans. Deformable Image Registration which matched daily MVCT with treatment planning kilovoltage computed tomography was performed. Using the resulting deformation vector field, all daily DMVCT were deformed to the planning kilovoltage computed tomography and resulting doses were accumulated voxel per voxel. Cumulative DMVCT was compared to planned dose distribution performing γ-analysis (2 mm, 2% of 2.2 Gy). Two single-intervention ART strategies were executed on the 18th fraction whose previous data had suggested to be a suitable timepoint for a single replanning intervention: (1) replanning on the original target and deformed organ at risks (OARs) (a "safer" approach regarding tumor coverage) and (2) replanning on both deformed target and deformed OARs. DMVCT showed differences between planned and delivered doses (3D-γ 2mm/2%-passing rate = 85 ± 1%, p < 0.001). Voxel by voxel dose accumulation showed an increase in average dose of warped PG of 3.0 Gy ± 3.3 Gy. With ART the average dose of warped PG decreased by 3.2 Gy ± 1.7 Gy in comparison to delivered dose without replanning when both target and OARs were deformed. Average dose of warped PG decreased by 2.0 Gy ± 1.4 Gy when only OARs were deformed. Anatomical variations lead to increased doses to PGs. Efficient single-intervention ART-strategies with replanning on the 18th MVCT result a reduced PG dose. A strategy with deformation of both target and OAR resulted in the lowest PG dose, while formally maintaining PTV coverage. Deformation of only OAR nevertheless reduces PG dose and has less uncertainties regarding PTV coverage.

Expert system classifier for adaptive radiation therapy in prostate cancer.

A classifier-based expert system was developed to compare delivered and planned radiation therapy in prostate cancer patients. Its aim is to automatically identify patients that can benefit from an adaptive treatment strategy. The study predominantly addresses dosimetric uncertainties and critical issues caused by motion of hollow organs. 1200 MVCT images of 38 prostate adenocarcinoma cases were analyzed. An automatic daily re-contouring of structures (i.e. rectum, bladder and femoral heads), rigid/deformable registration and dose warping was carried out to simulate dose and volume variations during therapy. Support vector machine, K-means clustering algorithms and similarity index analysis were used to create an unsupervised predictive tool to detect incorrect setup and/or morphological changes as a consequence of inadequate patient preparation due to stochastic physiological changes, supporting clinical decision-making. After training on a dataset that was considered sufficiently dosimetrically stable, the system identified two equally sized macro clusters with distinctly different volumetric and dosimetric baseline properties and defined thresholds for these two clusters. Application to the test cohort resulted in 25% of the patients located outside the two macro clusters thresholds and which were therefore suspected to be dosimetrically unstable. In these patients, over the treatment course, mean volumetric changes of 30 and 40% for rectum and bladder were detected which possibly represents values justifying adjustment of patient preparation, frequent re-planning or a plan-of-the-day strategy. Based on our research, by combining daily IGRT images with rigid/deformable registration and dose warping, it is possible to apply a machine learning approach to the clinical setting obtaining useful information for a decision regarding an individualized adaptive strategy. Especially for treatments influenced by the movement of hollow organs, this could reduce inadequate treatments and possibly reduce toxicity, thereby increasing overall RT efficacy.

SIS epidemiological model for adaptive RT: Forecasting the parotid glands shrinkage during tomotherapy treatment.

PURPOSE: A susceptible-infected-susceptible (SIS) epidemic model was applied to radiation therapy (RT) treatments to predict morphological variations in head and neck (H&N) anatomy. METHODS: 360 daily MVCT images of 12 H&N patients treated by tomotherapy were analyzed in this retrospective study. Deformable image registration (DIR) algorithms, mesh grids, and structure recontouring, implemented in the RayStation treatment planning system (TPS), were applied to assess the daily organ warping. The parotid's warping was evaluated using the epidemiological approach considering each vertex as a single subject and its deformed vector field (DVF) as an infection. Dedicated IronPython scripts were developed to export daily coordinates and displacements of the region of interest (ROI) from the TPS. matlab tools were implemented to simulate the SIS modeling. Finally, the fully trained model was applied to a new patient. RESULTS: A QUASAR phantom was used to validate the model. The patients' validation was obtained setting 0.4 cm of vertex displacement as threshold and splitting susceptible (S) and infectious (I) cases. The correlation between the epidemiological model and the parotids' trend for further optimization of alpha and beta was carried out by Euclidean and dynamic time warping (DTW) distances. The best fit with experimental conditions across all patients (Euclidean distance of 4.09 ± 1.12 and DTW distance of 2.39 ± 0.66) was obtained setting the contact rate at 7.55 ± 0.69 and the recovery rate at 2.45 ± 0.26; birth rate was disregarded in this constant population. CONCLUSIONS: Combining an epidemiological model with adaptive RT (ART), the authors' novel approach could support image-guided radiation therapy (IGRT) to validate daily setup and to forecast anatomical variations. The SIS-ART model developed could support clinical decisions in order to optimize timing of replanning achieving personalized treatments.

Radiosurgery Using Tomotherapy for Patients with Brain Oligo-metastasis: A Retrospective Analysis on Feasibility and Tolerance.

AIM: Aim of the study was to evaluate feasibility and toxicities of exclusive radiosurgery using tomotherapy in patients with brain oligo-metastases. PATIENTS AND METHODS: Between 2008 and 2013 68 patients underwent stereotactic radiosurgery (SRS). Mean patient age was 63 years. Brain was the only site involved in 32 patients, while 36 had extracranial disease. Pre-SRS MRI 56 patients had sovratentorial lesions, 10 subtentorial and 2 patients had both. Fifty-two patients had 1 brain lesion, 11 had 2, and 5 patients had three. All patients underwent SRS using Tomotherapy. The median delivered dose was 18 Gy. RESULTS: After a mean follow-up of 13 months, 14 patients were alive, while 54 patients had died. Two patients had complete response, 32 had partial response, 21 stable disease and 13 disease progression. Overall response rate was 80.9%. One- and two-year overall survival were 41,2% and 24,7%, while local control 61.5% and 37.7%. Toxicity was acceptable. CONCLUSION: SRS using tomotherapy has been proven feasible as non-invasive exclusive treatment for oligometastatic patients with good prognostic score.

Survival in patients with newly diagnosed conventional glioblastoma: a modified prognostic score based on a single-institution series.

AIMS AND BACKGROUND: Recursive partioning analysis (RPA) is commonly used to define the stratification of patients with glioblastoma. Epigenetic silencing of the O6-methylguanine methyltransferase (MGMT) gene by promoter methylation plays an important role in regulating MGMT expression in gliomas and this is an established independent prognostic factor. We tested a prognostic scoring system including all clinical variables used by RPA classification (age, ECOG performance status and type of surgery) and MGMT gene promoter methylation status. METHODS: Seventy-eight consecutive patients with newly diagnosed, histopathologically confirmed conventional glioblastoma were included. Information about MGMT promoter methylation status was available for all of them. Based on the patients' age (<50 vs ≥50 years), ECOG performance status (0 vs ≥1), type of surgery (gross tumor resection versus partial resection/biopsy) and MGMT promoter methylation status (methylated versus unmethylated), three classes of risk were generated where the prognostic score was defined assigning 1 point to every favorable parameter (Class I: ≥3; Class II: 2; Class III: 0-1). All classes were correlated with overall survival. RESULTS: The median survival times were 32.4, 8.6 and 8.8 months for Class I, II and III, respectively, corresponding to 2-year survival rates of 69%, 13.5% and <1%. The same analysis was performed on 54 patients treated with postoperative concomitant chemoradiotherapy. The median survival times were 32.5, 13.4 and 8.9 months for Class I, II and III, respectively, corresponding to 2-year survival rates of 68.6%, 26.9% and <1%. In both groups of 78 and 54 patients the differences in survival between Class I and III were statistically significant ( P <0.0001). CONCLUSIONS: The proposed prognostic scoring system including clinical variables and MGMT promoter methylation status proved valuable in patients with primary conventional glioblastoma, especially those treated with postoperative chemoradiotherapy.

Pancreatic metastases from renal cell carcinoma: the state of the art.

Pancreatic metastases are rare, with a reported incidence varying from 1.6% to 11% in autopsy studies of patients with advanced malignancy. In clinical series, the frequency of pancreatic metastases ranges from 2% to 5% of all pancreatic malignant tumors. However, the pancreas is an elective site for metastases from carcinoma of the kidney and this peculiarity has been reported by several studies. The epidemiology, clinical presentation, and treatment of pancreatic metastases from renal cell carcinoma are known from single-institution case reports and literature reviews. There is currently very limited experience with the surgical resection of isolated pancreatic metastasis, and the role of surgery in the management of these patients has not been clearly defined. In fact, for many years pancreatic resections were associated with high rates of morbidity and mortality, and metastatic disease to the pancreas was considered to be a terminal-stage condition. More recently, a significant reduction in the operative risk following major pancreatic surgery has been demonstrated, thus extending the indication for these operations to patients with metastatic disease.