Description: Publication date: Available online 29 June 2018 Source: Radiotherapy and Oncology Author(s): Matthias Müller, Yimin Wang, Michael R. Squillante, Kathryn D. Held, R. Rox Anderson, Martin Purschke Background and purpose Radiation therapy is the gold standard treatment for inoperable malignant tumors. However, due to the heterogeneity of the tumor, some regions are more radio resistant and can lead to metastasis and tumor recurrence. In this study, we propose combining traditional X-ray treatment with UVC-emitting LuPO 4 :Pr 3+ nanoparticles (NPs) to increase the tumor control as well as to reduce tumor recurrence and metastasis. These NPs convert ionizing radiation into UVC-photons (UVC range: 200–280 nm) locally at the tumor site. Unlike X-ray, UVC-photons damage DNA directly via an oxygen-independent mechanism, which could improve treatment of radioresistant tumors such as hypoxic tumors. Materials and methods The effect of X-ray generated UVC-photons was tested on human fibroblasts incubated with NPs prior to radiation treatment. The surviving fraction of the cells was assessed by means of colony formation assay. Experiments were performed on normal and UVC sensitive cell lines to demonstrate the presence of UVC photons during treatment. In addition, UV-specific DNA damages were investigated using an immunofluorescence assay to measure cyclopyrimidine dimers (CPDs). Results Combined treatment showed an increased cell death of over 50%, compared to radiation alone. This results in a dose equivalent of 4 Gy for the combined treatment with 2 Gy irradiation. The formation of CPDs and the increased effect on UV sensitive cells indicate the presence of UV photons. The generated amount of CPDs is comparable to an UVC exposure of about 15 J × m −2 . Conclusion Combining NPs with ionizing radiation results in a localized dose surge, which could increase tumor control. It could also allow lowering the total applied dose to minimize unwanted side effects to the surrounding normal tissue while maintaining tumor control.

Description: Publication date: Available online 30 June 2018 Source: Radiotherapy and Oncology Author(s): Ben Heijmen, Peter Voet, Dennie Fransen, Joan Penninkhof, Maaike Milder, Hafid Akhiat, Pierluigi Bonomo, Marta Casati, Dietmar Georg, Gregor Goldner, Ann Henry, John Lilley, Frank Lohr, Livia Marrazzo, Stefania Pallotta, Roberto Pellegrini, Yvette Seppenwoolde, Gabriele Simontacchi, Volker Steil, Florian Stieler, Stuart Wilson, Sebastiaan Breedveld Background and purpose Reported plan quality improvements with autoplanning of radiotherapy of the prostate and seminal vesicles are poor. A system for automated multi-criterial planning has been validated for this treatment in a large international multi-center study. The system is configured with training plans using a mechanism that strives for quality improvements relative to those plans. Material and methods Each of the four participating centers included thirty manually generated clinical Volumetric Modulated Arc Therapy prostate plans (manVMAT). Ten plans were used for autoplanning training. The other twenty were compared with an automatically generated plan (autoVMAT). Plan evaluations considered dosimetric plan parameters and blinded side-by-side plan comparisons by clinicians. Results With equivalent Planning Target Volume (PTV) V 95% , D 2% , D 98% , and dose homogeneity autoVMAT was overall superior for rectum with median differences of 3.4 Gy ( p  〈 0.001) in D mean , 4.0% ( p  〈 0.001) in V 60Gy , and 1.5% ( p  = 0.001) in V 75Gy , and for bladder D mean (0.9 Gy, p  〈 0.001). Also the clinicians’ plan comparisons pointed at an overall preference for autoVMAT. Advantages of autoVMAT were highly treatment center- and patient-specific with overall ranges for differences in rectum D mean and V 60Gy of [−4,12] Gy and [−2,15]%, respectively. Conclusion Observed advantages of autoplanning were clinically relevant and larger than reported in the literature. The latter is likely related to the multi-criterial nature of the applied autoplanning algorithm, with for each center a dedicated configuration that aims at plan improvements relative to its (clinical) training plans. Large variations among patients in differences between manVMAT and autoVMAT point at inconsistencies in manual planning.

Description: Publication date: Available online 29 June 2018 Source: Radiotherapy and Oncology Author(s): Claudio Fiorino, Calogero Gumina, Paolo Passoni, Anna Palmisano, Sara Broggi, Giovanni M. Cattaneo, Alessandra Di Chiara, Antonio Esposito, Martina Mori, Roberta Raso, Monica Ronzoni, Riccardo Rosati, Najla Slim, Francesco De Cobelli, Riccardo Calandrino, Nadia G. Di Muzio Purpose Introducing a radiobiological index based on early tumor regression during neo-adjuvant radio-chemotherapy (RCT, including oxaliplatin) of rectal adenocarcinoma and testing its discriminative power in predicting the tumor response. Methods Seventy-four patients were treated with Helical Tomotherapy following an adaptive (ART) protocol (41.4 Gy/18 fr, 2.3 Gy/fr) delivering a simultaneous integrated boost on the residual tumor in the last 6 fractions up to 45.6 Gy. T2-weighted MRI were taken before (MRI pre ) and at mid (MRI mid ) therapy and the corresponding tumor volumes were considered ( V pre , V mid ). The “Early Regression Index” ( ER I TCP = - ln [ ( 1 - ( V mid / V pre ) ) V pre ] ) was introduced and its discriminative power was assessed in terms of AUC, sensitivity/specificity, positive/negative predictive value (PPV/NPV). Two end-points were considered: (a) pathological complete response (pCR) or clinical complete response followed by watch-and-wait, (cCR); (b) limited response (residual vital cells (RVC) in the surgical specimen >10%). Results Complete data were available for 65 patients: pCR, cCR and RVC >10% were 20, 2 and 19 respectively. The discriminative power of ERI TCP was moderately high (AUC = 0.81/0.75 for /pCRorcCR/RVC >10% respectively, p  〈 0.0005). ERI TCP was highly sensitive (86–89%) with very high NPV (90–94%). The discriminative power of ERI TCP was confirmed on a subgroup of 44/65 patients when considering tumor volumes delineated by a skilled radiologist. Conclusion A radiobiologically consistent index based on early regression showed high performances in predicting the pathological response after neo-adjuvant RCT for rectal cancer with relevant potentialities for ART/treatment customization.

Description: Publication date: Available online 28 June 2018 Source: Radiotherapy and Oncology Author(s): Mona Kamal, Abdallah S.R. Mohamed, Stefania Volpe, Jhankruti Zaveri, Martha Portwood Barrow, G. Brandon Gunn, Stephen Y. Lai, Renata Ferrarotto, Jan S. Lewin, David I. Rosenthal, Amit Jethanandani, Mohamed Ahmed Mohamed Meheissen, Samuel L. Mulder, Carlos E. Cardenas, Clifton D. Fuller, Katherine A. Hutcheson Purpose Our primary aim was to prospectively validate retrospective dose–response models of chronic radiation-associated dysphagia (RAD) after intensity modulated radiotherapy (IMRT) for oropharyngeal cancer (OPC). The secondary aim was to validate a grade ≥2 cut-point of the published videofluoroscopic dysphagia severity (Dynamic Imaging Grade for Swallowing Toxicity, DIGEST) as radiation dose-dependent. Material and methods Ninety-seven patients enrolled on an IRB-approved prospective registry protocol with stage I–IV OPC underwent pre- and 3–6 month post-RT videofluoroscopy. Dose–volume histograms (DVH) for swallowing regions of interest (ROI) were calculated. Dysphagia severity was graded per DIGEST criteria (dichotomized with grade ≥2 as moderate/severe RAD). Recursive partitioning analysis (RPA) and Bayesian Information Criteria (BIC) were used to identify dose–volume effects associated with moderate/severe RAD. Results 31% developed moderate/severe RAD (i.e. DIGEST grade ≥2) at 3–6 months after RT. RPA found DVH-derived dosimetric parameters of geniohyoid/mylohyoid (GHM), superior pharyngeal constrictor (SPC), and supraglottic region were associated with DIGEST grade ≥2 RAD. V61 ≥ 18.57% of GHM demonstrated optimal model performance for prediction of DIGEST grade ≥2. Conclusion The findings from this prospective longitudinal registry validate prior observations that dose to submental musculature predicts for increased burden of dysphagia after oropharyngeal IMRT. Findings also support dichotomization of DIGEST grade ≥2 as a dose-dependent split for use as an endpoint in trials or predictive dose–response analysis of videofluoroscopy results.

Description: Publication date: Available online 28 June 2018 Source: Radiotherapy and Oncology Author(s): Damien C. Weber, Carmen Ares, Salvador Villa, Saskia M. Peerdeman, Laurette Renard, Brigitta G. Baumert, Anna Lucas, Theo Veninga, Alessia Pica, Sarah Jefferies, Umberto Ricardi, Raymond Miralbell, Jean-Jacques Stelmes, Yan Liu, Laurence Collette, Sandra Collette Purpose The therapeutic strategy for non-benign meningiomas is controversial. The objective of this study was to prospectively investigate the impact of high dose radiation therapy (RT) on the progression-free survival (PFS) rate at 3 years in WHO grade II and III meningioma patients. Materials and methods In this multi-cohorts non-randomized phase II and observational study, non-benign meningioma patients were treated according to their WHO grade and Simpson’s grade. Patients with atypical meningioma (WHO grade II) and Simpson’s grade 1–3 [Arm 1] entered the non-randomized phase II study designed to show a 3-year PFS > 70% (primary endpoint). All other patients entered the 3 observational cohorts: WHO grade II Simpson grade 4–5 [Arm 2] and Grade III Simpson grade 1–3 or 4–5 [Arm 3&4] in which few patients were expected. Results Between 02/2008 and 06/2013, 78 patients were enrolled into the study. This report focuses on the 56 (median age, 54 years) eligible patients with WHO grade II Simpson’s grade 1–3 meningioma who received RT (60 Gy). At a median follow up of 5.1 years, the estimated 3-year PFS is 88.7%, hence significantly greater than 70%. Eight (14.3%) treatment failures were observed. The 3-year overall survival was 98.2%. The rate of late signs and symptoms grade 3 or more was 14.3%. Conclusions These data show that 3-year PFS for WHO grade II meningioma patients undergoing a complete resection (Simpson I–III) is superior to 70% when treated with high-dose (60 Gy) RT.

Description: Publication date: Available online 28 June 2018 Source: Radiotherapy and Oncology Author(s): Raphaël Jumeau, Mahmut Ozsahin, Raphaël Moeckli, Etienne Pruvot, Jean Bourhis

Description: Publication date: Available online 27 June 2018 Source: Radiotherapy and Oncology Author(s): Prashant Gabani, Benjamin W. Fischer-Valuck, Tanner M. Johanns, Leonel F. Hernandez-Aya, Jesse W. Keller, Keith M. Rich, Albert H. Kim, Gavin P. Dunn, Clifford G. Robinson, Michael R. Chicoine, Jiayi Huang, Christopher D. Abraham Purpose Preclinical studies have suggested that radiation therapy (RT) enhances antitumor immune response and can act synergistically when administered with immunotherapy. However, this effect in melanoma brain metastasis is not well studied. We aim to explore the clinical effect of combining RT and immunotherapy in patients with melanoma brain metastasis (MBM). Materials and methods Patients with MBM between 2011 and 2013 were obtained from the National Cancer Database. Patients who did not have identifiable sites of metastasis and who did not receive RT for the treatment of their MBM were excluded. Patients were separated into cohorts that received immunotherapy versus patients who did not. Univariable and multivariable analyses were performed using Cox model to determine predictors of OS. Kaplan–Meier method was used to compare OS. Univariable and multivariable analyses using logistic regression model were used to determine the factors predictive for the use of immunotherapy. Propensity score analysis was used to account for differences in baseline patient characteristics between the RT and RT + immunotherapy groups. Significance was defined as a P value ≤ 0.05. Results A total of 1104 patients were identified: 912 received RT alone and 192 received RT plus immunotherapy. The median follow-up time was 6.4 (0.1–56.8) months. Patients with extracranial disease (OR 1.603, 95% CI 1.146–2.243, P  = 0.006), and patients receiving SRS (OR 1.955, 95% CI 1.410–2.711, P  〈 0.001) as compared to WBRT, had a higher likelihood of being treated with immunotherapy. The utilization of immunotherapy had nearly doubled between 2011 and 2013 (12.9–22.8%). On multivariable analysis, factors associated with superior OS were younger age, lower medical comorbidities, lack of extracranial disease, and treatment with immunotherapy and SRS. The median OS was 11.1 (8.9–13.4) months in RT plus immunotherapy vs. 6.2 (5.6–6.8) months in RT alone ( P  〈 0.001), which remained significant after propensity score matching. Conclusions An increase in trend for the use of immunotherapy was noted, however, an overwhelming majority of the patients with this disease are still treated without immunotherapy. Addition of immunotherapy to RT is associated with improved OS in MBM. Given the selection biases that are inherent in this analysis, prospective trials investigating the combination of RT, especially SRS and immunotherapy are warranted.

Description: Publication date: Available online 26 June 2018 Source: Radiotherapy and Oncology Author(s): Lisanne V. van Dijk, Maria Thor, Roel J.H.M. Steenbakkers, Aditya Apte, Tian-Tian Zhai, Ronald Borra, Walter Noordzij, Cherry Estilo, Nancy Lee, Johannes A. Langendijk, Joseph O. Deasy, Nanna M. Sijtsema Purpose This study investigated whether Magnetic Resonance image biomarkers (MR-IBMs) were associated with xerostomia 12 months after radiotherapy (Xer 12m ) and to test the hypothesis that the ratio of fat-to-functional parotid tissue is related to Xer 12m . Additionally, improvement of the reference Xer 12m model based on parotid gland dose and baseline xerostomia, with MR-IBMs was explored. Methods Parotid gland MR-IBMs of 68 head and neck cancer patients were extracted from pre-treatment T1-weighted MR images, which were normalized to fat tissue, quantifying 21 intensity and 43 texture image characteristics. The performance of the resulting multivariable logistic regression models after bootstrapped forward selection was compared with that of the logistic regression reference model. Validity was tested in a small external cohort of 25 head and neck cancer patients. Results High intensity MR-IBM P90 (the 90th intensity percentile) values were significantly associated with a higher risk of Xer 12m . High P90 values were related to high fat concentration in the parotid glands. The MR-IBM P90 significantly improved model performance in predicting Xer 12m (likelihood-ratio-test; p  = 0.002), with an increase in internally validated AUC from 0.78 (reference model) to 0.83 (P90). The MR-IBM P90 model also outperformed the reference model (AUC = 0.65) on the external validation cohort (AUC = 0.83). Conclusion Pre-treatment MR-IBMs were associated to radiation-induced xerostomia, which supported the hypothesis that the amount of predisposed fat within the parotid glands is associated with Xer 12m . In addition, xerostomia prediction was improved with MR-IBMs compared to the reference model.

Description: Publication date: Available online 23 June 2018 Source: Radiotherapy and Oncology Author(s): Maddalena Mambretti, Chiara Romanò, Giulia Marvaso, Stefania Comi, Raffaella Cambria, Delia Ciardo, Francesca Emiro, Cristiana Fodor, Dario Zerini, Giulia Riva, Giuseppe Petralia, Ottavio De Cobelli, R. Orecchia, Federica Cattani, Barbara Alicja Jereczek-Fossa Purpose Formulation of a global Unified Dosimetry Index (gUDI) for the evaluation of prostate simultaneous integrated boost Volumetric Modulated Arc Therapy (VMAT by RapidArc) radiotherapy plans. Methods and materials Dose coverage, conformity, homogeneity and dose gradient index could be included in the Unified Dosimetry Index (UDI). We developed a global UDI to evaluate treatment plans containing volumes irradiated with different dose prescriptions: Intensity Modulated Radiation Therapy with simultaneous integrated boost (IMRT-SIB) with 2 dose levels (36.25 Gy/5 fz for the whole prostate gland and 37.5 Gy/5 fz for Dominant Intraprostatic Lesion (DIL)). To validate gUDI scoring system, 65 prostate cancer patients were evaluated. Mean ( µ ) and standard deviations ( σ ) were calculated for all dosimetry indices and gUDI. Furthermore, gUDI µ and σ were analyzed to compare and classify treatment plans: plans can be ranked as “excellent”, “good”, “average” or “poor”. Results Prostate Dose Gradient, Prostate Conformity and DIL Conformity indices had highlighted a major deviation from ideal scores. gUDI index classification showed most of the plans scored as “average” and “good”. Conclusion gUDI score can be a useful tool to quantify treatment plans quality also when volumes with different dose-prescription are treated.

Description: Publication date: Available online 22 June 2018 Source: Radiotherapy and Oncology Author(s): Liv B. Hysing, Christian Ekanger, Ándras Zolnay, Svein Inge Helle, Mana Rasi, Ben J.M. Heijmen, Marcin Sikora, Matthias Söhn, Ludvig Paul Muren, Sara Thörnqvist Purpose Planned doses are used as surrogate for the actually delivered dose in radiotherapy. We have estimated the delivered dose in a dose-escalation trial of locally advanced prostate cancer by statistical dose-accumulation and by DVH-summation, and compared to planned dose. Materials and method Prescribed dose-escalation to the prostate was 67.5 Gy/25fr., corresponding to 81GyEQD2 assuming α/β  = 1.5. The 21 patients had three targets (i.e. CTV67.5 + 2 mm, CTV60 + 5 mm, CTV50 + 10 mm) irradiated by a simultaneous-integrated-boost technique. Analysis was based on 213 CT scans and 5-years of follow-up. For statistical dose-accumulation, we modelled 10 000 possible treatment courses based on planned dose and deformation-vector-fields from contour-based registration. For DVH-summation we recalculated dose on repeat-CTs and estimated median D98%/EUD. Groups with/without disease recurrence were compared. Results Discrepancies between planned and accumulated dose were mostly seen for CTV67.5, where under-dosage was found at different locations in the prostate in 12/21 patients. Delivered dose-escalation (D98%) was on average 73.9GyEQD2 (range: 68.3–78.7GyEQD2). No significant difference in accumulated-D98% was found in patients with ( n  = 8) and without ( n  = 13) recurrence ( p  > 0.05). Average D98%/EUD with statistical dose-accumulation vs DVH-summation was significantly different in CTV60, CTV50, rectum and bladder but not in CTV67.5. Conclusion The planned dose escalation was not received by more than half-of-the patients. Robustness of the prostate target (CTV67.5) should therefore be better prioritized in these patients given the low toxicity profile. Estimates of delivered dose were less conservative for dose-accumulation due to interaction of random organ motion with the dose matrix.