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  • Radiation therapy to the primary tumor for de novo metastatic breast cancer and overall survival in a retrospective multicenter cohort analysis
    Radiother. Oncol. (IF 5.252) Pub Date : 2020-01-10
    Elvire Pons-Tostivint; Youlia Kirova; Amélie Lusque; Mario Campone; Julien Geffrelot; Sofia Rivera; Audrey Mailliez; David Pasquier; Nicolas Madranges; Nelly Firmin; Agathe Crouzet; Anthony Gonçalves; Clémentine Jankowski; Thibault De La Motte Rouge; Nicolas Pouget; Brigitte De La Lande; Delphine Mouttet-Boizat; Jean-Marc Ferrero; Florence Dalenc

    Background The impact of locoregional treatment (LRT) on overall survival (OS) in de novo metastatic breast cancer (dnMBC) is still under debate, with very few data available regarding exclusive radiotherapy (ERT) as a therapeutic modality. Methods We evaluated the impact of ERT, exclusive surgery, or a combination of surgery plus radiotherapy (bimodality therapy, BMT) on survival outcomes in a national real-life dnMBC cohort. The primary and secondary end points were OS and progression free survival (PFS) according to LRT (ERT, exclusive surgery, BMT) and no LRT. Sensitivity analyses were performed using propensity score matched analyses. Results From 2008 to 2014, 4507 dnMBC patients were identified. Only patients alive and free from progression under systemic therapy at least 1 year after diagnosis were included (n = 1965). Forty-five percent of patients (891/1965) underwent LRT: 41.1% (n = 366) ERT, 13.7% (n = 122) exclusive surgery, and 45.2% (n = 403) BMT. OS adjusted for major prognostic factors was significantly longer in the ERT and BMT group compared with no-LRT group, but not exclusive surgery (hazard ratio (HR) = 0.63, 95% confidence interval (CI) [0.49, 0.80], p < 0.001, HR = 0.61, 95%CI [0.47, 0.78], p < 0.001 and HR = 0.87, 95%CI [0.61, 1.26], p = 0.466 respectively). Results were similar after matching on a propensity score. ERT, surgery and BMT were all associated with a significantly better PFS in multivariable analysis. Conclusion ERT was significantly associated with better OS in dnMBC, in the same magnitude as BMT, compared with no-LRT. However, even with statistical models adjusted for known prognostic factors and propensity score analysis, selection biases cannot be eliminated from observational studies.

    更新日期:2020-01-11
  • Lymphopenia during radiotherapy in patients with oropharyngeal cancer
    Radiother. Oncol. (IF 5.252) Pub Date : 2020-01-10
    Sweet Ping Ng; Houda Bahig; Amit Jethanandani; Courtney Pollard; Joel Berends; Erich M. Sturgis; Faye M. Johnson; Baher Elgohari; Hesham Elhalawani; David I. Rosenthal; Heath D. Skinner; G. Brandon Gunn; Jack Phan; Steven J. Frank; Abdallah S.R. Mohamed; Clifton D. Fuller; Adam S. Garden

    Purpose/Objective Radiation-induced lymphopenia has been associated with poor survival outcomes in certain solid tumors such as esophageal, lung, cervical and pancreatic cancers. We aim to determine the effect of treatment-related lymphopenia during radiotherapy on outcomes of patients with oropharyngeal cancer. Materials/Methods A retrospective analysis of all patients who completed definitive radiotherapy for oropharyngeal cancer at The University of Texas MD Anderson Cancer Center and had blood counts taken during radiotherapy from 2002 to 2013 were included. Patient, tumor and treatment characteristics, clinical outcomes and lymphocyte counts during radiotherapy were recorded. Lymphopenia was graded according to the CTCAE v4.0. Survival rates were estimated using the Kaplan-Meier method and compared with log-rank tests. Results 850 patients were evaluated. The median age was 57 years. The majority of the cohort had p16/HPV-positive disease (71%), 8% had HPV-negative disease and 21% were unknown. The median radiation total dose was 70 Gy. 45% of patients had induction chemotherapy, and 87% had concurrent chemotherapy. 703 (83%) patients developed ≥grade 3 (G3) lymphopenia and 209 (25%) had grade 4 (G4) lymphopenia during radiotherapy. The median follow-up was 59 months; the 5-year overall survival rate was 81%. There were no significant differences in overall survival rates nor in disease control rates, in those who developed G3/G4 lymphopenia compared with those who did not. No significant effect of lymphopenia on survival was observed when analyzed according to p16/HPV status. Conclusion In this large cohort of patients with oropharyngeal cancer, the development of lymphopenia during radiotherapy did not impact outcomes.

    更新日期:2020-01-11
  • MRI-detected residual retropharyngeal lymph node after intensity-modulated radiotherapy in nasopharyngeal carcinoma: Prognostic value and a nomogram for the pretherapy prediction of it
    Radiother. Oncol. (IF 5.252) Pub Date : 2020-01-10
    Wang-Zhong Li; Guo-Ying Liu; Lan-Feng Lin; Shu-Hui Lv; Meng-Yun Qiang; Xing Lv; Yi-Shan Wu; Hu Liang; Liang-Ru Ke; De-Ling Wang; Ya-Hui Yu; Wen-Ze Qiu; Kui-Yuan Liu; Xiang Guo; Jian-Peng Li; Yu-Jian Zou; Yan-Qun Xiang; Wei-Xiong Xia

    Background and purpose To evaluate the prognostic value of MRI-detected residual retropharyngeal lymph node (RRLN) at three months after intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC) and second, to establish a nomogram for the pretherapy prediction of RRLN. Materials and methods We included 1103 patients with NPC from two hospitals (Sun Yat-Sen University Cancer Center [SYSUCC, n = 901] and Dongguan People's Hospital [DGPH, n = 202]). We evaluated the prognostic value of RRLN using Cox regression model in SYSUCC cohort. We developed a nomogram for the pretherapy prediction of RRLN using logistic regression model in SYSUCC training cohort (n = 645). We assessed the performance of this nomogram in an internal validation cohort (SYSUCC validation cohort, n = 256) and an external independent cohort (DGPH validation cohort, n = 202). Results RRLN was an independent prognostic factor for OS (HR 2.08, 95% CI 1.32–3.29), DFS (HR 2.45, 95% CI 1.75–3.42), DMFS (HR 3.31, 95% CI 2.15–5.09), and LRRFS (HR 3.04, 95% CI 1.70–5.42). We developed a nomogram based on baseline Epstein–Barr virus DNA level and three RLN status-related features (including minimum axial diameter, extracapsular nodal spread, and laterality) that predicted an individual's risk of RRLN. Our nomogram showed good discrimination in the training cohort (C-index = 0.763). The favorable performance of this nomogram was confirmed in the internal and external validation cohorts. Conclusion MRI-detected RRLN at three months after IMRT was an unfavorable prognostic factor for patients with NPC. We developed and validated an easy-to-use nomogram for the pretherapy prediction of RRLN.

    更新日期:2020-01-11
  • Automatic reconstruction of the delivered dose of the day using MR-linac treatment log files and online MR imaging
    Radiother. Oncol. (IF 5.252) Pub Date : 2020-01-10
    Martin J. Menten; Jonathan K. Mohajer; Rahul Nilawar; Jenny Bertholet; Alex Dunlop; Angela U. Pathmanathan; Michel Moreau; Spencer Marshall; Andreas Wetscherek; Simeon Nill; Alison C. Tree; Uwe Oelfke

    Background and purpose Anatomical changes during external beam radiotherapy prevent the accurate delivery of the intended dose distribution. Resolving the delivered dose, which is currently unknown, is crucial to link radiotherapy doses to clinical outcomes and ultimately improve the standard of care. Material and methods In this study, we present a dose reconstruction workflow based on data routinely acquired during MR-guided radiotherapy. It employs 3D MR images, 2D cine MR images and treatment machine log files to calculate the delivered dose taking intrafractional motion into account. The developed pipeline was used to measure anatomical changes and assess their dosimetric impact in 89 prostate radiotherapy fractions delivered with a 1.5 T MR-linac at our institute. Results Over the course of radiation delivery, the CTV shifted 0.6 mm ± 2.1 mm posteriorly and 1.3 mm ± 1.5 mm inferiorly. When extrapolating the dose changes in each case to 20 fractions, the mean clinical target volume D98% and clinical target volume D50% dose-volume metrics decreased by 1.1 Gy ± 1.6 Gy and 0.1 Gy ± 0.2 Gy, respectively. Bladder D3% did not change (0.0 Gy ± 1.2 Gy), while rectum D3% decreased by 1.0 Gy ± 2.0 Gy. Although anatomical changes and their dosimetric impact were small in the majority of cases, large intrafractional motion caused the delivered dose to substantially deviate from the intended plan in some fractions. Conclusions The presented end-to-end workflow is able to reliably, non-invasively and automatically reconstruct the delivered prostate radiotherapy dose by processing MR-linac treatment log files and online MR images. In the future, we envision this workflow to be adapted to other cancer sites and ultimately to enter widespread clinical use.

    更新日期:2020-01-11
  • MRI-based contouring of functional sub-structures of the lower urinary tract in gynaecological radiotherapy
    Radiother. Oncol. (IF 5.252) Pub Date : 2020-01-10
    Sofia Spampinato; Kari Tanderup; Edvard Marinovskij; Susanne Axelsen; Erik M. Pedersen; Richard Pötter; Jacob C. Lindegaard; Lars Fokdal

    Introduction Research in radiation-induced urinary morbidity is limited by lack of guidelines for contouring and dose assessment of the lower urinary tract. Based on literature regarding anatomy, physiology and imaging of the lower urinary tract, this study aimed to provide advice on contouring of relevant sub-structures, reference points and reference dimensions for gynaecological radiotherapy. Material and methods 210 MRIs for Image-Guided Adaptive Brachytherapy (IGABT) were analysed in 105 locally advanced cervical cancer patients treated with radio(chemo)therapy. Sub-structures (trigone, bladder neck and urethra) were contoured and trigone height (TH) and width (TW) were measured. Internal urethral ostium (IUO) and Posterior inferior border of pubic symphysis-urethra (PIBS-U) points were used to identify proximal and middle/low urethra, respectively. Urethra reference length (URL) was defined as IUO and PIBS-U distance. TH, TW and URL were also quantified on 54 MRIs acquired for External Beam Radiotherapy (EBRT). Results Median absolute differences in volumes and dimensions between first and second IGABT fraction were 0.7 cm3, 4.3 cm3, 0.2 cm, 0.3 cm and 0.2 cm for trigone, bladder neck, TH, TW and URL, respectively. Mean(±SD) TH and TW were 2.7(±0.4)cm and 4.4(±0.4)cm, respectively, with no significant difference (p = 0.15 and p = 0.06, respectively) between IGABT and EBRT. URL was significantly shorter in EBRT than in IGABT MRIs (p < 0.001). Conclusions This study proposed relevant urinary sub-structures and dose points and showed that standardized contouring is reproducible. Trigone reference dimensions are robust despite different bladder filling and treatment conditions. Standardized contouring and reference points may improve understanding of urinary morbidity.

    更新日期:2020-01-11
  • Margin reduction in radiotherapy for glioblastoma through 18F-fluoroethyltyrosine PET? – A recurrence pattern analysis
    Radiother. Oncol. (IF 5.252) Pub Date : 2020-01-07
    Daniel F. Fleischmann; Marcus Unterrainer; Rudolph Schön; Stefanie Corradini; Cornelius Maihöfer; Peter Bartenstein; Claus Belka; Nathalie L. Albert; Maximilian Niyazi

    Background and purpose 18F-fluoroethyltyrosine (18F-FET) PET is increasingly used in radiation treatment planning for the primary treatment of glioblastoma (GBM) patients additionally to contrast-enhanced MRI. To answer the question, whether a margin reduction in the primary treatment setting could be achieved through 18F-FET PET imaging, a recurrence pattern analysis was performed. Patients and methods GBM patients undergoing 18F-FET PET examination before primary radiochemotherapy from 05/2009 to 11/2014 were included into the recurrence pattern analysis. Biological tumour volumes were semi-automatically created and fused with MR-based gross tumour volumes (MRGTVs). The pattern of recurrence was examined for MRGTVs and for PET-MRGTVs. The minimal margin including all recurrent tumour sites was assessed by gradual expansion of the PET-MRGTVs and MRGTVs until inclusion of all contrast-enhancing areas at recurrence. Results 36 GBM patients were included to the analysis. The minimal margin including all contrast enhancing tumour at recurrence was significantly smaller for the PET-MRGTVs compared to the MRGTVs (median 12.5 mm vs. 16.5 mm; p < 0.001, Wilcoxon-Test). PET-MRGTVs with 15 mm CTV margins were significantly smaller than MRGTVs with 20 mm CTV margins (median volume 255.92 vs. 258.35 cm3; p = 0.020, Wilcoxon-Test; excluding 3 cases with large non-contrast enhancing tumours). The pattern of recurrence of PET-MRGTVs with 15 mm CTV margins was comparable to MRGTVs with 20 mm CTV margins (32 vs. 30 central, 2 vs. 4 in-field, 2 vs. 2 ex-field and no marginal recurrences). Conclusion Target volume delineation of GBM patients can be improved through 18F-FET PET imaging prior to primary radiation treatment, since vital tumour can be detected more accurately. Furthermore, the results suggest that CTV margins could be reduced through 18F-FET PET imaging prior to primary RT of GBM.

    更新日期:2020-01-07
  • Comparisons between radiofrequency ablation and stereotactic body radiotherapy for liver malignancies: Meta-analyses and a systematic review
    Radiother. Oncol. (IF 5.252) Pub Date : 2020-01-07
    Jeongshim Lee; In-Soo Shin; Won Sup Yoon; Woong Sub Koom; Chai Hong Rim

    Introduction Radiofrequency ablation (RFA) is a standard ablative modality for small liver malignancies. Stereotactic body radiotherapy (SBRT) has emerged although yet suffers a lack of high-level evidence. We performed meta-analyses and a systematic review to integrate the literature and help in clinical decision-making. Methods Systemic searches were performed of the PubMed, Medline, and EMBASE databases to identify controlled studies comparing RFA and SBRT. Results Eleven studies involving 2238 patients were included. Among them, eight studies were for treating early hepatocellular carcinomas (HCCs) and three for liver metastases. Including HCCs and liver metastases studies, the pooled two-year local control (LC) rate was higher in the SBRT arm (83.8%, 95% confidence interval [CI]: 77.6–88.4) than that in the RFA arm (71.8%, 95% CI: 61.5–80.2) (p = 0.024). Among studies on liver metastases, the pooled two-year LC rate was higher in the SBRT arm (83.6% vs. 60.0%, p < 0.001). No significant difference was found between arms in HCC studies (SBRT vs. RFA: 84.5 vs. 79.5% p = 0.431). Pooled analysis of overall survival (OS) in HCC studies showed an odds ratio of 1.43 (95% CI: 1.05–1.95, p = 0.023), favoring RFA. Among the two liver metastases studies with comparative survival data, no significant difference was observed. Conclusion LC was equivalent between RFA and SBRT for HCC and better for SBRT for the treatment of liver metastases. RFA was associated with better OS for HCC, but discrepancy between LC and OS requires further investigation, as they are local modalities having comparable efficacy.

    更新日期:2020-01-07
  • Late toxicity and quality of life with prostate only or whole pelvic radiation therapy in high risk prostate cancer (POP-RT): A randomised trial
    Radiother. Oncol. (IF 5.252) Pub Date : 2020-01-07
    Vedang Murthy; Priyamvada Maitre; Jatin Bhatia; Sadhana Kannan; Rahul Krishnatry; Gagan Prakash; Ganesh Bakshi; Mahendra Pal; Santosh Menon; Umesh Mahantshetty

    Aim To report toxicity and quality of life (QOL) outcomes from a randomised trial of prostate only versus whole pelvic radiotherapy in high risk, node negative prostate cancer. Materials/methods Patients with localised prostate adenocarcinoma and nodal involvement risk > 20%, were randomised to prostate only (PORT, 68 Gy/25# to prostate) and whole pelvis (WPRT, 68 Gy/25# to prostate and 50 Gy/25# to pelvis) arms with stratification for TURP, Gleason score, baseline PSA, and type of androgen deprivation therapy (ADT). Image guided intensity modulated radiotherapy (IG-IMRT) and two years of ADT were mandatory. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were graded using RTOG grading. QOL was assessed using EORTC QLQ-C30 and PR-25 questionnaire pre-treatment and every 3–6 months post RT. Results Total 224 patients were randomised (PORT 114, WPRT 110) from November 2011 to August 2017. Median follow up was 44.5 months. No RTOG grade IV toxicity was observed. Acute GI and GU toxicities were similar between both the arms. Cumulative ≥ grade II late GI toxicity was similar for WPRT and PORT (6.5% vs. 3.8%, p = 0.39) but GU toxicity was higher (17.7% vs. 7.5%, p = 0.03). Dosimetric analysis showed higher bladder volume receiving 30–40 Gy in the WPRT arm (V30, 60% vs. 36%, p < 0.001; V40, 41% vs. 25%, p < 0.001). There was no difference in QOL scores of any domain between both arms. Conclusion Pelvic irradiation using hypofractionated IG-IMRT resulted in increased grade II or higher late genitourinary toxicity as compared to prostate only RT, but the difference was not reflected in patient reported QOL. Clinicaltrials.gov NCT02302105 Prostate Only or Whole Pelvic Radiation Therapy in High Risk Prostate Cancer (POP-RT).

    更新日期:2020-01-07
  • Stereotactic body radiation therapy planning for liver tumors using functional images from dual-energy computed tomography
    Radiother. Oncol. (IF 5.252) Pub Date : 2020-01-07
    Shingo Ohira; Naoyuki Kanayama; Masayasu Toratani; Yoshihiro Ueda; Yuhei Koike; Tsukasa Karino; Ono Shunsuke; Masayoshi Miyazaki; Masahiko Koizumi; Teruki Teshima

    Purpose This study aimed to generate a functional image of the liver using dual-energy computed tomography (DECT) and a functional-image-based stereotactic body radiation therapy plan to minimize the dose to the volume of the functional liver (Vfl). Material and methods A normalized iodine density (NID) map was generated for fifteen patients with liver tumors. The volume of liver with an NID < 0.46 was defined as Vfl, and the ratio between Vfl and the total volume of the liver (FLR) was calculated. The relationship between the FLR and Fibrosis-4 (FIB-4) was assessed. For patients with 15% < FLR < 85%, functional volumetric modulated-arc therapy plans (F-VMAT) were retrospectively generated to preserve Vfl, and compared to the clinical plans (C-VMAT). Results FLR showed a significantly strong correlation with FIB-4 (r = −0.71, p < 0.01). For ten generated F-VMAT plans, the dosimetric parameters of D99%, D50%, D1% and the conformity index were comparable to those of the C-VMAT (p > 0.05). For Vfl, F-VMAT plans achieved lower V5Gy (122.4 ± 31.7 vs 181.1 ± 57.3 cc), V10Gy (44.4 ± 22.2 vs 98.2 ± 33.3 cc), V15Gy (22.6 ± 20.3 vs 49.8 ± 33.7 cc), V20Gy (11.6 ± 14.1 vs 24.9 ± 25.1 cc), and Dmean (3.9 ± 2.3 vs 5.8 ± 3.0 Gy) values than the C-VMAT plans (p < 0.01). Conclusions The functional image derived from DECT was successfully used, allowing for a reduction in the dose to the Vfl without compromising target coverage.

    更新日期:2020-01-07
  • Combined proton–photon treatments – A new approach to proton therapy without a gantry
    Radiother. Oncol. (IF 5.252) Pub Date : 2020-01-07
    Silvia Fabiano; Panagiotis Balermpas; Matthias Guckenberger; Jan Unkelbach

    Purpose Although the number of proton therapy centres is growing worldwide, proton therapy is still a limited resource. The primary reasons are gantry size and cost. Therefore, we investigate the potential of a new design for proton therapy, which may facilitate proton treatments in conventional bunkers and allow the widespread use of protons. Materials and methods The treatment room consists of a standard Linac for IMRT, a motorized couch for treatments in lying position, and a horizontal proton beamline equipped with pencil beam scanning. As proton beams are limited to a coronal plane, treatment plans may be suboptimal for many tumour sites. However, high-quality plans may be realized by combining protons and photons. Treatment planning is performed by simultaneously optimizing IMRT and IMPT plans based on their cumulative physical dose. We demonstrate this concept for three head&neck cancer cases. Results Optimal combinations use photons to improve dose conformity while protons reduce the integral dose to normal tissues. In fact, combined treatments improve on single-modality IMRT and fixed beamline IMPT plans for quality-of-life-limiting OARs and retain most of the integral dose reduction in the healthy tissues of the pure IMPT plans. The lower doses that can be obtained with multi-modality treatments reduce the risk for side effects compared to single-modality IMRT plans. Conclusion Combined proton–photon treatments may play a role in developing a new solution for proton therapy without a gantry. Optimal combinations improve on IMRT plans and reduce the risk of side effects while making protons available to more patients.

    更新日期:2020-01-07
  • The role of postoperative thoracic radiotherapy and prophylactic cranial irradiation in early stage small cell lung cancer: Patient selection among ESTRO experts
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-27
    Paul M. Putora; Dirk De Ruysscher; Markus Glatzer; Joachim Widder; Paul Van Houtte; Esther G.C. Troost; Ben J. Slotman; Sara Ramella; Christoph Pöttgen; Stephanie Peeters; Ursula Nestle; Fiona McDonald; Cecile Le Pechoux; Rafal Dziadziuszko; José Belderbos; Corinne Faivre-Finn

    Background The role of prophylactic cranial irradiation (PCI) and thoracic radiotherapy (TRT) is unclear in resected small cell lung cancer (SCLC). Methods: Thirteen European radiotherapy experts on SCLC were asked to describe their strategies on PCI and TRT for patients with resected SCLC. The treatment strategies were converted into decision trees and analyzed for consensus and discrepancies. Results: For patients with resected SCLC and positive lymph nodes most experts recommend prophylactic cranial irradiation and thoracic radiotherapy. For elderly patients with resected node negative SCLC, most experts do not recommend thoracic radiotherapy or prophylactic cranial irradiation. Conclusion: PCI and TRT are considered in patients with resected SCLC and these treatments should be discussed with the patient in the context of shared decision-making.

    更新日期:2019-12-29
  • Recommendations from gynaecological (GYN) GEC-ESTRO working group – ACROP: Target concept for image guided adaptive brachytherapy in primary vaginal cancer
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-23
    Maximilian P. Schmid; Lars Fokdal; Henrike Westerveld; Cyrus Chargari; Lisbeth Rohl; Philippe Morice; Nicole Nesvacil; Renaud Mazeron; Christine Haie-Meder; Richard Pötter; Remi A. Nout

    Background and aim External beam radiotherapy (EBRT) combined with brachytherapy has an essential role in the curative treatment of primary vaginal cancer. EBRT is associated with significant tumour shrinkage, making primary vaginal cancer suitable for image guided adaptive brachytherapy (IGABT). The aim of these recommendations is to introduce an adaptive target volume concept for IGABT of primary vaginal cancer. Methods In December 2013, a task group was initiated within GYN GEC-ESTRO with the purpose to introduce an IGABT target concept for primary vaginal cancer. All participants have broad experience in IGABT and vaginal cancer brachytherapy. The target concept was elaborated as consensus agreement based on an iterative process including target delineation and dose planning comparison, retrospective analysis of clinical data and expert opinions. Results Gynaecological examination and MR imaging are the modalities of choice for local tumour assessment. A specific template for standardised documentation with clinical drawings for vaginal cancer was developed. The adaptive target volume concept comprises different response-related target volumes. For EBRT these are related to the primary tumour and the lymph nodes, while for IGABT these are related to the primary tumour and are consisting of the residual gross tumour volume (GTV-Tres) and the high-, and intermediate risk clinical target volumes (CTV-THR, CTV-TIR). Conclusion This target concept for IGABT of primary vaginal cancer defines adaptive target volumes for volumetric dose prescription and should improve comparability of different radiotherapy schedules of this rare disease. A prospective evaluation of the target volume concept within a multicentre study is planned.

    更新日期:2019-12-25
  • Partial breast irradiation with the 1.5 T MR-Linac: First patient treatment and analysis of electron return and stream effects
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-23
    Marcel Nachbar; David Mönnich; Simon Boeke; Cihan Gani; Nicola Weidner; Vanessa Heinrich; Monica lo Russo; Lorenzo Livi; Jasmin Winter; Savas Tsitsekidis; Oliver Dohm; Daniela Thorwarth; Daniel Zips; Chiara De-Colle

    Introduction External beam partial breast irradiation (PBI) provides equal oncological outcomes compared to whole breast irradiation when applied to patients with low risk tumours. Recently, linacs with an integrated magnetic resonance image-guidance system have become clinically available. Here we report the first-in-human PBI performed at the 1.5 T MR-Linac, with a focus on clinical feasibility and investigation of the air electron stream effect (ESE) and the electron return effect (ERE) in the presence of the 1.5 T magnetic field, which might influence the dose on the chin (out-of-field dose, due to the ESE), the skin and the lung/chest wall interface (in-field dose, ERE). Methods A 59 years old patient affected by a 15 mm unifocal grade 1 carcinoma not special type of the right breast staged pT1c pN0 cM0 was planned and treated at Unity 1.5 T MR-Linac. To investigate the ERE and the ESE, an MR-Linac treatment plan was simulated without considering the 1.5 T B field using a research version of Monaco (V. 5.19.03). In vivo dosimetry was performed using Gafchromic® EBT3 films placed on top and underneath a 1 cm bolus which was placed on the patient’s chin. The plans with and without 1.5 T magnetic field were compared in terms of dose to the chin, to the skin and to the interface lung/chest wall. Finally, the dose on the chin measured with the in vivo dosimetry was compared with the dose calculated by Monaco. Results PBI using the 1.5 T MR-Linac was successfully performed with a 7 MV photon 7-beams IMRT step-and-shoot plan. The treatment was well tolerated, the patient developed a slight acute toxicity, i.e. breast skin erythema and breast oedema CTC V.4 grade 1. The plan with 1.5 T magnetic field documented a fractional dose of 0.17 Gy in the chin area (2.6 Gy in 15 fractions), which was reduced to 0.05 Gy (0.75 in 15 fractions) by the presence of 1 cm bolus. The simulated plan without magnetic field showed a dose reduced by 2.3 Gy in the chin area. With the in vivo dosimetry a fractional dose of, respectively, 0.12 Gy and 0.034 Gy on top and underneath the bolus were measured (1.8 and 0.51 Gy in 15 fractions). The plan with 1.5 T magnetic field showed a skin D2 of 40 Gy and a skin V35 of 40.2%, which were reduced to, respectively, 39.7 Gy and 24.9% in the simulation without magnetic field. At the interface lung/chest there were no differences in DVH statistics. Conclusion PBI with the 1.5 T MR-Linac was performed for the first time. ESE is accurately calculated by the treatment planning system, can be effectively reduced with a 1 cm bolus and is comparable to dose of cone beam-CT based position verification. The additional dose caused by ERE is not associated with an increased risk of acute toxicity.

    更新日期:2019-12-25
  • International consensus recommendations for target volume delineation specific to sacral metastases and spinal stereotactic body radiation therapy (SBRT)
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-23
    Emma M. Dunne; Arjun Sahgal; Simon S. Lo; Alanah Bergman; Robert Kosztyla; Nicolas Dea; Eric L. Chang; Ung-Kyu Chang; Samuel T. Chao; Salman Faruqi; Amol J. Ghia; Kristin J. Redmond; Scott G. Soltys; Mitchell C. Liu

    Background and purpose To interrogate inter-observer variability in gross tumour volume (GTV) and clinical target volume (CTV) delineation specific to the treatment of sacral metastases with spinal stereotactic body radiation therapy (SBRT) and develop CTV consensus contouring recommendations. Materials and methods Nine specialists with spinal SBRT expertise representing 9 international centres independently contoured the GTV and CTV for 10 clinical cases of metastatic disease within the sacrum. Agreement between physicians was calculated with an expectation minimisation algorithm using simultaneous truth and performance level estimation (STAPLE) and with kappa statistics. Optimised confidence level consensus contours were obtained using a voxel-wise maximum likelihood approach and the STAPLE contours for GTV and CTV were based on an 80% confidence level. Results Mean GTV STAPLE agreement sensitivity and specificity was 0.70 (range, 0.54–0.87) and 1.00, respectively, and 0.55 (range, 0.44–0.64) and 1.00 for the CTV, respectively. Mean GTV and CTV kappa agreement was 0.73 (range, 0.59–0.83) and 0.59 (range, 0.41–0.70), respectively. Optimised confidence level consensus contours were identified by STAPLE analysis. Consensus recommendations for the CTV include treating the entire segment containing the disease in addition to the immediate adjacent bony anatomic segment at risk of microscopic extension. Conclusion Consensus recommendations for CTV target delineation specific to sacral metastases treated with SBRT were established using expert contours. This is a critical first step to achieving standardisation of target delineation practice in the sacrum and will serve as a baseline for meaningful pattern of failure analyses going forward.

    更新日期:2019-12-25
  • High dose radiation therapy based on normal tissue constraints with concurrent chemotherapy achieves promising survival of patients with unresectable stage III non-small cell lung cancer
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-21
    Qian Zhao; Ming Liu; Zhongtang Wang; Wei Huang; X. Allen Li; Tao Zhou; Jian Zhang; Zicheng Zhang; Qiang Wang; Shuzeng Yu; Dan Han; Hongfu Sun; Hongsheng Li; Haiqun Lin; Baosheng Li

    Background and purpose We aimed to investigate the potential of individual isotoxic dose escalation based on normal tissue constraints (NTC), hypothesizing that high dose radiation therapy would be superior to standard-dose in concurrent chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC). Materials and methods Individually prescribed radiation doses were calculated based on NTC. Patients with total tumour radiation doses ≥66 Gy were assigned to the high dose (HD, ≥66 Gy) group, and all other patients were assigned to the standard-dose (SD, <66 Gy) group. Each patient was retrospectively assigned an Eighth edition of American Joint Committee on Cancer disease stage based on the imaging data of initial diagnosis to avoid over- and under-staging. Intensity modulated radiation therapy plans were optimized to minimize the volumes of organs at risk exposed to radiation. The primary endpoint was overall survival. Results From March 2006 to September 2012, 140 patients were enrolled and assigned to two groups: 71 patients into the HD group and 69 patients into the SD group. The median survival time (MST) was significantly higher in the HD group (33.5 months) than in the SD group (21 months), (p < 0.0001). Overall 5-year survival rates were significantly higher in the HD group than in the SD group (37.8% vs 16.7%). Median progression-free survival was 19 months in the HD group and 11 months in the SD group (p < 0.0001). No difference in severe (grade 3–5) toxic effects was noted between the two groups. Conclusions The significant positive association observed between prescribed dose and survival suggests that individualized isotoxic dose-escalated radiation based on NTC might improve survival in this cohort of stage III NSCLC Chinese patients.

    更新日期:2019-12-21
  • Development and validation of a CT-based radiomic nomogram for preoperative prediction of early recurrence in advanced gastric cancer
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-21
    Wenjuan Zhang; Mengjie Fang; Di Dong; Xiaoxiao Wang; Xiaoai Ke; Liwen Zhang; Chaoen Hu; Lingyun Guo; Xiaoying Guan; Junlin Zhou; Xiuhong Shan; Jie Tian

    Background In the clinical management of advanced gastric cancer (AGC), preoperative identification of early recurrence after curative resection is essential. Thus, we aimed to create a CT-based radiomic model to predict early recurrence in AGC patients preoperatively. Materials and methods We enrolled 669 consecutive patients (302 in the training set, 219 in the internal test set and 148 in the external test set) with clinicopathologically confirmed AGC from two centers. Radiomic features were extracted from preoperative diagnostic CT images. Machine learning methods were applied to shrink feature size and build a predictive radiomic signature. We incorporated the radiomic signature and clinical risk factors into a nomogram using multivariable logistic regression analysis. The area under the curve (AUC) of operating characteristics (ROC), accuracy, and calibration curves were assessed to evaluate the nomogram’s performance in discriminating early recurrence. Results A radiomic signature, including three hand crafted features and six deep learning features, was significantly associated with early recurrence (p-value <0.0001 for all sets). In addition, clinical N stage, carbohydrate antigen 199 levels, carcinoembryonic antigen levels, and Borrmann type were considered useful predictors for early recurrence. The nomogram, combining all these predictors, showed powerful prognostic ability in the training set and two test sets with AUCs of 0.831 (95% CI, 0.786–0.876), 0.826 (0.772–0.880) and 0.806 (0.732–0.881), respectively. The predicted risk yielded good agreement with the observed recurrence probability. Conclusions By incorporating a radiomic signature and clinical risk factors, we created a radiomic nomogram to predict early recurrence in patients with AGC, preoperatively, which may serve as a potential tool to guide personalized treatment.

    更新日期:2019-12-21
  • Clinical evaluation of a full-image deep segmentation algorithm for the male pelvis on cone-beam CT and CT
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-20
    Jan Schreier; Angelo Genghi; Hannu Laaksonen; Tomasz Morgas; Benjamin Haas

    Aim The segmentation of organs from a CT scan is a time-consuming task, which is one hindrance for adaptive radiation therapy. Through deep learning, it is possible to automatically delineate organs. Metrics like dice score do not necessarily represent the impact for clinical practice. Therefore, a clinical evaluation of the deep neural network is needed to verify the segmentation quality. Methods In this work, a novel deep neural network is trained on 300 CT and 300 artificially generated pseudo CBCTs to segment bladder, prostate, rectum and seminal vesicles from CT and cone beam CT scans. The model is evaluated on 45 CBCT and 5 CT scans through a clinical review performed by three different clinics located in Europe, North America and Australia. Results The deep learning model is scored either equally good (prostate and seminal vesicles) or better (bladder and rectum) than the structures from routine clinical practice. No or minor corrections are required for 97.5% of the segmentations of the bladder, 91.5% of the prostate, 94% of the rectum and seminal vesicles. Overall, for 82.5% of the patients none of the organs need major corrections or a redraw. Conclusion This study shows that modern deep neural networks are capable of producing clinically applicable organ segmentation for the male pelvis. The model is able to produce acceptable structures as frequently as current clinical routine. Therefore, deep neural networks can simplify the clinical workflow by offering initial segmentations. The study further shows that to retain the clinicians’ personal preferences a structure review and correction is necessary for structures both created by other clinicians and deep neural networks.

    更新日期:2019-12-20
  • Dose response and architecture in volume staged radiosurgery for large arteriovenous malformations: A multi-institutional study
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-10
    Zachary A. Seymour, Jason W. Chan, Penny K. Sneed, Hideyuki Kano, Craig A. Lehocky, Rachel C. Jacobs, Hong Ye, Tomas Chytka, Roman Liscak, Cheng-Chia Lee, Huai-che Yang, Dale Ding, Jason Sheehan, Caleb E. Feliciano, Rafael Rodriguez-Mercado, Veronica L. Chiang, Judith A. Hess, Samuel Sommaruga, Michael W. McDermott

    Background Optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. Volume-staged stereotactic radiosurgery (VS-SRS) provides an effective option for these high-risk lesions, but optimizing treatment for these recalcitrant and rare lesions has proven difficult. Methods This is a multi-centered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM with volume stages separated by intervals of 3–6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. We evaluated near complete response (nCR), obliteration, cure, and overall survival. Results With a median age of 33 years old at the time of first SRS volume stage, patients received 2–4 total volume stages and a median follow up of 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cc (range: 7.7–94.4 cc) with a median margin dose per stage of 17 Gy (range: 12–20 Gy). Total AVM volume, margin dose per stage, compact nidus, lack of prior embolization, and lack of thalamic location involvement were all associated with improved outcomes. Dose >/= 17.5 Gy was strongly associated with improved rates of nCR, obliteration, and cure. With dose >/= 17.5 Gy, 5- and 10-year cure rates were 33.7% and 76.8% in evaluable patients compared to 23.7% and 34.7% of patients with 17 Gy and 6.4% and 20.6% with <17 Gy per volume-stage (p = 0.004). Obliteration rates in diffuse nidus architecture with <17 Gy were particularly poor with none achieving obliteration compared to 32.3% with doses >/= 17 Gy at 5 years (p = 0.007). Comparatively, lesions with a compact nidus architecture exhibited obliteration rates at 5 years were 10.7% vs 9.3% vs 26.6% for dose >17 Gy vs 17 Gy vs >/=17.5 Gy. Conclusion VS-SRS is an option for upfront treatment of large AVMs. Higher dose was associated with improved rates of nCR, obliteration, and cure suggesting that larger volumetric responses may facilitate salvage therapy and optimize the chance for cure.

    更新日期:2019-12-11
  • Macrophage exclusion after radiation therapy (MERT): A new and effective way to increase the therapeutic ratio of radiotherapy
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-05
    J Martin Brown, Reena Thomas, Seema Nagpal, Lawrence Recht

    Here we review a variety of preclinical studies and a first-in-human clinical trial of newly diagnosed glioblastoma (GBM) patients that have investigated the significance of the influx of tumor associated macrophages (TAMs) into tumors after irradiation. We summarize the effects on the response of the tumors and normal tissues to radiation of various agents that either reduce the influx of TAMs into tumors after radiation or change their M1/M2 polarization. The studies show that following irradiation there is an accumulation of bone marrow derived TAMs in the irradiated tumors. These TAMs stimulate the resumption of blood flow in the irradiated tumors thereby promoting recurrence of the tumors. A key mechanism for this accumulation of TAMs is driven by the SDF-1/CXCR4 chemokine pathway though other pathways could also be involved for some tumors. Blocking this pathway to prevent the TAM accumulation in the tumors both enhances tumor response to radiation and protects irradiated tissues. A clinical trial in which the CXCR4 antagonist plerixafor was added to standard therapy of glioblastoma validated the preclinical findings by demonstrating i) reduced blood flow in the irradiated site, and ii) significantly improved tumor local control compared to GBM patients not treated with plerixafor. We conclude that macrophage exclusion after radiation therapy (MERT) is an effective way both to enhance the tumor response to radiation and to protect the irradiated normal tissues. Further clinical trials are warranted.

    更新日期:2019-12-06
  • Brain metastases from non-small cell lung cancer with EGFR or ALK mutations: A systematic review and meta-analysis of multidisciplinary approaches
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-05
    Raj Singh, Eric J. Lehrer, Stephen Ko, Jennifer Peterson, Yanyan Lou, Alyx B. Porter, Rupesh Kotecha, Paul D. Brown, Nicholas G. Zaorsky, Daniel M. Trifiletti

    Background and purpose To analyze outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases harboring EGFR or ALK mutations and examine for differences between tyrosine kinase inhibitors (TKIs) alone, radiotherapy (RT) alone (either whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS)), or combined TKIs and RT. Materials and methods Thirty studies were identified. Patients: with brain metastases from NSCLC. Intervention: initial TKIs alone with optional salvage RT, RT alone, or TKIs and RT. Control: wild-type NSCLC and TKIs alone for mutational and treatment analysis, respectively. Outcomes: overall survival (OS) and intracranial progression-free survival (PFS). Setting: studies with mutation information. Results A total of 2649 patients were included. Patients with ALK and EGFR mutations had significantly higher median OS (48.5 months, p < 0.0001; and 20.9 months; p = 0.0006, respectively) compared to wild-type patients (9.9 months). Similar median OS was noted between TKIs and RT (28.3 months), RT alone (32.2 months; p = 0.22), or TKIs alone (23.9 months; p = 0.2). Patients treated with TKIs and RT had higher median PFS (18.6 months; p = 0.06) compared to TKIs alone (13.6 months) with no difference between TKIs and RT vs. RT alone (16.9 months; p = 0.72). No PFS difference was found between WBRT and TKI (23.2 months; p = 0.72) vs. WBRT alone (24 months) or SRS and TKI (16.7 months; p = 0.56) vs. SRS alone (13.6 months). Conclusion NSCLC patients with brain metastases harboring EGFR or ALK mutations have superior OS compared to wild-type patients. No PFS or OS benefit was found with the addition of TKIs to RT.

    更新日期:2019-12-06
  • On the limitations of the area under the ROC curve for NTCP modelling
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-05
    Emanuel Bahn, Markus Alber

    The area under the ROC curve (AUC) is commonly used as a measure for the discriminative performance of NTCP models. Here, we demonstrate that for typical patient cohorts, the AUC is an unsuitable measure for that purpose since it is typically limited to values below 0.8 and it exhibits large statistical variation.

    更新日期:2019-12-05
  • Comparing deep learning-based auto-segmentation of organs at risk and clinical target volumes to expert inter-observer variability in radiotherapy planning
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-05
    Jordan Wong, Allan Fong, Nevin McVicar, Sally Smith, Joshua Giambattista, Derek Wells, Carter Kolbeck, Jonathan Giambattista, Lovedeep Gondara, Abraham Alexander

    Background Deep learning-based auto-segmented contours (DC) aim to alleviate labour intensive contouring of organs at risk (OAR) and clinical target volumes (CTV). Most previous DC validation studies have a limited number of expert observers for comparison and/or use a validation dataset related to the training dataset. We determine if DC models are comparable to Radiation Oncologist (RO) inter-observer variability on an independent dataset. Methods Expert contours (EC) were created by multiple ROs for central nervous system (CNS), head and neck (H&N), and prostate radiotherapy (RT) OARs and CTVs. DCs were generated using deep learning-based auto-segmentation software trained by a single RO on publicly available data. Contours were compared using Dice Similarity Coefficient (DSC) and 95% Hausdorff distance (HD). Results Sixty planning CT scans had 2–4 ECs, for a total of 60 CNS, 53 H&N, and 50 prostate RT contour sets. The mean DC and EC contouring times were 0.4 vs 7.7 min for CNS, 0.6 vs 26.6 min for H&N, and 0.4 vs 21.3 min for prostate RT contours. There were minimal differences in DSC and 95% HD involving DCs for OAR comparisons, but more noticeable differences for CTV comparisons. Conclusions The accuracy of DCs trained by a single RO is comparable to expert inter-observer variability for the RT planning contours in this study. Use of deep learning-based auto-segmentation in clinical practice will likely lead to significant benefits to RT planning workflow and resources.

    更新日期:2019-12-05
  • Long-term follow-up experience in anal canal cancer treated with Intensity-Modulated Radiation Therapy: Clinical outcomes, patterns of relapse and predictors of failure
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-03
    Maïlys de Meric de Bellefon, Claire Lemanski, Florence Castan, Emmanuelle Samalin, Thibault Mazard, Alexis Lenglet, Sylvain Demontoy, Olivier Riou, Carmen Llacer-Moscardo, Pascal Fenoglietto, Norbert Aillères, Simon Thezenas, Charles Debrigode, Sabine Vieillot, Sophie Gourgou, David Azria

    Background and purpose To assess the long-term outcomes of patients with squamous cell carcinoma of the anal canal (SCCAC) treated with Intensity-Modulated Radiation Therapy (IMRT). Material and methods From 2007 to 2015, 193 patients were treated by IMRT for SCCAC. Radiotherapy delivered 45 Gy in 1.8 Gy daily-fractions to the primary tumor and elective nodal areas, immediately followed by a boost of 14.4–20 Gy to the primary tumor and involved nodes. Concurrent chemotherapy with 5-FU-mitomycin (MMC) or cisplatin was added for locally advanced tumors. Survivals were estimated by Kaplan–Meier method. Locoregional (LR) relapses were precisely assessed. Prognostic factors were evaluated by uni- and multivariate analyses. Late toxicity was scored according to the Common Toxicity Criteria for Adverse Events v4.0. Results Median follow-up was 70 months (range, 1–131). Forty-nine men (25%) and 144 women (75%) were analyzed. Median age was 62 years. Tumor stages were I, II, III and IV in 7%, 24%, 63% and 6% of cases, respectively. Chemotherapy was delivered in 167 patients (87%), mainly MMC (80%). Five-year OS, DFS, CFS and LR control rates were 74%, 68%, 66% and 85%, respectively. Forty-one patients (21%) had a relapse: 22 were LR, mostly in-field (68%). Predictors for LR failure were exclusive radiotherapy, chemotherapy lacking MMC and treatment breaks >3 days. Overall late toxicity ≥grade 2 occurred in 43% of patients, with 24% grade 3 and one case of grade 4 (hematuria). Conclusion CRT with IMRT assures excellent local control in locally advanced SCCAC with manageable long-term toxicity. Multicentric prospective trials are required to reinforce those results.

    更新日期:2019-12-04
  • Dosimetric predictors of toxicity and quality of life following prostate stereotactic ablative radiotherapy
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-03
    Yasir Alayed, Melanie Davidson, Harvey Quon, Patrick Cheung, William Chu, Hans T. Chung, Danny Vesprini, Aldrich Ong, Amit Chowdhury, Stanley K. Liu, Dilip Panjwani, Joelle Helou, Hima B. Musunuru, Geordi Pang, Renee Korol, Ananth Ravi, Boyd McCurdy, Liying Zhang, Andrew Loblaw

    Purpose SABR offers an effective treatment option for clinically localized prostate cancer. Here we report the dosimetric predictors of late toxicity and quality of life (QOL) in a pooled cohort of patients from four phase II trials. Methods The combined cohort included all three prostate cancer risk groups. The prescription dose was 35–40 Gy in 5 fractions. Toxicity (CTCAE) and QOL (EPIC) were collected. Multiple dosimetric parameters for the bladder, rectum and penile bulb were collected. Univariate (UVA) followed by multivariate (MVA) logistic regression analysis was conducted to search for significant dosimetric predictors of late GI/GU toxicity, or minimal clinically important change in the relevant QOL domain. Results 258 patients were included with median follow up of 6.1 years. For QOL, bladder Dmax, V38, D1cc, D2cc, D5cc and rectal V35 were predictors of urinary and bowel MCIC on UVA. On MVA, only bladder V38 remained significant. For late toxicity, various parameters were significant on UVA but only rectal Dmax, V38 and bladder D2cc were significant predictors on MVA. Conclusions This report confirms that the high-dose regions in the bladder and rectum are more significant predictors of late toxicity and QOL after prostate SABR compared to low-dose regions. Caution must be taken to avoid high doses and hotspots in those organs.

    更新日期:2019-12-03
  • Radiotherapy in the treatment of extracranial hemangiopericytoma/solitary fibrous tumor: Study from the Rare Cancer Network
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-02
    Marco Krengli, Tiziana Cena, Thomas Zilli, Barbara A. Jereczek-Fossa, Berardino De Bari, Salvador Villa Freixa, Johannes H.A.M. Kaanders, Sara Torrente, David Pasquier, Claudio V. Sole, Myroslav Lutsyk, Fazilet O. Dincbas, Yacob Habboush, Laura Fariselli, Tatiana Dragan, Brigitta G. Baumert, Kaouthar Khanfir, Gamze Ugurluer, Juliette Thariat

    Background and purpose The role of radiotherapy (RT) in the treatment of hemangiopericytoma/solitary fibrous tumor (HPC/SFT) is still under debate. We aimed at investigating whether radiotherapy can improve the results in patients operated for extracranial HPC/SFT. Materials and methods Data from patients with HPC/SFT, treated from 1982 to 2012, were retrospectively reviewed within the Rare Cancer Network framework. Actuarial local control (LC), disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS) were calculated with Kaplan-Meyer method. Patient and tumor parameters were analyzed by univariate and multivariate analysis. Results Of 114 HPC/SFT, 58 (50.9%) occurred in the extremities/superficial trunk and 56 (49.1%) in intra-thoracic/retroperitoneum. Seventy-eight patients (68.4%) underwent surgery only (Sx), and 36 (31.6%) Sx and RT (Sx + RT). Median RT dose was 60 Gy (range 45–68.4 Gy) in 1.6–2.2 Gy fractions. In the extremities/superficial trunk group of patients, actuarial 5-year LC rates were 50.4% after Sx and 91.6% after Sx + RT (p < 0.0001) for LC, and 50.4% after Sx and 83.1% after Sx + RT (p = 0.008) for DFS. In the intra-thoracic/retroperitoneum group of patients, actuarial 5-year rates were 89.3% after Sx and 77.8% after Sx + RT (p = 0.99) for LC, and 73.8% after Sx and 77.8% after Sx + RT (p = 0.93) for DFS. At multivariate analysis, the addition of RT resulted in better LC and DFS in the whole series. The advantage was confirmed for LC in the group of patients affected by extremity/superficial trunk tumors. Conclusion Addition of RT to Sx could improve the prognosis, in terms of LC and DFS, essentially in patients with extremities/superficial trunk tumor locations.

    更新日期:2019-12-02
  • Diffusion MRI outlined viable tumour volume beats GTV in intra-treatment stratification of outcome
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-02
    Faisal Mahmood, Helle Hjorth Johannesen, Poul Geertsen, Rasmus Hvass Hansen

    Background and purpose In radiotherapy, treatment response is generally evaluated many weeks after end of the treatment course. If the treatment outcome could be predicted during radiotherapy better tumour control could be achieved through timely adaptation of the treatment strategy. In this study intra-treatment change based on the diffusion MRI outlined viable tumour volume (VTV) was assessed and compared to the standard GTV to study their outcome prediction capacity. Materials and methods Thirty-eight brain metastases from twenty-one cancer patients were analysed in this prospective trial. Diffusion and structural MRI was acquired on a 1 T machine before, during, and at follow-up 2–3 months after radiotherapy. The VTV was defined as a region with high cellularity using high b-value diffusion MRI scans. Further, the diffusivity of the VTV was derived as the apparent diffusion coefficient (ADC). Treatment outcome was determined using RECIST defined bounds in the T1W MRI follow-up scan. Longitudinal statistical analysis was performed using a linear mixed effect model. Results The GTV declined in both responding and non-responding (significantly) tumours with inseparable rates during radiotherapy. The VTV volume fraction reduced significantly in the responding tumours only. The ADC of the VTV increased significantly in responding metastases whereas it decreased in non-responding metastases. Furthermore, no association between baseline tumour size or primary disease and outcome was observed. Conclusion GTV size change during radiotherapy is not a reliable predictor of outcome in brain metastases. On the other hand, change in the volume fraction of VTV and diffusivity of VTV shows ability to stratify treatment outcome.

    更新日期:2019-12-02
  • Modelling the risk of radiation induced alopecia in brain tumor patients treated with scanned proton beams
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-12-02
    Giuseppe Palma, Alberto Taffelli, Francesco Fellin, Vittoria D'Avino, Daniele Scartoni, Francesco Tommasino, Emanuele Scifoni, Marco Durante, Maurizio Amichetti, Marco Schwarz, Dante Amelio, Laura Cella

    Purpose To develop normal tissue complication probability (NTCP) models for radiation-induced alopecia (RIA) in brain tumor patients treated with proton therapy (PT). Methods and materials We analyzed 116 brain tumor adult patients undergoing scanning beam PT (median dose 54 GyRBE; range 36–72) for CTCAE v.4 grade 2 (G2) acute (≤90 days), late (>90 days) and permanent (>12 months) RIA. The relative dose-surface histogram (DSH) of the scalp was extracted and used for Lyman-Kutcher-Burman (LKB) modelling. Moreover, DSH metrics (Sx: the surface receiving ≥ X Gy, D2%: near maximum dose, Dmean: mean dose) and non-dosimetric variables were included in a multivariable logistic regression NTCP model. Model performances were evaluated by the cross-validated area under the receiver operator curve (ROC-AUC). Results Acute, late and permanent G2-RIA was observed in 52%, 35% and 19% of the patients, respectively. The LKB models showed a weak dose-surface effect (0.09 ≤ n ≤ 0.19) with relative steepness 0.29 ≤ m ≤ 0.56, and increasing tolerance dose values when moving from acute and late (22 and 24 GyRBE) to permanent RIA (44 GyRBE). Multivariable modelling selected S21Gy for acute and S25Gy, for late G2-RIA as the most predictive DSH factors. Younger age was selected as risk factor for acute G2-RIA while surgery as risk factor for late G2-RIA. D2% was the only variable selected for permanent G2-RIA. Both LKB and logistic models exhibited high predictive performances (ROC-AUCs range 0.86–0.90). Conclusion We derived NTCP models to predict G2-RIA after PT, providing a comprehensive modelling framework for acute, late and permanent occurrences that, once externally validated, could be exploited for individualized scalp sparing treatment planning strategies in brain tumor patients.

    更新日期:2019-12-02
  • A framework for modeling radiation induced lymphopenia in radiotherapy
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-30
    Jian-Yue Jin, Todd Mereniuk, Anirudh Yalamanchali, Weili Wang, Mitchell Machtay, Feng-Ming (Spring)Kong, Susannah Ellsworth

    Introduction Associations between radiation-induced lymphopenia (RIL) and survival have been extensively reported. However, the immune system is not considered as an organ-at-risk (OAR) in radiotherapy. This study aimed to develop the framework of an immune OAR model that may be utilized to predict and minimize RIL. Methods A dynamic model was first developed for lymphocyte trafficking among 5 compartments of the immune system. Radiation dose to the circulating lymphocytes in each compartment was calculated based on the doses to fixed structures of each immune compartment and blood flow patterns. A RIL model was developed based on lymphocyte dynamics, lymphocyte radiosensitivity and reproductivity, and the dose to the lymphocytes. The model was tested in 51 patients by fitting it to weekly-measured absolute lymphocyte counts (ALC) for each patient, considering lymphocyte radiosensitivity and reproductivity as patient-dependent fitting parameters. Results The fitting was almost perfect for 20 patients, with sum of square of errors (SSE) between measured and predicted ALCs < 0.5. It was acceptable for another 27 patients, with SSE = 0.5~4.0. Only 4 patients had SSE > 4.0. The fitting also provided a method of in vivo estimation of radiosensitivity (α) for each patient. The median α was 0.40 Gy−1 for the 51 patients, consistent with in vitro measured data of 0.41 Gy−1 in the literature. Conclusion We have presented a framework of developing an immune OAR model that has the potential to predict and minimize RIL in radiotherapy.

    更新日期:2019-11-30
  • Systematic review of educational interventions to improve contouring in radiotherapy
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-28
    Jon Cacicedo, Arturo Navarro-Martin, Susana Gonzalez-Larragan, Berardino De Bari, Ahmed Salem, Max Dahele

    Background and purpose Contouring is a critical step in the radiotherapy process, but there is limited research on how to teach it and no consensus about the best method. We summarize the current evidence regarding improvement of contouring skills. Methods and materials Comprehensive literature search of the Pubmed-MEDLINE database, EMBASE database and Cochrane Library to identify relevant studies (independently examined by two investigators) that included baseline contouring followed by a re-contouring assessment after an educational intervention. Results 598 papers were identified. 16 studies met the inclusion criteria representing 370 participants (average number of participants per study of 23; range (4–141). Regarding the teaching methodology, 5/16 used onsite courses, 8/16 online courses, and 2/16 used blended learning. Study quality was heterogenous. There were only 3 randomized studies and only 3 analyzed the dosimetric impact of improving contouring homogeneity. Dice similarity coefficient was the most common evaluation metric (7/16), and in all these studies at least some contours improved significantly post-intervention. The time frame for evaluating the learning effect of the teaching intervention was almost exclusively short-time, with only one study evaluating the long-term utility of the educational program beyond 6 months. Conclusion The literature on educational interventions designed to improve contouring performance is limited and heterogenous. Onsite, online and blended learning courses have all been shown to be helpful, however, sample sizes are small and impact assessment is almost exclusively short-term and typically does not take into account the effect on treatment planning. The most effective teaching methodology/format is unknown and impact on daily clinical practice is uncertain.

    更新日期:2019-11-29
  • Utilization and factors precluding the initiation of consolidative durvalumab in unresectable stage III non-small cell lung cancer
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-28
    Narek Shaverdian, Michael D. Offin, Andreas Rimner, Annemarie F. Shepherd, Abraham J. Wu, Charles M. Rudin, Matthew D. Hellmann, Jamie E. Chaft, Daniel R. Gomez

    Durvalumab after concurrent chemoradiation has significantly improved survival in stage III non-small cell lung cancer (NSCLC). However, there is limited data evaluating the utilization and challenges to deliver durvalumab consolidation in the real world. We assessed the use of consolidative durvalumab at a large academic center to examine clinical limitations to delivery of this practice-changing regimen. We found that despite incorporating consolidative durvalumab into standard practice for stage III unresectable NSCLC, 27% patients did not initiate this treatment, largely due to disease progression or toxicity from chemoradiation.

    更新日期:2019-11-29
  • Fully automated detection of heart irradiation in cine MV images acquired during breast cancer radiotherapy
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-28
    Per Rugaard Poulsen, Mette Skovhus Thomsen, Rune Hansen, Esben Worm, Harald Spejlborg, Birgitte Offersen

    Purpose To develop robust automated detection of heart irradiation in continuous portal images (cine MV images) of tangential breast cancer treatments. Methods Cine MV images of 302 tangential field deliveries were recorded for ten left-sided breast cancer patients receiving deep-inspiration breath-hold radiotherapy. An algorithm for fully automated heart edge detection in cine MV images was developed and tested for all images. The algorithm first enhances the heart edge contrast greatly by exploiting that pixels on the heart edge change their intensity cyclically, and highly correlated, at 1–3 Hz due to heartbeat. The algorithm then detects the heart edge in the enhanced image and calculates the exposed heart area within the field aperture. Results The algorithm correctly identified the heart edge in all cine MV series with heart exposure (169 of 302 field deliveries). With conservative selection criteria the algorithm on average identified 70 heart edge pixels in the heart-including field deliveries (range: 10–230) without false positives. With less strict criteria 106 heart edge pixels were identified on average (range: 13–262) with 0.6% being false positives. The heart edge bordering the lung was segmented highly reliably even a few millimeters outside the field edge. For six patients with frequent heart irradiation, the exposed heart area showed large interfraction variations and smaller intrafraction variations. Conclusions Automated heart edge detection in cine MV images was proposed, developed and shown to be highly efficient for heart exposure detection in tangential breast fields. It may allow unsupervised surveillance of heart exposure at all tangential breast cancer treatments in a clinic.

    更新日期:2019-11-29
  • Simulated multileaf collimator tracking for stereotactic liver radiotherapy guided by kilovoltage intrafraction monitoring: Dosimetric gain and target overdose trends
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-28
    Per R. Poulsen, Ghulam Murtaza, Esben S. Worm, Thomas Ravkilde, Ricky O'Brien, Cai Grau, Morten Høyer, Paul Keall

    Purpose To investigate the potential benefit of multileaf collimator (MLC) tracking guided by kilovoltage intrafraction monitoring (KIM) during stereotactic body radiotherapy (SBRT) in the liver, and to understand trends of target overdose with MLC tracking. Methods Six liver SBRT patients with 2–3 implanted gold markers received SBRT delivered with volumetric modulated arc therapy (VMAT) in three fractions using daily cone-beam CT setup. The CTV-to-PTV margins were 5 mm in the axial plane and 10 mm in the cranio-caudal directions, and the plans were designed to give minimum target doses of 95% (CTV) and 67% (PTV). The three-dimensional marker trajectory estimated by post-treatment analysis of kV fluoroscopy images acquired throughout treatment delivery was assumed to represent the tumor motion. MLC tracking guided by real-time KIM was simulated. The reduction in CTV D95 (minimum dose to 95% of the clinical target volume) relative to the planned D95 (ΔD95) was compared between actual non-tracking and simulated MLC tracking treatments. Results MLC tracking maintained a high CTV dose coverage for all 18 fractions with ΔD95 (mean: 0.2 percentage points (pp), range: −1.7 to 1.9 pp) being significantly lower than for the actual non-tracking treatments (mean: 6.3 pp range: 0.6–16.0 pp) (p = 0.002). MLC tracking of large target motion perpendicular to the MLC leaves created dose artifacts with regions of overdose in the CTV. As a result, the mean dose in spherical volumes centered in the middle of the CTV was on average 2.4 pp (5 mm radius sphere) and 1.3 pp (15 mm radius sphere) higher than planned (p = 0.002). Conclusions Intrafraction tumor motion can deteriorate the CTV dose of liver SBRT. The planned CTV dose coverage may be restored with KIM-guided MLC tracking. However, MLC tracking may have a tendency to create hotspots in the CTV.

    更新日期:2019-11-28
  • Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-27
    Indrajit N. Fernando, Sarah J. Bowden, Kathryn Herring, Cassandra L. Brookes, Ikhlaaq Ahmed, Andrea Marshall, Robert Grieve, Mark Churn, David Spooner, Talaat N. Latief, Rajiv K. Agrawal, Adrian M. Brunt, Andrea Stevens, Andrew Goodman, Peter Canney, Jill Bishop, Diana Ritchie, Janet Dunn, Daniel W. Rea

    Background The optimal sequence of adjuvant chemotherapy and radiotherapy for breast cancer is unknown. SECRAB assesses whether local control can be improved without increased toxicity. Methods SECRAB was a prospective, open-label, multi-centre, phase III trial comparing synchronous to sequential chemo-radiotherapy, conducted in 48 UK centres. Patients with invasive, early stage breast cancer were eligible. Randomisation (performed using random permuted block assignment) was stratified by centre, axillary surgery, chemotherapy, and radiotherapy boost. Permitted chemotherapy regimens included CMF and anthracycline-CMF. Synchronous radiotherapy was administered between cycles two and three for CMF or five and six for anthracycline-CMF. Sequential radiotherapy was delivered on chemotherapy completion. Radiotherapy schedules included 40 Gy/15F over three weeks, and 50 Gy/25F over five weeks. The primary outcome was local recurrence at five and ten years, defined as time to local recurrence, and analysed by intention to treat. ClinicalTrials.gov NCT00003893. Findings Between 02-July-1998 and 25-March-2004, 2297 patients were recruited (1150 synchronous and 1146 sequential). Baseline characteristics were balanced. With 10.2 years median follow-up, the ten-year local recurrence rates were 4.6% and 7.1% in the synchronous and sequential arms respectively (hazard ratio (HR) 0.62; 95% confidence interval (CI): 0.43–0.90; p = 0.012). In a planned sub-group analysis of anthracycline-CMF, the ten-year local recurrence rates difference were 3.5% versus 6.7% respectively (HR 0.48 95% CI: 0.26–0.88; p = 0.018). There was no significant difference in overall or disease-free survival. 24% of patients on the synchronous arm suffered moderate/severe acute skin reactions compared to 15% on the sequential arm (p < 0.0001). There were no significant differences in late adverse effects apart from telangiectasia (p = 0.03). Interpretation Synchronous chemo-radiotherapy significantly improved local recurrence rates. This was delivered with an acceptable increase in acute toxicity. The greatest benefit of synchronous chemo-radiation was in patients treated with anthracycline-CMF. Funding Cancer Research UK (CR UK/98/001) and Pharmacia.

    更新日期:2019-11-28
  • Tumor mutation burden, immune checkpoint crosstalk and radiosensitivity in single-cell RNA sequencing data of breast cancer
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-22
    Bum-Sup Jang, Wonsik Han, In Ah Kim

    Introduction We analyzed transcriptional and mutational profile mainly focused on tumor mutation burden (TMB), immune checkpoint crosstalk, and radiosensitivity using scRNA-seq data derived from breast cancer and immune cells. Materials and methods scRNA-seq transcriptome data were acquired from the GEO database (GSE75688). The radiosensitivity index (RSI) was used to evaluate radiosensitivity of each cell. CD274 mRNA expression was used to surrogate PD-L1 expression status. A computational approach was utilized for the immune and tumor cell group (N = 492) to identify potential interactions between tumor and immune cells with respect to immune checkpoint ligand–receptor gene pairs. Mutation data was profiled from raw scRNA-seq data of tumor cells acquired from both primary tumor and metastatic lymph node (N = 317). TMB and mutational signatures were compared between radiosensitive (RS) and radioresistant (RR) tumor cells. Results Most RR cells were a basal subtype and showed the higher rate of PD-L1 positivity. The patients with TNBC or HER2 subtype showed increased number of immune checkpoint ligand-receptor interactions between tumor and immune cells. PD-L1 ligand–receptor interactions between tumor cells and T cells were differentially increased in patients with the HER2 subtype compared to patients with the luminal subtype. Meanwhile, CTLA-4 ligand–receptor interactions were increased in patients with the TNBC subtype. TMB was significantly higher in RR cells than RS cells. Mutational signatures including microsatellite instability (MSI) and NRF2 pathway were altered in RR cells. Conclusions RR cells exhibited a basal subtype, high PD-L1 expression, and high TMB with mutational signature found in tumors having MSI. Differential crosstalk between tumor and immune cells was associated with the patient subtype of breast cancer. These findings could be useful to identify potential biomarker(s) and optimal combination strategies of immune checkpoint blockades and radiation therapy in the management of breast cancer.

    更新日期:2019-11-22
  • A randomised assessment of image guided radiotherapy within a phase 3 trial of conventional or hypofractionated high dose intensity modulated radiotherapy for prostate cancer
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-22
    Julia Murray, Clare Griffin, Sarah Gulliford, Isabel Syndikus, John Staffurth, Miguel Panades, Christopher Scrase, Chris Parker, Vincent Khoo, Jamie Dean, Helen Mayles, Philip Mayles, Simon Thomas, Olivia Naismith, Angela Baker, Helen Mossop, Clare Cruickshank, Emma Hall, David Dearnaley

    Background and purpose Image-guided radiotherapy (IGRT) improves treatment set-up accuracy and provides the opportunity to reduce target volume margins. We introduced IGRT methods using standard (IGRT-S) or reduced (IGRT-R) margins in a randomised phase 2 substudy within CHHiP trial. We present a pre-planned analysis of the impact of IGRT on dosimetry and acute/late pelvic side effects using gastrointestinal and genitourinary clinician and patient-reported outcomes (PRO) and evaluate efficacy. Materials and methods CHHiP is a randomised phase 3, non-inferiority trial for men with localised prostate cancer. 3216 patients were randomly assigned to conventional (74 Gy in 2 Gy/fraction (f) daily) or moderate hypofractionation (60 or 57 Gy in 3 Gy/f daily) between October 2002 and June 2011. The IGRT substudy included a second randomisation assigning to no-IGRT, IGRT-S (standard CTV-PTV margins), or IGRT-R (reduced CTV-PTV margins). Primary substudy endpoint was late RTOG bowel and urinary toxicity at 2 years post-radiotherapy. Results Between June 2010 to July 2011, 293 men were recruited from 16 centres. Median follow-up is 56.9(IQR 54.3–60.9) months. Rectal and bladder dose-volume and surface percentages were significantly lower in IGRT-R compared to IGRT-S group; (p < 0.0001). Cumulative proportion with RTOG grade ≥ 2 toxicity reported to 2 years for bowel was 8.3(95% CI 3.2–20.7)%, 8.3(4.7–14.6)% and 5.8(2.6–12.4)% and for urinary 8.4(3.2–20.8)%, 4.6(2.1–9.9)% and 3.9(1.5–9.9)% in no IGRT, IGRT-S and IGRT-R groups respectively. In an exploratory analysis, treatment efficacy appeared similar in all three groups. Conclusion Introduction of IGRT was feasible in a national randomised trial and IGRT-R produced dosimetric benefits. Overall side effect profiles were acceptable in all groups but lowest with IGRT and reduced margins. ISRCTN 97182923.

    更新日期:2019-11-22
  • Dose–volume predictors of early esophageal toxicity in non-small cell lung cancer patients treated with accelerated-hyperfractionated radiotherapy
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-22
    Rebecca Bütof, Steffen Löck, Maher Soliman, Robert Haase, Rosalind Perrin, Christian Richter, Steffen Appold, Mechthild Krause, Michael Baumann

    Background and purpose Early radiation-induced esophageal toxicity (RIET) is one of the major side effects in patients with non-small cell lung cancer (NSCLC) and can be a reason for treatment interruptions. As the age of patients with NSCLC and corresponding comorbidities continue to increase, primary radiotherapy alone is a commonly used alternative treatment in these cases. The aim of the present study is to compare dosimetric and clinical parameters from the previously reported CHARTWEL trial for their ability to predict esophagitis and investigate potential differences in the accelerated and conventional fractionation arm. Material and methods 146 patients of the Dresden cohort of the randomized phase III CHARTWEL trial were included in this post-hoc analysis. Side effects were prospectively scored weekly during the first 8 weeks from start of radiotherapy. To compare both treatment arms, recorded dose–volume parameters were adjusted for the different fractionation schedules. Logistic regression was performed to predict early RIET for the entire study group as well as for the individual treatment arms. Different dosimetric and clinical parameters were tested. Results Patients receiving the accelerated CHARTWEL schedule experienced earlier and more severe esophagitis (e.g. 20.5% vs. 9.6% ≥grade 2 at week 3, respectively). In contrast, the median time period for recovery of grade 1 esophagitis was significantly longer for patients with conventional fractionation compared to the CHARTWEL group (median [range]: 21 [12–49] days vs. 15 [7–84] days, p = 0.028). In univariable logistic regression none of the dose–volume parameters showed a significant correlation with early RIET grade ≥ 2 in the conventional irradiation group. In contrast, for patients receiving CHARTWEL, the physical dose–volumes parameters V40 and V50; and re-scaled values VEQD2,50 and VEQD2,60 were significant predictors of early RIET grade ≥ 2. Dose–volume parameters remained different between CHARTWEL and conventional fractionation even after biological rescaling. Conclusion Our results show a more dominant dose-volume effect in the CHARTWEL arm compared to conventional fractionation, especially for higher esophageal doses. These findings support the notion that dose–volume parameters for radiation esophagitis determined in a specific and time dependent setting of field arrangements can not be easily transferred to another setting. In clinical practice esophageal volumes receiving 40 Gy or more should be strictly limited in hyperfractionated-accelerated fraction schemes.

    更新日期:2019-11-22
  • Variation in current prescription practice of stereotactic body radiotherapy for peripherally located early stage non-small cell lung cancer: Recommendations for prescribing and recording according to the ACROP guideline and ICRU report 91
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-22
    Evelyn E.C. de Jong, Matthias Guckenberger, Nicolaus Andratschke, Karin Dieckmann, Mischa S. Hoogeman, Maaike Milder, Ditte Sloth Møller, Tine Bisballe Nyeng, Stephanie Tanadini-Lang, Eric Lartigau, Thomas Lacornerie, Suresh Senan, Wilko Verbakel, Dirk Verellen, Geert De Kerf, Coen Hurkmans

    Background and purpose In 2017 the ACROP guideline on SBRT for peripherally located early stage NSCLC was published. Later that year ICRU-91 about prescribing, recording and reporting was published. The purpose of this study is to quantify the current variation in prescription practice in the institutions that contributed to the ACROP guideline and to establish the link between the ACROP and ICRU-91 recommendations. Material and methods From each of the eight participating centres, 15 SBRT plans for stage I NSCLC were analyzed. Plans were generated following the institutional protocol, centres prescribed 3 × 13.5 Gy, 3 × 15 Gy, 3 × 17 Gy or 3 × 18 Gy. Dose parameters of the target volumes were reported as recommended by ICRU-91 and also converted to BED10Gy. Results The intra-institutional variance in D98%, Dmean and D2% of the PTV and GTV/ITV is substantially smaller than the inter-institutional spread, indicating well protocollised planning procedures are followed. The median values per centre ranged from 56.1 Gy to 73.1 Gy (D2%), 50.4 Gy to 63.3 Gy (Dmean) and 40.5 Gy to 53.6 Gy (D98%) for the PTV and from 57.1 Gy to 73.6 Gy (D2%), 53.7 Gy to 68.7 Gy (Dmean) and 48.5 Gy to 62.3 Gy (D98%) for the GTV/ITV. Comparing the variance in PTV D98% with the variance in GTV Dmean per centre, using an F-test, shows that four centres have a larger variance in GTV Dmean, while one centre has a larger variance in PTV D98% (p values <0.01). This shows some centres focus on achieving a constant PTV coverage while others aim at a constant GTV coverage. Conclusion More detailed recommendations for dose planning and reporting of lung SBRT in line with ICRU-91 were formulated, including a minimum PTV D98% of 100 Gy BED10Gy and minimum GTV/ITV mean dose of 150 Gy BED10Gy and a D2% in the range of 60–70 Gy.

    更新日期:2019-11-22
  • Local and regional treatment response by 18FDG-PET-CT-scans 4 weeks after concurrent hypofractionated chemoradiotherapy in locally advanced NSCLC
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-22
    Judi N.A. van Diessen, Matthew La Fontaine, Michel M. van den Heuvel, Erik van Werkhoven, Iris Walraven, Wouter V. Vogel, José S.A. Belderbos, Jan-Jakob Sonke

    Background and purpose To investigate associations of early post-treatment 18Fluorodeoxyglucose-positron-emission-tomography (FDG-PET)-scans with local (LF), regional (RF), distant failure (DF) and overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC)-patients treated with concurrent chemoradiotherapy. Materials and methods Forty-seven stage IIIA-B NSCLC-patients included in a randomized phase II-trial (NTR2230) received 66 Gy (24x2.75 Gy) with low dose Cisplatin +/− Cetuximab. FDG-PET-scans were performed at baseline and 4 weeks post-treatment (range, 1.6–10.1). SUVmax, SUVmean, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and gross tumor volume were calculated separately for the primary tumor and the involved lymph nodes to generate baseline, post-treatment, and relative response metrics defined as (metricpre-metricpost)/metricpre. Univariable cox regression analyses were performed to investigate associations between PET-metrics and outcomes. Results Metrics resulted from the post-treatment scan and relative response were associated with outcome, but baseline metrics were not. Primary tumor metrics were stronger associated with all outcomes than lymph node metrics. Both the volumetric (TLG/MTV) and intensity (SUVmax/SUVmean) PET-metrics were associated with OS. The intensity metrics were associated with LF, while the volumetric PET-metrics were associated with RF/DF. This was in contrast to the nodal metrics, demonstrating only an association between RF and the relative response of TLG/MTV. No preference was found between PET volumetric and intensity metrics associated with outcome. Conclusion Early post-treatment PET-metrics are associated with treatment outcome in LA-NSCLC patients treated with chemoradiotherapy. Both volumetric and intensity PET-metrics are useful, but more for the primary tumor than for lymph nodes.

    更新日期:2019-11-22
  • The impact of baseline shifts towards the heart after image guidance on survival in lung SABR patients
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-15
    Corinne Johnson-Hart, Gareth Price, Eliana Vasquez Osorio, Corinne Faivre-Finn, Marcel van Herk

    Background and purpose A recent study of NSCLC patients showed small residual shifts of the high dose region towards/away from the heart after image-guidance were significantly related to overall survival. This study investigates whether the effect is observed in a SABR cohort, who have significantly different baseline outlook and are treated using an imaging protocol matching on the tumour rather than bony-anatomy alone. Materials and methods 136 NSCLC patients treated with SABR were studied. The mean baseline shift of the tumour in the direction of the heart over the course of treatment was determined for each patient and used to categorise patients into risk groups. Kaplan-Meier survival curves were plotted and multivariable analysis performed to assess significance of the vector shift to the heart alongside common clinical variables. Results The vector shift to the heart was independent of all tested clinical variables. A significant difference was seen in patient survival, with patients with shifts towards the heart having significantly worse prognosis as compared to patients with shifts away. Multivariable analysis found a hazard ratio of 1.262 per mm (p = 0.013) for the vector shift to the heart, i.e. for every 1 mm shift of the high dose region towards the heart there is a 1.262 higher chance of death. Conclusions Baseline shifts towards the heart significantly correlate with overall survival in a cohort of NSCLC SABR patients, with increased risk with increasing shifts towards the heart. These results provide further evidence for the use of stricter heart dose planning constraints for thoracic radiotherapy and suggest a heart planning organ at risk volume may be required for SABR treatments to account for baseline shifts.

    更新日期:2019-11-15
  • Axial cortical involvement of metastatic lesions to identify impending femoral fractures; a clinical validation study
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-14
    C.W.P.G. van der Wal, F.E. Eggermont, M. Fiocco, H.M. Kroon, O. Ayu, A. Slot, A. Snyers, T. Rozema, N.J.J. Verdonschot, P.D.S. Dijkstra, E.J. Tanck, Y.M. van der Linden

    Background and purpose Patients with advanced cancer may develop painful bone metastases, potentially resulting in pathological fractures. Adequate fracture risk assessment is of key importance to prevent fracturing and maintain mobility. This study aims to validate the clinical reliability of axial cortical involvement with a 30 mm threshold on conventional radiographs to assess fracture risk in femoral bone metastases. Materials and methods All patients with bone metastases who received radiotherapy for pain included in two multicentre prospective studies were selected. Conventional radiographs obtained at a maximum of two months prior to radiotherapy were collected. Three experts independently measured lesions and scored radiographic characteristics. Sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were calculated. Results Hundred patients were included with a median follow-up of 23.0 months (95%CI: 10.6–35.5). Two fractures occurred in lesions with axial cortical involvement <30 mm, and 12 in lesions ≥30 mm. Sensitivity, specificity, PPV and NPV of axial cortical involvement for predicting femoral fractures were 86%, 50%, 20% and 96%, respectively. Patients with lesions ≥30 mm had a 5.3 times higher fracture risk than patients with smaller lesions. Conclusion Our validation study confirmed the use of 30 mm axial cortical involvement to assess fracture risk in femoral bone metastases. Until a more accurate and practically feasible method has been developed, this clinical parameter remains an easy method to assess femoral fracture risk to aid patients and clinicians to choose the optimal individual treatment modality.

    更新日期:2019-11-14
  • Health-related quality of life after prophylactic cranial irradiation for stage III non-small cell lung cancer patients: Results from the NVALT-11/DLCRG-02 phase III study
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-14
    W.J.A. Witlox, B.L.T. Ramaekers, M.A. Joore, A.-M.C. Dingemans, J. Praag, J. Belderbos, C. Tissing-Tan, G. Herder, T. Haitjema, J.F. Ubbels, J. Lagerwaard, S.Y. El Sharouni, J.A. Stigt, E.F. Smit, H. van Tinteren, V. van der Noort, H.J.M. Groen, D.K.M. De Ruysscher

    Background and purpose The NVALT-11/DLCRG-02 phase III trial (clinicaltrials.gov identifier: NCT01282437) showed that, after standard curative intent treatment, prophylactic cranial irradiation (PCI) decreased the incidence of symptomatic brain metastases (BM) in stage III non-small cell lung cancer (NSCLC) patients compared to observation. In this study we assessed the impact of PCI on health-related quality of life (HRQoL). In addition, an exploratory analysis was performed to assess the impact of neurocognitive symptoms and symptomatic BM on HRQoL. Materials and methods Stage III NSCLC patients were randomized between PCI and observation. HRQoL was measured using the EuroQol 5D (EQ-5D-3L), EORTC QLQ-C30 and QLQ-BN20 instruments at completion of standard curative intent treatment and 4 weeks, 3, 6, 12, 24 and 36 months thereafter. Generalized linear mixed effects (GLM) models were used to assess the impact of PCI compared to observation over time on three HRQoL metrics: the EORTC QLQ-C30 global health status and the EQ-5D-3L utility and visual analogue scale (EQ VAS) scores. Results In total, 86 and 88 patients were included in the PCI and observation arm, with a median follow-up of 48.5 months (95% CI 39–54 months). Baseline mean HRQoL scores were comparable between the PCI and observation arm for the three HRQoL metrics. In the GLM models, none of the HRQoL metrics were clinically relevant or statistically significantly different between the PCI and the observation arm (p-values ranged between 0.641 and 0.914). Conclusion No statistically significant nor a clinically relevant impact of PCI on HRQoL was observed.

    更新日期:2019-11-14
  • Heterogeneity in tumours: Validating the use of radiomic features on 18F-FDG PET/CT scans of lung cancer patients as a prognostic tool
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-14
    Marie Manon Krebs Krarup, Lotte Nygård, Ivan Richter Vogelius, Flemming Littrup Andersen, Gary Cook, Vicky Goh, Barbara Malene Fischer

    Aim The aim was to validate promising radiomic features (RFs)1 on 18F-flourodeoxyglucose positron emission tomography/computed tomography-scans (18F-FDG PET/CT) of non-small cell lung cancer (NSCLC) patients undergoing definitive chemo-radiotherapy. Methods 18F-FDG PET/CT scans performed for radiotherapy (RT) planning were retrieved. Auto-segmentation with visual adaption was used to define the primary tumour on PET images. Six pre-selected prognostic and reproducible PET texture -and shape-features were calculated using texture respectively shape analysis. The correlation between these RFs and metabolic active tumour volume (MTV)3, gross tumour volume (GTV)4 and maximum and mean of standardized uptake value (SUV)5 was tested with a Spearman's Rank test. The prognostic value of RFs was tested in a univariate cox regression analysis and a multivariate cox regression analysis with GTV, clinical stage and histology. P-value ≤ 0.05 were considered significant. Results Image analysis was performed for 233 patients: 145 males and 88 females, mean age of 65.7 and clinical stage II-IV. Mean GTV was 129.87 cm3 (SD 130.30 cm3). Texture and shape-features correlated more strongly to MTV and GTV compared to SUV-measurements. Four RFs predicted PFS in the univariate analysis. No RFs predicted PFS in the multivariate analysis, whereas GTV and clinical stage predicted PFS (p = 0.001 and p = 0.008 respectively). Conclusion The pre-selected RFs were insignificant in predicting PFS in combination with GTV, clinical stage and histology. These results might be due to variations in technical parameters. However, it is relevant to question whether RFs are stable enough to provide clinically useful information.

    更新日期:2019-11-14
  • MRI-based IMPT planning for prostate cancer
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-14
    Nicolas Depauw, Jani Keyriläinen, Sami Suilamo, Lizette Warner, Karl Bzdusek, Christine Olsen, Hanne Kooy

    Purpose Treatment planning for proton therapy requires the relative proton stopping power ratio (RSP) information of the patient for accurate dose calculations. RSP are conventionally obtained after mapping of the Hounsfield units (HU) from a calibrated patient computed tomography (CT). One or multiple CT are needed for a given treatment which represents additional, undesired dose to the patient. For prostate cancer, magnetic resonance imaging (MRI) scans are the gold standard for segmentation while offering dose-less imaging. We here quantify the clinical applicability of converted MR images as a substitute for intensity modulated proton therapy (IMPT) treatment of the prostate. Methods MRCAT (Magnetic Resonance for Calculating ATtenuation) is a Philips-developed technology which produces a synthetic CT image consisting of five HU from a specific set of MRI acquisitions. MRCAT and original planning CT data sets were obtained for ten patients. An IMPT plan was generated on the MRCAT for each patient. Plans were produced such that they fulfill the prostate protocol in use at Massachusetts General Hospital (MGH). The plans were then recomputed onto the nominal planning CT for each patient. Robustness analyses (±5 mm setup shifts and ±3.5 % range uncertainties) were also performed. Results Comparison of MRCAT plans and their recomputation onto the planning CT plan showed excellent agreement. Likewise, dose perturbations due to setup shifts and range uncertainties were well within clinical acceptance demonstrating the clinical viability of the approach. Conclusions This work demonstrate the clinical acceptability of substituting MR converted RSP images instead of CT for IMPT planning of prostate cancer. This further translates into higher contouring accuracy along with lesser imaging dose.

    更新日期:2019-11-14
  • Assessment of risk factors associated with development of oronasal fistula as a late complication after carbon-ion radiotherapy for head and neck cancer
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-13
    Tapesh Bhattacharyya, Masashi Koto, Hiroaki Ikawa, Kazuhiko Hayashi, Yasuhito Hagiwara, Hiroshi Tsuji

    Background Oronasal fistulae (ONF) are one of the rare but serious complications of conventional photon radiotherapy. This study aimed to identify the risk factors for the development of ONF after carbon-ion radiotherapy (C-ion RT). Materials and Methods The data of 62 cases of sinonasal and oral cavity cancers treated with C-ion RT and followed-up in excess of 5 years were retrospectively reviewed. The correlation between the clinical and dosimetric parameters and the development of ONF was analysed. Results A total of 80.6% cases had sinonasal malignancies, and most tumours had advanced T stages (96.8%). Maxillary invasion was observed in 16 cases (25.8%), and malignant melanoma was the most common histology (46.8 %). All the cases received a dose of between 57.6 Gy (RBE) and 64 Gy (RBE) in 16 fractions over 4 weeks. At a median follow up of 88.8 months, 23 cases (37.1%) developed small localised ONF; however, none were of grade III severity. On separate multivariate analyses of clinical parameters in the entire cohort and in cases without maxillary invasion, the number of teeth irradiated with more than 50 Gy (RBE) was found to be the common significant independent risk factor for development of ONF. Conclusion The number of teeth irradiated with more than 50 Gy (RBE) is a significant independent risk factor for the development of ONF, which is a late complication of C-ion RT delivered in 16 fractions.

    更新日期:2019-11-13
  • The risk of distant metastases in rectal cancer managed by a watch-and-wait strategy – A systematic review and meta-analysis
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-08
    Joanna Socha, Lucyna Kępka, Wojciech Michalski, Karol Paciorek, Krzysztof Bujko

    Background The watch-and-wait (w&w) strategy is associated with frequent local regrowth (LR). Distant metastases (DM) occur more often in the patients with LR than in those without. However, it is unknown whether omitting immediate surgery results in the additional risk of DM. Materials/methods A systematic review and meta-analysis were performed to determine the maximum risk of additional DM. To estimate this, we used data showing the proportions of DM in patients with and without LR, assuming that the excess DM in patients with LR may develop in two ways: from subclinical DM already present at baseline and due to seeding from the uncontrolled primary tumor, and that the incidence of subclinical DM at baseline in the LR subgroup is at least not lower than in the non-LR subgroup. Based on the calculated rate of excess DM in the LR subgroup we have obtained the rate for the whole group of patients undergoing w&w. Results The maximum estimated risk of additional DM was 3.0% (95% CI: 1.2–4.9%) in the total group. After correction for short follow-up, the maximum risk at 5 years was 6.5%. Thus, the risk of excess DM is between 0% and 6.5%. Other evidence from a systematic review and the conservative assumptions taken for the calculation of the correction suggest that this maximum risk may be overestimated. Conclusions The additional risk of DM seems to be low. However, the high probability of bias, heterogeneity of the patients’ population and low quality of evidence make our estimation uncertain.

    更新日期:2019-11-11
  • A prospective, multi-centre trial of multi-parametric MRI as a biomarker in anal carcinoma
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-08
    Michael Jones, George Hruby, Catherine Coolens, Brandon Driscoll, Peter Stanwell, Mahesh Kumar, Anne Capp, Swetha Sridharan, Jameen Arm, Sarah Gallagher, Carl Holder, Christopher Oldmeadow, Jarad Martin

    Background and purpose To investigate the role of multi-parametric magnetic resonance imaging (MP-MRI) as a biomarker for squamous cell carcinoma of the anal canal (SCCAC). Materials and methods From January 2013 to January 2017, 25 patients with non-metastatic SCCAC were enrolled in a multi-centre prospective clinical trial, of whom 20 completed protocol treatment. MP-MRIs, incorporating diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) sequences, were performed before (baseline), during the second and fourth weeks of chemo-radiotherapy (CRT), and 8 weeks following treatment completion. Histogram analysis of multi-parametric maps generated maximum, mean, median, minimum, skewness, kurtosis, and standard deviation metrics. Exact logistic regression and ROC AUC analyses were performed for each metric at every timepoint. An elastic net LASSO logistic regression was also performed using all measures at each timepoint. Results With a median follow up of 17.1 months, 3/20 patients had a local recurrence, and 5/20 had any recurrence. Several apparent diffusion coefficient (ADC) metrics extracted from DW-MRIs correlated with local recurrence and demonstrated excellent discrimination: baseline skewness (p = 0.04, ROC AUC 0.90) and standard deviation (SD) (p = 0.02, ROC AUC 0.90), week 2 skewness (p = 0.02, ROC AUC 0.91) and SD (p = 0.01, ROC AUC 0.94), week 4 kurtosis (p = 0.01, AUC 0.92) and SD (p = 0.01, ROC AUC 0.96). Changes in minimum ADC between baseline and week 2 (p = 0.02, ROC AUC 0.94) and baseline and week 4 (p = 0.02, ROC AUC 0.94) were prognostic for local recurrence. For prediction of any recurrence, ADC minimum (p = 0.02, ROC AUC 0.87) and SD (p = 0.01, ROC AUC 0.85) at baseline, and ADC maximum (p = 0.03, ROC AUC 0.77) and SD (p = 0.02, ROC AUC 0.81) at week 4 were significant. On LASSO logistic regression, ADC minimum and SD at baseline were retained for any recurrence. The only significant finding for DCE-MRI was a correlation of k-trans min at the second follow-up with local recurrence (p = 0.05, AUC 0.84). Conclusion Several ADC parameters at various time points correlate with recurrence suggesting DW-MRI is a potential biomarker for SCCAC.

    更新日期:2019-11-11
  • Prognostic factors for local control and survival for inoperable pulmonary colorectal oligometastases treated with stereotactic body radiotherapy
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-09
    Aman Sharma, Sarah Baker, Marloes Duijm, Esther Oomen-de Hoop, Robin Cornelissen, Cornelis Verhoef, Mischa Hoogeman, Joost Jan Nuyttens

    Purpose The study aimed to evaluate overall survival and local control, and to identify factors independently associated with overall survival (OS) and local control (LC). Materials and methods This retrospective study examined 118 patients with primary colorectal cancer, in whom 202 inoperable pulmonary oligometastases were treated with stereotactic body radiotherapy between 2005 and 2015. Primary endpoint was to evaluate OS and identify prognostic factors associated with OS. Secondary aim was to evaluate LC and identify prognostic factors associated with LC. Results Median follow-up was 31 months (range 3–88 months). Median OS was 39.2 months (95% CI 34.8–43.6 months). Two-, three-, and five-year OS was 69%, 55% and 36%, respectively. LC at 2-, 3-, and 5-year was 83%, 81% and 77% respectively. Factors independently associated with OS in the multivariable analysis included BED10 ≥ 100 Gy (HR 0.52), male gender (HR 0.52), age < 70 years (HR 0.52) and presence of single metastasis (HR 0.37). BED10 < 100 Gy (HR 3.67) and pre-SBRT chemotherapy (HR 2.66) were independently associated with poor LC in a multivariable analysis. Conclusions SBRT was associated with 2- year OS of 69% and 2-year LC of 83%. SBRT dose ≥ 100 Gy BED10 was independently associated with both better overall survival and local control.

    更新日期:2019-11-11
  • Microscopic intramural extension of rectal cancer after neoadjuvant chemoradiation: A meta-analysis based on individual patient data
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-09
    An-Sofie Verrijssen, José Guillem, Rodrigo Perez, Krzysztof Bujko, Nathalie Guedj, Angelita Habr-Gama, Ruud Houben, Danny Goudkade, Jarno Melenhorst, Jeroen Buijsen, Ben Vanneste, Heike I. Grabsch, Murillo Bellezzo, Gabriel Paiva Fonseca, Frank Verhaegen, Maaike Berbee, Evert J. Van Limbergen

    Objective In selected rectal cancer patients with residual local disease following neoadjuvant chemoradiation (CRT) and the preference of an organ preservation pathway, additional treatment with dose escalation by endoluminal radiotherapy (RT) may ultimately result in a clinical complete response. To date, the widespread introduction of selective endoluminal radiation techniques is hampered by a lack of evidence-based guidelines that describe the radiation treatment volume in relation to the residual tumor mass. In order to convert an incomplete response into a complete one with additional treatment such as dose-escalation with endoluminal RT from a theoretical perspective, it seems important to treat all remaining microscopic tumor cells after CRT. In this setting, residual tumor extension beneath normal appearing mucosa (microscopic intramural spread – MIS) becomes relevant for accurate tumor volume and margin estimation. With the goal of providing evidence-based guidelines that define an appropriate treatment volume and patient selection, we present results from a meta-analysis based on individual patient data of studies that have assessed the extent or range of MIS of rectal cancers after neoadjuvant CRT. This meta-analysis should provide an estimate of the residual tumor volume/extension that needs to be targeted by any additional radiation therapy boost in order to achieve complete tumor eradication after initial incomplete or near-complete response following standard CRT. Methods and materials A PubMed search was performed. Additional articles were selected based on identification from reference lists. Papers were eligible when reporting MIS in patients who were treated by total mesorectal excision or local excision/transanal endoscopic microsurgery (TEM) after neo-adjuvant long-course CRT. The mean MIS was calculated for the entire group along with the 70th until 95th percentiles. Additional exploratory subgroup analyses were performed. Results Individual patient data from 349 patients with residual disease from five studies were analyzed. 80% of tumors showed no MIS. In order to appropriately treat MIS in 95% of rectal cancer patients after CRT, a margin of 5.5 mm around the macroscopic tumor would suffice. An exploratory subgroup analysis showed that T-stage after CRT (ypT) and time interval between neoadjuvant CRT and surgery are significant factors predicting the extent of MIS (p < 0.001.) The group of ypT1 had the smallest MIS, followed by the ypT3-4 group, while the ypT2 group had the largest MIS (p < 0.001). Regarding time interval between CRT and surgery, a statistically significant difference was seen when comparing the three time-interval groups (less than 8 weeks, 8–12 weeks, and more than 12 weeks), where waiting more than 12 weeks after CRT resulted in the largest MIS (p < 0.0001). Conclusion Based on this meta-analysis, in order to treat the MIS for 95% of rectal cancer patients after CRT, a Clinical Target Volume (CTV) margin of 5.5 mm from the lateral most edge of the macroscopic tumor would suffice. 80% of tumors showed no MIS and would not require an extra CTV margin for treatment. These findings support the feasibility of localized radiotherapy boosts for dose-escalation to improve response among patients with incomplete response after standard CRT and can also be applied in the surgical setting.

    更新日期:2019-11-11
  • RBE-weighted dose conversions for carbon ionradiotherapy between microdosimetric kinetic model and local effect model for the targets and organs at risk in prostate carcinoma
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-08
    Weiwei Wang, Zhijie Huang, Yinxiangzi Sheng, Jingfang Zhao, Kambiz Shahnazi, Qing Zhang, Guoliang Jiang

    Background and purpose The aim of this study was to establish curves for the conversion of RBE-weighted doses for targets and organs at risk (OARs) from the microdosimetric kinetic model (MKM) calculation to that of the local effect model I (LEM) for carbon ion radiotherapy (CIRT) for prostate carcinoma (PCA). Materials and methods This study was performed in the experimental treatment planning system (eTPS, V8A, Raystation, Sweden), which incorporates both MKM and LEM. CIRT plans from 10 PCA patients were collected. There were 5 steps to establish the curves: (1) design MKM plans in eTPS; (2) recalculate the physical doses from MKM to LEM and create a LEM plan in eTPS; (3) plot the RBE-weighted MKM to LEM conversion curves; (4) convert the MKM rectum constraint dose volume histogram (DVH) from NIRS to a LEM DVH; and (5) compare patients’ rectum DVHs and follow-up with the converted constraint DVH. Results The conversion factors for MKM doses of 0.18 Gy (RBE) to 4.55 Gy (RBE) per fraction to LEM doses were 2.72–1.06. For fraction sizes of >1 Gy (RBE), the conversion factors matched Fossati’s curve and for fraction sizes of <1.00 Gy (RBE) the values were on the extrapolated Fossati’s curve. A LEM rectum constraint DVH was established. Ten patients’ rectum DVHs were all lower than LEM constraint DVHs. No complications were reported clinically. Conclusion For PCA receiving CIRT, the RBE-weighted doses using MKM for targets and OARs could be converted to LEM doses using conversion curves.

    更新日期:2019-11-11
  • Prognostic importance of radiologic extranodal extension in HPV-positive oropharyngeal carcinoma and its potential role in refining TNM-8 cN-classification
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-08
    Shao Hui Huang, Brian O'Sullivan, Jie Su, Eric Bartlett, John Kim, John N. Waldron, Jolie Ringash, John R. de Almeida, Scott Bratman, Aaron Hansen, Andrew Bayley, John Cho, Meredith Giuliani, Andrew Hope, Ali Hosni, Anna Spreafico, Lillian Siu, Douglas Chepeha, Eugene Yu

    Purpose This study examines outcome heterogeneity and potential to refine the TNM-8 cN-classification using radiologic extranodal extension (rENE) in a contemporary HPV-positive (HPV+) oropharyngeal carcinoma (OPC) cohort. Methods All HPV+ OPC treated with definitive IMRT from 2010-2015 were included. Pre-treatment CT/MR of cN+ cases were reviewed by a head-neck radiologist for rENE. Overall survival (OS) and disease-free survival (DFS) were compared between rENE-positive (rENE+) vs rENE-negative (rENE−). Multivariable analysis (MVA) for OS confirmed the prognostic value of rENE. Refined cN-classifications for new TNM staging proposals were evaluated against TNM-8 using established criteria. Results A total of 517 cN+ (rENE+: 97; rENE−: 420) and 41 cN0 cases were identified. The rENE+ proportion increased with rising N-category (N1/N2/N3: 11%/19%/84%, p < 0.001). Median follow-up was 5.1 years. Compared to rENE−, rENE+ patients had a lower 5-year OS (56% vs 85%) and DFS (46% vs 83%) overall, and in N1 (OS: 57% vs 89%; DFS: 51% vs 87%) and N2 subsets (OS: 45% and 76%; DFS: 33% vs 74%) (all p < 0.001). MVA confirmed the prognostic value of rENE for OS (HR = 3.86, p < 0.001) and DFS (HR = 3.89, p < 0.001). We proposed two new cN-classifications: Schema1 reclassified any N_rENE+ as New_N3; Schema2 reclassified N1_rENE+ as New_N2 and N2_rENE+ as New_N3. Stage incorporating either Schema1 (ranked 1st) or Schema2 (ranked 2nd) cN-categories outperformed TNM-8. Conclusion This study confirms that rENE is prognostically important and facilitates understanding of known outcome heterogeneity within TNM-8 in HPV+ OPC patients. rENE is a promising parameter to refine the TNM-8 cN-classifications.

    更新日期:2019-11-11
  • Stereotactic MR-guided adaptive radiation therapy for peripheral lung tumors
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-11-09
    Tobias Finazzi, Miguel A. Palacios, Cornelis J.A. Haasbeek, Marjan A. Admiraal, Femke O.B. Spoelstra, Anna M.E. Bruynzeel, Berend J. Slotman, Frank J. Lagerwaard, Suresh Senan

    Background and purpose We studied the benefits of using stereotactic MR-guided adaptive radiation therapy (SMART) for delivery of SABR in peripherally located lung tumors. Methods and materials Twenty-three patients (25 peripheral lung tumors) underwent SMART in 3–8 fractions on an MR Linac or Cobalt-60 system. Before each fraction, a breath-hold MR scan was acquired, followed by on-table plan adaptation based on the anatomy-of-the-day. Breath-hold gated delivery was performed under continuous MR-guidance using an in-room monitor. Benefits of on-table adaptation were studied by comparing 112 «predicted» plans, which are the baseline plans recalculated on the anatomy-of-the-day, with the on-table reoptimized plans. Results The full SMART procedure took a median of 48 and 62 minutes on the MR Linac and Cobalt-60 system, respectively. Median SMART-PTVs were 9.5 cm3 (range, 3.1–55.6). In 14 patients who had undergone a free-breathing 4DCT, SMART-PTVs measured 53.7% (range, 31.9–75.0) of PTVs that would have been generated using a motion-encompassing internal target volume approach. On-table adaptation improved prescription dose coverage of the PTV from a median of 92.1% in predicted plans, to 95.0% in reoptimized ones, thereby increasing the proportion of fractions delivering ≥100 Gy (BED10Gy) to 95% of PTV, from 90.2% to 100.0%. Conclusion Delivery of gated breath-hold SABR using MR-guidance resulted in significantly smaller target volumes than would have been the case with an ITV-based approach. Although on-table adaptation ensured delivery of ablative doses in all fractions, the dosimetric benefits were modest, suggesting that daily online plan adaptation may not benefit most patients with peripheral lung tumors.

    更新日期:2019-11-11
  • Intrapulmonary percussive ventilation leading to 20-minutes breath-hold potentially useful for radiation treatments
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-10-25
    Nicolas Audag, Geneviève Van Ooteghem, Giuseppe Liistro, Armand Salini, Xavier Geets, Gregory Reychler

    We developed a training protocol based on Intrapulmonary Percussive Ventilation in order to prolong breath-hold while nearly suppressing the thorax motion. This protocol allowed ten subjects to achieve a 20-minutes-breath-hold, while reducing the residual surface motion to 1 mm around its mean position for more than 95% of the breath-hold duration.

    更新日期:2019-10-25
  • Radiomic signature: A novel magnetic resonance imaging-based prognostic biomarker in patients with skull base chordoma
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-10-25
    Wei Wei, Ke Wang, Zhenyu Liu, Kaibing Tian, Liang Wang, Jiang Du, Junpeng Ma, Shuo Wang, Longfei Li, Rui Zhao, Luo Cui, Zhen Wu, Jie Tian

    Background and purpose We used radiomic analysis to establish a radiomic signature based on anatomical magnetic resonance imaging (MRI) sequences and explore its effectiveness as a novel prognostic biomarker for skull base chordoma (SBC). Materials and methods In this retrospective study, radiomic analysis was performed using preoperative axial T1 FLAIR, T2-weighted, and enhanced T1 FLAIR from a single hospital. The primary clinical endpoint was progression-free survival. A total of 1860 3-D radiomic features were extracted from manually segmented region of interest. Pearson correlation coefficient was used for feature dimensional reduction and a ridge regression-based Cox proportional hazards model was used to determine a radiomic signature. Afterwards, radiomic signature and nine other potential prognostic factors, including age, gender, histological subtype, dural invasion, blood supply, adjuvant radiotherapy, extent of resection, preoperative KPS, and postoperative KPS were analyzed to build a radiomic nomogram and a clinical model. Finally, we compared the nomogram with each prognostic factor/model by DeLong’s test. Results A total of 148 SBC patients were enrolled, including 64 with disease progression. The median follow-up time was 52 months (range 4–122 months). The Harrell’s concordance index of the radiomic signature was 0.745 (95% CI, 0.709–0.781) for the validation cohort, and its discrimination accuracy in predicting progression risk at 5 years in the same cohort was 82.4% (95% CI, 72.6–89.7%). Conclusions The radiomics is a low-cost, non-invasive method to predict SBC prognosis preoperatively. Radiomic signature is a potential prognostic biomarker that may allow the individualized evaluation of patients with SBC.

    更新日期:2019-10-25
  • ESTRO ACROP consensus guideline on the use of image guided radiation therapy for localized prostate cancer
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-10-23
    Pirus Ghadjar, Claudio Fiorino, Per Munck af Rosenschöld, Michael Pinkawa, Thomas Zilli, Uulke A. van der Heide

    Use of image-guided radiation therapy (IGRT) helps to account for daily prostate position changes during radiation therapy for prostate cancer. However, guidelines for the use of IGRT are scarce. An ESTRO panel consisting of leading radiation oncologists and medical physicists was assembled to review the literature and formulate a consensus guideline of methods and procedure for IGRT in prostate cases. Advanced methods and procedures are also described which the committee judged relevant to further improve clinical practice. Moreover, ranges for margins for the three most popular IGRT scenarios have been suggested as examples.

    更新日期:2019-10-24
  • PSMA-PET guided dose-escalated volumetric arc therapy (VMAT) for newly diagnosed lymph node positive prostate cancer: Efficacy and toxicity outcomes at two years
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-10-23
    Thomas Philip Shakespeare, Elizabeth Eggert, Maree Wood, Justin Westhuyzen, Kirsty Turnbull, Natalie Rutherford, Noel Aherne

    Purpose/objectives There are no published reports of prostate specific membrane antigen (PSMA) positron emission tomography (PET) guided dose-escalated intensity-modulated radiation therapy (DE-IMRT) in newly diagnosed lymph node (LN) positive prostate cancer. We report early toxicity and efficacy outcomes with this approach. Materials/methods Patients with newly diagnosed high-risk prostate cancer were staged using PSMA PET, computed tomography (CT) and bone scans. Patients with LN positive-only metastases were offered curative therapy using 3 months androgen deprivation therapy (ADT) followed by DE-IMRT (using volumetric arc therapy), and 3 years adjuvant ADT. All patients had fiducial marker insertion, with privately insured patients having spacer hydrogel insertion. PET and prostate magnetic resonance imaging were fused with the planning CT. We aimed to deliver 81 Gy in 45 fractions (Fx) to the prostate and PET-positive LNs, and 60 Gy in 45Fx to bilateral elective pelvic LNs. Results In all, 46 patients were treated, with 83% Gleason 8–10, 67% T3/T4, median number of LNs 2 (range 1–6), and median PET-positive LN volume 1.14 cc (range 0.15–4.14). LNs were outside of standard contouring guidelines in 37% of patients. The mean PET-positive LN clinical target volume dose ranged from 73.3 to 85.9 Gy (median 83.6 Gy). With 24 months median follow-up, two year failure-free survival was 100%, and 2 year overall survival 95.7%. Acute grade 1 and 2 GI toxicity occurred in 48 and 11% of patients, and GU toxicity in 72 and 24%. Late grade 1, 2 and 3 GI toxicity occurred in 13, 2 and 0%, and GU toxicity 28, 13 and 4%. No toxicity was attributable to the high dose LN boost. Conclusions PSMA PET-guided DE-IMRT up to 81 Gy to the prostate and involved LNs, and long term ADT, is a promising approach for newly diagnosed LN positive prostate cancer. LN contouring guidelines require re-evaluation in the era of PSMA PET imaging.

    更新日期:2019-10-24
  • Improving automatic delineation for head and neck organs at risk by Deep Learning Contouring
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-10-22
    Lisanne V. van Dijk, Lisa Van den Bosch, Paul Aljabar, Devis Peressutti, Stefan Both, Roel. J.H.M. Steenbakkers, Johannes A. Langendijk, Mark J. Gooding, Charlotte L. Brouwer

    Introduction Adequate head and neck (HN) organ-at-risk (OAR) delineation is crucial for HN radiotherapy and for investigating the relationships between radiation dose to OARs and radiation-induced side effects. The automatic contouring algorithms that are currently in clinical use, such as atlas-based contouring (ABAS), leave room for improvement. The aim of this study was to use a comprehensive evaluation methodology to investigate the performance of HN OAR auto-contouring when using deep learning contouring (DLC), compared to ABAS. Methods The DLC neural network was trained on 589 HN cancer patients. DLC was compared to ABAS by providing each method with an independent validation cohort of 104 patients, which had also been manually contoured. For each of the 22 OAR contours – glandular, upper digestive tract and central nervous system (CNS)-related structures – the dice similarity coefficient (DICE), and absolute mean and max dose differences (|Δmean-dose| and |Δmax-dose|) performance measures were obtained. For a subset of 7 OARs, an evaluation of contouring time, inter-observer variation and subjective judgement was performed. Results DLC resulted in equal or significantly improved quantitative performance measures in 19 out of 22 OARs, compared to the ABAS (DICE/|Δmean dose|/|Δmax dose|: 0.59/4.2/4.1 Gy (ABAS); 0.74/1.1/0.8 Gy (DLC)). The improvements were mainly for the glandular and upper digestive tract OARs. DLC significantly reduced the delineation time for the inexperienced observer. The subjective evaluation showed that DLC contours were more often preferable to the ABAS contours overall, were considered to be more precise, and more often confused with manual contours. Manual contours still outperformed both DLC and ABAS; however, DLC results were within or bordering the inter-observer variability for the manual edited contours in this cohort. Conclusion The DLC, trained on a large HN cancer patient cohort, outperformed the ABAS for the majority of HN OARs.

    更新日期:2019-10-23
  • Mechanically-assisted and non-invasive ventilation for radiation therapy: A safe technique to regularize and modulate internal tumour motion
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-10-22
    Geneviève Van Ooteghem, Damien Dasnoy-Sumell, John Aldo Lee, Xavier Geets

    Background and purpose Current motion mitigation strategies, like margins, gating, and tracking, deal with geometrical uncertainties in the tumour position, induced by breathing during radiotherapy (RT). However, they often overlook motion variability in amplitude, respiratory rate, or baseline position, when breathing spontaneously. Consequently, this may negatively affect the delivered dose conformality in comparison to the plan. We previously demonstrated on volunteers that 3 different modes of mechanically-assisted and non-invasive ventilation (MANIV) may reduce variability in breathing motion. The volume-controlled mode (VC) constraints the amplitude and respiratory rate (RR) in physiologic condition. The shallow-controlled mode (SH), derived from VC, increases the RR and decreases amplitude. The slow-controlled mode (SL) induces repeated breath holds with constrained ventilation pressure. In this study, we compared these mechanical ventilation modes to spontaneous breathing or breath hold and assessed their tolerance and effects on internal tumour motion in patients receiving RT. Material and methods The VC and SH modes were evaluated in ten patients with lung or liver cancers (cohort A). The SL mode was evaluated in 12 left breast cancer patients (cohort B). After a training and simulation session, the patients underwent 2 MRI sessions to analyze the internal motion of breast and tumour. Results MANIV was well tolerated, without any adverse events or oxymetric changes, even in patients with respiratory comorbidities. In cohort A, when compared to spontaneous breathing (SP), VC reduced significantly inter-session variations of the tumour motion amplitude (p = 0.01), as well as intra- and inter-session variations of the RR (p < 0.05). As to SH, the RR increased, while its variations within and across sessions decreased when compared to SP (p < 0.001). SH reduced the median amplitude of the tumour motion by 6.1 mm or 38.2% (p ≤ 0.01) compared to VC. In cohort B, breast position stability over the end-inspiratory plateaus obtained spontaneously or with SL remained similar. Median duration of the plateaus in SL was 16.6 s. Conclusion MANIV is a safe and well tolerated ventilation technique for patients receiving radiotherapy. MANIV could thus make current motion mitigation strategies less critical and more robust. Clinical implementation might be considered, provided the ventilation mode is carefully selected with respect to the treatment indication and patient individualities.

    更新日期:2019-10-23
  • Radiotherapy can increase the risk of ischemic cerebrovascular disease in head and neck cancer patients: A Korean population-based cohort study
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-10-17
    Jin Yong Lee, Young Ae Kim, Ho Seob Kim, Joung Hwan Back, Young Ho Jung, Duk-Hyoung Lee, Suzy Kim

    Background and purpose Several reports suggested that radiotherapy (RT) was related to an increased risk of cerebrovascular disease (CVD) in head and neck cancer (HNC) patients, but other risk factors of CVD were not properly considered in estimating the risk of RT. The purpose of this study is to analyze the effect of RT on the risk of CVD in HNC patients. Materials and methods The Korean Central Cancer Registry data and Korean National Health Insurance Service data were used. A total of 5570 patients with newly diagnosed HNC between the years 2003–2005 was included in our study cohort. We analyzed the effect of treatment modality and other socioeconomic variables on ischemic CVD incidence using the Cox proportional hazard regression model both in the entire cohort (n = 5570) and in the propensity score matching (PSM) cohort (n = 3310). Results RT increased the CVD risk by 40.8% (aHR: 1.408, p = 0.006) in the entire cohort and by 44.3% (aHR: 1.443, p = 0.047) in the PSM cohort, respectively. Conclusion The risk of ischemic CVD increased by RT after adjusting for other socioeconomic and clinical risk factors. Regular follow up and appropriate screening for CVD are required for HNC patients who received RT, and focus should be on advanced-age patients with a low socioeconomic status and known clinical risk factors of CVD.

    更新日期:2019-10-17
  • Critical review and quality-assessment of cost analyses in radiotherapy: How reliable are the data?
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-10-17
    Defourny Noémie, Monten Chris, Grau Cai, Lievens Yolande, Perrier Lionel

    Purpose/objective Health economic evaluations (HEE) are increasingly having an impact on policymakers, although the results greatly depend on the quality of the methodology used and on transparent reporting. The two main objectives of this study were to evaluate the quality of cost analyses of external beam radiotherapy (EBRT) and to assess the comprehensiveness and relevance of cost criteria defined in three validated quality-assessment instruments. Materials and methods The selection of articles was based on a previous systematic literature review of EBRT-costing studies retrieved from January 2004 to January 2015 (Period 1) in MEDLINE, Embase, and NHS-EED databases and completed in a second time period from January 2015 to November 2018 (Period 2). Three validated instruments to assess the methodology quality with the CHEC and the QHES, and the methodology with the CHEERS checklists were used. The quality was evaluated by both quantitative and qualitative analyses. The scoring robustness was examined with the Kendall coefficient of concordance and inter-class correlation coefficients. Results In total, twenty-three articles were selected. The main geographic areas of cost analyses were Canada (n = 5), France (n = 4), and the USA (n = 4). The most commonly studied pathologies and technologies were prostate (n = 7) and head and neck cancer (n = 5) and IMRT (n = 8) and IGRT (n = 2), respectively. The mean instrument scores demonstrated a fair degree of methodological quality, with 69.7% for the CHEC, 73.6% for the QHES, as well as for the reporting quality, with 59.4% for CHEERS for Period 1 (74.4%, 71.5%, and 66.1%, respectively, for Period 2). An additional qualitative analysis per criterion revealed that certain items, essential for understanding the costing methodology and the results (e.g., the time horizon, discount rate, sensitivity analysis) were often only partially completed. Statistical analysis confirmed that the reviewers’ scoring was consistent. The instruments identified the same top three articles, albeit with a degree of variation in the ranking. Conclusion Qualitative and quantitative assessment of cost analyses in EBRT exhibits a fair level of study quality in terms of the methodology and reporting transparency. The impact of cost calculations on the final HEE result appears to be underestimated, and increased transparency of the data sources and the methodologies is needed.

    更新日期:2019-10-17
  • Cross-modality applicability of rectal normal tissue complication probability models from photon- to proton-based radiotherapy
    Radiother. Oncol. (IF 5.252) Pub Date : 2019-10-17
    Jesper Pedersen, Stella Flampouri, Curtis Bryant, Xiaoying Liang, Nancy Mendenhall, Zuofeng Li, Mitchell Liu, Ludvig P Muren

    Background and purpose Proton therapy (PT) is currently being studied to improve normal tissue (NT) sparing beyond what can be achieved with conventional photon-based therapy. Compared to photons, PT dose distributions have a reduced NT low-to-intermediate ‘dose bath’ and a different biological effectiveness, questioning the applicability of photon-based NT complication probability (NTCP) models to PT. The aim of this study was to assess the applicability of photon-based NTCP models to rectum morbidity outcomes following PT. Materials and methods Treatment planning and morbidity data from 1151 prostate cancer patients treated with passive scattering PT and from 159 patients treated with conventional 3D conformal four-field photon therapy were analysed. Prospectively scored gastrointestinal morbidities (grade >=2) were analysed, with a total of 184 events (protons; medical and procedural) and 12 events (photons; procedural only), respectively. Rectal dose volume histograms were extracted for all patients in both cohorts and used as input to two different NTCP models, with up to six different published photon-based parameter sets. Results Photon-based rectal NTCP models either over- or underestimated the clinically observed gastrointestinal morbidity when used on the proton cohort, depending on the choice of endpoint (p < 0.05 for all parameter sets, for both morbidity classifications). Four of the six photon-based NTCP models showed a good fit to the photon outcome data (p > 0.05). Conclusion There were large differences in morbidity predictions between cohorts and modalities, indicating that the validity of NTCP models and parameters across institutions and treatment modalities should be carefully investigated prior to clinical application.

    更新日期:2019-10-17
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