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A second intensification is an option at first relapse in multiple myeloma (MM) after more than 36 months of initial remission. Many conditioning regimens have been tested, with or without total body irradiation (TBI). Recently, it was found that TBI could be replaced by total marrow irradiation (TMI) using helical tomotherapy, with promising results. This study was a prospective multicenter phase 1 trial that aimed to determine the maximum tolerated dose (MTD) of TMI administered in association with melphalan 140 mg/m², followed by autologous stem cell transplantation as consolidation at first relapse in MM. Four dose levels were explored: 8 Gy, 10 Gy, 12 Gy, and 14 Gy. The dose-limiting toxicity (DLT) was defined as grade 4 neutropenia >15 days, grade 4 thrombopenia >28 days, and all other grade 4 nonhematologic toxic effects except nausea, vomiting, alopecia, mucositis, and reaction to autologous stem cell infusion. Thirteen patients were included; only 1 DLT at the third escalated dose level (12 Gy) was observed, whereas 1 patient was treated at 14 Gy with no adverse events. The MTD was not reached. The rate of acute toxicity was low: 38% of grade 3-4 diarrhea, mucositis, or unexplained fever. Regarding the lungs, the mean dose administered was systematically less than 8 Gy. After a median follow-up of 55 months, 70% of participants were alive. Of these 13 patients, 38.5% were in very good partial response and 30.8% were in complete response. Three of them were progression-free. Six patients were long survivors, still alive after 55 months of follow-up. Total marrow irradiation provides good results with a good tolerance profile at first relapse in MM and makes it possible to increase the dose delivered to the planning target volume while sparing organs at risk. This technique could be discussed for all regimens before auto- or allo-stem cell rescue when TBI is required. [ABSTRACT FROM AUTHOR]

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Indication for adjuvant chemotherapy in ypN0 rectal cancer patients after chemoradiotherapy (CRT) is debated. The clinical significance of the presence of sterilized lymph nodes (LNS) in ypN0 patients remains to be determined. To assess the prognostic value of LNS in ypN0 rectal cancers after neoadjuvant CRT. From 2006-2016, 235 patients underwent TME surgery for non-metastatic mid-low rectal cancer after CRT. A lymph node was considered sterilized if there were signs of treatment response (fibrosis, necrosis or mucus) without residual tumor cells. 180 patients (77%) were classified ypN0 and 55 (23%) ypN+. LNS was present in 20 patients (9%). In ypN0 patients, 5-year OS was similar between patients with and without LNS. In contrast, 5-year DFS was significantly lower in ypN0/LNS + patients (58% vs. 78%, p = 0.043) and was similar to those staged ypN+. In multivariate analysis, two factors were independent predictors of DFS: mesorectal grading (OR = 3.14; 95%CI: 1.10-8.34; p = 0.033) and the presence of LNS (OR = 3.93, 95% CI: 1.06-11.81, p = 0.042) The presence of LNS in ypN0 rectal cancer after neoadjuvant CRT is associated with an increased risk of recurrence and may be taken into account for the discussion of adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Highlights • This review is a homogeneous monocentric series. • The treatments were performed using a unique tomotherapy technique. • This study focuses on a population of homogeneous diseases. • A dose escalation technique was performed with results similar to other series. Abstract Meningiomas account for 30–35% of intracranial tumors. Grade I meningiomas are most common and carry the best prognosis. Grade II and III meningiomas are more aggressive and the outcomes after surgical resection alone remain unsatisfactory. The main objective of this retrospective, single-center study was to assess our results of treatment of grade II–III intracranial meningioma with helical tomotherapy (HT). We retrospectively reviewed patients with histologically proven (WHO 2007) grade II–III meningioma irradiated with HT. Patients were treated one session a day, 5 days a week, to a total dose of 59.4 Gy and 68.4 Gy delivered in 33 and 38 fractions of 1.8 Gy each to the LR PTV and HR PTV, with or without simultaneous integrated boost. From May 2011 to January 2015, 19 patients (15 with grade II and 4 with grade III meningiomas) were treated. Median follow-up for patients with Grade II or Grade III meningiomas, was 29.2 months (range, 10.7–52.4) and 21.3 months (range, 2.4–51.3), respectively. Disease free survival at 1, 2 and 3 years was 89.2%, 83.6% and 56.3% respectively. Overall survival at 1, 2 and 3 years was 94.7%, 94.7% and 78.9%, respectively. No patient had neurological toxicity greater than grade 2 in the acute period. During follow-up, only one patient had neurological toxicity greater than or equal to grade 3. The management of grade II to III meningiomas using HT with doses exceeding 60 Gy is associated with good local control and acceptable survival results. [ABSTRACT FROM AUTHOR]

Radiotherapy plays a key role in cancer treatments, but tumor cell death differs from one tumor to another. The response of patients to radiotherapy varies considerably and adverse side effects are difficult to prevent. The mechanisms involved in the heterogeneity of this response are not well understood. In order to enhance the efficacy and safety of radiotherapy, it is important to identify subpopulations most at risk of developing a late adverse response to radiotherapy. Telomeres are composed of multiple repeats of a unique sequence of nucleotides forming a TTAGGG pattern. They protect chromosomes from end-to-end fusion and maintain genomic stability. Telomeres have been shown to be extremely sensitive to radiotherapy especially because of their atypical DNA damage repair response, which includes partial inhibition of the non-homologous end joining repair pathway. Ionizing Radiation (IR)-induced damage to telomere DNA could lead to chromosome instability and the initiation or progression of tumor processes. Telomeres could thus be a reliable marker of IR exposure and as such become a new parameter for predicting radiosensitivity. Furthermore, short telomeres are more sensitive to radiotherapy, which could partially explain differences in tumor cell death and in inter-individual sensitivity to radiotherapy. Telomere length could be used to identify subpopulations of patients who could benefit from higher or lower doses per fraction. Finally, pharmacological interference with tumor-cell telomere biology to reduce telomere length and/or telomere stability could also enhance the effectiveness and safety of radiotherapy. Telomeres could play a key role in radiotherapy in the era of personalized medicine. [ABSTRACT FROM AUTHOR]

Summary Background Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. Methods Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , number NCT02295033 . Findings Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17·2 years (IQR 13·0–19·0). 20-year overall survival was 59·7% (99% CI 56·3–63·0) in the boost group versus 61·1% (57·6–64·3) in the no boost group, hazard ratio (HR) 1·05 (99% CI 0·92–1·19, p=0·323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0·65 (99% CI 0·52–0·81, p<0·0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16·4% (99% CI 14·1–18·8) in the no boost group versus 12·0% (9·8–14·4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1·8% (99% CI 1·1–2·5) in the no boost group versus 5·2% (99% CI 3·9–6·4) in the boost group (p<0·0001). Interpretation A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. Funding Fonds Cancer, Belgium. [ABSTRACT FROM AUTHOR]

Abstract: Background: For gastric cancers, the benefits of adjuvant radiochemotherapy and of perioperative chemotherapy have been demonstrated since 2001 and 2006 respectively. The aim of this study was to evaluate the diffusion of adjuvant treatments in a French population. Methods: 334 incident gastric cancers UICC Stage IB, II, III or IVM0 resected for cure and recorded in the Burgundy digestive cancer registry were retrospectively included. Patients were classified as having received an effective adjuvant treatment if they had been treated by adjuvant radiochemotherapy since 2001 or perioperative chemotherapy since 2006. Results: The proportion of patients treated with an effective adjuvant treatment increased from 21.8% (2001–2005) to 40.1% (2006–2009). Patients treated in 2006–2009 were twice as likely to receive effective adjuvant treatment as those treated during the period 2001–2005. During the 2004–2009 period, 62.4% of cases were presented in a multidisciplinary team meeting. These patients were almost three times more likely to receive effective adjuvant treatment than patients excluded from multidisciplinary team consultation. Age was a significant factor, independent of comorbidities. Conclusion: Administration of adjuvant treatment is still far from being considered a reference regimen in routine practice for R0 resected gastric cancer. The increase in multidisciplinary team meetings should improve the situation. [Copyright &y& Elsevier]

Abstract: Background: The simultaneous integrated boost (SIB) technique with dose per fraction slightly higher than 2Gy offers the advantages of shortening the treatment time and increasing the biologically equivalent dose to the tumor. This study was designed to evaluate the feasibility of a dose-escalating radiotherapy treatment by using a SIB-IMRT approach in patients with early and moderately advanced head and neck cancers. Materials and methods: Fifty-seven consecutive patients with pharyngo-laryngeal T2N0 or T2N1, or laryngeal T3N0 SCC were included. The therapeutic PTVs were treated according to three consecutive dose levels i.e., 69Gy in 30 fractions of 2.3Gy (dose level I), 72Gy in 30 fractions of 2.4Gy (dose level II) or 75Gy in 30 fractions of 2.5Gy (dose level III). The prophylactic PTVs received a dose of 55.5Gy delivered in 30 fractions of 1.85Gy. The primary endpoint of the study was acute toxicity assessed during treatment and during the first 3months following the completion of radiotherapy. The secondary endpoints included loco-regional control, disease-free survival, overall survival and late toxicity at 2years of follow-up. The study design allowed patients to be enrolled in the second dose level group if no more than 10% of grade 4 acute toxicity was observed on the first dose level group within 3months after the completion of IMRT, and so on for the third level group. Results: Forty-four men and 13 women were included in the trial. The majority of them presented with oropharyngeal cancer (53%) and laryngeal cancer (33%). Only 3 patients developed grade 4 acute mucositis during treatment, one in each dose level. Thirty-two patients (56%) experienced grade 3 toxicity, mostly dermatitis and mucositis, without any significant difference between the groups. Late grade 1 and 2 xerostomia was seen in 53% and 33% of patients, respectively. Transient grade 4 late toxicity was observed in 16% of all patients and was equally distributed among the groups. The 2-year loco-regional control was 82% for all 3 groups (79% dose level I, 88% dose level II, 79% dose level III). The 2-year overall survival was 89% for dose level I and II, and 95% for dose level III. Conclusions: This dose escalation SIB-IMRT protocol was safe and effective as the sole treatment of early and moderately advanced SCC of head and neck. No toxicity difference was observed between the groups. [Copyright &y& Elsevier]

After the foundation of the EORTC in 1962, the Radio-Chemotherapy Group within this organization split in 1973 into two groups. One of these groups, concentrating on Hodgkin's and Non-Hodgkin's Lymphoma, later became the Lymphoma Group while the other became the Radiotherapy Group. During the 1990's the latter changed its name to the Radiation Oncology Group (ROG), underscoring its position within the field of multidisciplinary oncology research. By 2011 the ROG had initiated or participated in 83 clinical studies, of which more than 73% were randomized phase III trials. It has concentrated on almost every disease site from brain to gynecological tumors with emphasis on brain, head and neck, breast, prostate, and lower gastro-intestinal tumours. The ROG has published several hundreds peer-reviewed articles, including publications in prestigious journals such as the New England Journal of Medicine or Lancet Oncology. Since its foundation, the ROG has understood the importance of conducting a proper Radiotherapy Quality Assurance (RT-QA) program for every clinical trial aiming at guaranteeing the quality of radiotherapy, i.e. minimizing any uncertainties in the conduction of trials. As radiotherapy evolved from two-dimensional to Intensity Modulated Radio Therapy, this program has progressively matured with time to be part of a worldwide RT-QA consortium in 2012. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: This work describes the clinical validation of an automatic segmentation algorithm in CT-based radiotherapy planning for prostate cancer patients. Material and methods: The validated auto-segmentation algorithm (Smart Segmentation, version 1.0.05) is a rule-based algorithm using anatomical reference points and organ-specific segmentation methods, developed by Varian Medical Systems (Varian Medical Systems iLab, Baden, Switzerland). For the qualitative analysis, 39 prostate patients are analysed by six clinicians. Clinicians are asked to rate the auto-segmented organs (prostate, bladder, rectum and femoral heads) and to indicate the number of slices to correct. For the quantitative analysis, seven radiation oncologists are asked to contour seven prostate patients. The individual clinician contour variations are compared to the automatic contours by means of surface and volume statistics, calculating the relative volume errors and both the volume and slice-by-slice degree of support, a statistical metric developed for the purposes of this validation. Results: The mean time needed for the automatic module to contour the four structures is about one minute on a standard computer. The qualitative evaluation using a score with four levels (“not acceptable”, “acceptable”, “good” and “excellent”) shows that the mean score for the automatically contoured prostate is “good”; the bladder scores between “excellent” and “good”; the rectum scores between “acceptable” and “not acceptable”. Using the concept of surface and volume degree of support, the degree of support given to the automatic module is comparable to the relative agreement among the clinicians for prostate and bladder. The slice-by-slice analysis of the surface degree of support pinpointed the areas of disagreement among the clinicians as well as between the clinicians and the automatic module. Conclusion: The efficiency and the limits of the automatic module are investigated with both a qualitative and a quantitative analysis. In general, with efficient correction tools at hand, the use of this auto-segmentation module will lead to a time gain for the prostate and the bladder; with the present version of the algorithm, modelling of the rectum still needs improvement. For the quantitative validation, the concept of relative volume error and degree of support proved very useful. [Copyright &y& Elsevier]

Abstract: Background and purposes: The appropriate application of 3-D conformal radiotherapy, intensity modulated radiotherapy or image guided radiotherapy for patients undergoing radiotherapy for prostate cancer requires a standardisation of target delineation as well as clinical quality assurance procedures. Patients and methods: Pathological and imaging studies provide valuable information on tumour extension. In addition, clinical investigations on patient positioning and immobilisation as well as treatment verification data offer an abundance of information. Results: Target volume definitions for different risk groups of prostate cancer patients based on pathological and imaging studies are provided. Available imaging modalities, patient positioning and treatment preparation studies as well as verification procedures are collected from literature studies. These studies are summarised and recommendations are given where appropriate. Conclusions: On behalf of the European Organisation for Research and Treatment of Cancer (EORTC) Radiation Oncology Group this article presents a common set of recommendations for external beam radiotherapy of patients with prostate cancer. [Copyright &y& Elsevier]

Abstract: RTOG and EORTC randomised phase III trials investigated combination of radiation therapy and hormonal treatment in locally advanced prostate cancer T2c-T4 N0-1 M0 (UICC 2002). Complete androgen blockade initiated 2 months prior to starting radiotherapy and stopped at the completion of radiotherapy vs radiation therapy alone, increased overall survival in patients with Gleason score 2–6. Adjuvant androgen suppression started at the end of the radiotherapy and continued indefinitely improved significantly overall survival of patients Gleason score 8 to 10. Complete androgen blockade in two months before and two months during radiation followed by 24 additional months of LHRH analogue alone improved overall survival of patients Gleason score 8–10 with respect to CAB alone. EORTC trial 22861 has shown that androgen suppression with LHRH analogue given during and for 3 years after external irradiation improved overall survival whatever the Gleason score. The role of hormonal treatment is currently assessed in localized prostate cancer (T1-2 N0) with poor prognostic factors: Gleason score 8–10, PSA>20 ng/ml. [Copyright &y& Elsevier]

Life expectancy of patients treated for brain tumors has lengthened due to the therapeutic improvements. Cognitive impairment has been described following brain radiotherapy, but the mechanisms leading to this adverse event remain mostly unknown. Technical evolutions aim at enhancing the therapeutic ratio. Sparing of the healthy tissues has been improved using various approaches; however, few dose constraints have been established regarding brain structures associated with cognitive functions. The aims of this literature review are to report the main brain areas involved in cognitive adverse effects induced by radiotherapy as described in literature, to better understand brain radiosensitivity and to describe potential future improvements. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the time course response of prostate metabolism to irradiation using magnetic resonance spectroscopy (MRS) at 3-month intervals and its impact on biochemical control. Methods and Materials: Between January 2008 and April 2010, 24 patients with localized prostate cancer were prospectively enrolled in the Evaluation of the Response to Irradiation with MR Spectroscopy (ERIS) trial. All the patients had been treated with intensity-modulated radiation therapy with or without long-term adjuvant hormonal therapy (LTHT) and underwent 3-T MRS and prostate-specific antigen (PSA) assays at baseline and every 3 months thereafter up to 12 months. Results: After radiation, the mean normalized citrate level (citrate/water) decreased significantly over time, both in the peripheral zone (PZ) (p = 0.0034) and in the entire prostate (p = 0.0008), whereas no significant change was observed in mean normalized choline levels (choline/water) in the PZ (p = 0.84) and in the entire prostate (p = 0.95). At 6 months after radiation, the mean choline level was significantly lower in the PZ for patients with a PSA value of ≤0.5 ng/mL at 12 months (4.9 ± 1.7 vs. 7.1 ± 1.5, p = 0.0378). Similar results were observed at 12 months in the PZ (6.2 ± 2.3 vs. 11.4 ± 4.1, p = 0.0117 for choline level and 3.4 ± 0.7 vs. 16.1 ± 6.1, p = 0.0054 for citrate level) and also in the entire prostate (6.2 ± 1.9 vs. 10.4 ± 3.2, p = 0.014 for choline level and 3.0 ± 0.8 vs. 13.3 ± 4.7, p = 0.0054 for citrate level). For patients receiving LTHT, there was no correlation between choline or citrate levels and PSA value, either at baseline or at follow-up. Conclusions: Low normalized choline in the PZ, 6 months after radiation, predicts which patients attained a PSA ≤0.5 ng/mL at 1 year. Further analyses with longer follow-up times are warranted to determine whether or not these new biomarkers can conclusively predict the early radiation response and the clinical outcome for patients with or without LTHT. [ABSTRACT FROM AUTHOR]

• The RIS development area was almost always in full beam. • Reassuringly, new RT techniques such as VMAT should not have an impact on the incidence of RIS. • Patients developing RIS in low dose areas may have an individual predisposition. The Radiation Induced Sarcoma (RIS) is a rare but serious adverse event following radiotherapy (RT). Current RT techniques are more precise, but irradiate a larger volume at a low dose. This study aimed to describe radiation characteristics in a large series of patients suffering from RIS. Patient-representative voxel-based anthropomorphic phantoms were used to reconstruct patient-specific RT fields for 125 patients diagnosed with RIS after primary breast cancer. For each patient, the location of the RIS onset site was determined and transferred onto the phantom as a contour. Using a treatment planning system (TPS), the dose distribution on the RIS in the phantom was calculated. The mean dose (Dmean) received in the area where RIS subsequently developed was 47.8 ± 11.6 Gy. The median dose in the zones where RIS later developed ranged from 11 Gy to 58.8 Gy. The median time from RT to RIS development was 8 years (range 2–32 years). Analysis for predictors of time to radiation-induced sarcoma development highlighted a significant impact of age of patient during the RT whereas in multivariable analysis chemotherapy and hormonotherapy for primary breast cancer were not associated with a significant difference in time to diagnosis of RIS. This study highlights that the dose received by the tissue in which the RIS developed was almost 47 Gy. These results are encouraging for the use of new RT techniques increasing volumes receiving low doses, without fear of an excess of RIS over the next 10 years. [ABSTRACT FROM AUTHOR]

• In total, more than 4000 adult patients are currently treated with PT across Europe annually. • CNS and HNC tumours are the most frequently treated tumour sites. • Most centres use national or institutional guidelines for selecting patients for PT. • Treatments are usually reimbursed by national health care systems. • Most patients are included in prospective data registries and clinical trials. Major differences exist among proton therapy (PT) centres regarding PT delivery in adult cancer patient. To obtain insight into current practice in Europe, we performed a survey among European PT centres. We designed electronic questionnaires for eight tumour sites, focusing on four main topics: 1) indications and patient selection methods; 2) reimbursement; 3) on-going or planned studies, 4) annual number of patients treated with PT. Of 22 centres, 19 (86%) responded. In total, 4233 adult patients are currently treated across Europe annually, of which 46% consists of patients with central nervous system tumours (CNS), 15% head and neck cancer (HNC), 15% prostate, 9% breast, 5% lung, 5% gastrointestinal, 4% lymphoma, 0.3% gynaecological cancers. CNS are treated in all participating centres (n = 19) using PT, HNC in 16 centres, lymphoma in 10 centres, gastrointestinal in 10 centres, breast in 7 centres, prostate in 6 centres, lung in 6 centres, and gynaecological cancers in 3 centres. Reimbursement is provided by national health care systems for the majority of commonly treated tumour sites. Approximately 74% of centres enrol patients for prospective data registration programs. Phase II-III trials are less frequent, due to reimbursement and funding problems. Reasons for not treating certain tumour types with PT are lack of evidence (30%), reimbursement issues (29%) and/or technical limitations (20%). Across European PT centres, CNS tumours and HNC are the most frequently treated tumour types. Most centres use indication protocols. Lack of evidence for PT and reimbursement issues are the most reported reasons for not treating specific tumour types with PT. [ABSTRACT FROM AUTHOR]

Background: Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups.Methods: For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3-4 months to 6-9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4-6 months to 18-36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855.Findings: Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0-15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 [95% CI 0·77-0·89], p<0·0001), as did adjuvant ADT prolongation (0·84 [0·78-0·91], p<0·0001), but neoadjuvant ADT extension did not (0·95 [0·83-1·09], p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group.Interpretation: Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended.Funding: University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology. [ABSTRACT FROM AUTHOR]

Purpose: To propose an automatic atlas-based segmentation framework of the dental structures, called Dentalmaps, and to assess its accuracy and relevance to guide dental care in the context of intensity-modulated radiotherapy. Methods and Materials: A multi-atlas–based segmentation, less sensitive to artifacts than previously published head-and-neck segmentation methods, was used. The manual segmentations of a 21-patient database were first deformed onto the query using nonlinear registrations with the training images and then fused to estimate the consensus segmentation of the query. Results: The framework was evaluated with a leave-one-out protocol. The maximum doses estimated using manual contours were considered as ground truth and compared with the maximum doses estimated using automatic contours. The dose estimation error was within 2-Gy accuracy in 75% of cases (with a median of 0.9 Gy), whereas it was within 2-Gy accuracy in 30% of cases only with the visual estimation method without any contour, which is the routine practice procedure. Conclusions: Dose estimates using this framework were more accurate than visual estimates without dental contour. Dentalmaps represents a useful documentation and communication tool between radiation oncologists and dentists in routine practice. Prospective multicenter assessment is underway on patients extrinsic to the database. [ABSTRACT FROM AUTHOR]

The importance of local failure (LF) after treatment of high-grade prostate cancer (PCa) with definitive radiotherapy (RT) remains unknown. To evaluate the clinical implications of LF after definitive RT. Individual patient data meta-analysis of 992 patients (593 Gleason grade group [GG] 4 and 399 GG 5) enrolled in six randomized clinical trials. Multivariable Cox proportional hazard models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), and distant metastasis (DM)-free survival (DMFS) and LF as a time-dependent covariate. Markov proportional hazard models were developed to evaluate the impact of specific transitions between disease states on these endpoints. Median follow-up was 6.4 yr overall and 7.2 yr for surviving patients. LF was significantly associated with OS (hazard ratio [HR] 1.70 [95% confidence interval {CI} 1.37–2.10]), PCSS (3.10 [95% CI 2.33–4.12]), and DMFS (HR 1.92 [95% CI 1.54–2.39]), p < 0.001 for all). Patients who had not transitioned to the LF state had a significantly lower hazard of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.13 [95% CI 0.04–0.41], p < 0.001). Additionally, patients who transitioned to the LF state had a greater hazard of DM or death (HR 2.46 [95% CI 1.22–4.93], p = 0.01) than those who did not. LF is an independent prognosticator of OS, PCSS, and DMFS in high-grade localized PCa and a subset of DM events that are anteceded by LF events. LF events warrant consideration for intervention, potentially suggesting a rationale for upfront treatment intensification. However, whether these findings apply to all men or just those without significant comorbidity remains to be determined. Men who experience a local recurrence of high-grade prostate cancer after receiving upfront radiation therapy are at significantly increased risks of developing metastases and dying of prostate cancer. Using individual patient-level data from six randomized trials, we have found that local failure events after definitive radiotherapy for high-grade prostate cancer are independent, significant predictors of distant metastasis–free survival, prostate cancer–specific survival, and overall survival. Using multistate modeling, we identify that most distant metastatic events occur from an apparent disease-free state, but an increasing proportion occurs over time subsequent to local failure events. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this analysis was to assess the 5-year tolerance and survival in patients undergoing hypofractionated stereotactic boost after external beam radiation therapy (EBRT) for intermediate-risk prostate cancer.Methods and Materials: Between August 2010 and April 2013, 76 patients with intermediate-risk prostate carcinoma were included in the study. A first course delivered 46 Gy using conventional fractionation. The second course delivered a boost of 18 Gy (3 × 6 Gy) within 10 days using stereotactic body radiation therapy (SBRT). Gastrointestinal and genitourinary toxicities were assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.0. Secondary outcome measures were overall, biochemical relapse-free, and relapse-free survival; prostate-specific antigen kinetics; and patient functional status (urinary and sexual) according to the International Index of Erectile Function and International Prostate Symptom Score questionnaires.Results: Sixty patients (79%) were treated by CyberKnife and 16 (21%) by linear accelerator. Median follow-up was 62 months (range, 29-69). The cumulative incidence of genitourinary and gastrointestinal grade ≥2 toxicities at month 60 after the end of radiation therapy was 1.4% (95% confidence interval [CI], 0.1%-6.6%) and 9.3% (95% CI, 4.1%-17.1%), respectively. Biochemical relapse-free and relapse-free survival rates at 5 years were 87.4% (95% CI, 77.1%-93.2%) and 86.2% (95% CI, 75.8-92.3), respectively. The mean (standard deviation) prostate-specific antigen variation within 3 months and 5 years post-radiation therapy was -1.20 ng/mL/mo (0.79) and -1.30 ng/mL/y (1.05), respectively. There was no significant difference between the International Prostate Symptom quality of life score between inclusion and month 60. For the International Index of Erectile Function, there was a significant difference between inclusion and month 60 (P = .005), with a higher proportion of severe/noninterpretable disorders at 60 months.Conclusions: The results of the trial demonstrate that the EBRT and SBRT combination is well tolerated and yields good efficacy results. These data provide a good basis for comparing EBRT and brachytherapy boost to EBRT and SBRT boost in future prospective studies. [ABSTRACT FROM AUTHOR]

Purpose: Defective mismatch repair system (dMMR) has been shown to have a favorable impact on outcome in patients with colorectal cancer treated with surgery or immunotherapy, with adjuvant chemotherapy being discouraged unless there is nodal involvement. Its impact on radiosensitivity is unknown in patients with colorectal cancer.Methods and Materials: Patients treated for locally advanced rectal cancer between 2000 and 2016 were studied. Reported points included age, sex, clinical and radiologic tumor stages at diagnosis, modalities of neoadjuvant treatment, posttreatment pathologic staging, tumor regression score, and local, distant relapse-free, and overall survival. An inverse probability of treatment weighting propensity score analysis was performed to evaluate the association of mismatch repair proficiency with surgical and clinical outcomes.Results: Among the 296 patients included, 23 (7.8%) had dMMR. Median follow-up was 43.0 months (interquartile range, 27.9-66.7). Patients with dMMR were significantly younger than the others. After inverse probability of treatment weighting propensity score matching, dMMR patients had higher pathologic downstaging rate (P < .0001), higher tumor regression grade (P = .024), and a longer recurrence-free survival (P < .0001).Conclusions: dMRR was associated with significant tumor downstaging after neoadjuvant chemoradiation and with increased recurrence-free survival. dMMR patients may have more radiosensitive tumors. [ABSTRACT FROM AUTHOR]

Concomitant external-beam radiochemotherapy (5-fluorouracil-mitomycin C) has become the standard of care in anal cancer since the '90s. A pooled analysis of individual patient data from 7 major trials was performed quantifying the effect of radiation therapy (RT)–related parameters on the outcome of patients with anal cancer. Pooling databases from combined modality trials, the impact of RT parameters (total dose, gap duration, OTT: overall treatment time) on outcome including locoregional failure (LRF), 5-year progression free survival (PFS) and toxicities were investigated. Individual patient data were received for 10/13 identified published studies conducted from 1987 to 2008 (n = 3031). A Cox regression model was used (landmark = 3 months after RT for first follow-up). After data inspection indicating severe heterogeneity between trials, only 1343 patients from 7/10 studies received were analysed (the most recent ones, since 1994; median follow-up = 4.1 years). A higher overall 5-year LRF rate [22.8% (95% confidence interval [CI] 22.3–27.3%)] significantly correlated with longer OTT (p = 0.03), larger tumour size (p < 0.001) and male gender (p = 0.045). Although significant differences were not observed, subset analyses for LRF (dose range: 50.4–59 Gy) seemed to favour lower doses (p = 0.412), and when comparing a 2-week gap versus 3 (dose: 59.4 Gy), results suggested 3 weeks might be detrimental (p = 0.245). For a 2-week gap versus none (dose range: 55–59.4 Gy), no difference was observed (p = 0.89). Five-year PFS was 65.7% (95% CI: 62.8–68.5%). Higher PFS rates were observed in women (p < 0.001), smaller tumour sizes (p < 0.001) and shorter OTT (p = 0.025). Five-year overall survival [76.7% (95% CI: 73.9%–79.3%)] correlated positively with female gender (p < 0.001), small tumour size (p = 0.027) and short OTT (p = 0.026). Descriptive toxicity data are presented. For patients receiving concurrent external-beam doublet chemoradiation, a longer OTT seems detrimental to outcome. Further trials involving modern techniques may better define optimal OTT and total dose. • Radiochemotherapy remains the standard treatment for anal cancer since the '90s. • Our results suggest that a longer overall treatment time may be detrimental to outcome. • In the dose range of 50.4–59 Gy, lower doses seem to be preferred. • A longer than 2-week gap might be detrimental. • Findings may guide trials to define optimal overall treatment time and dose level. [ABSTRACT FROM AUTHOR]

Target volume selection and delineation for both the primary tumor and the lymph nodes are critical steps in the treatment of head and neck tumors with Intensity Modulated Radiation therapy (IMRT). These steps should be based on a probabilistic approach, which is that selection and delineation will be considered as optimal when reaching the best compromise between a too tight volume that could be associated to an unacceptable rate of local recurrence, and a too large volume, which could be associated to an unacceptable rate of treatment morbidity. Failure to do so have been reported to be associated to a higher risk of loco-regional recurrences and/or morbidity after treatment. In this framework, groups of experts proposed sets of guidelines for the radiation oncology community, aiming at standardizing radiotherapy practices of head and neck cancer patients. Although in constant improvement, such guidelines have been shown to translate into more consistent treatment approaches. This review article summarizes the knowledge accumulated over the years on target volume selection and delineation and tries to reconcile the various schools of thoughts on the topic. [ABSTRACT FROM AUTHOR]

Background and purpose To evaluate clinical results and safety of a dose adaptive protocol based on tumor volume coverage and critical structure constraints, for the treatment of skull base chordomas. Material and methods Between May 2006 and October 2012, 106 patients with skull base chordoma were treated by combined photon and proton irradiation. Prescribed dose levels were 68.4, 70.2, 72 and 73.8 Gy(RBE) in once daily fractionation of 1.8 Gy(RBE). Dose level and dosimetric constraints to organs at risk depended on postoperative residual Gross Tumor Volume (GTV) coverage. Local control (LC) and overall survival (OS) were evaluated using the Kaplan–Meier method. Results With a median follow-up of 61 months, the 2-year, 4-year, and 5-year LC rates were 88.6%, 78.3%, and 75.1%, respectively. GTV > 25 mL ( p  = 0.034 , HR = 2.22; 95%CI 1.06–4.62) was an independent unfavorable prognostic factor of LC. The 2-year, 4-year, and 5-year OS rates were 99%, 90.2%, and 88.3%, respectively. Grade 3–5 late toxicity was observed in 7 patients, resulting in 93% 5-year freedom from high-grade toxicity. Conclusions This study suggests that the probability of LC of skull base chordomas depends on postoperative GTV. The dose adaptive protocol achieves acceptable local control. Future studies should investigate whether further dose escalation to doses in excess of 74 Gy(RBE) would achieve better results. [ABSTRACT FROM AUTHOR]

Objective: To analyze the outcome of N3 patients treated with very accelerated radiotherapy (VART) or different schedules of concurrent chemoradiotherapy (CRT) within two phase III trials.Patients and Methods: Data of 179 patients with N3 HNSCC from two GORTEC randomized trials (96-01 and 99-02) were pooled. Patients received either VART: 64.8Gy/3.5weeks or one of the 3 following CRT regimens: Conventional CRT: 70Gy/7weeks+3 cycles carboplatin-5FU; Moderately accelerated CRT: 70Gy/6weeks+2 cycles carboplatin-5FU; Strongly intensified CRT: 64Gy/5weeks+cisplatin (days 2, 16, 30) and 5 FU (days 1-5, 29-33) followed by 2 cycles adjuvant cisplatin-5FU.Results: Median follow-up was 13.3 and 5.2years for GORTEC 96-01 and GORTEC 99-02, respectively. Five-year overall survival (OS) was 13.8%. No significant difference was observed between CRT versus VART in terms of OS (hazard ratio [HR]: 0.93, p=0.68), loco-regional progression (HR: 0.70, p=0.13), or distant progression (HR: 0.86, p=0.53). OS was worse for patients with T3-4 tumors versus early T stage (11.0% versus 25.7%, p=0.015). In multivariate analysis, the oropharyngeal subsite presented a higher risk of distant metastasis (as first event 46.5% vs 19.2%, p<0.001),). A significant interaction between treatment modalities and subsites has been observed concerning loco-regional and distant failures.Conclusion: The outcome of N3 HNSCC was extremely poor despite treatment intensification and no difference between CRT and VART. Both distant metastases and loco-regional failures remain important treatment challenge. [ABSTRACT FROM AUTHOR]

Purpose Salvage prostate permanent implant (sPPI) for postradiation local failure provides high rates of biochemical control. The cumulative dose delivered to the prostate and the rectum is still unknown. Methods and Materials We reviewed the postimplant CT-based dosimetry of 18 selected patients who underwent sPPI with 125 I seeds for isolated biopsy-proven local failure several years after external beam radiation therapy. Ten patients had whole-prostate sPPI, and 8 patients had multiparametric MRI-based focal sPPI. In 8 patients, hyaluronic acid (HA) gel was injected into the prostate–rectum space. Results The median cumulative biological effective dose after EBRT + sPPI for the prostate and the rectum was higher in patients treated with whole-gland sPPI than in patients treated with focal sPPI (313.5 Gy 2 vs. 174.4 Gy 2 ; p = 0.06 and 258.1 Gy 3 vs. 172.6 Gy 3 ; p < 0.01, respectively). The median D 0.1cc for the rectum was significantly lower in patients who had HA gel: 63.3 Gy (29.0–78.3) vs. 83.9 Gy (34.9–180.0) ( p = 0.04). Conclusions Cumulative prostate and rectum biological effective doses were lower with focal sPPI. D 0.1cc delivered to the rectum was significantly lower with HA gel, while there was no difference between focal or whole-gland plans. [ABSTRACT FROM AUTHOR]

Purpose To determine whether post-implant MRI-based dosimetry of the Dominant Intra-prostatic Lesion (DIL) could best predict the occurrence of PSA bounce after prostate brachytherapy. Methods and materials We selected 66 patients with a low risk prostate cancer treated with 125 I prostate brachytherapy as monotherapy. Post-implant dosimetry based on day 30 CT-scan and multiparametric MRI co-registration was generated: planned D 90, D 95, V 100, V 150 values were calculated for each DIL. Bounce was defined as a PSA elevation ⩾0.2 ng/mL from the previous baseline value followed by a decrease to or below the prior nadir with no additional treatment. Results After a median follow-up of 35.5 months (range 13.2–72.5), a PSA bounce occurred in 24 (36.4%) patients. The mean planned D 90 of the DIL was significantly lower in bouncers: 196 ± 61 Gy vs. 234 ± 62 Gy, p = 0.018. The mean planned V 150 of the DIL was 56 ± 32% for bouncers while it was 75 ± 30% for non-bouncers, p = 0.026. Conclusion A lower planned D 90 or V 150 in the DIL were predictive of PSA bounce after prostate brachytherapy. PSA bounce could be caused by delayed cell death related to sublethal damage accumulation in the tumor. [ABSTRACT FROM AUTHOR]

Purpose The objective of this project was to define consensus guidelines for delineating organs at risk (OARs) for head and neck radiotherapy for routine daily practice and for research purposes. Methods Consensus guidelines were formulated based on in-depth discussions of a panel of European, North American, Asian and Australian radiation oncologists. Results Twenty-five OARs in the head and neck region were defined with a concise description of their main anatomic boundaries. The Supplemental material provides an atlas of the consensus guidelines, projected on 1 mm axial slices. The atlas can also be obtained in DICOM-RT format on request. Conclusion Consensus guidelines for head and neck OAR delineation were defined, aiming to decrease interobserver variability among clinicians and radiotherapy centers. [ABSTRACT FROM AUTHOR]

Purpose To retrospectively analyze the efficacy of 36 Gy of elective node irradiation and report patterns of recurrence in patients with anal cancer treated by chemoradiation with the same radiotherapy (RT) treatment scheme. Methods and materials Between January1996 and December 2013, 142 patients with anal squamous cell cancer were scheduled to receive a dose of 36 Gy of elective node irradiation (ENI) to the inguinal area and whole pelvis over 4 weeks followed after a 2-week gap by a boost dose of 23.4 Gy over 17 days to the macroscopic disease. Mitomycin C combined with fluorouracil, capecitabin or cisplatin was given at day 1 of each sequence of RT. Results Disease stages were I: 3, II: 78, III A : 23, III B : 38. Compliance rates were 97.2% with RT and 87.9% with chemotherapy. After a median follow up of 48 months [3.6–192], estimated 5-year overall survival and colostomy-free survival were 75.4% and 85.3% respectively. Eleven patients (7.7%) never achieved a complete response, 15 had a local component of recurrence and 5 a regional one. One patient had failure in the common iliac node area outside the treatment fields. The inguinal control rate was 98.5%. The 5-year tumor and nodal control rates were 81.5% and 96.0%, respectively. Conclusion Chemoradiation with a dose of 36 Gy ENI achieved excellent nodal control. However, it is necessary to improve the 5-year control rate of the primary tumor. Omitting the gap and using additional doses per fraction or hyper-fractionation are to be explored. [ABSTRACT FROM AUTHOR]

Background and purpose We aimed to evaluate the patterns of loco-regional failure (LRF) after exclusive chemoradiotherapy (eCRT) for esophageal cancer with respect to planned dose and/or the incidental (unplanned) dose outside target volumes. Materials and methods Co-image registration of CT or 18 F-FDG PET-CT at the time of failure (tf) and at the time of CRT (t0) was performed in 34 patients with LRF. Dosimetric parameters with regard to local failure (LF), nodal failure (NF) and involved nodal stations (NS) were derived. Results Twenty-two patients (64.7%) had LF, the majority of which (95.5%) were located at the epicenter of the GTV of the primary tumor. The mean doses recalculated to the NS at tf were more likely to be lower than the planned dose delivered to the PTV at t0: D mean = 33.9 ± 20.8 Gy vs 52.2 ± 8.5 Gy ( p = 0.0009), D 95% = 27.5 ± 21 Gy vs 46.1 ± 4.8 Gy ( p = 0.004). Among the 12 patients with NF outside the elective nodal irradiation (ENI) volume, D mean of NS outside the ENI was significantly lower (19.4 ± 21.4 Gy) than the D mean of NS with failure within the ENI (45.1 ± 6.1 Gy, p = 0.01). Conclusion Loco-regional failure after exclusive chemoradiotherapy for esophageal cancer may be due to an inadequately low dose. [ABSTRACT FROM AUTHOR]

Background Chemoradiotherapy (CHRT) is often advocated for locally-advanced biliary tract cancer (LABTC). However there was not comparative study with chemotherapy alone (CH). Patients and methods Patients with hilar or extrahepatic non-metastatic, LABTC could be included in this phase II trial. The inclusion criteria required World Health Organisation (WHO) performance status ⩽2, bilirubinemia ⩽50 μM/L after biliary drainage if necessary, and possibility of external radiotherapy. Fluorouracil (5 FU) infusion and cisplatin, were given in association to radiotherapy (50 Gy) in the CHRT arm. Gemcitabine + oxaliplatin (GEMOX) was planned for 6 months in the CH arm. End-points were progression-free survival (PFS), overall survival (OS), toxicity and rate of biliary complications. Results The trial was closed before completion due to slow recruitment. Eighteen and 16 patients were included in the CHRT and CH arms, respectively. Median follow up was 27.9 months (±2.8). Grade III–IV toxicities were mostly haematological (23% and 25%), and gastrointestinal (11% and 6%), in the CHRT and CH arm, respectively. Biliary complications occurred in 28% of patients in the CHRT arm and 44% of patients in the CH arm (risk ratio (RR): 1.60 [0.65–3.92]). Median PFS was 5.8 months in the CHRT group and 11.0 months in the CH group (hazard ratio (HR): 0.65 [0.32–1.33]). Median OS was 13.5 months in the CHRT group and 19.9 months in the CH group (HR: 0.69 [0.31–1.55]). Conclusions Combination of gemcitabine plus cisplatin seems to be at least as efficient as chemoradiotherapy (50 Gy plus 5 FU and cisplatin) in LABTC. [ABSTRACT FROM AUTHOR]

Background and purpose The Facility Questionnaire (FQ) of the European Organisation for Research and Treatment of Cancer Radiation Oncology Group (EORTC-ROG) evaluates the human, technical and organizational resources at each EORTC member institution. The purpose of this study is to use the FQ database to assess the improvement of radiation therapy (RT) structures and resources within the EORTC compared to the previous surveys performed by our group. Material and methods We report the content of the current FQ database, completed online by 156 EORTC candidate member institutions from 22 countries between February 2011 and February 2013. Results are compared to FQ-published data from 1992 and 2007. Results The average number of patients per year per EORTC institution is 2381 (range 350–12,000) an 18.2% increase compared to the 2007 figures. From 2007 to 2013 the average number of radiation oncologists, physicists and radiation technologists per EORTC institution has increased by 27% (from 8.5 to 10.8), 41% (from 5.2 to 7.4) and 38% (from 26.1 to 36.1) respectively. Consequently the number of patients per year per radiation oncologist has decreased from 258 to 243, for physicists from 426 to 354 and for radiation technologists from 107 to 86. One hundred and forty-six (94%) and 101 (65%) institutions can now deliver IMRT and SBRT, compared to 77 (79%) and 53 (54%) in 2007. Conclusions The standards set by the EORTC-ROG are met by a continually improving number of institutions, helping to safeguard use of advanced technologies in EORTC-ROG clinical trials. [ABSTRACT FROM AUTHOR]