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Background: Radiotherapy (RT) is a mainstay of treatment for patients with glioblastoma (GB). Early clinical trials show that short course hypofractionation showed no survival benefit compared to conventional regimens with or without temozolomide chemotherapy (TMZ) but reduces the number of doses required. Concerns around delayed neurological deficits and reduced cognition from short course hypofractionated RT remain a concern. The aim of this study was to evaluate the effect of increased interfractional time using two different radiation fractionation regimens on GB.Methods: The radiobiological effect of increasing doses 0-20 Gy x-ray photon RT on Gl261 and CT2A GB cell lines was compared by colony forming assay, DNA damage by alkaline comet assay, oxidative stress, DNA damage, cell cycle, and caspase-3/7 by MUSE® flow cytometric analyses, and protein expression by western blot analyses. Conventional (20 Gy/10 fractions) and hypofractionated (20 Gy/4 fractions spaced 72 h apart) RT regimens with and without TMZ (200 mg/kg/day) were performed in syngeneic Gl261 and CT2A intracranial mouse models using the Small Animal Radiation Research Platform (Xstrahl Inc.).Results: X-ray photon radiation dose-dependently increased reactive oxygen species, DNA damage, autophagy, and caspase 3/7-mediated apoptotic cell death. While the conventional fractionated dose regimen of 20 Gy/10 f was effective at inducing cell death via the above mechanism, this was exceeded by a 20 Gy/4 f regimen which improved median survival and histopathology in Gl261-tumor bearing mice, and eradicated tumors in CT2A tumors with no additional toxicity.Conclusions: Spacing of hypofractionated RT doses 72 h apart showed increased median survival and tumor control via increased activation of RT-mediated cell death, with no observed increased in radiotoxicity. This supports further exploration of differential RT fractionated regimens in GB clinical trials to reduce delayed neurological radiotoxicity. [ABSTRACT FROM AUTHOR]

Gallbladder disease and need for cholecystectomy are common and significant contributors to patient morbidity and healthcare costs. Childhood cancer survivors are at elevated risk for developing cholelithiasis. However, their incidence of and risk factors for late (>5 years from diagnosis) cholecystectomy have not been studied. A total of 25,549 survivors (median age at diagnosis 6.9 years, range 0–21.0; current age 30.7 years, range 5.6–65.9) diagnosed between 1970 and 1999 and 5037 siblings were queried for self-reported cholecystectomy occurring five or more years from primary cancer diagnosis. Piecewise exponential models evaluated associations between cancer treatment exposures and late cholecystectomy. Over a median follow-up period of 21.9 and 26.0 years, respectively, 789 survivors and 168 siblings underwent late cholecystectomy (cumulative incidence 7.2%, 95% confidence interval [CI] = 6.5–7.8% and 6.6%, 95% CI = 5.4–7.6%, respectively; rate ratio [RR] = 1.3, 95% CI = 1.1–1.5). Compared with siblings, survivors of acute lymphoblastic leukaemia (RR = 1.4, 95% CI = 1.2–1.8), soft tissue sarcoma (RR = 1.4, 95% CI = 1.0–1.8) and bone cancer (RR = 1.3, 95% CI = 1.0–1.8) were at the greatest risk. In addition to attained age, female sex and increasing body mass index, exposure to high-dose (≥750 mg/m2) platinum chemotherapy (RR = 2.6, 95% CI = 1.5–4.5), vinca alkaloid chemotherapy (RR = 1.4, 95% CI = 1.1–1.8) or total body irradiation (TBI; RR = 2.2, 95% CI = 1.2–4.2) were each associated with late cholecystectomy. Independent of traditional risk factors for gallbladder disease, exposure to high-dose platinum chemotherapy, vinca alkaloid chemotherapy or TBI increased risk for late cholecystectomy. These findings should inform current long-term follow-up guidelines and education regarding risk for late cholecystectomy. • Cholecystectomy rates are 30% higher in childhood cancer survivors than in siblings. • High-dose platinum agents, vinca alkaloids and TBI increase risk for cholecystectomy. • These agents confer increased risk in survivors without classical risk factors. • These data will inform long-term follow-up guidelines for survivors. [ABSTRACT FROM AUTHOR]

Background: Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment.Methods: We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk.Findings: Among 23 601 survivors with a median follow-up of 21 years (IQR 15-25), the 20-year cumulative incidence of at least one grade 3-5 chronic condition decreased significantly from 33·2% (95% CI 32·0-34·3) in those diagnosed 1970-79 to 29·3% (28·4-30·2; p<0·0001) in 1980-89, and 27·5% (26·4-28·6; p=0·012 vs 1980-89) in 1990-99. By comparison, the 20-year cumulative incidence of at least one grade 3-5 condition in 5051 siblings was 4·6% (95% CI 3·9-5·2). The 15-year cumulative incidence of at least one grade 3-5 condition was lower for survivors diagnosed 1990-99 compared with those diagnosed 1970-79 for Hodgkin lymphoma (17·7% [95% CI 15·0-20·5] vs 26·4% [23·8-29·1]; p<0·0001), non-Hodgkin lymphoma (16·9% [14·0-19·7] vs 23·8% [19·9-27·7]; p=0.0053), astrocytoma (30·5% [27·8-33·2] vs 47·3% [42·9-51·7]; p<0·0001), Wilms tumour (11·9% [9·5-14·3] vs 17·6% [14·3-20·8]; p=0·034), soft tissue sarcoma (28·3% [23·5-33·1] vs 36·5% [31·5-41·4]; p=0·021), and osteosarcoma (65·6% [60·6-70·6] vs 87·5% [84·1-91·0]; p<0·0001). By contrast, the 15-year cumulative incidence of at least one grade 3-5 condition was higher (1990-99 vs 1970-79) for medulloblastoma or primitive neuroectodermal tumour (58·9% [54·4-63·3] vs 42·9% [34·9-50·9]; p=0·00060), and neuroblastoma (25·0% [21·8-28·2] vs 18·0% [14·5-21·6]; p=0·0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3-5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0·77, 95% CI 0·64-0·92; HR with treatment in the model=0·89, 95% CI 0·72-1·11; pmediation=0·0085) and Hodgkin lymphoma (HR without treatment=0·75, 95% CI 0·65-0·85; HR with treatment=0·91, 95% CI 0·73-1·12; pmediation=0·024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970-79 to survivors diagnosed 1990-99 were noted for endocrinopathies (5·9% [5·3-6·4] vs 2·8% [2·5-3·2]; p<0·0001), subsequent malignant neoplasms (2·7% [2·3-3·1] vs 1·9% [1·6-2·2]; p=0·0033), musculoskeletal conditions (5·8% [5·2-6·4] vs 3·3% [2·9-3·6]; p<0·0001), and gastrointestinal conditions (2·3% [2·0-2·7] vs 1·5% [1·3-1·8]; p=0·00037), while hearing loss increased (3·0% [2·6-3·5] vs 5·7% [5·2-6·1]; p<0·0001).Interpretation: Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population.Funding: National Cancer Institute and the American Lebanese-Syrian Associated Charities. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown.Methods: Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS).Results: PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 × 10-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 × 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways.Conclusions: The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation. [ABSTRACT FROM AUTHOR]

Background: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial.Methods: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336.Findings: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy.Interpretation: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified.Funding: Research for Patient Benefit Programme from the UK National Institute for Health Research. [ABSTRACT FROM AUTHOR]

Purpose: This work proposes a theoretical framework that enables comparative risk predictions for second cancer incidence after particle beam therapy for different ion species for individual patients, accounting for differences in relative biological effectiveness (RBE) for the competing processes of tumor initiation and cell inactivation. Our working hypothesis was that use of carbon-ion therapy instead of proton therapy would show a difference in the predicted risk of second cancer incidence in the breast for a sample of Hodgkin lymphoma (HL) patients.Methods and Materials: We generated biologic treatment plans and calculated relative predicted risks of second cancer in the breast by using two proposed methods: a full model derived from the linear quadratic model and a simpler linear-no-threshold model.Results: For our reference calculation, we found the predicted risk of breast cancer incidence for carbon-ion plans-to-proton plan ratio, , to be 0.75 ± 0.07 but not significantly smaller than 1 (P=.180).Conclusions: Our findings suggest that second cancer risks are, on average, comparable between proton therapy and carbon-ion therapy. [ABSTRACT FROM AUTHOR]

Purpose: The expanded prostate cancer index composite-26 (EPIC-26) instrument is a validated research tool used for capturing patient-reported quality-of-life outcomes related to the domains of bowel, bladder, and sexual functioning for men undergoing curative treatment for prostate cancer. The purpose of this pilot study was to explore the perceptions and experiences of clinicians with using EPIC-26 in a clinical setting for patients receiving curative radiotherapy.Methods: Ten clinicians reviewed EPIC-26 scores either before or during weekly clinical encounters with patients receiving curative radiation treatment for prostate cancer. After a period of 2 months, clinicians underwent individual semi-structured interviews where they were asked about their views on measuring patient-reported outcomes in practice, the value of EPIC-26, impressions on patient acceptability, and operational issues.Results: There was a general willingness and acceptance by clinicians to use EPIC-26 for routine clinical practice. Clinician participants found EPIC-26 to be generally informative, and added value to the clinical encounter by providing additional information that was specific to prostate cancer patients. EPIC-26 was also felt to improve overall communication and provide additional insight into the patient experience.Conclusions: Our qualitative findings suggest that there may be a role for incorporating patient-reported outcome measure assessment tools like EPIC-26 routinely into clinical practice. However, further qualitative and quantitative research is required in order to assess the impact of patient-reported outcome information on communication, patient and clinician satisfaction, and how these and other related outcomes can be used for guiding treatment decision-making. [ABSTRACT FROM AUTHOR]