The impact of baseline health factors on second primary cancer risk after radiotherapy for prostate cancer.

PURPOSE: In evaluating second primary cancers (SPCs) following External Beam Radiotherapy (EBRT), the role of lifestyle factors is frequently not considered due to data limitations. We investigated the association between smoking, comorbidities, and SPC risks within EBRT-treated patients for localized prostate cancer (PCa). PATIENTS & METHODS: The study included 1,883 PCa survivors aged 50-79, treated between 2006 and 2013, with intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT). Clinical data were combined with SPC and survival data from the Netherlands Cancer Registry with a 12-month latency period. Standardized Incidence Ratios (SIRs) were calculated comparing the EBRT cohort with the general Dutch population. To explore the effect of patient and treatment characteristics on SPCs we conducted a Cox regression analysis. Lastly, we estimated cumulative incidences of developing solid SPC, pelvis SPC, and non-pelvis SPC using a competing risk analysis. RESULTS: Significantly increased SIRs were observed for all SPC (SIR = 1.21, 95% confidence interval [CI]: 1.08-1.34), pelvis SPC (SIR = 1.46, 95% CI: 1.18-1.78), and non-pelvis SPC (SIR = 1.18, 95% CI [1.04-1.34]). Smoking status was significantly associated with pelvic and non-pelvic SPCs. Charlson comorbidity index (CCI) ≥ 1 (Hazard Ratio [HR] = 1.45, 95% CI: 1.10-1.91), cardiovascular disease (HR = 1.41, 95% CI: 1.05-1.88), and chronic obstructive pulmonary disease (COPD) (HR = 1.91, 95% CI: 1.30-2.79) were significantly associated with non-pelvis SPC. The proportion of active smoking numbers in the cohort was similar to the general population. INTERPRETATION: We conclude that the presence of comorbidities in the EBRT population might be a relevant factor in observed excess non-pelvis SPC risk, but not for excess pelvis SPC risk.

Guidelines for Sexual Health Care for Prostate Cancer Patients: Recommendations of an International Panel.

BACKGROUND: Patients with prostate cancer suffer significant sexual dysfunction after treatment which negatively affects them and their partners psychologically, and strain their relationships. AIM: We convened an international panel with the aim of developing guidelines that will inform clinicians, patients and partners about the impact of prostate cancer therapies (PCT) on patients' and partners' sexual health, their relationships, and about biopsychosocial rehabilitation in prostate cancer (PC) survivorship. METHODS: The guidelines panel included international expert researchers and clinicians, and a guideline methodologist. A systematic review of the literature, using the Ovid MEDLINE, Scopus, CINAHL, PsychINFO, LGBT Life, and Embase databases was conducted (1995-2022) according to the Cochrane Handbook for Systematic Reviews of Interventions. Study selection was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Each statement was assigned an evidence strength (A-C) and a recommendation level (strong, moderate, conditional) based on benefit/risk assessment, according to the nomenclature of the American Urological Association (AUA). Data synthesis included meta-analyses of studies deemed of sufficient quality (3), using A Measurement Tool to Assess Systematic Reviews (AMSTAR). OUTCOMES: Guidelines for sexual health care for patients with prostate cancer were developed, based on available evidence and the expertise of the international panel. RESULTS: The guidelines account for patients' cultural, ethnic, and racial diversity. They attend to the unique needs of individuals with diverse sexual orientations and gender identities. The guidelines are based on literature review, a theoretical model of sexual recovery after PCT, and 6 principles that promote clinician-initiated discussion of realistic expectations of sexual outcomes and mitigation of sexual side-effects through biopsychosocial rehabilitation. Forty-seven statements address the psychosexual, relationship, and functional domains in addition to statements on lifestyle modification, assessment, provider education, and systemic challenges to providing sexual health care in PC survivorship. CLINICAL IMPLICATIONS: The guidelines provide clinicians with a comprehensive approach to sexual health care for patients with prostate cancer. STRENGTHS & LIMITATIONS: The strength of the study is the comprehensive evaluation of existing evidence on sexual dysfunction and rehabilitation in prostate cancer that can, along with available expert knowledge, best undergird clinical practice. Limitation is the variation in the evidence supporting interventions and the lack of research on issues facing patients with prostate cancer in low and middle-income countries. CONCLUSION: The guidelines document the distressing sexual sequelae of PCT, provide evidence-based recommendations for sexual rehabilitation and outline areas for future research. Wittmann D, Mehta A, McCaughan E, et al. Guidelines for Sexual Health Care for Prostate Cancer Patients: Recommendations of an International Panel. J Sex Med 2022;19:1655-1669.

Sexual problems in patients with hematological diseases: a systematic literature review.

PURPOSE: Sexual problems are frequently reported by recipients of hematopoietic stem cell transplantation (HCT). However, little is known about the impact of hematological malignancies and their treatments, without HCT being a part of the treatment regimen. The goal of this systematic review was to examine the prevalence of various sexual problems among patients treated for hematological malignancies without HCT. METHODS: The work focused on online databases available from their inception until 11 November 2020. The data related to sexuality in adult patients diagnosed with hematological malignancies. Selected studies were appraised for methodological quality. RESULTS: Twenty-four studies were included. Twenty-two studies were observational cross-sectional cohort studies, and two studies had a prospective longitudinal design; fourteen studies used non-validated instruments; only two studies used the multidimensional concept of sexuality; six studies compared sexual problems in the target population with reference data. Based on the few high-quality studies, sexual problems occurred in 18-50% of acute leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma patients. CONCLUSION: Understanding sexual problems in patients treated for hematological malignancies without HCT is not only hampered by the variability in methodology, but also by the lack of research on patients using novel therapies. The exact impact of the diagnosis and treatment of a hematological malignancy on sexual function remains to be answered. Longitudinal studies focusing on the effects of the diagnosis and treatment of hematological malignancies on sexuality using validated questionnaires and comparison with normative data are hugely needed.

Challenges in Reporting the Effect of Radiotherapy on Erectile Function.

BACKGROUND: Erectile dysfunction (ED) is the most common side effect of prostate radiotherapy (RT), but reported rates over time and across modalities have varied widely. AIM: To evaluate the published literature between 2002 and 2018 for high quality data utilizing prospectively gathered patient-reported ED, and to summarize the challenges in reporting of RT-induced ED (RIED). METHODS: A PubMed search and literature review was performed to identify articles describing rates of ED before and after definitive external beam RT or brachytherapy without androgen deprivation. OUTCOMES: Patient-reported ED, patient and treatment variables, and study follow-up constituted the main outcomes of this study. RESULTS: 24 articles were identified, reporting RIED rates between 17% and 90%. Variables contributing to this range included patient, treatment, and study characteristics known to impact ED reporting. CLINICAL IMPLICATIONS: For future studies, we recommend the use of validated patient-reported questionnaires and reporting of baseline function and comorbidities, RT type and dose, and use of androgen deprivation therapy and erectile aids at the time of ED measurement. With sufficient follow-up to understand the late nature of RIED, these recommendations will improve comparison of results between studies and the applicability of results to patients undergoing pretreatment counseling regarding the risks of RIED. STRENGTHS & LIMITATIONS: The literature search and formulation of results were based on a broad understanding of the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and the literature, but because of the focus on data reporting, a comprehensive systematic review of all RIED literature was not performed. CONCLUSION: Reported rates of ED after RT vary widely due to differences in patients' baseline reported erectile function, age, comorbidities, and characteristics of the treatment delivered. The methodology of ED measurement has significant impact on the applicability and comparability of results to other studies and clinical practice. Nukala V, Incrocci L, Hunt AA, et al. Challenges in Reporting the Effect of Radiotherapy on Erectile Function. J Sex Med 2020;17:1053-1059.

Bayesian Sigmoid-Type Time Series Forecasting with Missing Data for Greenhouse Crops.

This paper follows an integrated approach of Internet of Things based sensing and machine learning for crop growth prediction in agriculture. A Dynamic Bayesian Network (DBN) relates crop growth associated measurement data to environmental control data via hidden states. The measurement data, having (non-linear) sigmoid-type dynamics, are instances of the two classes observed and missing, respectively. Considering that the time series of the logistic sigmoid function is the solution to a reciprocal linear dynamic model, the exact expectation-maximization algorithm can be applied to infer the hidden states and to learn the parameters of the model. At iterative convergence, the parameter estimates are then used to derive a predictor of the measurement data several days ahead. To evaluate the performance of the proposed DBN, we followed three cultivation cycles of micro-tomatoes (MicroTom) in a mini-greenhouse. The environmental parameters were temperature, converted into Growing Degree Days (GDD), and the solar irradiance, both at a daily granularity. The measurement data were Leaf Area Index (LAI) and Evapotranspiration (ET). Although measurement data were only available scarcely, it turned out that high quality measurement data predictions were possible up to three weeks ahead.

Sexual Function in Patients Treated With Stereotactic Radiotherapy For Prostate Cancer: A Systematic Review of the Current Evidence.

INTRODUCTION: Sexual function can be impaired by all prostate cancer treatment modalities, but studies specifically addressing the impact of stereotactic body radiotherapy (SBRT) on sexual function are scarce. AIM: To systematically evaluate sexual outcomes in patients treated by SBRT for prostate cancer and determine clinical factors associated with erectile dysfunction (ED). METHODS: A systematic review of the available literature was performed on PubMed/Medline, Scopus, and Cochrane Library databases in June 2017 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Only articles providing data on baseline and post-treatment sexual function after SBRT (≥5 Gy/fraction) were included in this analysis (n = 12). MAIN OUTCOME MEASURE: Sexual function deteriorates after SBRT of the prostate. RESULTS: Deterioration of sexual health was found, with Expanded Prostate Cancer Index Composite-26 sexual domain scores showing a median decrease of 9.2 at 12 months and a median decrease of the Sexual Health Inventory for Men subdomain score by 2.7 at 12 months (from baseline median value of 56.3 and 16, respectively). At 60 months, ED was reported by 26-55% of previously sexually functioning patients in 5 of the 12 studies. CLINICAL IMPLICATIONS: ED affects ≤55% of previously sexually functioning patients at 5 years, as reported for other non-surgical treatment modalities. STRENGTHS & LIMITATIONS: This study enforced strict inclusion criteria of selected studies and exclusion of patients receiving concurrent androgen deprivation therapy. However, inconsistencies in the choice of assessment tool and definition of ED hamper a robust meta-analysis of pooled data. CONCLUSION: Sexual function decline after SBRT for prostate cancer appears to be similar to other modalities and should be specifically addressed in future studies. Loi M, Wortel RC, Francolini G, et al. Sexual Function in Patients Treated With Stereotactic Radiotherapy For Prostate Cancer: A Systematic Review of the Current Evidence. J Sex Med 2019;16:1409-1420.

Evaluation of Chemical Composition of Two Linseed Varieties as Sources of Health-Beneficial Substances.

Linseed (Linum usitatissimum L.) is becoming more and more important in the health food market as a functional food, since its seeds and oil represent a rich source of bioactive compounds. Its chemical composition is strongly correlated with, and dependent on, genetic characteristics. The aim of this study was to evaluate the variation in seed yield, oil content, fatty acid composition and secondary metabolite profiles between a low-linolenic linseed variety, belonging to the Solin-type group (Solal), and a high-linolenic traditional one (Bethune), cultivated, both as spring crops, in open field conditions of Central Italy. The achieved results pointed out the different behavior of the two varieties in terms of growth cycle, oil content, and some important yield components, such as capsule number per plant and thousand seed weight. There were also significant differences in seed composition regarding total phenols, total flavonoids, antioxidant activities as well as in carotenoid, tocopherol, and tocotrienol profiles between the two varieties. In particular, Solal was characterized by the greatest contents of oil, phenols, flavonoids, α- and δ- tocotrienol, together with the highest antioxidant activity. Bethune, on the contrary, showed the highest amounts of carotenoids (lutein and ß-carotene). These results indicate a clear effect of the genetic characteristics on the biosynthesis of these secondary metabolites and, consequently, on the related antioxidant activity. Our findings suggest that the mutation process, responsible for the selection of the low-linolenic cultivar, is able to modify the biosynthetic pathways of carotenoids and phenolics.

Risk of diabetes after para-aortic radiation for testicular cancer.

BACKGROUND: While the risk of diabetes is increased following radiation exposure to the pancreas among childhood cancer survivors, its association among testicular cancer (TC) survivors has not been investigated. METHODS: Diabetes risk was studied in 2998 1-year TC survivors treated before 50 years of age with orchidectomy with/without radiotherapy between 1976 and 2007. Diabetes incidence was compared with general population rates. Treatment-specific risk of diabetes was assessed using a case-cohort design. RESULTS: With a median follow-up of 13.4 years, 161 TC survivors were diagnosed with diabetes. Diabetes risk was not increased compared to general population rates (standardised incidence ratios (SIR): 0.9; 95% confidence interval (95% CI): 0.7-1.1). Adjusted for age, para-aortic radiotherapy was associated with a 1.66-fold (95% CI: 1.05-2.62) increased diabetes risk compared to no radiotherapy. The excess hazard increased with 0.31 with every 10 Gy increase in the prescribed radiation dose (95% CI: 0.11-0.51, P = 0.003, adjusted for age and BMI); restricted to irradiated patients the excess hazard increased with 0.33 (95% CI: -0.14 to 0.81, P = 0.169) with every 10 Gy increase in radiation dose. CONCLUSION: Compared to surgery only, para-aortic irradiation is associated with increased diabetes risk among TC survivors.

Characteristics and outcome of prostate cancer patients with overall biopsy Gleason score 3 + 4 = 7 and highest Gleason score 3 + 4 = 7 or > 3 + 4 = 7.

AIM: Prostate cancer heterogeneity and multifocality might result in different Gleason scores (GS) at individual biopsy cores. According to World Health Organisation/International Society of Urologic Pathology (WHO/ISUP) guidelines, the GS in each biopsy core should be recorded with optional reporting of overall GS for the entire case. We aimed to compare the clinicopathological characteristics and outcome of men with overall biopsy GS 3 + 4 = 7 with highest GS 3 + 4 = 7 (HI = OV) to those with highest GS > 3 + 4 = 7 (HI > OV). METHODS AND RESULTS: Prostate cancer biopsies from the European Randomised Study of Screening for Prostate Cancer (ERSPC) were revised according to WHO/ISUP 2014 guidelines (n = 1031). In total, 370 patients had overall GS 3 + 4 = 7, 60 of whom (16%) had had at least one biopsy core with GS 4 + 3 = 7 or 4 + 4 = 8. Men with higher GS than 3 + 4 (HI > OV) in any of the cores had higher age, prostate-specific antigen (PSA) level, number of positive biopsies, percentage tumour involvement, percentage Gleason grade 4 and cribriform or intraductal growth (all P < 0.05) than those with GS 3 + 4 = 7 at highest (HI = OV). In multivariable Cox regression analysis, including PSA, percentage positive biopsies and percentage tumour involvement, biochemical recurrence-free survival after radical prostatectomy (P = 0.52) or radiotherapy (P = 0.35) was not statistically different between both groups. CONCLUSION: Among patients with overall GS 3 + 4 = 7, those with highest GS > 3 + 4 = 7 had worse clinicopathological features, but clinical outcome was not statistically significant. Therefore, the use of overall GS instead of highest GS for clinical decision-making is justified, potentially preventing overtreatment in prostate cancer patients.

Prognostic impact of nodal relapse in definitive prostate-only irradiation.

BACKGROUND: Whole pelvic irradiation in prostate cancer patients might prevent metastatic spread of cancer cells through lymphatic drainages in patients eligible for definitive radiotherapy, but its use has declined in the last decades in favor of prostate-only irradiation (POI). The aim of our study is to assess the incidence of pelvic lymph nodal relapse and outcome in prostate cancer patients receiving POI. MATERIALS AND METHODS: Data from 207 consecutive patients were collected. Clinical and treatment variables were collected. Biochemical relapse-free survival (BRFS), pelvic nodal relapse-free survival (PNRFS), distant metastasis-free survival (DMFS), disease-specific survival (DSS) and overall survival (OS) were calculated; analysis of prognostic variables was performed. RESULTS: Five-year BRFS, PNRFS, DMFS, DSS and OS were, respectively, 90, 98, 96, 97 and 91%. On multivariate analysis, independent negative predictors of BRFS were Gleason score ≥ 7 (HR: 3.25) and PSA nadir ≥ 0.08 (HR: 4.86). Pelvic nodal relapse was not correlated to impaired outcome. CONCLUSIONS: Lymph nodal pelvic relapse occurs in 2% of patients at 5 years and does not correlate with impaired outcome, suggesting the lack of theoretical benefit of a prophylactic nodal irradiation. Tumor biology and response to treatment are the main determinants of outcome.

Presence of invasive cribriform or intraductal growth at biopsy outperforms percentage grade 4 in predicting outcome of Gleason score 3+4=7 prostate cancer.

Relative increase of grade 4 and presence of invasive cribriform and/or intraductal carcinoma have individually been associated with adverse outcome of Gleason score 7 (GS 7) prostate cancer. The objective of this study was to investigate the relation of Gleason grade 4 tumor percentage (%GG4) and invasive cribriform and/or intraductal carcinoma in GS 3+4=7 prostate cancer biopsies. We reviewed 1031 prostate cancer biopsies from the European Randomized Study of Screening for Prostate Cancer. In total 370 men had G3+4=7. The relation of invasive cribriform and/or intraductal carcinoma and %GG4 with biochemical recurrence-free survival (BCRFS) after radical prostatectomy (n=146) and radiation therapy (n=195) was analyzed using Cox regression. Invasive cribriform and/or intraductal carcinoma occurred in 7/121 (6%) patients with 1-10% GG4, 29/131 (22%) with 10-25%, and 52/118 (44%) with 25-50% GG4 (P<0.001). In crude analysis, both invasive cribriform and/or intraductal carcinoma (HR 2.72; 95% CI: 1.33-5.95; P=0.006) and 10-50% GG4 (HR 2.43; 95% CI: 1.10-5.37; P=0.03) were associated with BCRFS after prostatectomy. In adjusted analysis, invasive cribriform and/or intraductal carcinoma was an independent predictor for BCRFS (HR 2.40; 95% CI: 1.03-5.60; P=0.04) after prostatectomy, whereas percentage %GG4 (HR 1.00; 95% CI: 0.97-1.03; P=0.80) was not. While invasive cribriform and/or intraductal carcinoma (HR 2.58; 95% CI: 1.59-4.21; P<0.001) performed better than 10-50% GG4 (HR 1.24; 95% CI: 0.67-2.29; P=0.49) for prediction of BCRFS after radiation therapy, both parameters were insignificant in analysis adjusted for prostate-specific antigen (P=0.001), positive biopsies (P<0.001) and tumor volume (P=0.05). In conclusion, increased %GG4 is associated with invasive cribriform and/or intraductal carcinoma in GS 3+4=7 prostate cancer biopsies. Invasive cribriform and/or intraductal carcinoma is an independent parameter for BCR after prostatectomy, whereas %GG4 is not. The presence of invasive cribriform and/or intraductal carcinoma has to be included in pathology reports and should act as exclusion criterion for active surveillance.

Reporting Erectile Function Outcomes After Radiation Therapy for Prostate Cancer: Challenges in Data Interpretation.

BACKGROUND: Choice of prostate cancer treatment is frequently influenced by the expected chance of treatment-induced side effects such as erectile dysfunction (ED). However, great discrepancy in cited ED rates exists in the contemporary radiation therapy literature. AIM: To analyze the reported ED rates and cause of discrepancies and explore the strengths and limitations in the literature on radiation-induced ED. METHODS: We performed a PubMed literature search and reviewed the literature on ED rates associated with external-beam radiotherapy and brachytherapy from the past 10 years. Eighteen studies were eligible for inclusion and subsequently reviewed. OUTCOMES: Variables required for interpretation of erectile function outcomes, including patient demographics, treatment characteristics, and sexual function outcomes. RESULTS: A large variety in the reported incidence of ED was found among studies. In part, these differences resulted from large variations in (i) study populations, (ii) patient characteristics, (iii) treatment characteristics, (iv) prescription of androgen deprivation therapy, (v) means of data acquisition, (vi) definitions of ED, (vii) temporal considerations, and (viii) erectile aid use. Relevant data required for adequate appraisal of sexual function outcomes were not always reported. CLINICAL IMPLICATIONS: Based on the present findings, we present general recommendations for reporting of erectile function outcomes after radiotherapy for prostate cancer. These should improve future reports. STRENGTHS AND LIMITATIONS: This is the first report that presents general requirements on reporting erectile function outcomes in the setting of radiotherapy for prostate cancer. We did not conduct a formal meta-analysis because we focused on concepts of research design; this might be considered a limitation. CONCLUSION: In this review, we have highlighted the strengths and deficiencies of the current literature on ED after external-beam radiotherapy and brachytherapy for prostate cancer. We have made general recommendations to achieve some degree of standardization among reports and improve clinical interpretability. Wortel RC, Incrocci L, Muhall JP. Reporting Erectile Function Outcomes After Radiation Therapy for Prostate Cancer: Challenges in Data Interpretation. J Sex Med 2017;14:1260-1269.

Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial.

BACKGROUND: Several studies have reported a low α to ß ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. We tested this theory in the phase 3 HYPRO trial for patients with intermediate-risk and high-risk prostate cancer. We have previously reported acute incidence of genitourinary and gastrointestinal toxicity; here we report data for late genitourinary and gastrointestinal toxicity. METHODS: In this randomised non-inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a prostate-specific antigen concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks (three fractions per week). Randomisation was done with the minimisation procedure, stratified by treatment centre and risk group. The primary endpoint was to detect a 10% enhancement in 5-year relapse-free survival with hypofractionation. A key additional endpoint was non-inferiority of hypofractionation in cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. We planned to reject inferiority of hypofractionation for late genitourinary toxicity if the estimated hazard ratio (HR) was less than 1·11 and for gastrointestinal toxicity was less than 1·13. We scored toxicity with the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer (RTOG/EORTC) criteria from both physicians' records (clinical record form) and patients' self-assessment questionnaires. Analyses were done in the intention-to-treat population. Patient recruitment for the HYPRO trial was completed in 2010. The trial was registered with www.controlled-trials.com, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients (410 in both groups) were randomly assigned. Analyses for late toxicity included 387 assessable patients in the standard fractionation group and 395 in the hypofractionation group. The median follow-up was 60 months (IQR 51·2-67·3). The database for all analyses (both groups and both genitourinary and gastrointestinal toxicities) was locked on March 26, 2015. The incidence of grade 2 or worse genitourinary toxicity at 3 years was 39·0% (95% CI 34·2-44·1) in the standard fractionation group and 41·3% (36·6-46·4) in the hypofractionation group. The estimated HR for the cumulative incidence of grade 2 or worse late genitourinary toxicity was 1·16 (90% CI 0·98-1·38), suggesting that non-inferiority could not be shown. The incidence of grade 2 or worse gastrointestinal toxicity at 3 years was 17·7% (14·1-21·9) in standard fractionation and 21·9% (18·1-26·4) hypofractionation. With an estimated HR of 1·19 (90% CI 0·93-1·52) for the cumulative incidence of grade 2 or worse late gastrointestinal toxicity, we could not confirm non-inferiority of hypofractionation for cumulative late gastrointestinal toxicity. Cumulative grade 3 or worse late genitourinary toxicity was significantly higher in the hypofractionation group than in the standard fractionation group (19·0% [95% CI 15·2-23·2] vs 12·9% [9·7-16·7], respectively; p=0·021), but there was no significant difference between cumulative grade 3 or worse late gastrointestinal toxicity (2·6% [95% CI 1·2-4·7]) in the standard fractionation group and 3·3% [1·7-5·6] in the hypofractionation group; p=0·55). INTERPRETATION: Our data could not confirm that hypofractionation was non-inferior for cumulative late genitourinary and gastrointestinal toxicity compared with standard fractionation. Before final conclusions can be made about the utility of hypofractionation, efficacy outcomes need to be reported. FUNDING: The Dutch Cancer Society.

Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: Studies have reported a low α/ß ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. In the multicentre phase 3, HYpofractionated irradiation for PROstate cancer (HYPRO) trial, hypofractionated radiotherapy was compared with conventionally fractionated radiotherapy for treatment of prostate cancer. We have previously reported acute and late incidence of genitourinary and gastrointestinal toxicity; here we report protocol-defined 5-year relapse-free survival outcomes. METHODS: We did an open-label, randomised, phase 3 trial at seven Dutch radiotherapy centres. We enrolled patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localised prostate cancer, a prostate-specific antigen concentration of 60 µg/L or less, and a WHO performance status of 0-2. We used a web-based application to randomly assign (1:1) patients to either hypofractionated radiotherapy of 64·6 Gy (19 fractions of 3·4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78·0 Gy (39 fractions of 2·0 Gy, five fractions per week). Based on an estimated α/ß ratio for prostate cancer of 1·5 Gy, the equivalent total dose in fractions of 2·0 Gy was 90·4 Gy for hypofractionation compared with 78·0 Gy for conventional fractionation. The primary endpoint was relapse-free survival. All analyses were done on an intention-to-treat basis in all eligible patients. The HYPRO trial completed recruitment in 2010 and follow-up is ongoing. This trial is registered with ISRCTN, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients were enrolled, of whom 804 were eligible and assessable for intention-to-treat analyses. Of these, 407 were assigned hypofractionated radiotherapy and 397 were allocated conventionally fractionated radiotherapy. 537 (67%) of 804 patients received concomitant androgen deprivation therapy for a median duration of 32 months (IQR 10-44). Median follow-up was 60 months (IQR 51-69). Treatment failure was reported in 169 (21%) of 804 patients, 80 (20%) in the hypofractionation group and 89 (22%) in the conventional fractionation group. 5-year relapse-free survival was 80·5% (95% CI 75·7-84·4) for patients assigned hypofractionation and 77·1% (71·9-81·5) for those allocated conventional fractionation (adjusted hazard radio 0·86, 95% CI 0·63-1·16; log-rank p=0·36). There were no treatment-related deaths. INTERPRETATION: Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer. FUNDING: Dutch Cancer Society.

Sexual Function After Hypofractionated Versus Conventionally Fractionated Radiotherapy for Prostate Cancer: Results From the Randomized Phase III HYPRO Trial.

INTRODUCTION: Hypofractionated radiotherapy could increase the radiobiological tumor dose for localized prostate cancer. The effects of hypofractionation on sexual function are not well known. AIM: To compare sexual function in patients with prostate cancer treated with 78 Gy in 39 fractions of 2 Gy or 64.6 Gy in 19 fractions of 3.4 Gy. METHODS: In total, 820 men with intermediate- to high-risk T1b-T4NX-0MX-0 prostate cancer were enrolled in the phase III HYPRO trial (2007-2010) and randomized to conventional fractionation (39 × 2 Gy) or hypofractionation (19 × 3.4 Gy). Sexual function was assessed at baseline and at 6, 12, 24, and 36 months after treatment using the International Index of Erectile Function (IIEF). For this analysis, patients (n = 322) with a baseline assessment, at least one follow-up assessment, and no or short-term (6-month) androgen-deprivation therapy were included. MAIN OUTCOME MEASURES: Mean IIEF domain scores were compared between treatments in the total population and the hormone-naïve population (n = 197) using the independent t-test. Incidences of severe erectile dysfunction (domain score < 11) at last follow-up were calculated in patients with partial or full baseline function. Binary logistic regression analyses were applied to calculate the odds ratio of hypofractionation vs conventional fractionation and to adjust for clinical factors. RESULTS: Median age was 71 years (interquartile range = 67-71) and median follow-up was 37 months (interquartile range = 25-38). Androgen-deprivation therapy was prescribed in 125 (39%). IIEF domain scores decreased after treatment but were comparable between treatment arms at baseline and during follow-up. Orgasmic function scores in hormone-naïve patients were significantly higher at 3 years after hypofractionation (4.08 vs 2.65, P = .031). In patients (n = 120) with partial or full baseline erectile function, the incidence of erectile dysfunction at last follow-up was 34.4% for hypofractionated treatment vs 39.3% for conventional treatment (adjusted odds ratio = 0.84, 95% CI = 0.37-1.90, P = .67). CONCLUSION: No significant differences in erectile functioning between conventional and hypofractionated radiotherapy were found. Hormone-naïve patients reported significantly higher orgasmic function scores at 3 years after hypofractionation.

Cancer, Benign Gynecology, and Sexual Function--Issues and Answers.

INTRODUCTION: The diagnosis, treatment, and survivorship of cancer have a profound effect on the quality of life and psychological well-being of men and women. Indeed, the perturbation of sexual function because of neoplasm has far-reaching implications. AIMS: To explore the prevalence, pathophysiology, and treatment of sexual issues in persons with cancer and offer evidence-based recommendations regarding optimal prevention and treatment strategies. METHODS: A committee of multidisciplinary specialists was formed as part of the larger International Sexual Medicine Consultation working with urologic and sexual medicine societies over a 1-year period to review the result of chronic-illness management on sexual function and satisfaction. The aims, goals, data collection techniques, and report format were defined by a central committee. MAIN OUTCOMES MEASURES: Expert consensus was based on evidence-based medical and psychosocial literature review, extensive group discussion, and an open presentation with a substantial discussion period. RESULTS: This summary evaluates contemporary literature concerning the prevalence, pathophysiology, and psychological impact of cancer diagnosis and treatment on sexual dysfunction. Evidence-based recommendations and guidelines for evaluation and management are presented. CONCLUSION: The diagnosis and treatment of cancer have a significant negative impact on sexual function and satisfaction. Comprehension of baseline sexual function, role of psychological supports, and available treatment options could attenuate the heavy burden of decreased sexual function.

Coronary Heart Disease, Diabetes, and Sexuality in Men.

Erectile dysfunction (ED) has been well recognized as a marker of increased cardiovascular risk for more than 15 years, especially in younger men. Early detection of ED represents an opportunity to intervene to decrease the risk of future cardiovascular events and limit the progression of ED severity. Evidence suggests there is a window of opportunity of 3 to 5 years from the onset of ED to subsequent cardiovascular events. This opportunity is usually missed if the onus is placed on the patient to seek care for his sexual problems. Unfortunately, these clear messages have not been incorporated into routine cardiovascular care. The reasons for these disparities within specialties are discussed in this article, in addition to management algorithms. Lifestyle modification is usually recommended as the first-line treatment to correct ED and lessen cardiovascular risk, but evidence suggests that this might be effective only in men without established cardiovascular comorbidities. In men with type 2 diabetes mellitus and established cardiovascular disease, lifestyle modification alone is unlikely to be effective. Cardiovascular medications are often associated with sexual dysfunction but changes in medication are more likely to be beneficial in men with milder recent-onset ED. A balanced view must be taken related to medication adverse events, taking into account optimal management of established cardiovascular disease. Testosterone deficiency has been associated with different metabolic disorders, especially metabolic syndrome and type 2 diabetes mellitus. Testosterone deficiency syndrome has been associated with an independent burden on sexual function globally and increased cardiovascular and all-cause mortality. Testosterone replacement therapy has been shown to improve multiple aspects of sexual function and, in some studies, has been associated with a decrease in mortality, especially in men with type 2 diabetes mellitus. Recent studies have suggested that phosphodiesterase type 5 inhibitors, the first-line medications to treat ED, could decrease cardiovascular and all-cause mortality, through multiple mechanisms, predominantly related to improved endothelial function.

Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial.

BACKGROUND: In 2007, we began the randomised phase 3 multicentre HYPRO trial to investigate the effect of hypofractionated radiotherapy compared with conventionally fractionated radiotherapy on relapse-free survival in patients with prostate cancer. Here, we examine whether patients experience differences in acute gastrointestinal and genitourinary adverse effects. METHODS: In this randomised non-inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a PSA concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3·4 Gy in 6·5 weeks (three fractions per week). Randomisation was done with minimisation procedure, stratified by treatment centre and risk group. The primary endpoint is 5-year relapse-free survival. Here we report data for the acute toxicity outcomes: the cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. Non-inferiority of hypofractionation was tested separately for genitourinary and gastrointestinal acute toxic effects, with a null hypothesis that cumulative incidences of each type of adverse event were not more than 8% higher in the hypofractionation group than in the standard fractionation group. We scored acute genitourinary and gastrointestinal toxic effects according to RTOG-EORTC criteria from both case report forms and patients' self-assessment questionnaires, at baseline, twice during radiotherapy, and 3 months after completion of radiotherapy. Analyses were done in the intention-to-treat population. Patient recruitment has been completed. This study is registered with www.controlled-trials.com, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients were randomly assigned to treatment with standard fractionation (n=410) or hypofractionation (n=410). 3 months after radiotherapy, 73 (22%) patients in the standard fractionation group and 75 (23%) patients in the hypofractionation group reported grade 2 or worse genitourinary toxicity; grade 2 or worse gastrointestinal toxicity was noted in 43 (13%) patients in the standard fractionation group and in 42 (13%) in the hypofractionation group. Grade 4 acute genitourinary toxicity was reported for two patients, one (<1%) in each group. No grade 4 acute gastrointestinal toxicities were observed. We noted no significant difference in cumulative incidence by 120 days after radiotherapy of grade 2 or worse acute genitourinary toxicity (57·8% [95% CI 52·9-62·7] in the standard fractionation group vs 60·5% (55·8-65·3) in the hypofractionation group; difference 2·7%, 90% CI -2·99 to 8·48; odds ratio [OR] 1·12, 95% CI 0·84-1·49; p=0·43). The cumulative incidence of grade 2 or worse acute gastrointestinal toxicity by 120 days after radiotherapy was higher in patients given hypofractionation (31·2% [95% CI 26·6-35·8] in the standard fractionation group vs 42·0% [37·2-46·9] in the hypofractionation group; difference 10·8%, 90% CI 5·25-16·43; OR 1·6; p=0·0015; non-inferiority not confirmed). INTERPRETATION: Hypofractionated radiotherapy was not non-inferior to standard fractionated radiotherapy in terms of acute genitourinary and gastrointestinal toxicity for men with intermediate-risk and high-risk prostate cancer. In fact, the cumulative incidence of grade 2 or worse acute gastrointestinal toxicity was significantly higher in patients given hypofractionation than in those given standard fractionated radiotherapy. Patients remain in follow-up for efficacy endpoints. FUNDING: The Dutch Cancer Society.

Orchiectomy and radiotherapy for stage I-II testicular seminoma: a prospective evaluation of short-term effects on body image and sexual function.

INTRODUCTION: Orchiectomy followed by infradiaphragmatic radiotherapy is a common treatment for stage I-II testicular seminoma. Long-term effects of orchiectomy and radiotherapy for testicular seminomas on body image and sexual function have been reported; however, few data are available on short-term effects. Patients are usually of reproductive age and sexually active; therefore, short-term effects on body image and sexual function should also be studied. AIMS: To prospectively evaluate short-term effects of orchiectomy and radiotherapy on body image and sexual function in testicular seminoma patients. METHODS: Questionnaires on body image and sexual function were prospectively distributed to all testicular seminoma patients treated between 1999 and 2013. The questionnaire distributed prior to radiotherapy was returned by 161 patients; 133 (82%) returned the second after 3 months, and 120 (75%) completed the questionnaire after 6 months. MAIN OUTCOME MEASURES: Body image and sexual function as assessed by a Dutch questionnaire on body image and sexuality after radiotherapy and orchiectomy. RESULTS: Median age was 36 years (range 18-70). After orchiectomy, 48% expressed fertility concerns, and 61% reported their body had changed. Six months after treatment, erectile rigidity was significantly decreased compared with prior to radiotherapy (P = 0.016), and 23% reported decreased sexual interest, activity, and pleasure. Changes in body image were significantly associated with decreased sexual interest, pleasure, and erectile function. Even though 45% reported that treatment negatively affected their sexual life, the number of sexually active patients remained stable at 91%. [Correction added on 12 November 2014, after first online publication: 'prior radiotherapy' was corrected to 'prior to radiotherapy'.] CONCLUSIONS: Short-term effects of treatment included fertility concerns and changes in body image. Reported erectile rigidity was significantly decreased after 6 months, as were sexual interest, activity, and pleasure. Disease and treatment had negative effects on sexual life, and changes in body image were associated with sexual dysfunction. Therefore, body image and sexual functioning should be addressed at an early stage in order to offer adequate treatment and counseling.