Dermatological Adverse Events in Prostate Cancer Patients Treated with the Androgen Receptor Inhibitor Apalutamide.

PURPOSE: Patients with prostate cancer (PCa) treated with apalutamide frequently develop rash. We aim to characterize apalutamide-related dermatological adverse events (dAEs) and management. MATERIALS AND METHODS: We assessed 303 patients with PCa treated with apalutamide. DAE frequency and time to onset were calculated and clinicopathological features and management described. Associations between dAE occurrence and clinical trial participation, as well as abiraterone/prednisone exposure were detected using logistic regression models. RESULTS: Seventy-one (23.4%) patients had all-grade dAE occurring at a median of 77 (IQR: 30-135) days post-exposure. Twenty (6.6%) dAE-related therapy interruptions included: 8 (2.6%) with dose maintained on rechallenge, 7 (2.3%) with dose reduction and 5 (1.7%) with discontinuation. Common dAEs were maculopapular rashes (33.8%) and xerosis (32.4%). Seven (77.8%) of 9 histological analyses of skin biopsies supported a drug reaction. No significant differences in laboratory hematological, hepatic and renal function were detected between dAE and no dAE cohorts. Most treated grade 1/2 dAEs (29, 40.8%) required topical steroids (14, 19.7%); few required oral steroids (3, 4.2%) ± oral antihistamines. Most grade 3 dAEs (8, 11.3%) required oral/topical steroids (5, 7.0%); few required topical steroids (3, 4.2%) ± oral antihistamines. Clinical trial patients (180, 59.4%) were more likely to report dAEs than those in the off-trial setting (OR=5.1 [95% CI 2.55-10.12]; p <0.001). Of clinical trial patients, concomitant abiraterone/prednisone recipients (109 of 180, 60.6%) were more likely to report dAEs (OR=3.1 [95% CI 1.53-6.17]; p=0.002). CONCLUSIONS: Apalutamide-related dAEs are frequent and can be managed with topical ± oral steroids. With expanded approval of apalutamide, dAE identification and management are essential.

Influence of hydrogel spacer placement with prostate brachytherapy on rectal and urinary toxicity.

OBJECTIVE: To determine the influence of rectal hydrogel spacer placement (HSP) on late rectal toxicity outcomes in prostate cancer patients treated with low-dose-rate (LDR) brachytherapy, with or without supplemental external beam radiotherapy (EBRT). PATIENTS AND METHODS: A total of 224 patients underwent LDR brachytherapy with HSP, as monotherapy or combined with EBRT, between January 2016 and December 2019. Dosimetric variables reflecting the extent of rectal sparing and late rectal toxicity outcomes were evaluated. This spacer cohort was retrospectively compared to a similar patient group (n = 139) in whom HSP was not used. RESULTS: Hydrogel spacer placement was associated with significantly reduced rectal doses for all dosimetric variables; the median percentage rectal dose to 1 cc of rectum and rectal dose to 2 cc of rectum of the spacer cohort were all significantly lower compared to the non-spacer cohort. The incidence rates of overall (any grade) and grade ≥2 rectal toxicity were lower in patients with HSP compared to patients who did not undergo HSP: 12% and 1.8% vs 31% and 5.8%, respectively. The 3-year cumulative incidence of overall rectal toxicity was significantly lower with HSP than without (15% vs 33%; P < 0.001), corresponding to an overall rectal toxicity reduction on univariable analysis (hazard ratio 0.45, 95% confidence interval 0.28-0.73; P = 0.001). In this patient cohort treated with prostate brachytherapy, none of the urethral dosimetric variables or the presence or absence of HSP was associated with late urinary toxicity. CONCLUSION: Hydrogel rectal spacer placement is a safe procedure, associated with significantly reduced rectal dose. HSP translates to a decrease in overall late rectal toxicity in patients receiving dose-escalated brachytherapy-based procedures.

Socioeconomic inequality and omission of adjuvant radiation therapy in high-risk, early-stage endometrial cancer.

OBJECTIVE: Gaps in access to appropriate cancer care, and associated cancer mortality, have widened across socioeconomic groups. We examined whether demographic and socioeconomic factors influenced receipt of adjuvant radiation therapy (RT) in patients with high-risk, early-stage endometrial cancer. METHODS: A retrospective study cohort was selected from 349,404 endometrial carcinoma patients from the National Cancer Database in whom adjuvant RT would be recommended per national guidelines. The study included surgically treated patients with endometrioid endometrial cancer with one of the following criteria: 1) FIGO 2009 stage IB, grade 1/2 disease, age ≥ 60 years; 2) stage IB, grade 3 disease; or 3) stage II disease. Logistic regression analysis was performed to identify factors associated with omission of adjuvant RT. Association between adjuvant RT, covariables, and overall survival (OS) was assessed with multivariable Cox proportional hazards models. RESULTS: 19,594 patients were eligible for analysis; 47% did not receive adjuvant RT. Omission of adjuvant RT was more prevalent among African-American, Hispanic, and Asian compared to non-Hispanic white patients (OR 0.79, 95%CI: 0.69-0.91; OR 0.75, 95%CI: 0.64-0.87; OR 0.75, 95%CI: 0.60-0.94, respectively). Lower median household income of patient's area of residence, lack of health insurance, treatment at non-academic hospitals, farther distance to treatment facilities, and residence in metropolitan counties were associated with omission of adjuvant RT. Such omission was independently associated with worse OS (HR1.43, p < 0.001). CONCLUSION: Adjuvant RT is omitted in 47% of patients with early-stage, high-risk endometrial cancer, which is associated with poor access to appropriate, high-quality care and worse outcome.

Sildenafil Citrate and Risk of Biochemical Recurrence in Prostate Cancer Patients Treated with Radiation Therapy: Post-Hoc Analysis of a Randomized Controlled Trial.

BACKGROUND: Sildenafil citrate has been shown to be protective of sexual function when given concurrently and following prostate radiation therapy (RT), but some evidence suggests an increased biochemical recurrence (BCR) risk in patients taking sildenafil after radical prostatectomy. AIM: To evaluate whether sildenafil use is associated with increased risk of BCR in patients receiving prostate RT, we performed a secondary analysis of a randomized placebo-controlled trial (RPCT) that compared sildenafil citrate to placebo during and after prostate RT. METHODS: The study population consisted of prostate cancer patients who initiated radiation treatment at our institution and participated in our multi-institutional RPCT that compared 6 months of sildenafil 50 mg once a day to placebo with a 24-month follow-up. Androgen deprivation therapy (ADT) was allowed. Prostate cancer prognostic risk grouping was not an exclusion criterion, but most study participants had low- or intermediate-risk prostate cancer. Statistical analysis was performed using Kaplan-Meier plots and log-rank testing. OUTCOMES: The primary outcomes of this report were biochemical recurrence and overall survival rates, where BCR was defined according to the Phoenix definition. RESULTS: Data of 162 men were analyzed. Nine men had inadequate PSA follow-up and the remaining 153 men were included in the final report. Median age was 61 years. At a median follow-up of 8.3 years (range: 3.0-12.2), 5/94 (5.3%) and 2/59 (3.4%) patients developed BCR in the sildenafil and placebo groups, respectively. The 6-year BCR-free survival was 98.8% for all patients, 98.1% for the sildenafil cohort, and 100% for the placebo cohort. The 10-year BCR-free survival was 94.4% for all patients, 95.6% for the sildenafil cohort, and 92.9% for the placebo cohort. There was no difference in BCR-free survival between the sildenafil and placebo groups by log-rank comparison (p = 0.36). CLINICAL IMPLICATIONS: This analysis informs clinical decision making about the safety of using sildenafil during and after prostate RT. STRENGTHS AND LIMITATIONS: This study included patients who were treated in the setting of a prospective, randomized placebo-controlled trial, and who attained high medication compliance. However, the study was limited by the post-hoc nature of the analysis, use of ADT in some patients, inadequate study power to detect a difference in BCR between sildenafil and placebo groups. CONCLUSION: Prophylactic sildenafil citrate was not associated with biochemical recurrence risk in prostate cancer patients treated with radiation. However, the study was inadequately powered to definitively conclude a negative finding.

A single-arm, prospective trial investigating the effectiveness of a non-hormonal vaginal moisturizer containing hyaluronic acid in postmenopausal cancer survivors.

PURPOSE: To assess the feasibility and efficacy of a non-hormonal hyaluronic acid (HLA) vaginal gel in improving vulvovaginal estrogen-deprivation symptoms in postmenopausal women with a history of hormone receptor-positive (HR+) cancer. METHODS: For this single-arm, prospective longitudinal trial, we identified disease-free patients with a history of HR+ breast cancer treated with aromatase inhibitors or HR+ endometrial cancer treated with surgery and postoperative radiation. Participants used HLA daily for the first 2 weeks, and then 3×/week until weeks 12-14; dosage was then increased to 5×/week for non-responders. Vulvovaginal symptoms and pH were assessed at 4 time points (baseline [T1], 4-6 weeks [T2], 12-14 weeks [T3], 22-24 weeks [T4]) with clinical evaluation, the Vaginal Assessment Scale (VAS), Vulvar Assessment Scale (VuAS), Female Sexual Function Index (FSFI), and Menopausal Symptom Checklist (MSCL). RESULTS: Of 101 patients, mean age was 55 years (range, 31-78), 68% (n = 69) were partnered, and 60% (n = 61) were sexually active. In linear mixed models, VAS/VuAS scores significantly improved at all assessment points (all p < 0.001). MSCL scores similarly improved (all p < 0.001). FSFI scores significantly improved from T1 to T2 (p < 0.03), T3 (p < 0.001), and T4 (p < 0.001). Severe vaginal pH (> 6.5) decreased from 26% at T1 to 19% at T4 (p = 0.18). CONCLUSIONS: HLA moisturization improved vulvovaginal health/sexual function of cancer survivors. While HLA administration 1-2×/week is recommended for women in natural menopause, a 3-5×/week schedule appears to be more effective for symptom relief in cancer survivors.

A single-arm clinical trial investigating the effectiveness of a non-hormonal, hyaluronic acid-based vaginal moisturizer in endometrial cancer survivors.

OBJECTIVE: To assess the efficacy of non-hormonal, hyaluronic acid (HLA)-based vaginal gel in improving vulvovaginal estrogen-deprivation symptoms in women with a history of endometrial cancer. METHODS: For this single-arm, prospective, longitudinal trial, we enrolled disease-free women with a history of endometrial cancer who underwent surgery (total hysterectomy) and postoperative radiation. Participants used HLA daily for the first 2 weeks, and then 3×/week until weeks 12-14; dosage was then increased to 5×/week for non-responders. Vulvovaginal symptoms and pH were assessed at 4 time points (baseline [T1]; 4-6 weeks [T2]; 12-14 weeks [T3]; 22-24 weeks [T4]) with clinical evaluation, the Vaginal Assessment Scale (VAS), Vulvar Assessment Scale (VuAS), Female Sexual Function Index (FSFI), and Menopausal Symptom Checklist (MSCL). RESULTS: Of 43 patients, mean age was 59 years (range, 38-78); 54% (23/43) were partnered; and 49% (21/43) were sexually active. VAS, VuAS, MSCL, and SAQ (Sexual Activity Questionnaire) scores significantly improved from baseline to each assessment point (all p < .002). FSFI total mean scores significantly increased from T1 to T2 (p < .05) and from T1 to T4 (p < .03). At T1, 41% (16/39) felt confident about future sexual activity compared to 68% (17/25) at T4 (p = .096). Severely elevated vaginal pH (>6.5) decreased from 30% (13/43) at T1 to 19% (5/26) at T4 (p = .41). CONCLUSION: The HLA-based gel improved vulvovaginal health and sexual function of endometrial cancer survivors in perceived symptoms and clinical exam outcomes. HLA administration 1-2×/week is recommended for women in natural menopause; a 3-5×/week schedule appears more effective for symptom relief in cancer survivors.

Long-Term Implications of a Positive Posttreatment Biopsy in Patients Treated with External Beam Radiotherapy for Clinically Localized Prostate Cancer.

PURPOSE: We determined the prognostic importance of a positive posttreatment biopsy after prostate radiotherapy. MATERIALS AND METHODS: A total of 382 patients underwent a posttreatment biopsy after external beam radiotherapy for clinically localized prostate cancer. Posttreatment biopsies were classified as positive (prostatic adenocarcinoma without typical radiation induced changes), negative (no evidence of carcinoma) or adenocarcinoma with a severe treatment effect. Median followup in survivors was 9 years. Competing risks regression was used to assess relationships between prognostic predictors and cause specific mortality, distant metastasis and prostate specific antigen failure. RESULTS: The prevalence of positive biopsy, treatment effect and negative biopsy was 30%, 22% and 48%, respectively. Androgen deprivation therapy omission and high risk disease were associated with a 2.6 and 1.8-fold increase, respectively, in the odds of positive posttreatment biopsy. The 15-year PSA relapse rate associated with negative, severe treatment effect and positive posttreatment biopsies was 34%, 36% and 79%, respectively (p <0.001). After controlling for known predictors the risk of distant metastasis was 2.6-fold higher in patients with a positive biopsy (p <0.001) and cause specific mortality was twice as high in patients with a positive biopsy compared to those with negative and severe treatment effect biopsy outcomes (HR 2.00, p = 0.022). CONCLUSIONS: A positive posttreatment biopsy after external beam radiotherapy was associated with a higher risk of distant metastasis and prostate cancer related death. Patients with severe treatment effect classified biopsies have biological characteristics more like patients with a negative biopsy than a positive biopsy. Posttreatment biopsies were more often positive in the setting of external beam radiotherapy alone without androgen deprivation therapy or in the presence of high risk disease.

Decrease in uterine perforations with ultrasound image-guided applicator insertion in intracavitary brachytherapy for cervical cancer: A systematic review and meta-analysis.

PURPOSE: To estimate uterine perforations rates during intracavitary brachytherapy for cervical cancer with and without ultrasound (US) image guidance. MATERIALS AND METHODS: A systematic search of databases (PubMed and EMBASE) was performed. The pooled summary uterine perforation rate (detected by postinsertion CT or MRI) for the un-guided insertion group and the guided insertion group was calculated by using the random-effects model weighted by the inverse variance. RESULTS: A total of 690 articles were initially found, resulting in 12 studies that met the inclusion criteria. A total of 1757 insertions and 766 patients were included in the meta-analysis. The overall uterine perforation rate per insertion was 4.56% (95%CI: 2.35-8.67) and per patient was 7.39% (95%CI: 3.92-13.50). The pooled perforation rate per insertion without image guidance was 10.54% (95%CI: 6.12-17.57) versus 1.06% (95%CI: 0.41-2.67) with image guidance (p < 0.01). The pooled perforation rate per patient without guidance was 16.67% (95%CI: 10.01-26.45) versus 2.54% (95%CI: 1.21-5.24) with image guidance (p < 0.01). The ratio of perforations in the un-guided/guided groups was 9.94 and 6.56, per insertion and per patient, respectively. The most common sites of perforation were the posterior wall (>47 events) and the uterine fundus (24 events). None of the studies reported significant acute clinical consequences. Prophylactic antibiotic after perforation was used in 3 of the 4 studies that described the management. CONCLUSION: Using postinsertion CT or MRI to detect the perforation, the rate of uterine perforation per insertion in patients who received US-guided intracavitary brachytherapy insertion is 90% lower than with un-guided insertion.

Unification of favourable intermediate-, unfavourable intermediate-, and very high-risk stratification criteria for prostate cancer.

OBJECTIVE: To improve on the existing risk-stratification systems for prostate cancer. PATIENTS AND METHODS: This was a retrospective investigation including 2 248 patients undergoing dose-escalated external beam radiotherapy (EBRT) at a single institution. We separated National Comprehensive Cancer Network (NCCN) intermediate-risk prostate cancer into 'favourable' and 'unfavourable' groups based on primary Gleason pattern, percentage of positive biopsy cores (PPBC), and number of NCCN intermediate-risk factors. Similarly, NCCN high-risk prostate cancer was stratified into 'standard' and 'very high-risk' groups based on primary Gleason pattern, PPBC, number of NCCN high-risk factors, and stage T3b-T4 disease. Patients with unfavourable-intermediate-risk (UIR) prostate cancer had significantly inferior prostate-specific antigen relapse-free survival (PSA-RFS, P < 0.001), distant metastasis-free survival (DMFS, P < 0.001), prostate cancer-specific mortality (PCSM, P < 0.001), and overall survival (OS, P < 0.001) compared with patients with favourable-intermediate-risk (FIR) prostate cancer. Similarly, patients with very high-risk (VHR) prostate cancer had significantly worse PSA-RFS (P < 0.001), DMFS (P < 0.001), and PCSM (P = 0.001) compared with patients with standard high-risk (SHR) prostate cancer. Moreover, patients with FIR and low-risk prostate cancer had similar outcomes, as did patients with UIR and SHR prostate cancer. RESULTS: Consequently, we propose the following risk-stratification system: Group 1, low risk and FIR; Group 2, UIR and SHR; and Group 3, VHR. These groups have markedly different outcomes, with 8-year distant metastasis rates of 3%, 9%, and 29% (P < 0.001) for Groups 1, 2, and 3, respectively, and 8-year PCSM of 1%, 4%, and 13% (P < 0.001) after EBRT. This modified stratification system was significantly more accurate than the three-tiered NCCN system currently in clinical use for all outcomes. CONCLUSION: Modifying the NCCN risk-stratification system to group FIR with low-risk patients and UIR with SHR patients, results in modestly improved prediction of outcomes, potentially allowing better personalisation of therapeutic recommendations.

Preoperative symptoms predict continence after post-radiation transurethral resection of prostate.

INTRODUCTION: Lower urinary tract symptoms and retention are known complications of radiation for prostate cancer and traditionally transurethral resection of the prostate (TURP) has been avoided in these patients because of the risk of incontinence. The purpose of this study was to evaluate the incidence and predictors of post-TURP incontinence in previously radiated patients. MATERIALS AND METHODS: One-hundred and eleven patients who underwent brachytherapy or external beam radiotherapy for prostate cancer with subsequent TURP performed between 1992 and 2012 at a single institution were identified. We tested for associations between post-TURP continence status and pre-TURP predictors including age, preoperative urinary symptoms and type and timing of radiation therapy. RESULTS: New-onset incontinence developed in 27% (95% CI 17%, 39%) of patients after first post-radiation TURP and 32% (95% CI 23%, 42%) of patients after any TURP, including repeat TURPs. Forty-three percent of patients had resolution of incontinence with first TURP (95% CI 25%, 63%); only 25% (95% CI 7%, 52%) of patients had resolution following repeat TURPs. Age was significantly associated with incontinence (OR per 10 years 2.02, 95% CI 1.10, 3.74, p = 0.024). Post-TURP incontinence was more common in men with pre-TURP urgency. CONCLUSIONS: Rates of post-TURP incontinence were higher in men who were older or had pre-TURP urinary urgency. Assessment of preoperative symptoms would allow for better patient selection. Further research should determine whether this results in better outcomes, including decreased incidence of new onset incontinence and increase in resolution of incontinence.

Genomic characterization of response to chemoradiation in urothelial bladder cancer.

BACKGROUND: The authors characterized the genetic landscape of chemoradiation-treated urothelial carcinoma of the bladder (UCB) with the objective of identifying potential correlates of response. METHODS: Primary tumors with (n = 8) or without (n = 40) matched recurrent tumors from 48 patients who had non-metastatic, high-grade UCB and received treatment primarily with chemoradiation were analyzed using a next-generation sequencing assay enriched for cancer-related and canonical DNA damage response (DDR) genes. Protein expression of meiotic recombination 11 homolog (MRE11), a previously suggested biomarker, was assessed in 44 patients. Recurrent tumors were compared with primary tumors, and the clinical impact of likely deleterious DDR gene alterations was evaluated. RESULTS: The profile of alterations approximated that of prior UCB cohorts. Within 5 pairs of matched primary-recurrent tumors, a median of 92% of somatic mutations were shared. A median 33% of mutations were shared between 3 matched bladder-metastasis pairs. Of 26 patients (54%) who had DDR gene alterations, 12 (25%) harbored likely deleterious alterations. In multivariable analysis, these patients displayed a trend toward reduced bladder recurrence (hazard ratio, 0.32; P = .070) or any recurrence (hazard ratio, 0.37; P = .070). The most common of these alterations, ERCC2 (excision repair cross-complementation group 2) mutations, were associated with significantly lower 2-year metastatic recurrence (0% vs 43%; log-rank P = .044). No impact of MRE11 protein expression on outcome was detected. CONCLUSIONS: A similar mutation profile between primary and recurrent tumors suggests that pre-existing, resistant clonal populations represent the primary mechanism of chemoradiation treatment failure. Deleterious DDR genetic alterations, particularly recurrent alterations in ERCC2, may be associated with improved chemoradiation outcomes in patients with UCB. A small sample size necessitates independent validation of these observations. Cancer 2016;122:3715-23. © 2016 American Cancer Society.

Impact of postoperative intensity-modulated radiation therapy (IMRT) on the rate of bowel obstruction in gynecologic malignancy.

OBJECTIVE: The purpose was to determine the potential impact of IMRT on the rate of bowel obstruction (BO), in patients with gynecologic malignancies undergoing postoperative pelvic RT. METHODS: We performed a retrospective review of all patients with endometrial or cervical cancer who received postoperative pelvic RT at our institution from 2000 to 2012. Patients who received definitive or palliative RT, or those with BO due to disease progression, were excluded. Standard two-sided statistical tests were used to evaluate for associated risk factors. Kaplan-Meier, Log rank and Cox proportional hazards regression analysis tests were performed for actuarial analysis. RESULTS: A total of 224 patients were identified, 120 (54%) received postoperative pelvic IMRT and 104 (46%) 3-dimentional (3-D) RT. Median follow-up time was 67months. BO was grade 1 (asymptomatic) in 2/228 (0.9%), grade 2 (conservative management) in 4 (1.8%), and grade 3≥ in 4 (1.8%). Overall, the 5-year actuarial rate of BO was 4.8%. The 5-year rate of BO in the IMRT group was 0.9% compared to 9.3% for 3-D RT (p=0.006). Patients with BMI≥30kg/m(2) were less likely to develop BO (2.6% vs. 8.3; p=0.03). On multivariate analysis, only IMRT retained its significance as an independent predictor of less BO (p=0.022). CONCLUSIONS: The use of postoperative IMRT for cervical and endometrial cancer was associated with significant reduction in the rate of bowel obstruction. This difference maintained its statistical significance on multivariate analysis. Such finding if confirmed by others will help further solidify the benefit of IMRT in gynecologic cancers.

Predictors of castration-resistant prostate cancer after dose-escalated external beam radiotherapy.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is a near uniformly fatal form of prostate cancer; however, information on time to development and predictors for progression to CRPC is limited. We report a detailed longitudinal study for development of CRPC in men initially treated with external beam radiotherapy (EBRT). METHODS: During 1991-2008, 2,478 patients with clinically localized prostate cancer were treated with dose-escalated EBRT at a single institution. The primary objective was to determine predictors of CRPC among men who failed definitive EBRT and progressed to salvage androgen-deprivation therapy (ADT). CRPC was defined as castrate levels of testosterone (<50 ng/dl) with progressive biochemical or radiographic disease. RESULTS: For the entire cohort (n = 2,478), the 10-year cumulative incidence rate for developing CRPC was 9.9%. For those that progressed to salvage ADT (n = 362), the 7-year cumulative incidence rates for developing CRPC from time of salvage ADT was 33.7%. Amongst this cohort, multivariable analysis demonstrated that PSA doubling-time (continuous; hazard ratio [HR], 0.98 [0.97-0.99], P < 0.001), higher Gleason score (HR, 1.96 [1.12-3.43]; P = 0.034), and duration of ADT at time of EBRT (continuous; HR, 1.02 [1.01-1.03]; P = 0.007) were associated with development of CRPC. CONCLUSIONS: This represents the first report of predictors of CRPC for patients treated with modern dose-escalated EBRT. We demonstrate that among the minority of patients not initially cured after EBRT, those treated with longer-course ADT have higher rates of resistance to the re-introduction of ADT. Future trials will need to test this subgroup with more aggressive or alternative forms of salvage therapies.

Anatomical Patterns of Recurrence Following Biochemical Relapse in the Dose Escalation Era of External Beam Radiotherapy for Prostate Cancer.

PURPOSE: We provide a comprehensive analysis of anatomical patterns of recurrence following external beam radiotherapy in patients with localized prostate cancer. MATERIALS AND METHODS: This retrospective analysis included 2,694 patients with localized prostate cancer who received definitive, dose escalated external beam radiotherapy from 1991 to 2008. First recurrence sites were defined as initial sites of clinically detected recurrence and any subsequent clinically detected recurrence within 3 months. Anatomical recurrence patterns were classified as local (prostate/seminal vesicles only), lymphotropic (lymph nodes only) and osteotropic (bones only) in patients with disease confined only to these respective sites for at least 2 years from the initial clinically detected recurrence. RESULTS: Prostate was the most common first recurrence site in the low, intermediate and high risk groups with an 8-year cumulative incidence of 3.5%, 9.8% and 14.6%, respectively. The 8-year risk of isolated pelvic lymph node relapse as the first recurrence site was 0%, 1.0% and 3.3%, respectively. In the 474 patients with clinically detected recurrence the most common first recurrence site was local in 55.3%, bone in 33.5%, pelvic lymph nodes in 21.3% and abdominal lymph nodes in 9.1%. Patients showed unique relapse distributions, including a pattern that was local in 41.6%, lymphotropic in 9.7%, osteotropic in 20.3% and multiorgan/visceral in 28.5%. Anatomical recurrence pattern was the strongest predictor of prostate cancer specific mortality on multivariate analysis of patients with clinically detected recurrence. CONCLUSIONS: The most common first recurrence site after dose escalated external beam radiotherapy for prostate cancer is in the prostate and seminal vesicles in all risk groups. In contrast, patients treated without elective pelvic lymph node irradiation are at relatively low risk for isolated pelvic lymph node relapse. Recurrence patterns revealed a tropism for specific anatomical distributions with divergent prognoses, suggesting underlying biological differences among tumors.

Cigarette smoking during external beam radiation therapy for prostate cancer is associated with an increased risk of prostate cancer-specific mortality and treatment-related toxicity.

OBJECTIVE: To evaluate whether a history of smoking or smoking during therapy after external beam radiotherapy (EBRT) for clinically localised prostate cancer is associated with increased treatment-related toxicity or disease progression. PATIENTS AND METHODS: Of 2358 patients receiving EBRT for prostate cancer between 1988 and 2005, 2156 had chart-recorded smoking histories. Patients were classified as 'never smokers', 'current smokers', 'former smokers', and 'current smoking unknown'. Variables considered included quantity of tobacco use in pack-years, duration of smoking, and, for former smokers, how long before initiation of RT the patient quit smoking, when available. The median EBRT dose was 8100 Gy and the median follow-up was 95 months. Toxicity was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events. RESULTS: Current smoking significantly increased the risks of both prostate-specific antigen relapse [hazard ratio (HR) 1.4, P = 0.02] and distant metastases (HR 2.37, P < 0.001), as well as prostate cancer-specific death (HR 2.25, P < 0.001). Multivariate analysis showed that smoking was also associated with increased risk of EBRT-related genitourinary toxicities (current smoker, HR 1.8, P = 0.02; former smoker, HR 1.45, P = 0.01). Smoking did not increase gastrointestinal toxicity. CONCLUSIONS: Current smokers with prostate cancer are at increased risk of biochemical recurrence, distant metastasis, and prostate cancer-related mortality after definitive RT to the prostate. Current and former smokers, regardless of duration and quantity of exposure, are at an increased risk of long-term genitourinary toxicity after EBRT. Oncologists should encourage patients to participate in smoking-cessation programmes before therapy to potentially lower their risk of relapsing disease and post-treatment toxicities.

Complementary Prognostic Value of Pelvic Magnetic Resonance Imaging and Whole-Body Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Pretreatment Assessment of Patients With Cervical Cancer.

OBJECTIVE: The aim of this study was to evaluate the incremental prognostic value of pelvic magnetic resonance imaging (MRI) and whole-body F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) findings compared with clinical-histopathologic factors in patients with newly diagnosed cervical cancer. METHODS: The institutional review board approved this retrospective study of 114 patients (median age, 40.6 years) with International Federation of Gynecology and Obstetrics (FIGO) stage I-IVB cervical cancer who underwent pretreatment MRI and PET/CT. All scans were reviewed for locoregional tumor extent, pelvic or/and para-aortic lymphadenopathy, and distant metastases. Univariate Cox proportional hazard regression was performed to evaluate associations between clinical-histopathologic factors, imaging findings, and progression-free survival (PFS). Multivariate models were built using independent predictors for PFS. Harrell C was used to measure concordance (C index). RESULTS: Forty patients progressed within a median time of 10.4 months (range, 0.4-40.3 months). At univariate analysis, age, FIGO stage, tumor histology, tumor grade, and all MRI and PET/CT features were significantly associated with PFS (P < 0.0001 to P = 0.0474). A multivariate model including clinical and imaging parameters (parametrial invasion on MRI and para-aortic lymphadenopathy/distant metastases on PET/CT) had significantly higher concordance for predicting PFS than a model including clinical parameters only (C index: 0.81 [95% confidence interval, 0.75-0.87] vs 0.68 [95% confidence interval, 0.59-0.78]; P < 0.001). The comparison of C indices for the combined clinical and imaging model approached significance when compared with a FIGO stage model (C index: 0.81 [95% confidence interval, 0.75-0.87] vs 0.75 [95% confidence interval, 0.69-0.82]; P = 0.058). CONCLUSIONS: In patients with newly diagnosed cervical cancer, a prognostic model including combined MRI and PET/CT findings provides information that complements clinical and histopathologic factors.

Prophylactic sildenafil citrate improves select aspects of sexual function in men treated with radiotherapy for prostate cancer.

PURPOSE: We studied adjuvant daily sildenafil citrate during and after radiotherapy for prostate cancer for erectile function preservation. MATERIALS AND METHODS: We performed a randomized, prospective trial of 279 patients with localized prostate cancer treated with radiotherapy who received sildenafil citrate (50 mg daily) or placebo (2:1 randomization). Medication/placebo was initiated 3 days before treatment and continued daily for 6 months. Before therapy and 3, 6, 9, 12, 18 and 24 months after radiotherapy patients completed the IIEF questionnaire, including the erectile function domain, the I-PSS questionnaire and the RAND SF-36®. All IIEF domains were scored. RESULTS: At 12 months erectile function scores were better for sildenafil citrate than placebo (p = 0.018), 73% of patients on sildenafil citrate vs 50% on placebo had mild/no erectile dysfunction (p = 0.024) and the sildenafil citrate arm had superior overall satisfaction (p = 0.027) and IIEF total scores (p = 0.043). At 24 months erectile function and IIEF scores were no longer significantly better for sildenafil citrate (p = 0.172 and 0.09, respectively) and yet overall satisfaction scores were higher (p = 0.033). Sexual desire scores in patients who received sildenafil citrate were higher at 24 months although they had completed drug therapy 18 months previously (p = 0.049). At 24 months 81.6% of patients on sildenafil citrate and 56.0% of those on placebo achieved functional erection with or without erectile dysfunction medication (p = 0.045). CONCLUSIONS: Daily sildenafil citrate during and after radiotherapy for prostate cancer was associated with improved overall sexual function compared with placebo for various sexual function domains. To our knowledge this is the largest randomized, prospective, controlled trial to show the usefulness of a phosphodiesterase-5 inhibitor as a rehabilitation strategy in patients with prostate cancer who received radiation therapy.

Comparison of outcomes in early stage uterine carcinosarcoma and uterine serous carcinoma.

OBJECTIVE: To assess whether contemporary adjuvant management of early stage uterine carcinosarcoma (CS) produces equal outcomes as in uterine serous carcinoma (USC). METHODS: We reviewed 172 women treated from 2000 to 2011 for stage I-II USC (n=112, 65%) or CS (n=60, 35%). Adjuvant therapy was initiated in 154 (90%) patients, with 111 patients receiving intravaginal radiotherapy (IVRT)/chemotherapy. Median follow up was 4.6 years for surviving patients. RESULTS: Characteristics for USC vs. CS did not differ significantly by age ≥60, pelvic or para-aortic node sampling, stage, lymphovascular invasion, chemotherapy use, RT use or omission of adjuvant therapy. Outcomes were better for USC vs. CS in 5-year actuarial rates of recurrence [17% (C.I. 10-25%) vs. 45% (C.I. 31-59%), p<0.001],disease-related mortality (DRM) [11% (5-17%) vs. 30% (16-44%), p=0.016], and all-cause mortality [12% (C.I. 6-18%) vs. 34% (C.I. 20-48%), p=0.007]. In multivariable analysis, CS histology remained a significant predictor of risk for recurrence [HR 3.1 (C.I. 1.7-5.7), p<0.001], DRM [HR 2.4 (C.I. 1.1-5.1), p=0.024], and all-cause mortality [HR 2.4 (C.I. 1.2-4.8), p=0.012]. On sub-group analysis of 111 patients (77 USC, 34 CS) able to receive IVRT/chemotherapy, CS no longer was associated significantly with increased recurrence (29% vs. 15%, p=0.18), DRM (22% vs. 10%, p=0.39), or all-cause mortality (22% vs. 10%, p=0.45). CONCLUSIONS: CS was associated with worse outcomes than USC. However, that difference was not maintained in patients able to receive IVRT and chemotherapy. While intriguing, this result may be due in part to selection against rapid early relapsing CS patients in this group.

Quantifying the risk of recurrence and death in stage III (FIGO 2009) endometrial cancer.

OBJECTIVE: Advanced endometrial cancer patients comprise a heterogeneous group. This study assessed the association of clinicopathological factors with relapse and death from endometrial cancer. METHODS: Eligible patients were treated for stage III (FIGO 2009) endometrial adenocarcinoma, had peritoneal cytology performed, and had no gross residual disease post-operatively. RESULTS: Of 192 patients, 59% were ≥60 years old, 48% had ≥50% myometrial invasion, 71% lymphovascular invasion, 25% cervical stromal invasion, 37% adnexal involvement, and 23% positive peritoneal cytology. High-grade histology (serous, clear cell, undifferentiated, or grade 3 endometrioid) was present in 45%. Pelvic lymphadenectomy was performed in 93% and para-aortic lymphadenectomy in 73%. Adjuvant chemotherapy and/or radiation therapy was administered to 93%. At a median follow-up of 42 months, the 5-year rate of relapse was 37% and of death from endometrial cancer was 30%. On multivariate analysis, both outcomes were associated with high-grade histology, positive peritoneal cytology, and deep myometrial invasion (p≤0.04). The cohort was divided into subgroups of patients with 0 (n=46), 1 (n=83), or ≥2 (n=63) of these high-risk characteristics. The 5-year relapse rate for patients with 0 risk factors was 13%, 1 risk factor was 27%, and ≥2 risk factors was 62% (p<0.001). The corresponding 5-year rates of death from endometrial cancer were 11%, 20%, and 56%, respectively (p<0.001). CONCLUSIONS: Stratification of stage III endometrial cancer according to high-grade histology, positive peritoneal cytology, and deep myometrial invasion is useful for prognostication and may grant insight into the optimal treatment for specific subgroups of patients.

Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer.

OBJECTIVE: To compare tumour control and toxicity outcomes with the use of high-dose intensity-modulated radiation therapy (IMRT) alone or brachytherapy combined with IMRT (combo-RT) for patients with intermediate-risk prostate cancer. PATIENTS AND METHODS: Between 1997 and 2010, 870 consecutive patients with intermediate-risk prostate cancer were treated at our institution with either 86.4 Gy of IMRT alone (n = 470) or combo-RT consisting of brachytherapy combined with 50.4 Gy of IMRT (n = 400). Brachytherapy consisted of low-dose-rate permanent interstitial implantation in 260 patients and high-dose-rate temporary implantation in 140 patients. The median (range) follow-up for the entire cohort was 5.3 (1-14) years. RESULTS: For IMRT alone vs combo-RT, 7-year actuarial prostate-specific antigen (PSA)-relapse-free survival (PSA-RFS) rates were 81.4 vs 92.0% (P < 0.001), and distant metastases-free survival (DMFS) rates were 93.0 vs 97.2% (P = 0.04), respectively. Multivariate analysis showed that combo-RT was associated with better PSA-RFS (hazard ratio [HR], 0.40 [95% confidence interval, 0.24-0.66], P < 0.001), and better DMFS (HR, 0.41 [0.18-0.92], P = 0.03). A higher incidence of acute genitourinary (GU) grade 2 (35.8 vs 18.9%; P < 0.01) and acute GU grade 3 (2.3 vs 0.4%; P = 0.03) toxicities occurred in the combo-RT group than in the IMRT-alone group. Most acute toxicity resolved. Late toxicity outcomes were similar between the treatment groups. The 7-year actuarial late toxicity rates for grade 2 gastrointestinal (GI) toxicity were 4.6 vs 4.1% (P = 0.89), for grade 3 GI toxicity 0.4 vs 1.4% (P = 0.36), for grade 2 GU toxicity 19.4 vs 21.2% (P = 0.14), and grade 3 GU toxicity 3.1 vs 1.4% (P = 0.74) for the IMRT vs the combo-RT group, respectively. CONCLUSIONS: Enhanced dose escalation using combo-RT was associated with superior PSA-RFS and DMFS outcomes for patients with intermediate-risk prostate cancer compared with high-dose IMRT alone at a dose of 86.4 Gy. While acute GU toxicities were more prevalent in the combo-RT group, the incidence of late GI and GU toxicities was similar between the treatment groups.