Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial.

BACKGROUND: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. METHODS: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. DISCUSSION: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial.

BACKGROUND: Transoral robotic surgery (TORS) with concurrent neck dissection has supplanted radiotherapy in the USA as the most common treatment for oropharyngeal squamous cell carcinoma (OPSCC), yet no randomised trials have compared these modalities. We aimed to evaluate differences in quality of life (QOL) 1 year after treatment. METHODS: The ORATOR trial was an investigator-initiated, multicentre, international, open-label, parallel-group, phase 2, randomised study. Patients were enrolled at six hospitals in Canada and Australia. We randomly assigned (1:1) patients aged 18 years or older, with Eastern Cooperative Oncology Group scores of 0-2, and with T1-T2, N0-2 (≤4 cm) OPSCC tumour types to radiotherapy (70 Gy, with chemotherapy if N1-2) or TORS plus neck dissection (with or without adjuvant chemoradiotherapy, based on pathology). Following stratification by p16 status, patients were randomly assigned using a computer-generated randomisation list with permuted blocks of four. The primary endpoint was swallowing-related QOL at 1 year as established using the MD Anderson Dysphagia Inventory (MDADI) score, powered to detect a 10-point improvement (a clinically meaningful change) in the TORS plus neck dissection group. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov (NCT01590355) and is active, but not currently recruiting. FINDINGS: 68 patients were randomly assigned (34 per group) between Aug 10, 2012, and June 9, 2017. Median follow-up was 25 months (IQR 20-33) for the radiotherapy group and 29 months (23-43) for the TORS plus neck dissection group. MDADI total scores at 1 year were mean 86·9 (SD 11·4) in the radiotherapy group versus 80·1 (13·0) in the TORS plus neck dissection group (p=0·042). There were more cases of neutropenia (six [18%] of 34 patients vs none of 34), hearing loss (13 [38%] vs five [15%]), and tinnitus (12 [35%] vs two [6%]) reported in the radiotherapy group than in the TORS plus neck dissection group, and more cases of trismus in the TORS plus neck dissection group (nine [26%] vs one [3%]). The most common adverse events in the radiotherapy group were dysphagia (n=6), hearing loss (n=6), and mucositis (n=4), all grade 3, and in the TORS plus neck dissection group, dysphagia (n=9, all grade 3) and there was one death caused by bleeding after TORS. INTERPRETATION: Patients treated with radiotherapy showed superior swallowing-related QOL scores 1 year after treatment, although the difference did not represent a clinically meaningful change. Toxicity patterns differed between the groups. Patients with OPSCC should be informed about both treatment options. FUNDING: Canadian Cancer Society Research Institute Grant (#701842), Ontario Institute for Cancer Research Clinician-Scientist research grant, and the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers grant.

A systematic review of expanded prostate cancer index composite (EPIC) quality of life after surgery or radiation treatment.

INTRODUCTION: The Expanded Prostate Cancer Index Composite (EPIC) is a validated and widely adopted instrument that measures patient quality of life. This study aims to describe and compare patient quality of life in the bowel, urinary, and sexual domains across different prostate cancer treatments. MATERIALS AND METHODS: A systematic review of English articles published prior to 2012 was conducted. Peer reviewed articles reporting longitudinal EPIC data in a statistically analyzable form with clearly defined time points were included. Articles were assessed by content experts to ensure optimal treatment quality. Screening of studies and extraction of data were completed using a predefined data abstraction tool. Data on bowel, urinary, and sexual domains were documented. Scores in each domain range from a low of 0 to a high of 100. RESULTS: Twenty-six articles, representing 8302 patients, were included. All treatments were associated with short term or long term reductions in urinary, bowel, and sexual domains. Surgery patients had better post-treatment bowel quality of life; however, average declines were small regardless of treatment. Post-treatment urinary incontinence scores were lower for surgery patients; while radiation patients had worse urinary irritation. Average urinary bother and function were similar between treatment groups at 18 months post-treatment. Surgery patients had better baseline sexual function. A greater decline in sexual function was observed in surgery patients compared to radiation patients. CONCLUSIONS: Prostate cancer treatments have different impacts on patient quality of life and function. The magnitude of difference between treatment-related adverse effects may be important to patients when choosing therapy.

Vascular progenitor clusters from peripheral blood in cancer patients following oncologic surgery.

INTRODUCTION: Vascular progenitor cells (VPCs) are recruited into the peripheral blood (PB) following ischemia and inflammation and correlate with vascular health. The impact of recruiting VPCs on surgical recovery and cancer progression following tumor resection remain unknown. METHODS: We measured VPC clusters and enumerated circulating CD34+ VEGFR2+ angiogenic cells in 18 patients with oral cancer (OC) undergoing resection and free flap reconstruction (high vascular injury) and in 18 patients undergoing colorectal cancer resection (CRC) (low vascular injury) at baseline and multiple timepoints after surgery. RESULTS: VPC clusters increased following OC resection, peaking on Day +3 and returning to baseline by Day 28. In contrast, VPC clusters decreased sharply on Day +3 in patients with CRC before returning to baseline. CD34+ VEGFR2+ cells did not increase significantly after surgery. More rapid clinical recovery following OC resection was observed in patients with greater VPC cluster levels on Day +3. Tumor size and subsequent progression of cancer did not correlate with recruitment of VPC cluster-forming cells. CONCLUSION: VPC recruitment following cancer resection may depend on cancer subtype and may relate to the degree of surgical stress and vascular injury. Recovery after surgery for OC may be accelerated in patients with greater VPC recruitment.

Early-stage squamous cell carcinoma of the oropharynx: radiotherapy vs. trans-oral robotic surgery (ORATOR)--study protocol for a randomized phase II trial.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has markedly increased over the last three decades due to newly found associations with human papillomavirus (HPV) infection. Primary radiotherapy (RT) is the treatment of choice for OPSCC at most centers, and over the last decade, the addition of concurrent chemotherapy has led to a significant improvement in survival, but at the cost of increased acute and late toxicity. Transoral robotic surgery (TORS) has emerged as a promising alternative treatment, with preliminary case series demonstrating encouraging oncologic, functional, and quality of life (QOL) outcomes. However, comparisons of TORS and RT in a non-randomized fashion are susceptible to bias. The goal of this randomized phase II study is to compare QOL, functional outcomes, toxicity profiles, and survival following primary RT (± chemotherapy) vs. TORS (± adjuvant [chemo] RT) in patients with OPSCC. METHODS/DESIGN: The target patient population comprises OPSCC patients who would be unlikely to require chemotherapy post-resection: Tumor stage T1-T2 with likely negative margins at surgery; Nodal stage N0-2, ≤3 cm in size, with no evidence of extranodal extension on imaging. Participants will be randomized in a 1:1 ratio between Arm 1 (RT ± chemotherapy) and Arm 2 (TORS ± adjuvant [chemo] RT). In Arm 1, patients with N0 disease will receive RT alone, whereas N1-2 patients will receive concurrent chemoradiation. In Arm 2, patients will undergo TORS along with selective neck dissections, which may be staged. Pathologic high-risk features will be used to determine the requirement for adjuvant radiotherapy +/- chemotherapy. The primary endpoint is QOL score using the M.D. Anderson Dysphagia Inventory (MDADI), with secondary endpoints including survival, toxicity, other QOL outcomes, and swallowing function. A sample of 68 patients is required. DISCUSSION: This study, if successful, will provide a much-needed randomized comparison of the conventional strategy of primary RT vs. the novel strategy of primary TORS. The trial is designed to provide a definitive QOL comparison between the two arms, and to inform the design of an eventual phase III trial for survival outcomes. TRIAL REGISTRATION: NCT01590355.

Pilot study on quality of life and sexual function in men-who-have-sex-with-men treated for prostate cancer.

INTRODUCTION: There is limited data on post-treatment quality of life (QoL) for men-who-have-sex-with-men (MSM) with prostate cancer (PCa). QoL in MSM may not be reflected by assessment tools designed for the heterosexual population. AIMS: Our goals were to evaluate post-treatment QoL in PCa patients who are MSM, and to investigate the utility of current QoL assessment tool. METHODS: PCa patients treated with surgery and/or radiation were recruited from the local MSM community. Each participant completed the Expanded Prostate Cancer Index Composite (EPIC) questionnaire, Male Sexual Health Questionnaire (MSHQ), and a questionnaire focused on insertive and receptive roles of anal intercourse. MAIN OUTCOME MEASURES: Response scores were calculated based on questionnaire design and compared by treatment modality. RESULTS: Seven participants treated with surgery (mean age 58) and eight participants treated with radiation (mean age 67) were recruited. No participant in the surgical group received androgen deprivation therapy (ADT) while two in radiation group were treated with ADT. The sample size of this study did not permit formal statistical analysis, although potential differences in Urinary and Bowel Domains from EPIC and Ejaculation Scale from MSHQ were observed. More participants from the radiation group seemed to be able to maintain both insertive and receptive anal intercourse roles after treatment compared to participants who received surgery. CONCLUSIONS: While the two validated assessment tools suggested similar QoL scores including sexual function for both surgical and radiation groups, post-treatment sexual function related to anal intercourse may be better in the radiation group, as compared to the surgical group. Larger studies in PCa patients from MSM community are warranted to verify these data.

Patient-Reported Outcomes From a Phase 3 Randomized Controlled Trial Exploring Optimal Sequencing of Short-Term Androgen Deprivation Therapy With Prostate Radiation Therapy in Localized Prostate Cancer.

PURPOSE: Two phase 3 randomized controlled trials (OTT-0101, RTOG-9413) and a meta-analysis have shown an impact of sequencing of androgen deprivation therapy (ADT) and radiation therapy on oncologic outcomes in prostate cancer (PCa). However, the impact of sequencing strategy on health-related quality of life (HR-QoL) is unclear. Here, we present the patient-reported HR-QoL outcomes from the OTT-0101 study. METHODS AND MATERIALS: In this trial, patients with PCa with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen level <30 ng/mL were randomly assigned to neoadjuvant and concurrent ADT for 6 months, starting 4 months before or concurrent with prostate radiation therapy, or concurrent and adjuvant ADT for 6 months, starting simultaneously with prostate radiation therapy. HR-QoL was assessed using European Organisation for Research and Treatment of Cancer QoL questionnaires. Time until definitive deterioration was defined as time from random allocation to the first deterioration of at least 10 points with no further improvement of ≥10 points or if the patient experienced progression, died, or dropped out after deterioration, resulting in missing data. Stratified log-rank tests were applied for between-group comparisons of time-to-event estimates. RESULTS: Overall, 393 patients (194 and 199 in the 2 arms, respectively) were evaluable, except 214 (101 and 113 in the 2 arms, respectively) for sexual function. Five-year rates of freedom from definitive deterioration of urinary symptoms, bowel symptoms, and sexual activity were 33.5%, 33.1%, and 38.5% in the neoadjuvant group and 34.1%, 35.4%, and 36.7% in the adjuvant group, respectively, with no significant between-group differences. The adjuvant approach was associated with a reduced risk of definitive deterioration of sexual function (hazard ratio, 0.68; 95% confidence interval, 0.49-0.94; P = .02). With respect to clinical relevance, the mean change in score for sexual function showed only a small to moderate difference favoring the adjuvant group at and beyond 3 years. CONCLUSIONS: In this study, no differences were found in the bowel or urinary symptoms between the adjuvant and neoadjuvant approach. Considering a significant likelihood of type I and type II errors and because of a lack of a persistent and clinically meaningful between-group difference in mean score changes over time, our findings do not confer a clear and conclusive picture of the impact of sequencing strategy on sexual function.

Impact of Treating Physician on Radiation Therapy Related Severe Toxicities in Men with Prostate Cancer.

PURPOSE: The impact of treating physician on radiation therapy (RT) related toxicity is unclear. We carried out a secondary analysis of a randomized controlled study to determine whether the risk of RT-related late toxicities in patients with prostate cancer varies depending on the treating radiation oncologist. METHODS AND MATERIALS: This is a secondary analysis of a phase 3 randomized controlled study in which patients with prostate cancer with Gleason score ≤7, clinical stage T1b-T3a, and prostate-specific antigen <30 ng/mL were randomized to receive androgen suppression for 6 months, starting either 4 months before or concurrently with definitive prostate radiation therapy. Incidence of late RT-related toxicity was estimated using Kaplan-Meier methods. We applied multivariable semiparametric shared frailty models with gamma distribution to determine the between-physician variation in the hazard of late RT-related grade ≥3 gastrointestinal, genitourinary, or overall toxicity. Patient level covariables included age, risk group, year of enrollment, and treatment regimen. Frailty variance, a measure of unexplained heterogeneity, was estimated with 95% confidence intervals (CIs). Statistical significance was suggested when the lower limit of the 95% CI for the frailty variance was >0. The Commenges-Andersen test was used for P value estimation. RESULTS: Overall, 426 patients were treated by 9 radiation oncologists. On log-rank test, there was a significant difference in the cumulative incidence of overall grade ≥3 toxicities (P = .001) and grade ≥3 gastrointestinal toxicity (P = .01) among the physician-based clusters. The frailty variance for overall late grade ≥3 toxicity was 0.31 (95% CI, 0.02-1.39; P = .01). The frailty variance for the grade ≥3 gastrointestinal and genitourinary toxicity was 0.84 (95% CI, 0.00-4.20; P = .11) and 0.11 (95% CI, 0.00-1.13; P = .31), respectively. CONCLUSIONS: In our study, the hazard of overall RT-related late grade ≥3 toxicity varied significantly depending on treating radiation oncologist. Further studies are required to explore the underlying processes that lead to such variations in clinical trials involving radiation therapy in prostate cancer.

Prostate Radiotherapy With Adjuvant Androgen Deprivation Therapy (ADT) Improves Metastasis-Free Survival Compared to Neoadjuvant ADT: An Individual Patient Meta-Analysis.

PURPOSE: There remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa. METHODS: MEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS). RESULTS: The median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups. CONCLUSION: The sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

Impact of Sequencing of Androgen Suppression and Radiation Therapy on Testosterone Recovery in Localized Prostate Cancer.

PURPOSE: We performed a secondary analysis of a phase 3 randomized trial to determine the influence of sequencing of radiation therapy and androgen deprivation therapy (ADT) on posttreatment testosterone recovery and implications of testosterone recovery on subsequent relapse. METHODS AND MATERIALS: Patients with localized prostate cancer with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen <30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate radiation therapy (NHT arm) or concurrent and adjuvant ADT for 6 months starting simultaneously with radiation therapy (CAHT arm). Full testosterone recovery (FTR) was defined as recovery of testosterone to >10.5 nmol/L in patients with baseline ≥10.5 nmol/L or to baseline level in patients with baseline <10.5 nmol/L. Restricted mean survival time (RMST) since ADT initiation to supracastrate testosterone level (>1.7 nmol/L), and to FTR was compared between the arms using a truncation time point of 36 months. RESULTS: The adjusted difference in RMST to supracastrate testosterone between the CAHT and NHT arm was 1.5 months (95% confidence interval [CI], 0.5-2.5; P = .005). No difference was noted in RMST to FTR between the arms (18.7 vs 18.5 months, adjusted difference: 0.5; 95% CI, -1.4 to 2.4; P = .61). There was no evidence of heterogeneity of treatment effect (interaction P = .76) on risk of relapse over subgroups stratified by testosterone recovery to supracastrate level at 15 months after start of ADT. Based on a multistate Markov model, no independent effect of time to FTR on risk of subsequent relapse was observed (adjusted hazard ratio: 1.02; 95% CI, 0.96-1.08). CONCLUSIONS: Patients should be counseled that an additional 12 months on average is needed for FTR to occur after treatment with prostate radiation therapy and 6 months of ADT. This is independent of the sequencing of ADT and radiation therapy. Furthermore, recovery of testosterone does not appear to affect the risk of subsequent relapse.

Sequencing of Androgen-Deprivation Therapy With External-Beam Radiotherapy in Localized Prostate Cancer: A Phase III Randomized Controlled Trial.

PURPOSE: Dose-escalated radiotherapy (RT) with androgen-deprivation therapy (ADT) is a standard definitive treatment of localized prostate cancer (LPCa). The optimal sequencing of these therapies is unclear. Our phase III trial compared neoadjuvant versus concurrent initiation of ADT in combination with dose-escalated prostate RT (PRT). PATIENTS AND METHODS: Patients with newly diagnosed LPCa with Gleason score ≤ 7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomly allocated to neoadjuvant and concurrent ADT for 6 months starting 4 months before RT (neoadjuvant group) or concurrent and adjuvant ADT for 6 months starting simultaneously with RT (concurrent group). The primary end point was biochemical relapse-free survival (bRFS). Stratified log-rank test was used to compare bRFS and overall survival (OS). Incidence of grade ≥ 3 late RT-related toxicities was compared by log-rank test. RESULTS: Overall, 432 patients were randomly assigned to the neoadjuvant (n = 215) or concurrent group (n = 217). At 10 years, bRFS rates for the two groups were 80.5% and 87.4%, respectively. Ten-year OS rates were 76.4% and 73.7%, respectively. There was no significant difference in bRFS (P = .10) or OS (P = .70) between the two groups. Relative to the neoadjuvant group, the hazard ratio for the concurrent group was 0.66 (95% CI, 0.41 to 1.07) for bRFS and 0.94 (95% CI, 0.68 to 1.30) for OS. No significant difference was observed in the 3-year incidence of late RT-related grade ≥ 3 GI (2.5% v 3.9%) or genitourinary toxicity (2.9% v 2.9%). CONCLUSION: In our study, there was no statistically significant difference in bRFS between the two treatment groups. Similarly, no difference was seen in OS or late RT-related toxicities. On the basis of these results, both neoadjuvant and concurrent initiations of short-term ADT with dose-escalated PRT are reasonable standards of care for LPCa.

Adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-positive prostate cancer: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Results following radical prostatectomy (RP) are suboptimal in patients found to have cancer extending beyond the prostatic capsule (pT3) or present at the resection margins (R1). The optimal postoperative management of such patients is undefined. Therapeutic alternatives include adjuvant radiotherapy (RT) or active surveillance. METHODS: Randomized controlled trials (RCTs) were eligible for inclusion in this systematic review if they compared adjuvant RT in the immediate period after RP to active surveillance - with therapies held in reserve for salvage - in prostate cancer patients with pT3 or R1 disease or both. The primary outcome of interest was overall survival. RESULTS: Three RCTs representing 1,743 patients satisfied the eligibility criteria. Two trials reported data on overall survival; a meta-analysis of the data showed no significant improvement associated with adjuvant RT (hazard ratio=0.91, 95% CI 0.67-1.22, p=0.52). All trials reported data on biochemical progression-free survival (bPFS). On meta-analysis, adjuvant RT significantly improved bPFS (hazard ratio=0.47, 95% CI 0.40-0.56, p<0.00001). One trial provided comparative graded toxicity data; there were no significant differences between arms in severe (grade 3) gastrointestinal or genitourinary toxicity at five years. CONCLUSIONS: To date, adjuvant RT has not been shown to improve overall survival compared with active surveillance. Longer follow-up from completed RCTs is required to accurately assess this outcome. Adjuvant RT does, however, significantly improve bPFS and is not associated with excess severe late toxicity.

Radiotherapy with radical cystectomy for bladder cancer: A systematic review and meta-analysis.

INTRODUCTION: Muscle-invasive bladder cancer (MIBC) is associated with high recurrence and mortality rates. The role of radiotherapy as an adjunct to radical cystectomy is not well-defined. We sought to evaluate the efficacy and safety of radiotherapy preoperatively or postoperatively for patients with MIBC receiving cystectomy compared to cystectomy alone. The primary outcome was overall survival. The secondary outcome was adverse effects. METHODS: MEDLINE, EMBASE, and CENTRAL were searched on August 30, 2016 for randomized controlled trials (RCTs) of patients undergoing cystectomy for bladder cancer. A control group receiving cystectomy alone and an intervention group with radiotherapy and cystectomy were required. The Jadad score was used to assess for bias. Fifteen studies representing 10 RCTs met eligibility criteria. RESULTS: A total of 996 patients were randomized in seven trials included in a meta-analysis of neoadjuvant radiotherapy. Insufficient data were available to complete a pooled analysis for adjuvant radiotherapy. There was a non-statistically significant improvement in overall survival for patients who received neo-adjuvant radiotherapy and cystectomy. At three years and five years, the odds ratios were 1.23 (95% confidence interval [CI] 0.72-2.09) and 1.26 (95% CI 0.76-2.09), respectively, in favour of neoadjuvant radiotherapy. Subgroup analyses including higher doses of radiotherapy showed greater effect on survival. CONCLUSIONS: These data suggest that radiotherapy prior to cystectomy may improve overall survival. This review was limited by old studies, heterogeneous patient populations, and radiotherapy treatment techniques that may not meet current standards. There is a need for current RCTs to further evaluate this effect.

Risk factors for loco-regional recurrence after radical cystectomy of muscle-invasive bladder cancer: A systematic-review and framework for adjuvant radiotherapy.

BACKGROUND: Radical cystectomy (RC) associated with pelvic lymph node dissection (PLND) is the most common local therapy in the management of non-metastatic muscle invasive bladder cancer (MIBC). Loco-regional recurrence (LRR), however, remains a common and important therapeutic challenge associated with poor oncologic outcomes. We aimed to systematically review evidence regarding factors associated with LRR and to propose a framework for adjuvant radiotherapy (RT) in patients with MIBC. METHODS: We performed this systematic review in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. We searched the PubMed database for articles related to MIBC and associated treatments, published between January 1980 and June 2015. Articles identified by searching references from candidate articles were also included. We retrieved 1383 publications from PubMed and 34 from other sources. After an initial screening, a review of titles and abstracts, and a final comprehensive full text analysis of papers assessed for eligibility, a final consensus on 32 studies was obtained. RESULTS: LRR is associated with specific patient-, tumor-, center- or treatment-related variables. LRR varies widely, occurring in as many as 43% of the cases and is strongly related to survival outcomes. While perioperative treatment does not impact on LRR, pathological factors such as pT, pN, positive margins status, extent of PLND, number of lymph nodes removed and/or invaded are correlated with LRR. Patients with pT3-T4a and/or positive lymph-nodes and/or limited pelvic lymph-node dissection and/or positive surgical margins have been distributed in LRR risk groups with accuracy. CONCLUSIONS: LRR patterns are well-known and for selected patients, adjuvant treatments could target this event. Intrinsic tumor subtype may guide future criteria to define a personalized treatment strategy. Prospective trials evaluating safety and efficacy of adjuvant RT are ongoing in several countries.

Mature results of the Ottawa phase II study of intermittent androgen-suppression therapy in prostate cancer: clinical predictors of outcome.

PURPOSE: To present the mature experience of a phase II trial of intermittent androgen suppression (IAS). METHODS AND MATERIALS: Intermittent androgen-suppression therapy was initiated in prostate-cancer patients to delay hormone resistance and minimize potential side effects of androgen-deprivation therapy (ADT). Patients received cyclical periods of ADT and observation (off-treatment interval [OTI]). Androgen-deprivation therapy was reinitiated when the level of prostate-specific antigen (PSA) rose above 10 ng/ml, or for disease progression. Associations between clinical factors and eligibility for OTI were measured. Kaplan-Meier and Cox regression analyses were used to determine factors predicting the duration of OTIs. RESULTS: Ninety-five patients completed 187 cycles of treatment. The median duration of OTIs was 8.5 months. Patients with higher PSA and metastatic disease were less likely to be eligible for the first OTI (p < 0.01). In multivariate analysis, patients with higher PSA and local relapse had significantly longer OTIs (p < 0.01) compared with metastatic patients. The median time to withdrawal from the study was 37 months. CONCLUSIONS: Intermittent androgen suppression appears to be a favorable treatment option for patients with biochemically (according to level of PSA) or locally recurrent prostate cancer with favorable long-term survival, a high probability of eligibility for OTIs, and durable OTIs.

A study of prostate delineation referenced against a gold standard created from the visible human data.

PURPOSE: To measure inter- and intra-observer variation and systematic error in CT based prostate delineation, where individual delineations are referenced against a gold standard produced from photographic anatomical images from the Visible Human Project (VHP). MATERIALS AND METHODS: The CT and anatomical images of the VHP male form the basic data set for this study. The gold standard was established based on 1mm thick anatomical photographic images. These were registered against the 3mm thick CT images that were used for target delineation. A total of 120 organ delineations were performed by six radiation oncologists. RESULTS: The physician delineated prostate volume was on average 30% larger than the "true" prostate volume, but on average included only 84% of the gold standard volume. Our study found a systematic delineation error such that posterior portions of the prostate were always missed while anteriorly some normal tissue was always defined as target. CONCLUSIONS: Our data suggest that radiation oncologists are more concerned with the unintentional inclusion of rectal tissue than they are in missing prostate volume. In contrast, they are likely to overextend the anterior boundary of the prostate to encompass normal tissue such as the bladder.

Radiovaccination Hypothesis.

The details of patients who have entered remission from metastatic melanoma following palliative radiotherapy are reported. We review the relevant immune physiology and radiotherapy particulars and propose the hypothesis that radiovaccination with high fractional dose to skin metastases can stimulate the development of a robust systemic anti-tumoral immune response capable of causing remission of metastatic disease.

Tolerance of Orthotopic Ileal Neobladders to Radiotherapy: A Multi-institutional Retrospective Study.

BACKGROUND: The present retrospective study analyzed the tolerance of orthotopic ileal neobladders to radiotherapy by reviewing the acute and late toxicity in patients who underwent postoperative radiotherapy after radical cystectomy/cystoprostatectomy. MATERIALS AND METHODS: A multi-institutional database was created for patients who had undergone radical cystectomy/cystoprostatectomy and neobladder reconstruction, followed by adjuvant radiotherapy (RT). The patient and tumor characteristics were recorded. The RT data were reviewed to determine the treatment technique used, the radiation dose received by the neobladder, and acute and late toxicity evaluated using the Common Terminology Criteria for Adverse Events, version 4.0, scale. RESULTS: A total of 25 patients were included, with a median age of 64 years. Of the 25 patients, 18 received a dose of 45 to 50.4 Gy. The most common reasons for postoperative radiotherapy were close or positive surgical margins and pT3-pT4 or N+ disease. Ten patients underwent intensity modulated RT. All but 1 patient completed the RT course. Of the patients who completed their RT schedule, none had grade ≥ 3 acute gastrointestinal toxicity. One patient who received concurrent chemotherapy developed grade 3 acute genitourinary toxicity. Three patients reported late grade 1 genitourinary toxicity (frequency of urination, mild leakage at night), with no reports of chronic gastrointestinal toxicity. None of the patients experienced neobladder perforation, leak, or fistula. CONCLUSION: The use of moderate doses of pelvic RT (range, 45-50.4 Gy) was well tolerated among the 25 patients who underwent RT after cystoprostatectomy with orthotopic neobladder creation. This finding supports the use of postoperative RT to moderate doses in this patient population when clinically indicated.

Primary Burkitt lymphoma of the supraglottic larynx: a case report and review of the literature.

BACKGROUND: Burkitt lymphoma is a high-grade B cell lymphoma which accounts for less than 1% of all adult cases of non-Hodgkin lymphoma. Rare instances of Burkitt lymphoma developing secondary to prior irradiation have been described in the literature. CASE PRESENTATION: We report a case of a 90-year-old white woman with a recent history of irradiation for Hodgkin lymphoma, who presented with primary Burkitt lymphoma of the supraglottic larynx. She underwent emergency awake tracheostomy with biopsy. A histopathological examination confirmed non-Hodgkin, B cell lymphoma of Burkitt type. Given her age and poor functional status, she underwent treatment with palliative radiotherapy. CONCLUSIONS: A literature review was performed to clarify the clinical characteristics of radiation-induced Burkitt lymphoma in the head and neck, as well as its diagnosis and management. The present case represents the second case of radiation-induced Burkitt lymphoma in the head and neck in the reported literature, and the first in the supraglottic larynx. It highlights the need to maintain a broad differential in the assessment of malignancies of the larynx, particularly in patients with a prior history of radiation treatment.