Preliminary patient-reported outcomes analysis of 3-dimensional radiation therapy versus intensity-modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group (RTOG) 0126 prostate cancer trial.

BACKGROUND: The authors analyzed a preliminary report of patient-reported outcomes (PROs) among men who received high-dose radiation therapy (RT) on Radiation Therapy Oncology Group study 0126 (a phase 3 dose-escalation trial) with either 3-dimensional conformal RT (3D-CRT) or intensity-modulated RT (IMRT). METHODS: Patients in the 3D-CRT group received 55.8 gray (Gy) to the prostate and proximal seminal vesicles and were allowed an optional field reduction; then, they received 23.4 Gy to the prostate only. Patients in the IMRT group received 79.2 Gy to the prostate and proximal seminal vesicles. PROs were assessed at 0 months (baseline), 3 months, 6 months, 12 months, and 24 months and included bladder and bowel function assessed with the Functional Alterations due to Changes in Elimination (FACE) instrument and erectile function assessed with the International Index of Erectile Function (IIEF). Analyses included the patients who completed all data at baseline and for at least 1 follow-up assessment, and the results were compared with an imputed data set. RESULTS: Of 763 patients who were randomized to the 79.2-Gy arm, 551 patients and 595 patients who responded to the FACE instrument and 505 patients and 577 patients who responded to the IIEF were included in the completed and imputed analyses, respectively. There were no significant differences between modalities for any of the FACE or IIEF subscale scores or total scores at any time point for either the completed data set or the imputed data set. CONCLUSIONS: Despite significant reductions in dose and volume to normal structures using IMRT, this robust analysis of 3D-CRT and IMRT demonstrated no difference in patient-reported bowel, bladder, or sexual functions for similar doses delivered to the prostate and proximal seminal vesicles with IMRT compared with 3D-CRT delivered either to the prostate and proximal seminal vesicles or to the prostate alone.

A systematic review and meta-analysis of oncologic outcomes of pre- versus postoperative radiation in localized resectable soft-tissue sarcoma.

BACKGROUND: The goal of this study was to determine the oncologic outcomes in localized resectable soft-tissue sarcoma after pre- versus postoperative radiation. METHODS: Literature searches through MEDLINE, EMBASE, CancerLit, and the Cochrane Database were performed with the following search terms: sarcoma, radiation, preoperative, and postoperative. Two reviewers independently assessed all eligible publications with the Detsky Quality Scale for Randomized Trials and the Newcastle-Ottawa Quality Assessment Scale for case-control studies. The primary outcome measure was the pooled odds ratio and 95% confidence intervals (95% CI) for the risk of local recurrence calculated through the fixed- and random-effects methods. Time-dependent survival data were calculated as an average across all studies. RESULTS: Five eligible studies were identified including a total of 1,098 patients. The P value for heterogeneity was 0.259, and the variability (I (2)) in results across studies due to true differences in treatment effect was 25%. The risk for local recurrence was lower in the preoperative group with an odds ratio of 0.61 (95% CI 0.42-0.89) by means of the fixed-effects method, and an odds ratio of 0.67 (95% CI 0.39-1.15) by means of the random-effects method. Average survival was 76% (range 62-88%) in the preoperative group and 67% (range 41-83%) in the post-operative group. CONCLUSIONS: The delay in surgical resection necessary to complete preoperative radiation does not seem to increase the risk of lethal metastatic spread. The risk of local recurrence may be lower after preoperative radiation. These findings must be interpreted with caution because of the heterogeneity and bias in the available studies.

Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer.

PURPOSE: To determine whether maintaining HGB levels > or = 12.0 g/dL with recombinant human erythropoietin (R-HUEPO) compared to "standard" treatment (transfusion for HGB < or = 10.0 g/dL) improves progression-free survival (PFS), overall survival (OS) and local control (LC) in women receiving concurrent weekly cisplatin and radiation (CT/RT) for carcinoma of the cervix. In addition, to determine whether platinum-DNA adducts were associated with clinical characteristics or outcome. METHODS: Patients with stage IIB-IVA cervical cancer and HGB < 14.0 g/dL were randomly assigned to CT/RT+/-R-HUEPO (40,000 units s.c. weekly). R-HUEPO was stopped if HGB > 14.0 g/dL. Endpoints were PFS, OS and LC. Platinum-DNA adducts were quantified using immunocytochemistry assay in buccal cells. RESULTS: Between 08/01 and 09/03, 109 of 114 patients accrued were eligible. Fifty-two received CT/RT and 57 CT/RT+R-HUEPO. The study closed prematurely, with less than 25% of the planned accrual, due to potential concerns for thromboembolic event (TE) with R-HUEPO. Median follow-up was 37 months (range 9.8-50.4 months). PFS and OS at 3 years should be 65% and 75% for CT/RT and 58% and 61% for CT/RT+R-HUEPO, respectively. TE occurred in 4/52 receiving CT/RT and 11/57 with CT/RT+R-HUEPO, not all considered treatment related. No deaths occurred from TE. High-platinum adducts were associated with inferior PFS and LC. CONCLUSION: TE is common in cervical cancer patients receiving CT/RT. Difference in TE rate between the two treatments was not statistically significant. The impact of maintaining HGB level > 12.0 g/dL on PFS, OS and LC remains undetermined.

Effect of Standard vs Dose-Escalated Radiation Therapy for Patients With Intermediate-Risk Prostate Cancer: The NRG Oncology RTOG 0126 Randomized Clinical Trial.

Importance: Optimizing radiation therapy techniques for localized prostate cancer can affect patient outcomes. Dose escalation improves biochemical control, but no prior trials were powered to detect overall survival (OS) differences. Objective: To determine whether radiation dose escalation to 79.2 Gy compared with 70.2 Gy would improve OS and other outcomes in prostate cancer. Design, Setting, and Participants: The NRG Oncology/RTOG 0126 randomized clinical trial randomized 1532 patients from 104 North American Radiation Therapy Oncology Group institutions March 2002 through August 2008. Men with stage cT1b to T2b, Gleason score 2 to 6, and prostate-specific antigen (PSA) level of 10 or greater and less than 20 or Gleason score of 7 and PSA less than 15 received 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions. Main Outcomes and Measures: Time to OS measured from randomization to death due to any cause. American Society for Therapeutic Radiology and Oncology (ASTRO)/Phoenix definitions were used for biochemical failure. Acute (≤90 days of treatment start) and late radiation therapy toxic effects (>90 days) were graded using the National Cancer Institute Common Toxicity Criteria, version 2.0, and the RTOG/European Organisation for the Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme, respectively. Results: With a median follow-up of 8.4 (range, 0.02-13.0) years in 1499 patients (median [range] age, 71 [33-87] years; 70% had PSA <10 ng/mL, 84% Gleason score of 7, 57% T1 disease), there was no difference in OS between the 751 men in the 79.2-Gy arm and the 748 men in the 70.2-Gy arm. The 8-year rates of OS were 76% with 79.2 Gy and 75% with 70.2 Gy (hazard ratio [HR], 1.00; 95% CI, 0.83-1.20; P = .98). The 8-year cumulative rates of distant metastases were 4% for the 79.2-Gy arm and 6% for the 70.2-Gy arm (HR, 0.65; 95% CI, 0.42-1.01; P = .05). The ASTRO and Phoenix biochemical failure rates at 5 and 8 years were 31% and 20% with 79.2 Gy and 47% and 35% with 70.2 Gy, respectively (both P < .001; ASTRO: HR, 0.59; 95% CI, 0.50-0.70; Phoenix: HR, 0.54; 95% CI, 0.44-0.65). The high-dose arm had a lower rate of salvage therapy use. The 5-year rates of late grade 2 or greater gastrointestinal and/or genitourinary toxic effects were 21% and 12% with 79.2 Gy and 15% and 7% with 70.2 Gy (P = .006 [HR, 1.39; 95% CI, 1.10-1.77] and P = .003 [HR, 1.59; 95% CI, 1.17-2.16], respectively). Conclusions and Relevance: Despite improvements in biochemical failure and distant metastases, dose escalation did not improve OS. High doses caused more late toxic effects but lower rates of salvage therapy. Trial Registration: clinicaltrials.gov Identifier: NCT00033631.

Prospective comparison of rectal dose reduction during intracavitary brachytherapy for cervical cancer using three rectal retraction techniques.

PURPOSE: To compare three rectal retraction methods on dose to organs at risk, focusing on rectal dose, in cervix cancer patients treated with high-dose-rate intracavitary brachytherapy. METHODS AND MATERIALS: A prospective study was conducted on patients with cervical carcinoma treated with chemoradiotherapy, including external beam radiation and four fractions of high-dose-rate intracavitary brachytherapy prescribed to Point A using a ring and tandem applicator under conscious sedation. Rectal retraction methods included: a rectal retractor blade (RR), vaginal gauze packing (VP), and a tandem Foley balloon (FB). All three methods were used in all patients. The RR was used first, and the following applications were randomly assigned to VP or FB. CT planning was used to calculate D2cc for rectum, sigmoid, small bowel, and bladder. The Wilcoxon signed rank test was used to determine if the median dose differences between methods were statistically significant. RESULTS: In these 11 patients, median dose (min, max) in cGy to the rectum using RR, FB, and VP was 131 (102, 165), 199 (124, 243), and 218 (149, 299), respectively. The RR demonstrated lower median intrapatient doses to rectum compared with FB and VP (-55 cGy; p = 0.014 and -76 cGy; p = 0.004, respectively). The RR also resulted in lower sigmoid doses. No differences in dose were observed between the VP and FB methods. CONCLUSION: The rectal retractor significantly reduced the dose to rectum and sigmoid compared with FP and VP. In patients treated under conscious sedation, the RR method provides the best rectal sparing. There were no significant differences in dose observed between the FB and VP techniques.

Acute and late urinary toxicity following radiation in men with an intact prostate gland or after a radical prostatectomy: A secondary analysis of RTOG 94-08 and 96-01.

INTRODUCTION: To estimate the contribution of the prostate gland and prostatic urethral inflammation to urinary symptoms after radiation therapy for prostate cancer, we performed a secondary analysis of urinary toxicity after primary radiation to an intact prostate vs. postprostatectomy radiation to the prostatic fossa in protocols RTOG 94-08 and 96-01, respectively. MATERIALS AND METHODS: Patients randomized to the radiation-alone arms (without hormone therapy) of the 2 trials were evaluated, including 104 men receiving primary prostate radiation to 68.4Gy on RTOG 94-08 and 371 men receiving 64.8Gy to the prostatic fossa on RTOG 96-01. Acute and late urinary toxicity were scored prospectively by RTOG scales. Chi-square test/logistic regression and cumulative incidence approach/Fine-Gray regression model were used for analyses of acute and late toxicity, respectively. RESULTS: Grade≥2 acute urinary toxicity was significantly higher after primary prostatic radiation compared with postprostatectomy radiation (30.8% vs. 14.0%; P<0.001), but acute grade≥3 toxicity did not differ (3.8% vs. 2.7%; P = 0.54). After adjusting for age, primary radiation resulted in significantly higher grade≥2 acute urinary toxicity (odds ratio = 3.72; 95% CI: 1.65-8.37; P = 0.02). With median follow-up of 7.1 years, late urinary toxicity was not significantly different with primary vs. postprostatectomy radiation (5-year grade≥2: 16.7% vs. 18.3%; P = 0.65; grade≥3: 6.0% vs. 3.3%; P = 0.24). CONCLUSIONS: Primary radiation to an intact prostate resulted in higher grade≥2 acute urinary toxicity than radiation to the prostatic fossa, with no difference in late urinary toxicity. Thus, a proportion of acute urinary toxicity in men with an intact prostate may be attributable to inflammation of the prostatic gland or urethra.

Competition, inhibition, and semantic judgment errors in Parkinson's disease.

Semantic processing errors are symptoms of an up-regulation (schizophrenia) or degradation (Parkinsonism) of dopaminergic pathways. A recent connectionist model attributed errors in the schizophrenic processing of context to increased gain in competitive neural processes. This study extends this "gain hypothesis" by comparing the sensitivity to reduced gain of a simulation of semantic route activation to characteristic semantic judgment errors made by Parkinson's patients in an open search task. Under normal gain conditions, the dominant sense of polysemous words "wins" through competition and lateral inhibition at the word sense level (beta(inh)). For words with very different sense frequencies, decreasing gain by increasing beta(inh) resulted in the dominant word sense winning; however, for words with similar sense frequencies, increasing beta(inh) resulted in the dominant word sense winning only for low to moderate values. At high levels, no clear winner emerged after 200 epochs, with the least dominant sense reaching the maximum activation value. These results are discussed in the context of the Yerkes-Dodson Law, which may provide a theoretical basis for understanding normal and impaired semantic performance in catecholaminergic disorders.

Treatment options for multiple sclerosis: current and emerging therapies.

Multiple sclerosis is a chronic autoimmune disease affecting the central nervous system, more specifically, the myelin sheath covering of nerve fibers in the brain and spinal cord. This disease requires lifelong disease-modifying therapy, and all of the currently available first-line disease-modifying agents are parenteral formulations only. To date, eight drugs have entered or completed phases II and III clinical trials, four of which are oral drugs. These include five immunomodulators--cladribine, fingolimod, laquinimod, teriflunomide, and dimethyl fumarate--and three monoclonal antibodies--alemtuzumab, daclizumab, and rituximab. Although comparing these new drugs with available therapies is difficult, they do show promise as potential first-line agents for the treatment of multiple sclerosis. This marks a new frontier in the treatment of this disease, as the advent of new oral drugs will lead to increased patient compliance and contribute to longer sustained symptom-free periods and less marked disability.