Mark V. Mishra

Genomic Prostate Cancer Classifier Predicts Biochemical Failure and Metastases in Patients After Postoperative Radiation Therapy

Purpose To test the hypothesis that a genomic classifier (GC) would predict biochemical failure (BF) and distant metastasis (DM) in men receiving radiation therapy (RT) after radical prostatectomy (RP). Methods and Materials Among patients who underwent post-RP RT, 139 were identified for pT3 or positive margin, who did not receive neoadjuvant hormones and had paraffin-embedded specimens. Ribonucleic acid was extracted from the highest Gleason grade focus and applied to a high-density-oligonucleotide microarray. Receiver operating characteristic, calibration, cumulative incidence, and Cox regression analyses were performed to assess GC performance for predicting BF and DM after post-RP RT in comparison with clinical nomograms. Results The area under the receiver operating characteristic curve of the Stephenson model was 0.70 for both BF and DM, with addition of GC significantly improving area under the receiver operating characteristic curve to 0.78 and 0.80, respectively. Stratified by GC risk groups, 8-year cumulative incidence was 21%, 48%, and 81% for BF (P<.0001) and for DM was 0, 12%, and 17% (P=.032) for low, intermediate, and high GC, respectively. In multivariable analysis, patients with high GC had a hazard ratio of 8.1 and 14.3 for BF and DM. In patients with intermediate or high GC, those irradiated with undetectable prostate-specific antigen (PSA ≤0.2 ng/mL) had median BF survival of >8 years, compared with <4 years for patients with detectable PSA (>0.2 ng/mL) before initiation of RT. At 8 years, the DM cumulative incidence for patients with high GC and RTwith undetectable PSA was 3%, compared with 23% with detectable PSA (P=.03). No outcome differences were observed for low GC between the treatment groups. Conclusion The GC predicted BF and metastasis after post-RP irradiation. Patients with lower GC risk may benefit from delayed RT, as opposed to those with higher GC; however, this needs prospective validation. Genomic-based models may be useful for improved decision-making for treatment of high-risk prostate cancer.

A systematic review of the cost and cost‐effectiveness studies of proton radiotherapy

Economic analyses of new technologies, such as proton‐beam radiotherapy (PBT), are a public health priority. To date, no systematic review of the cost‐effectiveness of PBT has been performed.

Improving prognosis of glioblastoma in the 21st century: who has benefited most?

Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults. Temozolomide was rapidly incorporated into first‐line treatment following the publication of the pivotal European Organization for Research and Treatment of Cancer–National Cancer Institute of Canada phase 3 trial in 2005. However, in the trial, enrollment was limited to younger patients with good performance status. Therefore, this study performed a population‐based survival analysis of patients with newly diagnosed GBM covering the period before and after the introduction of temozolomide.

The Impact of Brachytherapy on Prostate Cancer–Specific Mortality for Definitive Radiation Therapy of High-Grade Prostate Cancer: A Population-Based Analysis

PURPOSE This population-based analysis compared prostate cancer-specific mortality (PCSM) in a cohort of patients with high-risk prostate cancer after nonsurgical treatment with external beam radiation therapy (EBRT), brachytherapy (BT), or combination (BT + EBRT). METHODS AND MATERIALS We identified from the Surveillance, Epidemiology and End Results database patients diagnosed from 1988 through 2002 with T1-T3N0M0 prostate adenocarcinoma of poorly differentiated grade and treated with BT, EBRT, or BT + EBRT. During this time frame, the database defined high grade as prostate cancers with Gleason score 8-10, or Gleason grade 4-5 if the score was not recorded. This corresponds to a cohort primarily with high-risk prostate cancer, although some cases where only Gleason grade was recorded may have included intermediate-risk cancer. We used multivariate models to examine patient and tumor characteristics associated with the likelihood of treatment with each radiation modality and the effect of radiation modality on PCSM. RESULTS There were 12,745 patients treated with EBRT (73.5%), BT (7.1%), or BT + EBRT (19.4%) included in the analysis. The median follow-up time for all patients was 6.4 years. The use of BT or BT + EBRT increased from 5.1% in 1988-1992 to 31.4% in 1998-2002. Significant predictors of use of BT or BT + EBRT were younger age, later year of diagnosis, urban residence, and earlier T-stage. On multivariate analysis, treatment with either BT (hazard ratio, 0.66; 95% confidence interval, 0.49-0.86) or BT + EBRT (hazard ratio, 0.77; 95% confidence ratio, 0.66-0.90) was associated with significant reduction in PCSM compared with EBRT alone. CONCLUSION In patients with high-grade prostate cancer, treatment with brachytherapy is associated with reduced PCSM compared with EBRT alone. Our results suggest that brachytherapy should be investigated as a component of definitive treatment strategies for patients with high-risk prostate cancer.

Nutrient Restriction and Radiation Therapy for Cancer Treatment: When Less Is More

Calorie restriction (CR), or a diet modification aiming to reduce the total intake of calories by 20%-40%, has been shown to increase longevity across multiple species. Recently, there has been growing interest in investigating the potential role of CR as a treatment intervention for age-related diseases, such as cancer, because an increasing body of literature has demonstrated a metabolic component to both carcinogenesis and tumor progression. In fact, many of the molecular pathways that are altered with CR are also known to be altered in cancer. Therefore, manipulation of these pathways using CR can render cancer cells, and most notably breast cancer cells, more susceptible to standard cytotoxic treatment with radiation and chemotherapy. In this review article we demonstrate the laboratory and clinical evidence that exists for CR and show compelling evidence through the molecular pathways CR induces about how it may be used as a treatment in tandem with radiation therapy to improve our rates of disease control.

Improving Outcomes for Esophageal Cancer using Proton Beam Therapy

Radiation therapy (RT) plays an essential role in the management of esophageal cancer. Because the esophagus is a centrally located thoracic structure there is a need to balance the delivery of appropriately high dose to the target while minimizing dose to nearby critical structures. Radiation dose received by these critical structures, especially the heart and lungs, may lead to clinically significant toxicities, including pneumonitis, pericarditis, and myocardial infarction. Although technological advancements in photon RT delivery like intensity modulated RT have decreased the risk of such toxicities, a growing body of evidence indicates that further risk reductions are achieved with proton beam therapy (PBT). Herein we review the published dosimetric and clinical PBT literature for esophageal cancer, including motion management considerations, the potential for reirradiation, radiation dose escalation, and ongoing esophageal PBT clinical trials. We also consider the potential cost-effectiveness of PBT relative to photon RT.

Safety and efficacy of radiation therapy as secondary prophylaxis for heterotopic ossification of non-hip joints.

Introduction: Prophylactic radiation therapy (RT) is an established adjuvant therapy for heterotopic ossification (HO) of the hip when delivered in the immediate pre‐ or postoperative setting. Its role in prevention of recurrence after excision of HO is supported by randomised trials for HO of the hip, but there is scant evidence to demonstrate the safety and efficacy of a similar approach in non‐hip joints. In the current study, we evaluate radiological and functional outcomes after prophylactic RT for prevention of HO of the knee and upper extremity.

Factors that influence patient preferences for prostate cancer management options: A systematic review

Purpose We performed a systematic review to evaluate evidence regarding factors that influence patient preferences for management options for localized prostate cancer. Methods We followed a prespecified search protocol (PROSPERO identifier CRD42014009173) to identify studies that evaluated patient preferences for prostate cancer management options for localized prostate cancer. We queried PubMed, the Cochrane Database of Systematic Reviews, Embase, Cumulative Index to Nursing & Allied Health Literature (CINAHL) Plus, and Econ-Lit databases. Two separate reviewers completed the article selection process and review, including coding of study characteristics. Study quality was scored according to the PREFS checklist, which consists of five criteria: Purpose, Respondents, Explanation, Findings, and Significance. Reviewers summarized the primary findings of each article included in the analysis. Results Of the 606 citations identified in the literature search, there were a total of 21 articles that met all selection criteria, reporting results for a total of 4,131 subjects. Themes identified in the studies included: the importance of patient perceptions of treatment efficacy and side effects; the influence of physician recommendations on patient decision-making; and the prioritization of concerns regarding treatment side effects among those men who prefer radiation therapy or active surveillance. The articles had an average PREFS score of 3.4 (standard deviation [SD] 1.0), which is similar to a recent study for breast cancer treatment preferences. Conclusion This systematic review of factors that influence patient preferences for prostate cancer management options identified a small, but high quality, group of articles that satisfied the selection criteria. The available evidence suggests that interventions aimed at informing patients regarding the comparative effectiveness of prostate cancer management alternatives should include the influence of physician recommendations and family members’ desires on patient decision-making.

Identifying barriers to patient acceptance of active surveillance: content analysis of online patient communications.

Objectives Qualitative research aimed at identifying patient acceptance of active surveillance (AS) has been identified as a public health research priority. The primary objective of this study was to determine if analysis of a large-sample of anonymous internet conversations (ICs) could be utilized to identify unmet public needs regarding AS. Methods English-language ICs regarding prostate cancer (PC) treatment with AS from 2002–12 were identified using a novel internet search methodology. Web spiders were developed to mine, aggregate, and analyze content from the world-wide-web for ICs centered on AS. Collection of ICs was not restricted to any specific geographic region of origin. NLP was used to evaluate content and perform a sentiment analysis. Conversations were scored as positive, negative, or neutral. A sentiment index (SI) was subsequently calculated according to the following formula to compare temporal trends in public sentiment towards AS: [(# Positive IC/#Total IC) - (#Negative IC/#Total IC) x 100]. Results A total of 464 ICs were identified. Sentiment increased from -13 to +2 over the study period. The increase sentiment has been driven by increased patient emphasis on quality-of-life factors and endorsement of AS by national medical organizations. Unmet needs identified in these ICs include: a gap between quantitative data regarding long-term outcomes with AS vs. conventional treatments, desire for treatment information from an unbiased specialist, and absence of public role models managed with AS. Conclusions This study demonstrates the potential utility of online patient communications to provide insight into patient preferences and decision-making. Based on our findings, we recommend that multidisciplinary clinics consider including an unbiased specialist to present treatment options and that future decision tools for AS include quantitative data regarding outcomes after AS.

Prognostic Factors and Outcomes After Definitive Treatment of Female Urethral Cancer: A Population-based Analysis

OBJECTIVE To evaluate the prognostic factors and outcomes for a large observational cohort of female patients with urethral cancer in the Surveillance, Epidemiology, and End Results database. METHODS We identified 722 women diagnosed with urethral cancer from 1983 to 2008 in the Surveillance, Epidemiology, and End Results database. Descriptive statistics were used to explore the epidemiology, standard treatment practices, and tumor characteristics. A total of 359 women with nonmetastatic primary urethral cancer were identified for cancer-specific and survival analysis. Kaplan-Meier plots and log-rank tests were performed for each potential covariate. A multivariate Cox proportional hazards model was performed to evaluate age, demographic factors, T stage, nodal status, histologic findings, surgery, and radiotherapy. RESULTS The median overall survival time was 42 months (95% confidence interval 35-57), and the 5- and 10-year overall survival rate was 43% and 32%, respectively. The median cancer-specific survival (CSS) time was 78 months, and the 5- and 10-year CSS rate was 53% and 46%, respectively. On multivariate analysis, black race, Stage T3-T4 tumors compared with T1, node-positive disease, nonsquamous histologic features, and advanced age were associated with shortened CSS. Surgery was associated with longer CSS. Black patients presented with a statistically significant greater T stage. CONCLUSION Advanced age, T stage, node-positive disease, nonsquamous histologic features, and black race were associated with reduced CSS, and surgical resection was associated with longer CSS. We found that black patients present with more advanced tumors and have shorter CSS than white women with urethral cancer.