Evan Wuthrick

Institutional Clinical Trial Accrual Volume and Survival of Patients With Head and Neck Cancer

PURPOSE National Comprehensive Cancer Network guidelines recommend patients with head and neck cancer (HNC) receive treatment at centers with expertise, but whether provider experience affects survival is unknown. PATIENTS AND METHODS The effect of institutional experience on overall survival (OS) in patients with stage III or IV HNC was investigated within a randomized trial of the Radiation Therapy Oncology Group (RTOG 0129), which compared cisplatin concurrent with standard versus accelerated fractionation radiotherapy. As a surrogate for experience, institutions were classified as historically low- (HLACs) or high-accruing centers (HHACs) based on accrual to 21 RTOG HNC trials (1997 to 2002). The effect of accrual volume on OS was estimated by Cox proportional hazards models. RESULTS Median RTOG accrual (1997 to 2002) at HLACs was four versus 65 patients at HHACs. Analysis included 471 patients in RTOG 0129 (2002 to 2005) with known human papillomavirus and smoking status. Patients at HLACs versus HHACs had better performance status (0: 62% v 52%; P = .04) and lower T stage (T4: 26.5% v 35.3%; P = .002) but were otherwise similar. Radiotherapy protocol deviations were higher at HLACs versus HHACs (18% v 6%; P < .001). When compared with HHACs, patients at HLACs had worse OS (5 years: 51.0% v 69.1%; P = .002). Treatment at HLACs was associated with increased death risk of 91% (hazard ratio [HR], 1.91; 95% CI, 1.37 to 2.65) after adjustment for prognostic factors and 72% (HR, 1.72; 95% CI, 1.23 to 2.40) after radiotherapy compliance adjustment. CONCLUSION OS is worse for patients with HNC treated at HLACs versus HHACs to cooperative group trials after accounting for radiotherapy protocol deviations. Institutional experience substantially influences survival in locally advanced HNC.

NCCN Guidelines® Insights Colon Cancer, Version 2.2018 Featured Updates to the NCCN Guidelines

The NCCN Guidelines for Colon Cancer provide recommendations regarding diagnosis, pathologic staging, surgical management, perioperative treatment, surveillance, management of recurrent and metastatic disease, and survivorship. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel discussions for the 2018 update of the guidelines regarding risk stratification and adjuvant treatment for patients with stage III colon cancer, and treatment of BRAF V600E mutation-positive metastatic colorectal cancer with regimens containing vemurafenib.

Perineural Invasion Predicts for Distant Metastasis in Locally Advanced Rectal Cancer Treated With Neoadjuvant Chemoradiation and Surgery

Objectives: The benefit of adjuvant chemotherapy in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) and surgery is controversial. We examined the association of perineural invasion (PNI) with outcomes to determine whether PNI could be used to risk-stratify patients. Materials and Methods: We performed a retrospective study of 110 patients treated with nCRT and surgery for LARC at our institution from 2004 to 2011. Eighty-seven patients were identified in our final analysis. We evaluated the association of PNI with locoregional control, distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival, using log-rank and Cox proportional hazard modeling. Results: Fourteen patients (16%) were PNI+ and 73 patients (84%) were PNI−. The median follow-up was 27 months (range, 0.9 to 84 mo). The median DMFS was 13.5 months for PNI+ and median not reached (>40 mo) for PNI− (P<0.0001). The median DFS was 13.5 months for PNI+ and 39.8 months for PNI− (P<0.0001). In a multivariate model including 7 pathologic variables, type of surgery, time to surgery from end of nCRT, and use of adjuvant chemotherapy, PNI remained a significant independent predictor of DMFS (hazard ratio 9.79; 95% confidence interval, 3.48-27.53; P<0.0001) and DFS (hazard ratio 5.72; 95% confidence interval, 2.2-14.9; P=0.0001). Conclusions: For patients with LARC treated with nCRT, PNI found at the time of surgery is significantly associated with worse DMFS and DFS. Our data support testing the role of adjuvant chemotherapy in patients with PNI and perhaps other high-risk features.

The Efficacy of Adjuvant Chemotherapy in Patients With Stage Ii/iii Resected Rectal Cancer Treated With Neoadjuvant Chemoradiation Therapy

Introduction: Patients with stage II/III rectal cancers are treated with neoadjuvant chemoradiation and surgical resection followed by adjuvant chemotherapy (CT) per practice guidelines. It is unclear whether adjuvant CT provides survival benefit, and the purpose of this study was to measure outcomes in patients who did and did not receive adjuvant CT. Materials and Methods: We used a prospectively collected database for patients treated at The Ohio State University, and analyzed overall survival (OS), time to recurrence, patient characteristics, tumor features, and treatments. Survival curves were estimated using Kaplan-Meier method and compared by the log-rank test. Age was compared using the Wilcoxon test, and other categorical variables were compared using the &khgr;2 or Fisher exact test. Results: Between August 2005 and July 2011, 110 patients were identified and 71 patients had received adjuvant CT. There was no significant difference in sex, race, pathologic tumor stage, and pathologic complete response between the 2 patient groups. Although patient characteristics showed a difference in age (median age 54.3 vs. 62 y, P=0.01) and advanced pathologic nodal status (43% vs. 19%, P=0.02), there was a significant difference in OS. Median OS was 72.6 months with CT versus 36.4 months without CT (P=0.0003). Median time to recurrence has not yet been reached. Conclusions: In this retrospective analysis, adjuvant CT was associated with a longer OS despite more advanced pathologic nodal staging. Prospective randomized studies are warranted to determine whether adjuvant CT provides a survival benefit for patients across the spectrum of stage II and III rectal cancer.

Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Rectal Cancer address diagnosis, staging, surgical management, perioperative treatment, management of recurrent and metastatic disease, disease surveillance, and survivorship in patients with rectal cancer. This portion of the guidelines focuses on the management of localized disease, which involves careful patient selection for curative-intent treatment options that sequence multimodality therapy usually comprised of chemotherapy, radiation, and surgical resection.

Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

The NCCN Guidelines for Anal Carcinoma provide recommendations for the management of patients with squamous cell carcinoma of the anal canal or perianal region. Primary treatment of anal cancer usually includes chemoradiation, although certain lesions can be treated with margin-negative local excision alone. Disease surveillance is recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is essential for optimal patient care.

Prognostic value of microRNA expression levels in pancreatic adenocarcinoma: a review of the literature

Background Clinical and pathologic markers of prognosis and patterns of failure help guide clinicians in selecting patients for adjuvant therapy after surgical resection for pancreatic adenocarcinoma (PDAC). Recent studies have reported the prognostic utility of microRNA profiling in numerous malignancies. Here, we review and summarize the current literature regarding associations between microRNA expression and overall survival in PDAC patients. Materials and Methods We conducted a systematic search in the PubMed database to identify all primary research studies reporting prognostic associations between tumor and/or serum microRNA expression and overall survival in PDAC patients. Eligible articles were reviewed by the authors and relevant findings are summarized below. Results We found 53 publications that fit our search criteria. In total, 23 up-regulated and 49 down-regulated miRNAs have been associated with worse overall survival. MiR-21 is the most commonly reported miRNA, appearing in 19 publications, all of which report aberrant over-expression and association with shorter survival in PDAC. Other miRNAs that appear in multiple publications include miR-10b, −21, −34a, −155, −196a, −198, −200c, −203, −210, −218, −222, and −328. We summarize the preclinical and clinical data implicating these miRNAs in various molecular signaling pathways and cellular functions. Conclusions There is growing evidence that miRNA expression profiles have the potential to provide tumor-specific prognostic information to assist clinicians in more appropriately selecting patients for adjuvant therapy. These molecules are often aberrantly expressed and exhibit oncogenic and/or tumor suppressor functions in PDAC. Additional efforts to develop prognostic and predictive molecular signatures, and further elucidate miRNA mechanisms of action, are warranted.

GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation, and intestinal dysfunction. Durable expression of GUCY2C, guanylin, and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess; Trulance) to prevent and treat RIGS in cancer therapy and nuclear disasters. Cancer Res; 77(18); 5095-106. ©2017 AACR.

Yttrium-90 microsphere selective internal radiation therapy for liver metastases following systemic chemotherapy and surgical resection for metastatic adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare malignancy with generally poor outcomes and limited treatment options. While surgical resection can be curative for early local disease, most patients present with advanced ACC owing to nonspecific symptoms. For those patients, treatment options include systemic chemotherapy and locoregional therapies including radiofrequency ablation and transarterial chemoembolization. We present the first reported case of utilizing yttrium-90 microsphere selective internal radiation therapy (SIRT) in combination with first line EDP-M (Etoposide, Doxorubicin, Cisplatin, Mitotane) chemotherapy and debulking surgical primary tumor resection for treatment of metastatic ACC. Stable complete radiologic response has been maintained after twelve months with resolution of clinical symptoms. These findings prompt the need for further consideration and studies to elucidate the role of SIRT in combination with systemic and surgical treatment for metastatic ACC.

Management of dysphagia in esophageal cancer (EC): A population-based study.

100 Background: Dysphagia is associated with significant morbidity in patients (pts) with EC. Our study is the first report of national trends in hospitalizations due to EC and dysphagia, with special emphasis on nutritional interventions and related outcomes. Methods: The analysis included all adult inpatients with EC and dysphagia in the Nationwide Inpatient Sample from 2002-2012. We examined temporal trends and performed multivariate analysis for key outcomes; controlling for demographics, hospital factors, comorbidities, and interventions. Results: Among 509,593 hospitalizations involving pts with EC, 12,205 were related to dysphagia. The percentage of all hospitalizations for EC (1.52 vs. 3.28%; p < 0.001) and EC with dysphagia (0.0025 vs. 0.0059%, p < 0.001) doubled over the study period. Among all pts with EC, inpatient mortality for EC with dysphagia was 4.39%. Mean length of stay (LOS) and cost of hospitalization were 8.1 days and