Aki Ohinata

Modern systemic chemotherapy in surgically unresectable neoplasms of appendiceal origin: a single-institution experience.

Appendiceal neoplasms include tumors ranging from benign‐appearing cells with widespread mucin deposits to aggressive poorly differentiated signet ring cell adenocarcinomas. Traditionally, these tumors are treated with cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy. For some patients, cytoreductive surgery is not an option, and minimal published data exist in the management and outcome of these patients. A retrospective analysis was conducted to determine the benefit of modern systemic chemotherapy in patients with disseminated appendiceal neoplasm who were not considered optimal candidates for cytoreductive surgery.

Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study

BACKGROUND Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. METHODS We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. RESULTS We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. INTERPRETATION To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. FUNDING National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

Clinicopathologic Features Associated With Human Papillomavirus/p16 in Patients With Metastatic Squamous Cell Carcinoma of the Anal Canal

BACKGROUND The incidence of anal carcinoma in the U.S. continues to increase steadily, and infection with the human papillomavirus (HPV) is an established risk factor for the development of anal carcinoma. However, the clinicopathologic characteristics of patients with metastatic squamous cell carcinoma of the anal canal according to HPV status have not yet been defined. MATERIALS AND METHODS The records of patients treated for metastatic squamous cell carcinoma of the anal canal at the MD Anderson Cancer Center from June 2005 to August 2013 were reviewed. The patients were tested for the presence of HPV DNA by in situ hybridization and/or the p16 oncoprotein by immunohistochemistry. Associations between the presence of HPV and clinicopathologic attributes were measured. RESULTS Of the 72 patients reviewed, 68 tumors (94%) had detectable HPV. Patients with HPV-negative tumors were more likely to be of nonwhite ethnicity (odds ratio, 8.7) and have a strong (>30 pack-year) tobacco history (odds ratio, 8.7). A trend toward improved survival from the time of diagnosis of metastatic disease was noted among patients with HPV-positive tumors. CONCLUSION Most patients with metastatic anal cancer had detectable HPV, with differences in tobacco history and ethnicity detected according to HPV status. The high frequency of HPV positivity for patients with metastatic anal cancer has important implications for novel immunotherapy treatment approaches, including ongoing clinical trials with immune checkpoint blockade agents using antibodies targeting the programmed death-1 receptor. IMPLICATIONS FOR PRACTICE Previous studies investigating the clinical features of patients with anal cancer focused on those with early-stage disease. The present study characterizes, for the first time, clinical and pathological features according to human papillomavirus (HPV) status for patients with metastatic anal cancer. A high frequency of HPV-positive tumors and correlations between HPV status and both ethnicity and tobacco history was found. No standard-of-care therapy is available for patients with metastatic anal cancer, and most receive cytotoxic chemotherapy. The high prevalence of HPV in the current population generates optimism for ongoing clinical trials investigating the role of immune checkpoint blockade agents as a novel treatment approach for this disease.

Long-term results of weekly/daily cisplatin-based chemoradiation for locally advanced squamous cell carcinoma of the anal canal

Weekly or daily cisplatin and 5‐fluorouracil (5‐FU)‐based chemoradiation was evaluated for patients with locally advanced squamous cell carcinoma (SCC) of the anal canal treated at a single institution over a 20‐year period.

Epidermal growth factor receptor inhibition in metastatic anal cancer.

Metastatic squamous cell carcinoma (SCCA) anal cancer is relatively rare. With limited data, cisplatin plus 5-fluorouracil has traditionally been utilized in the first-line setting. Treatment beyond front-line cisplatin progression is not well defined. Epidermal growth factor receptor (EGFR) is highly overexpressed in SCCA anal cancer and EGFR inhibition may represent a potential treatment target for this population in need. Our case series evaluated metastatic SCCA anal cancer patients who received an EGFR monoclonal antibody as second-line or third-line therapy. Data collected consisted of demographics, previous treatment, metastatic disease sites, localized therapy received, regimen received, first radiographic result, progression-free survival, and overall survival. A total of 17 patients were included, with most (76%) patients receiving an EGFR monoclonal antibody in the second-line setting. Common regimens identified combined cetuximab or panitumumab with a fluoropyrimidine plus platinum (35%), carboplatin plus paclitaxel (29%), or cisplatin plus vinorelbine (18%). Thirty-five percent of patients achieved a response and 24% had stable disease. The overall median progression-free survival and overall survival were 7.3 and 24.7 months, respectively. Compared with our large retrospective study in the front-line metastatic anal cancer setting, our study suggests that anti-EGFR therapy in combination with certain chemotherapy derived additional benefit in the refractory setting. In the metastatic setting, there is a need to discover effective therapies. We present a diverse metastatic SCCA anal cancer patient population who received cetuximab or panitumumab with chemotherapy in the second-line or third-line setting. Our case series strengthens the concept of EGFR inhibition in metastatic SCCA anal cancer.

Atypical Metastatic Presentations in Colorectal Cancer: A Case Series

Treatment strategies and survival differences depend on the metastatic colorectal cancer (mCRC) site. The liver and lungs are common locations of metastatic spread. Atypical sites, by definition, have been reported in only limited numbers, thus causing a lack of information regarding differences in prognosis and treatment. This article presents 6 cases of atypical mCRC presentations. All patients received standard chemotherapy biologic therapy for their mCRC. Localized therapy was used in most cases for symptom management or to eradicate the metastatic involvement. Unusual mCRC presentations can have a substantial effect on a patient’s quality of life and treatment. Until more information is available, treatment decisions remain problematic for atypical mCRC involvement.

Abstract CT131: NCI#9673 phase II study of nivolumab in refractory metastatic squamous cell carcinoma of the anal canal: Immunologic correlates of response

Introduction: The incidence of squamous cell carcinoma of the anal canal (SCCA) continues to increase, with no standardized treatment options for patients with refractory metastatic disease. The development of SCCA is associated with human papillomavirus infection (HPV) and impaired immunity. Nivolumab is a monoclonal antibody targeting the programmed-death 1 (PD-1) ligand on T cells and may restore T-cell activity against tumor cells. The efficacy for nivolumab for metastatic SCCA has not been evaluated. Methods: Patients with at least one prior treatment for metastatic SCCA were treated with nivolumab (3 mg/kg) intravenously every 2 weeks in this single-arm, Simon two-stage phase 2 trial. PD-L1 expression was not an inclusion criterion. A total of 39 patients were enrolled through the ETCTN network. At our institution, an exploratory correlative analysis of paired tumor biopsies (pre-treatment and on-treatment) and of serial peripheral blood samples was conducted. All tissues samples were analyzed by immunohistochemistry (IHC) and flow cytometry by the MDACC immunotherapy platform to identify various immune cell subsets. Results from radiographic responders and non-responders were compared by Mann-Whitney test to identify biomarkers associated with treatment response. Results: In this subset analysis, 17 patients consented to tissue collection. Four patients had inadequate sample for analysis. Immune monitoring studies of pre-treatment tumor samples by IHC (n = 13) revealed a significantly higher percentage of CD3 T cells (p = 0.02), CD8 T cells (p = 0.01), granzyme-B (p = 0.005), PD-1 (p = 0.02), and PD-L1 on tumor epithelial cells (p = 0.005) in samples from patients who were scored as responders (n = 4) as compared to non-responders (n = 9). Five additional markers (CD20, CD45R0, CD68, FoxP3, OX40) measured by IHC did not show statistically significant differences. In addition, flow cytometry studies on available tumor samples (n = 12) indicated that patients who scored as responders had a significantly higher frequency of TIM-3+ CD8 T cells (p = 0.003) and PD-L1+ CD45+ immune cells (p = 0.03) in pre-treatment samples. Of note, responder patients had a trend towards a decrease in frequency of TIM-3+ CD8 T cells in post-treatment tumor samples. Conclusions: In the first prospective phase II trial ever for refractory metastatic SCCA, our exploratory analysis of pre- and on-treatment tissue specimens revealed potential correlations between immunologic biomarkers and clinical outcomes to nivolumab. Additional immune monitoring data will be provided. Citation Format: Van Morris, Armeen Mahvash, Luis Vence, Jorge Blando, Robert A. Wolff, Aki Ohinata, Chimela Ohaji, James Allison, Padmanee Sharma, Cathy Eng. NCI#9673 phase II study of nivolumab in refractory metastatic squamous cell carcinoma of the anal canal: Immunologic correlates of response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT131.

The use of biologic therapy in the treatment of unresectable appendiceal neoplasms

15546 Background: Peritoneal dissemination of appendiceal neoplasms (AN) is traditionally treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with a reported median 10-yr overall survival (OS) of 50–60%. Treatment options are limited for those who are not optimal candidates for CRS. We have previously shown that systemic chemotherapy may help in selected patients (Shapiro et al; ASCO GI, 2007); however, the role for biologic agents has not been characterized in these poor prognosis patients. Increased vascular endothelial growth factor (VEGF) expression in tissue specimens has recently been associated with poor prognosis. The purpose of this study was to evaluate the role of biologic agents in patients who were not candidates for cytoreduction. Methods: A retrospective observational cohort study was conducted of AN pts who received systemic chemotherapy with anti-VEGF (bevacizumab) or anti-epidermal growth factor receptor-targeted therapy (cetuximab, panitumumab,...