Faculty Bibliography

Prior studies examining the risk of second primary malignancy (SPM) after a first primary cancer generally have used large datasets such as the Surveillance, Epidemiology, and End Results (SEER) registry and excluded survivors of previous primaries and developers of synchronous primaries. The goal of this study was to provide a more complete representation of multiple cancer risk in squamous cell carcinoma of the anus (SCCA) patients. A single-institution retrospective study of 46 patients treated definitively for SCCA between January 2006 and July 2017 was conducted. Of the 46 patients, 18 (39%) had either a primary malignancy before SCCA (n=9) or SPM after an index SCCA (n=9). Six patients had ≥3 total malignancies. In our cohort, patients without SPMs tended to die from SCCA recurrence, while patients with SPMs were more likely to die from their SPM than from SCCA. Our study suggests that patients with SCCA are often either survivors of previous cancers or develop later malignancies. Several risk factors may play a role including HPV infection, HPV-related or treatment-related immunosuppression, somatic mutations due to chemotherapy, and genetic factors. Patients with SCCA require lifelong surveillance given their elevated risk of malignancy. Future work should focus on identifying genomic or immunologic factors that may predispose SCCA patients to develop multiple primary malignancies.

Of all patients diagnosed with pancreatic adenocarcinoma, only 15-20% present with resectable disease. Despite curative-intent resection, the prognosis remains poor with the majority of patients recurring, prompting the need for adjuvant therapy. Historical data support the use of adjuvant 5-fluorouracil (5-FU) or gemcitabine, but recent data suggest either gemcitabine plus capecitabine or modified FOLFIRINOX can improve overall survival when compared to gemcitabine alone. The use of adjuvant chemoradiation therapy remains controversial, primarily due to limitations in study design and mixed results of historical trials. The ongoing Radiation Therapy Oncology Group (RTOG)-0848 trial hopes to further define the role of adjuvant chemoradiation therapy. Intraoperative radiation therapy (IORT) and adjuvant immunotherapy represent additional possibilities to improve outcomes, but evidence supporting their use is limited. This article reviews adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma, including chemotherapy, chemoradiation therapy, IORT and immunotherapy.

Liver cancer is the sixth most common cancer and the second leading cause of death worldwide. Only 30–40% of patients are candidates for curative intervention at the time of diagnosis, and up to 70% of those who undergo curative resection will recur. Cytotoxic chemotherapy in advanced disease is not effective and is often limited by concomitant hepatic dysfunction. Sorafenib, a multiple kinase inhibitor, is the only therapy to have shown an overall survival benefit that is only modest at best. Thus, there is a large unmet need to develop additional therapies. In recent years, a diverse array of phenotypic and genetic alterations have been identified in HCC patients. Following these advances, several phase III studies with therapies targeted toward these alterations have been conducted; however, none has shown a survival benefit. It remains to be seen if this new understanding in these alterations can be translated therapeutically. In this chapter, we will discuss these alterations, as well as the developing therapies targeting them.

IMPORTANCE/OBJECTIVE:Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known. OBJECTIVE:To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015. EXPOSURE/METHODS:Ipilimumab therapy. MAIN OUTCOMES AND MEASURES/METHODS:Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively. RESULTS:Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:To our knowledge, this is the largest series of patients with preexisting autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring.

Immunotherapy has revolutionized cancer therapy and has been named the cancer advance of the year for 2016. Checkpoint inhibitors have demonstrated unprecedented rates of durable responses in some of the most difficult-to-treat cancers; however, many treated patients do not respond, and the potential for serious side effects exists. There is a growing need to identify biomarkers that will improve the selection of patients who will best respond to therapy, further elucidate drug mechanisms of action, and help tailor therapy regimens. Biomarkers are being explored at the soluble, cellular, and genomic levels, and examples in immunotherapy include serum proteins, tumor-specific receptor expression patterns, factors in the tumor microenvironment, circulating immune and tumor cells, and host genomic factors. The search for reliable biomarkers is limited by our incomplete understanding of how immunotherapies modify the already complex immune response to cancer, as well as the contribution of immuno-editing to a dynamic and inducible tumor microenvironment and immune milieu. Furthermore, there has been little extension of any candidate assay into large, prospective studies, and the lack of standardization in measurement and interpretation restricts their validity. Both tumor-infiltrating lymphocytes and PD-L1 expression within the tumor microenvironment have been recognized as having both prognostic and predictive value for patients treated with immunotherapy. Alternately, a larger panel of gene signatures, chemokines, and other factors that correlate with response has been proposed. In this article, we will explore the status of current biomarker candidates.

Mucosal melanoma is an exceedingly rare variant of cutaneous melanoma that, due to its rarity, is poorly described and infrequently studied. Primary sites of origin include the head and neck, anorectum and vulvovaginal regions. It is uniquely different from cutaneous melanoma with respect to epidemiology, etiology, pathogenesis and prognosis. The etiology and pathogenesis remain unclear. Unlike cutaneous melanoma, exposure to UV light is not an apparent risk factor. Furthermore, distinct molecular features including a lower incidence of BRAF oncogene mutations but a higher incidence of KIT oncogene mutations suggest divergent genetic etiologies. Mucosal melanomas generally present at a later stage, are more aggressive and carry a worse prognosis regardless of the stage at diagnosis. Establishing standardized treatment guidelines has been challenging due to the rarity of the disease. Early detection provides the best chance at survival but is often difficult due to anatomic location. Surgery remains the primary therapeutic intervention if complete resection is technically feasible given the anatomic location. Radiotherapy may be used to achieve local control when resection is not feasible, or adjuvantly to enhance locoregional control, but most studies have failed to demonstrate an improvement in overall survival. There are no consensus guidelines on the optimal systemic therapy, and regimens are often extrapolated from data based on therapies used to treat advanced cutaneous melanoma. Clinical trials, particularly utilizing newer targeted therapies and immunotherapies, are investigating novel treatment approaches.

Ipilimumab is a fully human, monoclonal antibody directed against Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) that has demonstrated a survival benefit and durable disease control in patients with advanced melanoma. Ipilimumab is associated with potentially serious immune-related adverse events, including autoimmune hepatitis. Because clinical trials of ipilimumab excluded patients with pre-existing hepatitis B or C infection, there is a paucity of data on the safety of ipilimumab administration to that patient population. Here, we report the largest case series to date of patients with hepatitis B or C who received ipilimumab for advanced melanoma. Two of the nine patients described in this case series experienced fluctuations in their liver function tests (LFTs) and were subsequently treated with corticosteroids. Although this is a small series, the rate of hepatotoxicity appears similar to what has been seen in the general population treated with ipilimumab, and the ability to administer ipilimumab did not appear to be affected by concomitant hepatitis B or C infection. The use of ipilimumab in patients with metastatic melanoma who have pre-existing hepatitis can be considered among other therapeutic options.