Faculty Bibliography

PURPOSE:Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid tumors. METHODS:Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID). RESULTS:Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (N = 18; 51%), fatigue (N = 17; 49%), maculo-papular rash (N = 16; 46%), diarrhea (N = 12; 34%), anorexia (N = 11; 31%), and nausea (N = 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (N = 13) and primarily included fatigue (N = 5; 14%) and maculo-papular rashes (N = 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients. CONCLUSION:The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.

OBJECTIVES:The survival of patients with metastatic colorectal cancer (CRC) has been increasing over recent decades due to improvements in chemotherapy and surgery. There is a need to refine prognostic information to more accurately predict survival as patients survive for any given length of time to assist multidisciplinary cancer management teams in treatment decisions. MATERIALS AND METHODS:We performed a single center retrospective analysis of patients treated with metastatic CRC (unresectable and resectable) who survived >24 months between 2005 and 2015 (N=155). Patient tumor and treatment related variables were collected. Overall survival (OS) estimates conditional on surviving >24 months were compared with actuarial survival estimates of a cohort of patients (33,104 resected, 39,382 unresected) from the National Cancer Database (NCDB). RESULTS:With a median follow-up of 44.2 months, the median OS of resected patients (n=86) was not reached. The median OS of unresected patients was 75.9 months. The conditional survival probabilities of living 1, 2, or 3 years longer after 24 months of survival are 92%, 72%, and 52%, respectively, in unresectable patients and 98%, 92%, and 89% in patients who were resected. The corresponding NCDB 1, 2, and 3 year actuarial survival was 38%, 20%, and 11% for unresected patients and 68%, 46%, and 32% for resected. CONCLUSIONS:These results indicate that CRC patients who survive 24 months with metastatic colorectal cancer have an excellent prognosis and surgery may be appropriate in a subset of patients initially deemed unresectable.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, with a majority of HCC patients not suitable for curative therapies. Approximately 70% of initially diagnosed patients cannot undergo surgical resection or transplantation due to locally advanced disease, poor liver function/underlying cirrhosis, or additional comorbidities. Local therapeutic options for patients with unresectable HCC, who are not suitable for thermal ablation, include transarterial embolization (bland, chemoembolization, radioembolization) and/or external beam radiation therapy (EBRT). Regarding EBRT specifically, technological advancements provide a means for safe and effective radiotherapy delivery in a wide spectrum of HCC patients. In multiple prospective studies, EBRT delivery in a variety of different fractionation schemes or in combination with transcatheter arterial chemoembolization (TACE) demonstrate improved outcomes, particularly with combination therapy. The Barcelona Clinic Liver Cancer classification provides a framework for treatment selection; however, given the growing complexity of treatment strategies, this classification system tends to simplify decision-making. In this review, we discuss the current literature regarding unresectable HCC and propose a modified treatment algorithm that emphasizes the role of radiation therapy for Child-Pugh score A or B patients with ≤3 nodules measuring >3 cm, multinodular disease or portal venous thrombosis.

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.