Paul R. Kunk

From bench to bedside a comprehensive review of pancreatic cancer immunotherapy

The incidence of pancreatic cancer has been increasing while its 5-year survival rate has not changed in decades. In the era of personalized medicine, immunotherapy has emerged as a promising treatment modality in a variety of malignancies, including pancreatic cancer. This review will discuss the unique pancreatic tumor microenvironment, including the cells and receptors that transform the pancreas from its normal architecture into a complex mix of suppressor immune cells and dense extracellular matrix that allows for the unrestricted growth of cancer cells. Next, we will highlight the recently completed immunotherapy clinical trials in pancreatic cancer. Finally, we will explore the on-going immunotherapy clinical trials and future directions of this engaging and changing field.

Beyond melanoma: inhibiting the PD-1/PD-L1 pathway in solid tumors.

Immune checkpoint inhibitors have been identified as breakthrough treatment in melanoma given its dramatic response to PD-1/PD-L1 blockade. This is likely to extend to many other cancers as hundreds of clinical trials are being conducted or proposed using this exciting modality of therapy in a variety of malignancies. While immune checkpoint inhibitors have been extensively studied in melanoma and more recently in lung cancer, little is known regarding immune checkpoint blockade in other cancers. This review will focus on the tumor immune microenvironment, the expression of PD-1/PD-L1 and the effect of immune modulation using PD-1 or PD-L1 inhibitors in patients with head and neck, prostate, urothelial, renal, breast, gastrointestinal and lung cancers.

Immunotherapy for hepatocellular carcinoma patients: is it ready for prime time?

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second most common cause of cancer death worldwide. Current treatment options for patients with intermediate and advanced HCC are limited, and there is an unmet need for novel therapeutic approaches. HCC is an attractive target for immunomodulation therapy, since it arises in an inflammatory milieu due to hepatitis B and C infections and cirrhosis. However, a major barrier to the development and success of immunotherapy in patients with HCC is the liver’s inherent immunosuppressive function. Recent advances in the field of cancer immunology allowed further characterization of immune cell subsets and function, and created new opportunities for therapeutic modulation of the immune system. In this review, we present the different immune cell subsets involved in potential immune modulation of HCC, discuss their function and clinical relevance, review the variety of immune therapeutic agents currently under investigation in clinical trials, and outline future research directions.

Small Cell Carcinoma of the Gallbladder: Case Report and Comprehensive Analysis of Published Cases

Background. Gallbladder small cell carcinoma is a rare and highly aggressive malignancy with no established standard of care treatment. We described here a case report of small cell gallbladder cancer and we then performed a comprehensive review of 72 case reports of this disease. Methods. Published case reports of small cell carcinoma of the gallbladder between 1983 and 2014 were reviewed. Treatment modalities and survival were analyzed for metastatic and localized disease. Results. Median overall survival for all patients was 13 months. Metastatic disease was identified in 72% of cases. Treatment of metastatic disease with chemotherapy showed a significant survival benefit (p < 0.001) compared to no chemotherapy, and the use of platinum doublet with etoposide showed a nonsignificant 4-month improvement in survival compared to other chemotherapy regimens (p = 0.13). Adjuvant therapy did not demonstrate an improvement of median overall survival in local disease (p = 0.78). Conclusion. Given the limited available data, systemic therapy with platinum and etoposide should be considered for patients with metastatic small cell carcinoma of the gallbladder. Adjuvant chemoradiation or chemotherapy for treatment of local disease warrants further investigation.

Current debate in the oncologic management of rectal cancer

Despite the considerable amount of research in the field, the management of locally advanced rectal cancer remains a subject to debate. To date, effective treatment centers on surgical resection with the standard approach of total mesorectal resection. Radiation therapy and chemotherapy have been incorporated in order to decrease local and systemic recurrence. While it is accepted that a multimodality treatment regimen is indicated, there remains significant debate for how best to accomplish this in regards to order, dosing, and choice of agents. Preoperative radiation is the standard of care, yet remains debated with the option for chemoradiation, short course radiation, and even ongoing studies looking at the possibility of leaving radiation out altogether. Chemotherapy was traditionally incorporated in the adjuvant setting, but recent reports suggest the possibility of improved efficacy and tolerance when given upfront. In this review, the major studies in the management of locally advanced rectal cancer will be discussed. In addition, future directions will be considered such as the role of immunotherapy and ongoing trials looking at timing of chemotherapy, inclusion of radiation, and non-operative management.

Risk of Major Bleeding with Ibrutinib

&NA; Ibrutinib is a highly effective therapy for non‐Hodgkin lymphoma and chronic lymphocytic leukemia. However, ibrutinib has also been associated with an increased risk of bleeding, although major bleeding has been infrequent in clinical trials. In the present retrospective analysis, major bleeding occurred in 19% of patients receiving ibrutinib and was associated with baseline anemia, an elevated international normalized ratio, and concurrent antiplatelet and anticoagulant use. A risk versus benefit analysis of these factors is essential for treatment with ibrutinib. Background: The Bruton tyrosine kinase inhibitor, ibrutinib, is an effective therapy against mature B‐cell malignancies. Although generally well tolerated, serious bleeding emerged during developmental clinical trials as an unexpected, although uncommon, adverse event. As the use of ibrutinib increases outside of the clinical trial setting and in patients with more comorbidities, the rate of major bleeding could be greater. Materials and Methods: A retrospective analysis the data from all patients at our center and its regional clinics who had been prescribed ibrutinib from January 2012 to May 2016 were reviewed for demographic data, comorbid illnesses, bleeding events, and concurrent medications. Results: We identified 70 patients. Bleeding of any grade occurred in 56% of patients, mostly grade 1 to 2 bruising and epistaxis. Major bleeding, defined as grade ≥ 3, occurred in 19% of patients, greater than previously reported. Anemia (hemoglobin < 12 g/dL; hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.4‐18.2; P = .02) and an elevated international normalized ratio (> 1.5; HR, 9.5; 95% CI, 2.7‐33.5; P < .01) at ibrutinib initiation were associated with an increased risk of major bleeding. Of those with major bleeding, most patients were also taking an antiplatelet agent (70%), an anticoagulant (17%), or a CYP 3A4 inhibitor (7%), with 13% taking both antiplatelet and anticoagulant medications. The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3‐166.7; P < .01). Conclusion: The results of the present study have demonstrated a greater rate of major bleeding with ibrutinib use in a standard clinical setting than previously reported. Patients with anemia or an elevated international normalized ratio or requiring anticoagulant and/or antiplatelet medications during ibrutinib therapy have a significantly increased risk of major bleeding. Careful consideration of the risks and benefits for this population is needed. The combination of antiplatelet and anticoagulation medications with ibrutinib therapy is of particular concern.

Commentary on from Bench to Bedside: A Comprehensive Review of Pancreatic Cancer Immunotherapy. Slow Improvements in Meaningful Clinical Benefit

Paul R Kunk1 and Osama E Rahma2 1Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System, Charlottesville, VA, USA 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA *Corresponding author: Paul R Kunk, Department of Medicine, Division of Hematology-Oncology, University of Virginia Health System, Charlottesville, VA, E-mail: prk5r@virginia.edu

Real-World Evaluation of Hematologic Toxicity Associated with nab-Paclitaxel Plus Gemcitabine for Advanced Pancreatic Cancer

Albumin-bound paclitaxel (nab-paclitaxel), in combination with gemcitabine, is used for firstor second-line treatment of advanced pancreatic cancer (APC). The objectives of this retrospective single institution study are to report the rates of hematologic toxicity, febrile neutropenia (FN), growth factor utilization, progression-free and overall survival of nab-paclitaxel–gemcitabine in a real-world, non-clinical trial setting. Patients with APC treated with nab-paclitaxel—gemcitabine between January 1, 2012 and December 31, 2014 were identified. Data were retrospectively collected from the electronic medical record under an institutional IRB-approved protocol. A total of 29 patients treated with nab-paclitaxel—gemcitabine were included in the analyses. Half of the patients (52%) had received previous therapy for advanced disease, with the majority of those patients (80%) receiving FOLFIRINOX. Grade ≥3 neutropenia and thrombocytopenia were reported in 31% and 21% of patients. FN was observed in 1 patient (3%), and growth factor was utilized in 10% of patients. Most patients (86%) required at least one dose modification, with 76% of patients having dose omission due to toxicity. Median progression-free survival was 3.9 months and median overall survival was 5.4 months. Our results suggest that the rates of hematologic toxicity in the real-world setting are similar to those seen in clinical trial population, despite variances in clinical practice. It remains unclear whether the underutilization of growth factor support affects the incidence of neutropenia outside of clinical trials. The short overall and progression-free survival observed in this study population are not unexpected, as the majority of patients received nab-paclitaxel—gemcitabine as second-line therapy.