Multidisciplinary Management of Patients with Unresectable Hepatocellular Carcinoma: A Critical Appraisal of Current Evidence

Hepatocellular carcinoma (HCC) is a leading cause of new cancer diagnoses in the United States, with an incidence that is expected to rise. The etiology of HCC is varied and can lead to differences between patients in terms of presentation and natural history. Subsequently, physicians treating these patients need to consider a variety of disease and patient characteristics when they select from the many different treatment options that are available for these patients. At the same time, the treatment landscape for patients with HCC, particularly those with unresectable HCC, has been rapidly evolving as new, evidence-based options become available. The treatment plan for patients with HCC can include surgery, transplant, ablation, transarterial chemoembolization, transarterial radioembolization, radiation therapy, and/or systemic therapies. Implementing these different modalities, where the optimal sequence and/or combination has not been defined, requires coordination between physicians with different specialties, including interventional radiologists, hepatologists, and surgical and medical oncologists. As such, the implementation of a multidisciplinary team is necessary to develop a comprehensive care plan for patients, especially those with unresectable HCC

SWOG 1815: A phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers

Background: Biliary tract cancers (BTCs) are a heterogeneous group of malignancies with a dismal prognosis. Gemcitabine-based regimens are the standard of care in advanced disease, but median overall survival (OS) is roughly 12 months. The addition of albumin-bound paclitaxel to gemcitabine and cisplatin (GAP) demonstrated promising efficacy in a 60 patient, single-arm phase II study (Shroff et al, JAMA Oncol 2019), with observed median OS of 19.2 months. Methods: SWOG 1815 is a randomized, open-label, phase III trial comparing GAP to gemcitabine/cisplatin (GC). The study included newly diagnosed advanced BTC patients (pts), randomized 2:1 to GAP vs. GC. GAP included gemcitabine at 800 mg/m2, cisplatin at 25 mg/m2 and albumin-bound paclitaxel at 100 mg/m2 on days 1 and 8 of a 21-day cycle. GC included standard dosing of gemcitabine at 1000 mg/m2 and cisplatin at 25 mg/m2 on days 1 and 8 of a 21-day cycle. Pts were treated until progression. The primary endpoint was overall survival (OS) with a target hazard ratio of 0.7 with 90% power and a 1-sided alpha of 0.025; randomization was stratified by disease site (intrahepatic cholangiocarcinoma [CCA] vs gallbladder adenocarcinoma [GBC] vs extrahepatic CCA), disease stage (locally advanced vs metastatic), and Zubrod PS 0 vs 1. Results: Of 441 eligible pts randomized, 55% were female. 67% of patients had intrahepatic CCA, 16% had GBC and 17% had extrahepatic CCA. Most pts had metastases (73%). Median OS with GAP vs. GC was 14 vs. 12.7 mo respectively (HR 0.93, 95% CI 0.74-1.19, p=0.58), ORR (confirmed and unconfirmed) 34% vs25% (p=0.11) and median PFS 8.2 vs 6.4 mo (HR 0.92, 95% CI 0.72-1.16, p=0.47), respectively. Grade 3 and 4 treatment related adverse events (TRAEs) in ≥10% of pts for GAP and GC were anemia, neutropenia, and thrombocytopenia. GAP had more ≥ grade 3 hematologic AEs compared to the GC arm (60% vs. 45%, p=0.003). Discontinuation due to toxicity was at 24% vs 19% (p=0.26) with GAP vs GC. In exploratory subset analyses, GAP vs GC improved OS in pts with locally advanced disease (medians 19.2 vs 13.7 mo; HR 0.67, 95% CI 0.42- 1.06, p=0.09) and in GBC pts (medians 17.0 vs 9.3 mo; HR 0.74, 95% CI 0.41-1.35, p=0.33). ORR for GAP vs GC in GBC was 50% vs 24% (p=0.09) and for locally advanced disease 28 vs 21% p=0.74. Conclusions: SWOG 1815 did not result in a statistically significant improvement in median OS with GAP vs. GC. The GAP regimen had higher rates of TRAEs without a statistically significant difference in discontinuation rates. Pts with locally advanced disease and GBC may benefit from the use of GAP. Further analyses are ongoing to understand potential benefit of GAP in subsets of BTC pts. Funding: NIH/National Cancer Institute grants CA180888, CA180819, CA180820, CA180821, and CA180868; and in part by Celgene Corporation, Summit, NJ (subsidiary of Bristol Myer Squibb)

Poly(ADP-Ribose) Polymerase Inhibitors in Pancreatic Cancer: A New Treatment Paradigms and Future Implications

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy. Most of the patients of PDAC present at later stages of disease and have a five-year survival rate of less than 10%. About 5–10% PDAC cases are hereditary in nature and have DNA damage repair (DDR) mutations such as BRCA 1 and 2. Besides having implications on screening and prevention strategies, these mutations can confer sensitivity to platinum-based therapies and determine eligibility for poly(ADP-ribose) polymerase inhibitors (PARPi). In the presence of DDR mutations and PARPi, the cells are unable to utilize the error-free process of homologous recombination repair, leading to accumulation of double stranded DNA breaks and cell death eventually. Various PARPi are in clinical development in PDAC in different subgroup of patients as monotherapies and in combination with other therapeutics. This review would focus on the mechanism of action of PARPi, history of development in PDAC, resistance mechanisms and future directions

Targeted therapy in gastrointestinal malignancies

Increased understanding of cancer pathogenesis has identified several pathways that serve as potential targets for novel targeted agents in development. The selection of targeted cancer therapy based on biomarkers has instigated a new era of personalized medicine and changed the way we practice oncology. Many targeted agents are approved for treatment of gastrointestinal malignancies most targeting tumor angiogenesis, and many more are in different phases of development. Here we briefly summarize nine different targeted agents that are approved currently in the U.S. and several other agents currently being studied in various gastrointestinal cancers

Immunomodulation in hepatocellular cancer.

Hepatocellular carcinoma (HCC) is the fastest growing malignancy in the United States in relation to mortality. HCC relies on a complex immunosuppressive network to modify the host immune system and evade destruction. Intrinsic to the liver\u27s function and anatomy, native hepatic and immune cells produce many inhibitory cytokines that promote tolerogenicity and limit immune response. Since the introduction of sorafenib in 2008, no treatment has been able to demonstrate improved survival in patients with advanced HCC post disease progression treated with sorafenib. More recent studies have shown that sorafenib has an immunomodulatory function in addition to inhibition of multiple tyrosine kinases. Clinical trials have aimed to further enhance this immunomodulatory function with other treatments, most promisingly immune checkpoint inhibitors. Additionally, ongoing studies are using combinatorial approaches with immunomodulatory treatment and liver directed therapies such as transarterial chemoembolization (TACE), radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation. This article will review recent data describing the immunosuppressive network in HCC, recent results of immunotherapies, and combinatorial approaches to treat advanced HCC

Management of Typical and Atypical Pulmonary Carcinoids Based on Different Established Guidelines

Neuroendocrine tumors (NETs) are a group of malignancies that originated from neuroendocrine cells, with the most common sites being lungs and the gastrointestinal tract. Lung NETs comprise 25% of all lung malignancies. Small cell lung cancer is the most common form of lung NETs, and other rare forms include well-differentiated typical carcinoids (TCs) and poorly differentiated atypical carcinoids (ACs). Given the paucity of randomized studies, rational treatment is challenging. Therefore, it is recommended that these decisions be made using a multidisciplinary collaborative approach. Surgery remains the mainstay of treatment, when feasible. Following surgery, various guidelines offer different recommendations in the adjuvant setting. In this paper, we describe the adjuvant management of lung NETs, as recommended by different guidelines, and highlight their differences. In addition to that, we also discuss the management of metastatic lung NETS, including the use of peptide receptor radionucleotide therapy