The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.

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The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding locoregional therapy for treatment of patients with hepatocellular carcinoma.

The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and updated recommendations regarding systemic therapy for first-line and subsequent-line treatment of patients with hepatocellular carcinoma.

Background:Modifications of FOLFIRINOX are widely used despite the absence of prospective data validating efficacy in metastatic disease (metastatic pancreatic cancer (MPC)) or locally advanced pancreatic cancer (LAPC). We conducted a multicentre phase II study of modified FOLFIRINOX in advanced pancreatic cancer to assess the impact of dose attenuation in MPC and efficacy in LAPC.Methods:Patients with untreated MPC or LAPC received modified FOLFIRINOX (irinotecan and bolus 5-fluorouracil reduced by 25%). Adverse events (AEs) were compared with full-dose FOLFIRINOX. Response rate (RR), median progression-free survival (PFS) and median overall survival (OS) were determined.Results:In total, 31 and 44 patients with LAPC and MPC were enrolled, respectively. In MPC, efficacy of modified FOLFIRINOX was comparable with FOLFIRINOX with RR 35.1%, OS 10.2 months (95% CI 7.65–14.32) and PFS 6.1 months (95% CI 5.19–8.31). In LAPC, efficacy was notable with RR 17.2%, resection rate 41.9%, PFS 17.8 months (95% CI 11.0–23.9) and OS 26.6 months (95% CI 16.7, NA). Neutropenia (P<0.0001), vomiting (P<0.001) and fatigue (P=0.01) were significantly decreased. [18F]-Fluorodeoxyglucose positron emission tomography imaging response did not correlate with PFS or OS.Conclusions:In this first prospective study of modified FOLFIRINOX in MPC and LAPC, we observed decreased AEs compared with historical control patients. In MPC, the efficacy appears comparable with FOLFIRINOX. In LAPC, PFS and OS were prolonged and support the continued use of FOLFIRINOX in this setting.

Although FOLFIRINOX significantly increases survival in metastatic pancreatic cancer (MPC) compared to gemcitabine (Conroy et al. N Engl J Med 364:1817-1825, 2011), toxicities have tempered enthusiasm for its use in full doses. To assess the impact of dose attenuations on toxicity and efficacy, we reviewed our institution's experience with FOLFIRINOX in locally advanced pancreatic cancer (LAPC) and MPC. We performed a retrospective review of dose, toxicity, and efficacy of FOLFIRINOX in all patients with LAPC and MPC treated between June 2010 and July 2011 at Yale. Toxicities in all patients and response rate (RR) and survival in previously untreated MPC were compared to data reported by Conroy. Overall survival (OS) and progression-free survival were estimated by Kaplan-Meier method. Thirty-five patients were treated (16 LAPC; 19 MPC). Twenty-nine patients received dose attenuations with the first cycle. Median relative doses of irinotecan and bolus fluorouracil were less than those reported by Conroy (64 vs. 81 % and 66 vs. 82 %, respectively). RR was 50 % in LAPC and 47 % in MPC, and the latter did not differ significantly from the RR reported by Conroy (p = 0.19). OS at 6 and 12 months in MPC was comparable to OS reported by Conroy. Grade 3/4 toxicities were less than reported by Conroy, including fatigue (p = 0.009) and neutropenia (p < 0.0001). Nine patients experienced transient dysarthria during irinotecan administration. Our findings validate the efficacy and tolerability of FOLFIRINOX in LAPC and MPC and suggest that dose attenuations of irinotecan and bolus fluorouracil improve tolerability without compromising efficacy.

Sorafenib, a tyrosine kinase inhibitor, is approved for the treatment of patients with unresectable hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC). It is being evaluated in phase II and III clinical trials, which include treatment as a single agent (locally advanced/metastatic radioactive iodine-refractory differentiated thyroid cancer [DTC]), as part of multimodality care (HCC), and in combination with chemotherapeutic agents (metastatic breast cancer). Sorafenib-related adverse events (AEs) that commonly occur across these tumor types include hand-foot skin reaction (HSFR), rash, upper and lower gastrointestinal (GI) distress (ie, diarrhea), fatigue, and hypertension. These commonly range from grade 1 to 3, per the Common Terminology Criteria for Adverse Events (CTCAE), and often occur early in treatment. The goal for the management of these AEs is to prevent, treat, and/or minimize their effects, thereby enabling patients to remain on treatment and improve their quality of life. Proactive management, along with ongoing patient education (before and during sorafenib treatment), can help to effectively manage symptoms, often without the need for sorafenib dose modification or drug holidays. Effective management techniques for common sorafenib-related AEs, as well other important disease sequelae not directly related to treatment, are presented. Recommendations and observations are based on physician/author experience and recommendations from published literature.

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