Kundranda Discusses Options for Therapy in 2 HCC Patient Cases

Madappa Kundranda, MD, PhD

Madappa Kundranda, MD, PhD

Madappa Kundranda, MD, PhD, recently discussed the cases of 2 patients with hepatocellular carcinoma (HCC), and the treatment considerations and decisions he would make when treating these patients. Dr. Kundranda, Director of Gastrointestinal Oncology at Banner MD Anderson Cancer Center, Phoenix discussed these cases during aTargeted Oncologylive case-based peer perspectives dinner.

Case 1

February 2014

A 63-year-old Asian male with chronic hepatitis B (HBV) infection was referred for further imaging studies after suspicious findings on a routine ultrasound surveillance for HCC. An alpha-fetoprotein (AFP) blood test showed 5400 IU/ML. His Child-Pugh class was A. His platelets were 230,000 cells/mcL; bilirubin was 1.0 mg/dL; albumin was 3.5 g/dL. He did not have hepatic encephalopathy. Vascular invasion or ascites were not present. He was not a candidate for transplant.

A CT scan revealed 2 lesions in the right hepatic lobe, measuring 2 cm and 5 cm; no extrahepatic disease was visualized. Biopsy findings showed grade 2 HCC with moderate fibrosis. Both lesions were resected with R0 margin.

Targeted Oncology:What is the prognosis of the patient?

Kundranda:Hepatocellular carcinoma (HCC) is a disease that frequently occurs in the setting of chronic liver disease and cirrhosis. It is typically diagnosed late in the course of these diseases, and the median survival following diagnosis ranges from approximately 5 to 22 months A. Although a universally accepted prognostic system is not available-four key features can potentially determine survival: the severity of underlying liver disease, the size of the tumor, extension of the tumor into adjacent structures, and the presence of metastases

This patient specifically has 2 liver lesions, 2 cm and 5 cm, Child-Pugh class A, and no vascular invasion. With aggressive resection he has a relatively decent prognosis. Contrast this with patients that have the worst prognosis; these are pts with Child-Pugh class B or C, and a tumor of more than 8 cm. However its imperative to have a multidisciplinary evaluation of each patient before treatment plans are devised.

Targeted Oncology: Is there any evidence for use of adjuvant therapy in patients with HCC?

Kundranda:There is no role for the use of adjuvant chemotherapy in HCC in 2017. A large European study, STORM,  addressed this question. The bottom line was  that sorafenib was not effective in the aduvant setting

More than 1000 patients were randomized to either sorafenib (Nexavar) or placebo. Patients receiving sorafenib had no improvement in OS or PFS, and no improvement in time to recurrence. No other study since then has demonstrated unequivocal benefit of chemo in the adjuvant setting.

However, adjuvant antiviral therapy is certainly beneficial after potentially curative liver resection in patients with activeviral hepatitis.

August 2016

Routine follow-up imaging showed a new lesion in the liver, measuring 2.3 cm. A chest CT showed 3 small lesions (<1 cm) in the left upper lobe of the lung. The patient was started on sorafenib 400 mg BID and developed experienced grade 2 diarrhea.

Targeted Oncology: Is this patient a candidate for sorafenib? What factors do you consider when deciding when to initiate therapy with sorafenib?

Kundranda:It should be noted that if an appropriate clinical trial is available, those should always be considered in whatever line of therapy. However this patient is certainly a candidate for sorafenib, considering the Child-Pugh A, performance status and lab work.

Targeted Oncology: How will this change with the availability of lenvatinib (Lenvima)?

Kundranda:Based on the current data that is available with lenvatinib, it certainly is an alternate to frontline therapy, however, at the current time, sorafenib is the only drug that is FDA approved in the frontline setting for the treatment of advanced HCC.

Targeted Oncology: What are practical strategies to manage toxicities?

Kundranda:Early recognition and quick and appropriate intervention is the key in managing these patients. The most common toxicities in the pivotal SHARP data and in the real-life setting are &nbsp;hand-foot skin reaction and diarrhea. Patients need to be evaluated on a regular basis, at least on a biweekly basis for the first 1-2cycles, to identify toxicities earlier on and intervene accordingly. In addition to aggressive supportive case dose reduction should be considered. Specifically, for the hand-foot skin reaction, topical agents, such as urea creams and topical steroids, should be considered earlyin the treatment. For the management of diarrhea; aggressive hydration in addition to &nbsp;anti-diarrheal agents should be used in an appropriate and timely fashion.

April 2017

The patient complains of increasing fatigue. CT scans show widely scattered lung nodules. His ECOG status was 0. Liver functions are preserved.

Targeted Oncology: What are the options for therapy?

Kundranda:In this setting there are currently 2 options that are available: regorafenib and nivolumab.

Regorafenib (Stivarga) after sorafenib was evaluated in phase 3 RESORCE trial of&nbsp;573 patients with HCC in a 2:1 randomization ratio who received best supportive care (BSC) plus either regorafenib (n = 379) or placebo (n = 194). All patients in this study had progressed through sorafenib. The study met its primary endpoint with a median OS of 10.6 months with regorafenib vs. 7.8 months for placebo. The median PFS was 3.1 months in the regorafenib&nbsp;&nbsp;(vs. 1.5 months with placebo). The ORR with regorafenib was 10.6% versus 4.1% with placebo (P = .005). The disease control rate (DCR; ORR plus stable disease) was 65.2% with regorafenib (vs.36.1% with placebo).

This led to FDA granting approval for regorafenib as a second-line treatment for patients with hepatocellular carcinoma (HCC) who have previously received sorafenib.

The data for nivolumab (Opdivo) in the second-line after sorafenib is from the CheckMate-040 phase I/II trial of 262 patients with advanced HCC with or without hepatitis C virus (HCV) or HBV infection. There were 48 patients in the dose-escalation phase and 214 patients in the dose-expansion phase. In the sorafenib-exposed group (n = 145), the mRECIST ORR by blinded independent central review (BICR) was 19%. By RECIST v1.1 there were 2 complete responses (1%), 19 partial responses (13%), and 60 patients with stable disease (41%). The disease control rate (DCR; ORR plus stable disease) was 56%.

This led to the FDA granting an accelerated approval to nivolumab for the treatment of patients with HCC following prior sorafenib, regardless of PD-L1 status.

Case 6

January 2017

The patient was a 74-year-old female with a history of HCV infection. She had prior treatment with interferon, achieving sustained virologic response. She had recurrence of HCV. A CT scan showed a 6.5-cm single liver mass with arterial enhancement, venous phase washout, and main portal vein invasion. Her ECOG performance status was 1. Her Child-Pugh class was A.

Therapy was initiated with sorafenib at 400 BID. The patient experienced grade 3 hand-foot skin reaction. The dose was reduced to 400 QD. The patient experienced grade 3 diarrhea. Her dose was reduced to 400 QOD.

April 2017

Follow-up scans show radiographic progression with lung metastases. The patient has preserved liver functions and a PS of 1.

Targeted Oncology: Is this patient a good candidate for regorafenib?

Kundranda:This is certainly not a patient that you would consider starting off with 160 mg of regorafenib. Is this a good candidate for regorafenib? Yes, based on the maintenance of this performance status and his hematological parameters the patient is certainly a good candidate for therapy. If regorafenib is initiated, the dose of regorafenib in this patient with these toxicities previously experience sorafenib would be between 80 to 120 QOD. This could be escalated based on tolerance.