Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide with a rising incidence in the United States. BCLC B intermediate stage HCC, defined as patients with unresectable, liver-limited disease and preserved liver function, encompasses a broad range of patients with variable tumor size, number, and location.

Locoregional therapies (LRTs), including arterially-directed therapies, are the mainstay of treatment, and demonstrate an average survival benefit of approximately 2.5 years. However, the success of these interventions is challenging to characterize given the variability of techniques, patient eligibility, and the number of repeat treatment sessions.

For example, OPTIMIS (NCT01933945) was a real-world observational study of patients with unresectable HCC who underwent transarterial chemoembolization (TACE).

 Results from the study indicated that at the time of the inclusion visit, 39% of patients (n = 636) who underwent TACE were not eligible for this approach, deviating from practice guidelines. A total of 507 patients became TACE ineligible during the study; of those patients, 9% (n = 47) went on to receive systemic therapies like sorafenib (Nexavar) at the time of ineligibility, suggesting that TACE may be overutilized.

Of note, the study was conducted when sorafenib was the only FDA-approved systemic agent for patients with HCC, and so patients may have been overtreated when the alternative was long-term therapy with a considerable safety profile and limited efficacy. Additionally, although treatment-related mortality from LRT is less than 5%, complications include pancreatitis, cholecystitis, liver failure, and bone marrow suppression, all of which can potentially lead to patients being ineligible for systemic options.

With recent advances made in systemic therapies, redefining the management of patients with unresectable disease will be essential to improve outcomes. Recently, the combination of the an anti–PD-L1 antibody atezolizumab (Tecentriq) and the anti-VEGF antibody bevacizumab (Avastin) was evaluated in patients with unresectable HCC in the IMbrave150 trial (NCT03434379).

 Thirty-seven percent of patients on the trial had unresectable HCC without extrahepatic spread and 52% previously received local therapies.

The combination resulted in a 12-month overall survival rate of 67.2% (95% CI, 61.3%-73.1%) versus 54.6% with sorafenib (95% CI, 45.2%-64.0%), with an impressive objective response rate of 27.3% (95% CI, 22.5%-32.5%) versus 11.9% (95% CI, 7.4%-18.0%), respectively. The doublet also had a tolerable safety profile compared with sorafenib. Final analyses are pending, but this is the first trial in HCC to show a survival advantage with combination therapy in the first-line setting.

Based on the promising results of IMbrave150 trial, several ongoing trials are examining combination strategies. For example, the phase 3 LEAP-002 trial (NCT03713593) is evaluating lenvatinib (Lenvima) plus pembrolizumab (Keytruda), while the phase 3 HIMALAYA study (NCT03298451) is examining durvalumab (Imfinzi) plus tremelimumab in this population. Additionally, the phase 3 CheckMate-9DW trial (NCT04039607) is assessing nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with advanced disease, while the phase 3 COSMIC-312 trial (NCT03755791) is examining cabozantinib (Cabometyx) plus atezolizumab in these patients. If approved down the line by the FDA, there will be 5 first-line options beyond TKI monotherapy available for the treatment of patients with unresectable and advanced-stage HCC.

The treatment of HCC is evolving, and the effectiveness of combination systemic therapy may be comparable to LRT in patients with intermediate-stage HCC; however, this will need to be further investigated in controlled clinical trials where optimal patient selection can be explored. The IMbrave150 data show promise, and although LRT is considered to be standard practice, combination systemic therapies may be considered in the following scenarios:

Patients who have a high chance of residual disease post procedure (ie, large or multiple tumors, tumors that are difficult access)

Patients with a high chance of recurrence (ie, high alpha-fetoprotein, large multifocal bilobar tumors, and vascular invasion)

Patients who are considered to be refractory to LRT and maintain adequate liver function

Patients who could be downsized or bridged to surgery

Peck-Radosavljevic M, Kudo M, Raoul J-L, et al. Outcomes of patients (pts) with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE): Global OPTIMIS final analysis. 

. 2018;36(suppl 15):4018. doi:10.1200/JCO.2018.36.15_suppl.4018

Molinari M, Kachura JR, Dixon E, et al. Transarterial chemoembolism for advanced hepatocellular carcinoma: results from a North American cancer centre. 

. 2006;18(6):684-692. doi:10.1016/j.clon.2006.07.012

Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. 

. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

Articles

BCLC B intermediate stage hepatocellular carcinoma, defined as patients with unresectable, liver-limited disease and preserved liver function, encompasses a broad range of patients with variable tumor size, number, and location. 

Redefining BCLC B, Intermediate-Stage HCC: Is There a Role for Combination Systemic Therapy?

Gagandeep Brar, MD, assistant professor of medicine, Division of Hematologic and Medical Oncology, Weill Cornell Medicine, discusses the rise of new treatment approaches in hepatocellular carcinoma (HCC).

Prior to 2017, HCC was a challenging ​disease to treat, and ​patients had fairly dismal prognos​es, Brar says.

However, over the past 3 years, a host of new data and research ​efforts have emerged, Brar adds.

Notably, in light of new treatment options, patients with HCC are now experiencing prolonged survival and improved quality of life​, explains Brar.

Ultimately, ​these developments have been encouraging in HCC and additional efforts are underway to further advance the paradigm, Brar concludes.

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Gagandeep Brar, MD, discusses the rise of new treatment approaches in hepatocellular carcinoma. 

Dr. Brar on the Rise of New Treatment Approaches in HCC

Gagandeep Brar, MD, assistant professor of medicine, Division of Hematologic and Medical Oncology, Weill Cornell Medicine, discusses the need to identify biomarkers in hepatocellular carcinoma (HCC).

Currently, alpha-fetoprotein (AFP) is the only biomarker in HCC, Brar says. 

FGFR and MET appeared to be promising biomarkers, but were later found to be ineffective, explains Brar. 

As such, significant research is needed to develop biomarker-driven clinical trials, Brar adds.

Historically, when sorafenib (Nexavar) was the only available therapy for patients with HCC, biomarker research was not important because all patients received the same treatment, Brar explains.

As more treatment choices are introduced to the paradigm, developing biomarkers for each systemic therapy will become that much more important, concludes Brar.

Gagandeep Brar, MD, discusses the need to identify biomarkers in hepatocellular carcinoma.



Dr. Brar on the Need to Identify Biomarkers in HCC

I eagerly awaited the next patient to be put into a room. I had reviewed his large pile of medical records the night before and knew he was coming in to potentially enroll in a phase I/II clinical trial that was evaluating a new drug in patients with a specific actionable mutation. His tumor had developed this alteration as his metastatic disease worsened, which had already progressed through multiple lines of prior therapy. He came to us as a last resort.

As I walked into the room and greeted him and his wife, I vaguely caught a sense of anxiety but ignored it because I had more important things to discuss. After taking a history, which I already knew from the night before and upon finishing a complete physical exam, I launched into my usual sequence of discussion. I spoke about the natural history of this cancer type and what our trial entailed. I discussed that we didn’t know if this treatment would work or not, but the preclinical data were encouraging, and we were enrolling patients to determine dose and toxicity. I then went on to discuss the adverse effects (AEs) that we had seen thus far and, finally, ended with the overall poor prognosis of this disease. I then stated that if the treatment did not have the effect we were hoping for, altruistically enrolling into this trial could potentially help another patient in the future.

The patient nodded silently throughout my rehearsed monologue. His wife frantically wrote down notes without making eye contact, and I noted that her face was flushed and she was almost in tears. When asked if they had any questions, they both appeared overwhelmed, so I walked out of the room, passively stating that I would be back with the attending physician after we discussed his case. The patient ultimately enrolled onto our trial but over time, he progressed and died.

I reflect on this and similar patient interactions that I have encountered throughout my fellowship. On the one hand, I am on the cutting edge of research and have the opportunity to enroll patients into clinical trials involving experimental therapies, often stating that we are giving “tomorrow’s cure today.” I do believe that the future of oncology is now, and in my lifetime, I hope to see cancer cured.

On the other hand, I failed to truly recognize and understand the patients whom I treated. Somewhere during my short career, I had lost the ability to build genuine relationships with the person sitting in front of me. Sure, I knew everything about their oncologic history and the mechanisms behind tumorigenesis. I worked hard and long hours making sure each patient was properly cared for. I monitored for toxicities and managed AEs. But I knew nothing about a patient’s background, family, or values. I desensitized myself from my job. I later learned that this particular patient drove several hours to receive his treatment and had been laid off from work because of missed time. He had young children at home who did not know about his diagnosis or prognosis. His wife was barely able to cope with the unfortunate turn of events that had destabilized their livelihood, yet the patient remained stoic as a way to cope with his crumbling world.

I think this apathetic mentality develops as a coping method for oncologists when frequently exposed to death and dying. After all, we are people, too, each with set limitations of what we can psychologically handle. It is easy to keep patients at a distance and close ourselves off to feeling emotion when they die. It is overwhelming to open ourselves unconditionally and feel the effects of mortality on a regular basis. I used to think that oncologists were the “angels of death,” as patients often succumbed to their disease. I thought our role was simply to prolong life and, oftentimes, prolong suffering. This detachment led me astray from what my true focus should always have been— to help a person in need.

Learning from this case, we need to remember that building sincere and genuine patient—doctor relationships is just as important as treating their illness. We have a unique opportunity for a complete stranger to put their life in our hands, and we have the ability to provide comfort, hope, and assurance in a time of fear and doubt for a patient and their family. It isn’t easy, but remember that we are allowed to grieve. It’s not a failure or a fault to incorporate compassion with professionalism. Take time to get to know your patient and remember their life as they are. We treat people, not ID numbers.

Rachel Naomi Remen, MD, clinical professor of family and community medicine, University of California, San Francisco, School of Medicine has said: “The expectation that we can be immersed in suffering and loss daily and not be touched by it is as unrealistic as expecting to be able to walk through water without getting wet…We burn out not because we don’t care but because we don’t grieve.”

Gagandeep Brar, MD, reflects on patient interactions that she has encountered throughout her fellowship.

Gagandeep Brar, MD

Articles

Redefining BCLC B, Intermediate-Stage HCC: Is There a Role for Combination Systemic Therapy?

Dr. Brar on the Rise of New Treatment Approaches in HCC

Dr. Brar on the Need to Identify Biomarkers in HCC

Personalized Medicine in a Time of Depersonalized Patient-Doctor Relationships