Hepatocellular Carcinoma: Considerations for Managed Care Professionals

Abstract

Liver cancer is the most rapidly increasing cancer in the United States and is associated with a high cancer-related mortality. Seventy-five percent of liver cancers are hepatocellular carcinoma (HCC) resulting from cirrhosis. Patients are typically diagnosed late in the disease, with a relatively small percentage eligible for curative treatments. Despite the addition of several new therapies for advanced HCC, the 5-year survival rate is just 18%. The direct and indirect costs of HCC are substantial, and are expected to increase with the rise in disease incidence as well as a growing number of high-cost therapies entering the market. There are opportunities to improve the quality of care for patients with HCC through implementation of value-based reimbursement principles and pharmacist involvement in care.

Am J Manag Care. 2020;26:S220-S226. https://doi.org/10.37765/ajmc.2020.88513​

Introduction

Liver cancer is the most rapidly increasing cancer in the United States and is associated with a high cancer-related mortality.¹ Seventy-five percent of liver cancers are hepatocellular carcinoma (HCC), the consequence of high rates of hepatitis C virus, as well as increasing rates of nonalcoholic fatty liver disease.^1,2 Other risk factors include hepatitis B virus, type 2 diabetes, heavy alcohol consumption, and tobacco smoking.² There are recommendations provided for optimal screening of patients at high risk of developing HCC.³ Patients are typically diagnosed in the later stages of the disease, with just 5% or less eligible for resection at diagnosis.⁴ Even those diagnosed with early-stage disease have a 5-year survival rate of just 31%, with an overall 5-year relative survival rate of 18%.²

Patients with early-stage disease are eligible for surgical resection or liver transplantation. Other recommended options for locoregional disease include ablation, arterial directed therapies, and radiation. Systemic therapy with the immunotherapy combination regimen of atezolizumab plus bevacizumab, along with the tyrosine kinase inhibitors sorafenib or lenvatinib, are recommended as first-line treatment in later-stage patients, with newer systemic therapies and immunotherapies now available for second-line treatment.

Burden of HCC

HCC has a significant economic impact on both patients and payers in the United States.⁵ A recent systematic literature review of overall direct costs for patients with HCC found per-patient per-year (PPPY) costs ranged from $29,355 to $58,529, with median overall costs $176,456 per patient. Indirect costs related to lost productivity are estimated to be $3553 per patient.5 The biologic and immunotherapies used today to treat advanced HCC are associated with a high cost, although some have medication assistance programs to help mitigate copayments and coinsurance.^6-10

Literature shows the overall economic burden of treating HCC for patients with commercial insurance, Medicare, and for patients from the US Department of Veterans Affairs (VA). An analysis of treatment patterns and costs of care between 2008 and 2015 for 2285 patients with HCC with both commercial insurance and Medicare found total median costs after initial diagnosis to end of follow-up of $162,488, including patient out-of-pocket costs of $4431. Patient costs significantly increased over time at an average rate of 2% and payer costs at 3.4%, even adjusting for medical inflation.11 Factors contributing to increased costs included a higher number of concomitant medications (P <.001), longer time to first-line therapy (P = .0004), and commercial insurance (P = .01).¹¹

Many studies on the economic and medical outcomes of HCC come from the VA, which is the largest provider of liver cancer care in the country.¹² Results of a case-controlled study using data from the VA Corporate Data warehouse found the mean 3-year total cost in patients with HCC was $154,688 compared with $69,010 in matched controls with cirrhosis, driven by an increase in inpatient cost of care.¹³ Overall costs exceeded the typical 3-year expenses of veteran healthcare by an average of $129,500. Additionally, costs were higher for those undergoing liver transplant, with incremental costs of $422,007 versus controls and $396,735 versus patients with HCC not undergoing liver transplant. The estimated total costs for the US healthcare system for treating 40,000 cases of HCC in 2016 was $4.4 billion, with the total cost of care about $7.2 billion.¹³

There is a wide range of estimates of the overall economic burden resulting from the heterogeneity of populations studied.^5,11,13 Studies using Surveillance Epidemiology and End Results (SEER) Medicare data document elderly patients who may not receive more costly treatments such as liver transplantation, while several studies often cited in the literature were published before the advent of systemic treatments and immunotherapies.¹³

Economic Cost by Payer

There is evidence that the type of insurance affects not only the cost of care but also patient outcomes. A review of all-cause resource utilization in patients with chronic hepatitis B virus and HCC from 2005 to 2015 found total medical costs across all payer lines of business (ie, Medicare, Medicaid, commercial) of $271,544 (Table¹⁴), with most patients needing pharmacy coverage.

Much of the burden of HCC falls on Medicare, given the high rate of hepatitis C virus in this patient population. A systematic review of the epidemiology and burden of HCC in the United States found that Medicare covered 44% of inpatient visits with other visits covered by commercial insurers (27%), Medicaid (19%), and self-pay/other (10%).¹⁵

Indirect Costs

Indirect costs such as lost productivity due to treatment for both patients and caregivers must be considered in the expenses associated with HCC. A retrospective analysis specifically assessing productivity losses among patients and caregivers in the workforce with commercial or supplemental Medicare insurance found that 78.5% of patients used absence benefits, with an average of nearly 45 missed work hours per person per month (PPPM), at an estimated cost of $1424 PPPM. Nearly 90% of caregivers used absence benefits, with an average of 23 missed work hours PPPM, and an estimated $641 PPPM cost. About half of eligible patients (47.7%) and 17% of caregivers took short-term disability, accounting for $700 PPPM for patients and $61 PPPM for caregivers.¹⁶ Additionally, another study estimated indirect costs accounted for 10.8% ($49.1 million) of the $454.9 million in total costs for HCC incurred in 1999.¹⁷

Screening for HCC

Current guidelinesfrom both the National Comprehensive Cancer Network (NCCN) and American Association for the Study of Liver Diseases (AASLD) recommend semi-annual screening for HCC with ultrasound with or without α-fetoprotein (AFP) testing in patients at high risk, including those with cirrhosis or hepatitis B.^3,18 Data have shown that guideline-recommended screening for HCC is cost-effective, as it allows for potential earlier diagnosis of HCC and a higher probability of benefiting from curative treatment, leading to a potential positive impact on survival. In a Markov model simulating patients with a diagnosis of compensated cirrhosis, guideline-recommended surveillance was compared with real-life monitoring in patients with cirrhosis and HCC. The cost difference between the groups was $11,965 ($93,795 in gold-standard monitoring group vs $81,829 in the real-life monitoring group). Survival was increased by 0.37 years (7.18 vs 6.81 years), resulting in an incremental cost-effectiveness ratio (ICER) of $32,415 per life-years gained.¹⁹

An analysis of the economic burden and cost-effectiveness of surveillance found strong evidence of the cost-effectiveness of biannual surveillance with ultrasound in patients whose annual risk of HCC exceeded 0.8% to 1.5% a year. The cost-effectiveness continued even for patients at risk of HCC with a history of hepatitis C and ongoing cirrhosis.²⁰ Cost implications of surveillance frequencies have also been analyzed based on adherence to current hepatitis C virus and HCC surveillance rates in the VA health system: no surveillance, or surveillance with ultrasound every 3, 6, or 12 months at a willingness-to-pay threshold of $100,000.²¹ The preferred strategy was 3-month surveillance (ICER = $7159/quality-adjusted life-year [QALY]), resulting in a 16.44-year increase in life expectancy and a $180,000 decrease in cost per 1000 people screened, a 10.96-year increase for 6-month surveillance, $204,000 decrease in cost, and a 5.48-year increase for 12-month surveillance and $134,000 decrease in cost.²¹

Many patients with cirrhosis receive follow-up care with their primary care physician, which is a potential opportunity to identify and initiate appropriate HCC screening. However, a study of primary care physicians found 41.8% were not aware of current HCC surveillance guidelines, and approximately 30% reported that they did not consider such screening within their role, deferring surveillance to subspecialists who often used computed tomography or magnetic resonance imaging screening rather than the recommended ultrasound. The majority of primary care survey respondents (96.5%) requested more education about HCC and HCC surveillance. There are opportunities to improve screening through educating providers, including primary care physicians, of at-risk patients and the correct use of screening modalities, increase the use of reminders in the electronic health record, implement nurse-based protocols, and employ outreach interventions to patients.²²

Cost-Effectiveness of Current Treatments

NCCN recommends first-line therapy with sorafenib, lenvatinib, or combination atezolizumab and bevacizumab for the treatment of advanced HCC. Nivolumab with or without ipilimumab, ramucirumab, cabozantinib, regorafenib, sorafenib, or lenvatinib are supported by NCCN as second-line therapy in select patients with advanced HCC.³ Pembrolizumab has FDA approval in the second-line setting, with an NCCN category 2B recommendation, as there are no data showing benefit compared with placebo.^3,23,24

First-Line Therapies

Cost analyses have examined the use of both sorafenib and lenvatinib. In a Markov model, investigators looked at full or dose-adjusted sorafenib and transarterial chemoembolization (TACE), finding benefit for patients receiving drug therapy based on QALYs (0.435 and 0.482 for full and dose-adjusted sorafenib, respectively; 0.375 for TACE).²⁵ An analysis of Medicare beneficiaries with HCC from the SEER-Medicare database found that while those treated with sorafenib (n = 228) had significantly greater longevity at 150.5 days versus 62 days for controls, with a median survival among those with decompensated cirrhosis was just 31 days. Sorafenib was not cost-effective in patients with cirrhosis, suggesting sorafenib and possibly lenvatinib should be limited to those patients with a greater likelihood to benefit.²⁶

Additionally, in a systematic review of sorafenib comparing the drug to either best supportive care (BSC) or treatments such as TACE, transarterial radioembolization, or systemic chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), sorafenib was found to be more clinically effective than chemotherapy, concluding this may be a cost-effective treatment option.²⁷

In a simulation model comparing treatment with either sorafenib or lenvatinib in Canada, investigators found similar efficacy and a lower cost in those receiving lenvatinib in 64.9% of simulations. However, the availability of generic sorafenib in the future may impact these results.²⁸ Although there are no studies in the United States, there is literature showing potential for cost savings and increased QALY in those treated with lenvatinib compared with sorafenib in other countries.^29,30 At this time, there are no data available for the cost-effectiveness of combination atezolizumab and bevacizumab specifically in patients with HCC.

Second-Line Therapies

Second-line treatment options for advanced HCC include regorafenib, cabozantinib, ramucirumab, lenvatinib, nivolumab with or without ipilimumab, sorafenib, or pembrolizumab.³ There are limited cost data in patients with HCC with these agents, and available analyses have demonstrated a lack of cost-effectiveness with second-line therapies.

Regorafenib

Several studies conclude that regorafenib is not cost-effective in advanced HCC based on QALYs. In a Markov model of patients with advanced HCC with Child-Pugh class A cirrhosis and an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1, regorafenib provided an increase of 0.¹⁸ QALYs at a cost of $47,112, resulting in an ICER compared with BSC of $224,362.³¹ Additionally, another Markov model showed similar results, with an incremental gain of only about 20 weeks of life compared with placebo, resulting in an ICER for regorafenib compared with BSC between $201,797 and $268,506 per QALY.³² Parikh et al identified an ICER of $224,362 per QALY compared with BSC in several scenarios, which is far above willingness-to-pay thresholds between $50,000 and $200,000 per QALY. In addition, the authors suggested a need for greater individualization of therapy in patients most likely to benefit, given that regorafenib was cost-effective only in those with a survival benefit of 6 months or more.³¹

Cabozantinib

A cost-benefit analysis of cabozantinib assessed cost-effectiveness for a 28-day course of treatment at a cost of $9462 for the 36-mg daily dose and $15,858 with the 60-mg dose, resulting in an increased incremental gain of approximately 12 weeks. The total incremental cost of the drug plus treatment for adverse effects (AEs) was estimated to be $47,613 for the 36-mg daily dose and $76,406 for the 60-mg daily dose, resulting in an ICER between $292,496 and $469,374 per QALY.³³ The authors noted the cost-effectiveness could potentially be improved if reliable biomarkers or methods to identify patients most likely to benefit were available.^33,34

A Markov model of the cost-effectiveness of cabozantinib at a willing-to-pay threshold of $150,000 per QALY found an increase of 0.13 QALY and an ICER of $833,497 per QALY versus BSC. The authors noted a need for substantial discounts to meet the cost-effective threshold.³⁵ Another Markov model based on the CELESTRIAL trial data found a gain of 0.15 QALY compared with BSC at a mean cost per patient of $177,496 for cabozantinib and $4630 for BSC and incremental cost-effectiveness ratios of $972,049/LY and $1189,706/QALY.³⁶ An additional study performed a cost-threshold analysis, concluding that the maximum cost of cabozantinib would have to be $1500 per cycle ($50 per pill) to make it cost-effective at a willingness-to-pay threshold of $100,000 per QALY.³⁷

Ramucirumab

A cost-effectiveness model of ramucirumab also found no evidence of financial benefit in patients with advanced HCC and an AFP of at least 400 ng/mL who progressed on sorafenib, despite improved survival. The cost was $55,508 and generated only 0.54 QALYs, while placebo therapy had a lower cost of $761 with a similar QALY of 0.47. Treatment with ramucirumab led to an additional $54,747 in costs and 0.07 QALYs and an ICER of $782,104 per QALY. Based on this analysis, ramucirumab would be cost-effective at a price of $16.58 per 100 mg.³⁸

Immunotherapies

There are limited data on cost-effectiveness of immunotherapies such as pembrolizumab and nivolumab with or without ipilimumab in HCC. A study comparing pembrolizumab to regorafenib and cabozantinib in the second-line treatment of advanced HCC found pembrolizumab to be more cost-effective than the other therapies, using the single arm KEYNOTE-224 data for pembrolizumab. Regorafenib had incrementally higher costs of $6313 and cabozantinib of $7462 compared with pembrolizumab. Treatment with pembrolizumab also conferred additional life-years and QALY compared with regorafenib and cabozantinib (life-years, 0.12 and 0.07, respectively; QALYs, 0.08 and 0.03, respectively). However, the use of pembrolizumab data from the single-arm KEYNOTE-224 clinical trial limits the applicability of these results as data from the subsequent KEYNOTE-240 trial, not incorporated in this cost-effective analysis, failed to identify an overall survival benefit with pembrolizumab as compared with placebo^.24,39

Liver Transplantation

Current NCCN guidelines recommend liver transplantation in patients with early-stage disease who meet United Network for Organ Sharing criteria.³ In these patients, liver transplant appears cost-effective, particularly in those who do not need to wait more than 6 to 10 months for the transplant. Living donor liver transplant is also cost-effective at a $50,000 willingness-to-pay threshold if the wait list for deceased donor transplant exceeds 7 months.⁴⁰

Treatment Ambiguity

HCC is typically diagnosed late in the disease, when curative therapies are unlikely to be effective and many patients may not receive treatment.^12,41-43 One study found that among patients with early-stage HCC, 25% received potentially curative therapies, and 54% received palliative transarterial therapy. In those patients with a good performance status and potentially curable disease, 13% did not initiate active therapy. Other studies also find high rates of untreated patients.^41-43

There is heterogeneity in the use of newer systemic and immunotherapy drugs for advanced HCC.⁴⁴ A survey of 50 oncologists published in 2019 found differences in their approach to management. When deciding if a patient was a good candidate for systemic therapy, 74% focused on ECOG performance, 34% on Child-Pugh grading, and 18% on comorbidities. There were also differences in treatment of newly diagnosed patients with advanced HCC, with 38% initiating locoregional therapy before systemic therapy; and 20% conducting sequential locoregional therapy until recurrence.⁴⁴

Importantly, efficacy of the treatment regimen was ranked highest in the decision as to which approach to use (78%), with 34% citing affordability and 24% patient choice. The authors noted “understanding the comparative effectiveness of these new drugs, optimum sequencing, healthcare resource use and costs will be critical to their use in a patient centric and value-based healthcare delivery model.”⁴⁴

Value of Hospice Care

Patients with advanced HCC can have a high burden of symptoms attributed to cancer progression, toxicities of systemic therapies, and concomitant liver dysfunction. Hospice is a key component of quality end-of-life care. Sanoff and colleagues evaluated the extent of hospice use at end of life in a cohort of patients dying after diagnosis of HCC between 2004 and 2011 within the SEER-Medicare database. Of 7992 patients identified, just 14% received treatment with drug therapy or radiation, while the majority (51%) of patients never received treatment for HCC, speaking to the advanced nature of concomitant liver disease. Sixty-three percent of patients used hospice services before death, with a median time from first hospice claim to death of 18 days. The median survival from diagnosis was 1 month longer for hospice patients (9 months) versus no hospice (8 months). Those with a hospice claim were less likely to use hospital-based acute care services. The benefits of hospice enrollment were unmistakable, as hospice patients had fewer emergency department visits (6.1% vs 16.2%), hospital admissions (7.9% vs 47.8%), intensive care unit stays (2.8% vs 25.3%), and a lower risk of dying in the hospital (3.5% vs 58.4%).⁴⁵

Multispecialty Care Improves Outcomes

Managing patients with HCC is challenging for numerous reasons, including the late stage at diagnosis, degree of underlying liver dysfunction, patient comorbidities, and the growing number of treatment options with potential for significant AEs.^12,34,46 A multidisciplinary approach to individualized patient management is warranted to help guide treatment decisions and manage medications. An analysis of 3188 patients treated for HCC in the VA found that the use a multidisciplinary tumor board management (MDTB), guideline-recommended liver cancer surveillance, and management at academic medical centers were associated with higher 3-year costs but longer survival.¹³ Results of another study in a veteran population found that patients who received care at an academically affiliated VA hospital or receiving multispecialty evaluations were more likely to receive active HCC therapy. Those with subspecialist care within 30 days of diagnosis and an MDTB review were associated with reduced mortality.¹² Fragmented cancer care, defined as care received at more than 1 hospital, leads to worse outcomes, fewer active treatments, and greater time to treatment in patients with HCC, while care received at high-volume institutions has been shown to improve outcomes.⁴⁶

With the advent of oral chemotherapies, patient nonadherence has become a concern. Barriers to medication management include cost, AEs, and socioeconomic factors such as patient attitude and social support.⁴⁷ One study of patients with HCC treated with sorafenib and either commercial insurance or Medicare assessed adherence using a modified proportion of days covered measured with patient-specific sorafenib exposure from index date to treatment discontinuation. Investigators found that about a third of patients were nonadherent, with predictors of nonadherence including number of locoregional procedures, younger age, comorbid diagnoses, and concomitant medications.⁴⁸ A similar study in a veteran population also found about a 30% rate of nonadherence, with nonadherence associated with ethnicity and older age. Overall, there is also concern that the potential lack of patient understanding of adherence may impact overall outcomes.⁴⁹

Pharmacists play an important role on the multidisciplinary team, providing both patients and clinicians with evidence-based recommendations on medication use and AE management. Pharmacists can assist in medication adherence, identify and prevent drug interactions, and can educate patients and clinicians on potential AEs.⁵⁰ In a study of patients with HCC and other malignancies who were prescribed sorafenib or regorafenib, pharmacists called patients after initial medication education, assessing for AEs, and assisting with requests for ancillary medications or clinic referrals. Twenty-nine percent of the control group discontinued treatment compared with 13% of the intervention group, and 18% required dose reduction due to AEs compared with 13% in the intervention group. The intervention group had a 25% rate of treatment discontinuation and dose reduction due to AEs compared with 65% in the control group, showing that pharmacists have a positive impact on patient care.⁵¹

Biosimilar Opportunity

Although no studies are available assessing biosimilar bevacizumab products in HCC, there are data of cost-effectiveness of biosimilar bevacizumab or reference bevacizumab and chemotherapy for first-line advanced ovarian cancer. In one study, the impact of biosimilar bevacizumab was evaluated using a 30% price reduction over the reference product. Bevacizumab was not cost-effective when used according to the ICON-7 study protocol with an ICER of $225,515/QALY; however, biosimilar bevacizumab was cost-effective within this protocol in patients at high risk of progression with stage IV disease ($126,169/QALY), ECOG performance status of 1 ($116,575/QALY), and in those with suboptimal residual disease.⁵² Advances in cancer care become meaningless if patients cannot afford cancer treatment. The introduction of biosimilars on the market can positively impact patient access and improve the cost-effectiveness of complex therapies.⁵³

The NCCN endorses substitution of FDA-approved biosimilar bevacizumab in combination with atezolizumab in the first-line treatment of advanced HCC.3 Payers can reduce costs in HCC by supporting a biosimilar bevacizumab product over reference bevacizumab in combination with atezolizumab, leveraging step therapy to further steer toward the biosimilar, and develop medical policies with clear language stating the coverage criteria for biosimilar bevacizumab products in HCC to ease provider concerns over reimbursement.⁵³

Value-Based Healthcare in HCC

Given the rising costs in caring for patients with HCC, payers are adopting novel strategies to support value-based care. In performance-based contracts, payers reward oncologists based on quality indicators designed to improve outcomes and reduce costs in HCC, including rates of surveillance in individuals at high risk of HCC, high clinical pathway compliance with cost-effective evidence-based therapy, and reduced hospitalizations and emergency department visits.^12,54-56 Quality measurements for value-based care in HCC could also include medication adherence, guideline-compliant treatment, comprehensive medication review, and patient clinical status and satisfaction, all which pharmacists can assist with.⁵⁷ Other options include creating centers of excellence for the treatment of HCC, well-designed provider networks, and encouraging greater use of multidisciplinary tumor board management care.⁵⁷

Conclusions

There are opportunities to improve the quality of care for patients with HCC through optimal screening and medication management, in efforts to positively impact the total cost of care. Improvements in patient management are possible through coordination of care with the multidisciplinary team and engaging pharmacists to a greater degree through patient education and adherence monitoring. With the increasing costs of managing HCC, implementing value-based care strategies for this population offers a notable option for payer consideration.

Author affiliation: Laura Bobolts, PharmD, BCOP, is the senior vice president of Clinical Strategy and Growth, Oncology Analytics, Inc, Plantation, FL; clinical affiliate assistant professor, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL; and an adjunct assistant professor, Larkin University, College of Pharmacy, Miami, FL.

Funding source: This activity is supported by an educational grant from Genentech, a member of the Roche Group.

Author disclosure: Dr Bobolts has no relevant financial relationships with commercial interests to disclose.

Authorship information: Drafting of the manuscript and critical revision of the manuscript for intellectual content.

Address correspondence to: lbobolts@oncologyanalytics.com

Medical writing and editorial support provided by: Debra Gordon, MS, and Karina Abdallah, PharmD.

References

1. Pinheiro PS, Callahan KE, Jones PD, et al. Liver cancer: a leading cause of cancer death in the United States and the role of the 1945–1965 birth cohort by ethnicity. JHEP Rep. 2019;1(3):162-169. doi: 10.1016/j.jhepr.2019.05.008

2. American Cancer Society. Cancer Facts and Figures 2020.Accessed August 29, 2020.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf

3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Hepatobiliary cancers. Version 5.2020. Accessed August 29, 2020.

4. Saraswat VA, Pandey G, Shetty S. Treatment algorithms for managing hepatocellular carcinoma. J Clin Exp Hepatol. 2014;4(suppl 3):S80-S89. doi: 10.1016/j.jceh.2014.05.004

5. Kohn CG, Singh P, Korytowsky B, et al. Humanistic and economic burden of hepatocellular carcinoma: systematic literature review. Am J Manag Care. 2019;25(2 Spec No):SP61-SP73.

6. Siddiqui M, Rajkumar SV. The high cost of cancer drugs and what we can do about it. Mayo Clin Proc. 2012;87(10):935-943. doi: 10.1016/j.mayocp.2012.07.007

7. Grady D. Good news on early breast cancer: herceptin treatment can be shortened. New York Times. May 16, 2018. Accessed September 12, 2020. nytimes.com/2018/05/16/health/breast-cancer-herceptin-genentech.html

8. Patient Advocate Foundation. Hepatocellular carcinoma. Accessed July 16, 2020. copays.org/funds/hepatocellular-carcinoma/

9. Bayer provides financial support to eligible Nexavar (sorafenib) patients. Accessed July 16, 2020. www.nexavar-us.com/co-pay-assistance/

10. Association of Community Cancer Centers. Patient Assistance and Reimbursement Guide. Updated July 2020. Accessed July 16, 2020.

11. Hess L, Cui Z, Li X, Wu Y, Girvan A, Abada P. Treatment patterns and costs of care for patients diagnosed with hepatocellular carcinoma (HCC) in the United States (U.S.). Ann Oncol. 2018;29(suppl_5):mdy151.097. doi: 10.1093/annonc/mdy151.097

12. Serper M, Taddei TH, Mehta R, et al; VOCAL Study Group. Association of provider specialty and multidisciplinary care with hepatocellular carcinoma treatment and mortality. Gastroenterology. 2017;152(8):1954-1964. doi: 10.1053/j.gastro.2017.02.040

13. Kaplan DE, Chapko MK, Mehta R, et al; VOCAL Study Group. Healthcare costs related to treatment of hepatocellular carcinoma among veterans with cirrhosis in the United States. Clin Gastroenterol Hepatol. 2018;16(1):106-114.e105. doi: 10.1016/j.cgh.2017.07.024

14. Nguyen MH, Burak Ozbay A, Liou I, et al. Healthcare resource utilization and costs by disease severity in an insured national sample of US patients with chronic hepatitis B. J Hepatol. 2019;70(1):24-32. doi: 10.1016/j.jhep.2018.09.021

15. Aly A, Ronnebaum S, Patel D, Doleh Y, Concha-Benavente F. Epidemiology, economic burden, and humanistic burden among patients with hepatocellular carcinoma in the United States: a systematic literature review. Paper presented at: Academy of Managed Care Pharmacy; April 21-24, 2020.

16. Aly A, Malangone-Monaco E, Noxon V, Henriques C, Benavente F. Productivity loss costs among hepatocellular carcinoma patients and caregivers in a commercially-insured population in the United States. Paper presented at: Academy of Managed Care Pharmacy; April 23, 2020.

17. Lang K, Danchenko N, Gondek K, Shah S, Thompson D. The burden of illness associated with hepatocellular carcinoma in the United States. J Hepatol. 2009;50(1):89-99. doi: 10.1016/j.jhep.2008.07.029

18. Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Clin Liver Dis (Hoboken). 2019;13(1):1-1.

19. Cadier B, Bulsei J, Nahon P, et al; ANRS CO12 CirVir and CHANGH groups. Early detection and curative treatment of hepatocellular carcinoma: a cost-effectiveness analysis in France and in the United States. Hepatology. 2017;65(4):1237-1248. doi: 10.1002/hep.28961

20. Lidofsky SD. Screening for hepatocellular carcinoma in cirrhosis: challenges and unresolved issues. Gastroenterology. 2019;156(4):1217-1218. doi: 10.1053/j.gastro.2018.11.068

21. Uyei J, Taddei TH, Kaplan DE, Chapko M, Stevens ER, Braithwaite RS. Setting ambitious targets for surveillance and treatment rates among patients with hepatitis C related cirrhosis impacts the cost-effectiveness of hepatocellular cancer surveillance and substantially increases life expectancy: a modeling study. PLoS One. 2019;14(8):e0221614. doi: 10.1371/journal.pone.0221614

22. Simmons OL, Feng Y, Parikh ND, Singal AG. Primary care provider practice patterns and
barriers to hepatocellular carcinoma surveillance. Clini Gastroenterol Hepatol. 2019;17(4):766-773. doi: 10.1016/j.cgh.2018.07.029

23. Keytruda. Prescribing information. Merck & Co, Inc; June 2020. Accessed September 13, 2020. merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf

24. Finn RS, Ryoo BY, Merle P, et al; KEYNOTE-240 investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38(3):193-202. doi: 10.1200/JCO.19.01307

25. Chen S, Peng Z, Wei M, et al. Sorafenib versus transarterial chemoembolization for advanced-
stage hepatocellular carcinoma: a cost-effectiveness analysis. BMC Cancer. 2018;18(1):392.
doi: 10.1186/s12885-018-4308-7

26. Parikh ND, Marshall VD, Singal AG, et al. Survival and cost-effectiveness of sorafenib therapy in advanced hepatocellular carcinoma: an analysis of the SEER-Medicare database. Hepatology. 2017;65(1):122-133. doi: 10.1002/hep.28881

27. Motevalli MH, Peiravian F, Taheri S. Cost-effectiveness of sorafenib for hepatocellular carcinoma: a systematic review. Phar Pharm Res Open Acc J. 2019;1(1):14-21.

28. Kim JJ, McFarlane T, Tully S, Wong WW. Lenvatinib versus sorafenib as first-line treatment of unresectable hepatocellular carcinoma: a cost-utility analysis [published online ahead of print, November 20, 2019 ]. Oncologist. 2019;theoncologist.2019-0501. doi: 10.1634/theoncologist.2019-0501

29. Kobayashi M, Kudo M, Izumi N, et al. Cost-effectiveness analysis of lenvatinib treatment for patients with unresectable hepatocellular carcinoma (uHCC) compared with sorafenib in Japan. J Gastroenterol. 2019;54(6):558-570. doi: 10.1007/s00535-019-01554-0

30. Cai H, Zhang L, Li N, Zheng B,Liu M. Lenvatinib versus sorafenib for unresectable hepatocellular carcinoma: a cost-effectiveness analysis. J Comp Eff Res. 2020;9(8):553-562. doi: 10.2217/cer-2020-0041

31. Parikh ND, Singal AG, Hutton DW. Cost effectiveness of regorafenib as second-line therapy for patients with advanced hepatocellular carcinoma. Cancer. 2017;123(19):3725-3731. doi: 10.1002/cncr.30863

32. Shlomai A, Leshno M, Goldstein DA. Regorafenib treatment for patients with hepatocellular carcinoma who progressed on sorafenib—a cost-effectiveness analysis. PLoS One. 2018;13(11):e0207132. doi: 10.1371/journal.pone.0207132

33. Shlomai A, Leshno M, Goldstein DA. Cabozantinib for patients with advanced hepatocellular carcinoma: a cost-effectiveness analysis. Therap Adv Gastroenterol. 2019;12:1756284819878304. doi: 10.1177/1756284819878304

34. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63. doi: 10.1056/NEJMoa1717002

35. Liao W, Huang J, Hutton D, et al. Cost-effectiveness analysis of cabozantinib as second-line therapy in advanced hepatocellular carcinoma. Liver Int. 2019;39(12):2408-2416. doi: 10.1111/liv.14257

36. Sieg M, Hartmann M, Settmacher U, Arefian H. Comparative cost-effectiveness of cabozantinib as second-line therapy for patients with advanced hepatocellular carcinoma in Germany and the United States. BMC Gastroenterol. 2020;20(1):120. doi: 10.1186/s12876-020-01241-y

37. Soto-Perez-de-Celis E, Anguiar PN, Cordon ML, Chavarri-Guerra Y, de Lima Lopes, G. Cost-effectiveness of cabozantinib in the second-line treatment of advanced hepatocellular carcinoma. J Natl Compr Canc Netw. 2019;17(6):669-675. doi: 10.6004/jnccn.2018.7275

38. Zheng H, Qin Z, Qiu X, Zhan M, Wen F, Xu T. Cost-effectiveness analysis of ramucirumab treatment for patients with hepatocellular carcinoma who progressed on sorafenib with α-fetoprotein concentrations of at least 400 ng/ml. J Med Econ. 2020;23(4):347-352. doi: 10.1080/13696998.2019.1707211

39. Upadhyay N, Mistry R, Suri G, Phelps H, Guest S, Muston D. US cost-effectiveness of pembrolizumab compared to regorafenib and cabozantinib in second line treatment of advanced hepatocellular carcinoma. Value Health. 2019;22(suppl 2):S73-S74. doi: 10.1016/j.jval.2019.04.220

40. Likhitsup A, Parikh ND. Economic implications of hepatocellular carcinoma surveillance and treatment: a guide for clinicians. Pharmacoeconomics. 2020;38(1):5-24. doi: 10.1007/s40273-019-00839-9

41. Khalaf N, Ying J, Mittal S, et al. Natural history of untreated hepatocellular carcinoma in a US
cohort and the role of cancer surveillance. Clin Gastroenterol Hepatol. 2017;15(2):273-281.e271. doi: 10.1016/j.cgh.2016.07.033

42. Shaya FT, Breunig IM, Seal B, Mullins CD, Chirikov VV, Hanna N. Comparative and cost effectiveness of treatment modalities for hepatocellular carcinoma in SEER-Medicare. Pharmacoeconomics. 2014;32(1):63-74. doi: 10.1007/s40273-013-0109-7

43. Devaki P, Wong RJ, Marupakula V, et al. Approximately one-half of patients with early-stage hepatocellular carcinoma meeting Milan criteria did not receive local tumor destructive or curative surgery in the post-MELD exception era. Cancer. 2014;120(11):1725-1732. doi: 10.1002/cncr.28639

44. Klink A, Marshall A, Gricar J, et al. physician treatment choice in treating and managing patients with advanced hepatocellular carcinoma in U.S. community oncology practices. J Manag Care Spec Pharm. 2019;25:S-25.

45. Sanoff HK, Chang Y, Reimers M, Lund JL. Hospice utilization and its effect on acute care needs at the end of life in Medicare beneficiaries with hepatocellular carcinoma. J Oncol Pract. 2017;13(3):e197-e206. doi: 10.1200/JOP.2016.017814

46. Hester CA, Karbhari N, Rich NE, et al. Effect of fragmentation of cancer care on treatment use and survival in hepatocellular carcinoma. Cancer. 2019;125(19):3428-3436. doi: 10.1002/cncr.32336

47. Schneider SM, Hess K, Gosselin T. Interventions to promote adherence with oral agents. Semin Oncol Nurs. 2011;27(2):133-141. doi: 10.1016/j.soncn.2011.02.005

48. Mallick R, Cai J, Wogen J. Predictors of non-adherence to systemic oral therapy
for advanced hepatocellular carcinoma. Curr Med Res Opin. 2013;29(12):1701-1708.
doi: 10.1185/03007995.2013.842161

49. Malhotra S, Wu DP-H, Park Y-HA. National data on sorafenib therapy adherence for veterans with hepatocellular carcinoma. J Clin Oncol. 2015;33(15_suppl):9593-9593. doi: 10.1200/jco.2015.33.15_suppl.9593

50. Ma C. Role of pharmacists in optimizing the use of anticancer drugs in the clinical setting. Integrated Pharm Res Pract. 2014;3:11-24.

51. Nix R, Looney B, Lamb C, Peter M, Zuckerman A. A targeted approach to reducing rates of discontinuation and dose reduction in patients receiving sorafenib or regorafenib. J Drug Assess. 2019;8(suppl 1):30.

52. Mehta DA, Hay JW. Cost-effectiveness of adding bevacizumab to first line therapy for patients with advanced ovarian cancer. Gynecol Oncol. 2014;132(3):677-683. doi: 10.1016/j.ygyno.2014.01.021

53. Manolis CH, Rajasenan K, Harwin W, McClelland S, Lopes M, Farnum C. Biosimilars: opportunities to promote optimization through payer and provider collaboration. J Manag Care Spec Pharm. 2016;22(9 suppl):S3-S9. doi: 10.18553/jmcp.2016.22.9-a.s3

54. Strazzabosco M, Allen JI, Teisberg EO. Value-based care in hepatology. Hepatology. 2017;65(5):1749-1755. doi: 10.1002/hep.29042

55. Molina G, Qadan M. Addressing fragmentation of care requires strengthening of health systems and cross-institutional collaboration. Cancer. 2019;125(19):3296-3298. doi: 10.1002/cncr.32337

56. Newcomer LN. The problem of cancer drug costs. Cancer J. 2020;26(4):287-291. doi: 10.1097/PPO.0000000000000456

57. Pharmacy Quality Alliance. Strategies to Expand Value-Based Pharmacist-Provided Care Action Guide. 2018. Accessed September 13, 2020. pqaalliance.org/pharmacist-provided-care