This article is a commentary on:
Case Report: Lenvatinib for the treatment of recurrent hepatocellular carcinoma in people living with HIV: a report of two cases
Cuiming Sun
Ying Wen
Jin Zhou- 1The Second Department of Infectious Disease, The First Hospital of China Medical University, Shenyang, China
- 2Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital Institute, Cancer Hospital of Dalian University of Technology, Shenyang, China
A Commentary on
Case Report: Lenvatinib for the treatment of recurrent hepatocellular carcinoma in people living with HIV: a report of two cases
By Morsica G, Bertoni C, Hasson H, Messina E and Uberti Foppa C (2023). Front Oncol 13:1242741. doi: 10.3389/fonc.2023.1242741.
1 Introduction
Although higher HCC incidence risk was reported among people living with HIV (PLWH) compared to general population, it actually declined from 2001 to 2019 (1), especially among cases with tenofovir (TDF) usage (2). However, poor adherence to HCC screening (3), delayed HCC diagnosis (4) and scarce data about tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) (5) were observed among HIV/HBV or HIV/HCV patients.
The efficacy and tolerability of lenvatinib in treating HCC in PLWH were seldom reported. The recent publication of Morsica G et al, “Case Report: Lenvatinib for the treatment of recurrent HCC in people living with HIV: a report of two cases” firstly described the application of lenvatinib in two PLWH with unresectable HCC recurrence (6). We appreciated the authors for providing precious clinical experience. Whereas, there are several key issues deserved to be further addressed.
2 Commentary and discussion
Firstly, HIV-associated virological, immune status and integrase strand transfer inhibitors-containing anti-retroviral therapy (ART) regimens in these two reported cases did not cause negative impact on the efficacy, tolerability and drug-to-drug interactions of lenvatinib. Importantly, for these two cases, curative treatments for HCC with Barcelona Clinic Liver Cancer (BCLC) stage 0 were equally allocated according to HCC stage regardless of HIV status. HIV coinfection has no impact on the survival after diagnosis of HCC (7).
Secondly, lenvatinib related adverse events (AEs) in these two cases including uncontrolled hypertension and upper gastrointestinal bleeding should be discussed in detail. The common AEs of lenvatinib include hypertension, diarrhea, decreased appetite and weight, palmar-plantar erythrodysesthesia, and proteinuria, which usually occur in the first 1 to 2 months after lenvatinib treatment. In REFLECT trial, overall occurrence of hypertension in lenvatinib group was 42.2%, with grade≥ 3 hypertension occurring in 23.3% of patients, which was actually higher than sorafenib group (overall occurrence 30.3%, ≥ grade 3: 14.3%) (8). A total of ten real-world studies were literaturally reviewed (9), suggesting the tolerability and safety profile of lenvatinib were generally similar to that were seen in REFLECT trial. When detected early and managed appropriately, occurrence of hypertension did not impair the outcome of HCC patients treated with lenvatinib (10). Several studies showed in patients with liver transplantation (LT) receiving adjuvant lenvatinib treatment, incidence rate of hypertension was 42.9%-64.3% (11–13), consistent with the toxicity among non-LT HCC patients (8, 14–16). The available data about sorafenib treatment in PLWH showed its safety was similar to HIV-negative participants (17). Both lenvatinib and sorafenib are multikinase inhibitors, thus it is reasonable to speculate that the refractory hypertension was not ascribed to HIV infection in case 1.
HCC cases with cirrhosis increase the risk of bleeding from esophageal/gastric varices (EGV), which is a key concern in assessing the adoption of lenvatinib. The incidence of EGV bleeding was 3% in HCC patients treated with lenvatinib, with Child-Pugh B, portal vein thrombosis and platelet count <150,000/μl being the risk factors (18). It is necessary to perform gastroscopy to evaluate EGV status in these two cases before lenvatinib treatment because their platelet counts were <150,000/μl, though their Child-Pugh scores were level A. The level of albumin, prothrombin/international normalized ratio, and bilirubin in these two cases were relatively stable throughout 3-6 years of treatment, but liver function has limited value as a predictive biomarker for EVG. Other methods such as the new five-stage classification of liver cirrhosis might be better than Child-Pugh’s classification for EGV assessment (19). Furthermore, the stiffness measurement of the liver and spleen is also helpful in assessing portal hypertension or predicting variceal bleeding.
Thirdly, HCC progression was observed in case 1 after 6 months of lenvatinib, which suggested poor efficacy. In REFLECT trial, lenvatinib was shown to be non-inferior to sorafenib in overall survival in treating advanced HCC (8). In real-world studies, lenvatinib was superior to sorafenib in OS and PFS in patients with advanced HCC (20). The efficacy of lenvatinib in post-LT HCC recurrence patients was similar to non-LT HCC patients (12). The Blood concentration of FK506 was not influenced by lenvatinib (13). However, to decrease the risk for HCC recurrence post-LT, reducing the calcineurin inhibitors dosage, and combining or completely switching to the mammalian target of rapamycin inhibitors are the preferred immunosuppressor regimens (21). Late peritoneal metastasis with HCC recurrence (beyond 2 years post-transplant) happens sporadically, and peritoneal metastasectomy (without metastasis in other organs) or combining sorafenib was an effective therapy (22). HIV-positive or negative patients undergoing LT for HCC have comparable post-LT survival, while microvascular invasion, HCC diameter, and number of HCC nodules were predictors of recurrence post-LT (23). So far, radiofrequency ablation has no significant differences in OS between HIV-positive and HIV-negative patients (24).
Lastly, HCC survival prediction should be discussed. BCLC stage, decompensated cirrhosis, alpha-fetoprotein level, age, and radiological aggressiveness are associated with death. For cases with unresectable BCLC stage B HCC recurrence, noncurative treatments include trans-catheter arterial chemoembolization (TACE), trans-catheter arterial radioembolization, TKIs, and supportive care. The combination (sequential or alternating) of lenvatinib and TACE (even followed by conversion surgery), or regorafenib could be the beneficial therapeutic strategy (25). ICIs-based treatment should be considered as an alternative treatment after lenvatinib discontinuation. ICIs have been also evaluated in PLWH with advanced cancers including some HCC cases (26–28). When HCC progressed after lenvatinib treatment, regorafenib monotherapy (29) or regorafenib combined with PD-1 inhibitor (30), or atezolizumab plus bevacizumab (31), or nivolumab plus ipilimumab (32), could be the alternative options as the second-line therapy. However, for post-LT individuals, rejection incidence of ICIs and bleeding risk of antivascular targeted agents should be carefully assessed.
In conclusion, the efficacy and safety of lenvatinib in treating PLWH with HCC should be evidenced by increasing case reports and clinical trials. HCC treatment should be equally recommended in HIV-positive and HIV-negative individuals. Implementing HBV vaccination, adopting TDF-containing ART regimen, improving direct-acting-antivirals application, strengthening HCC surveillance and building a multidisciplinary team for PLWH are helpful in decreasing HCC incidence in PLWH, diagnosing HCC at earlier stages, and detecting HCC recurrence timely.
Author contributions
CS: Writing – original draft, Writing – review & editing. YW: Conceptualization, Supervision, Writing – original draft, Writing – review & editing. JZ: Conceptualization, Investigation, Writing – original draft, Writing – review & editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
1. McGee-Avila JK, Argirion I, Engels EA, O'Brien TR, Horner MJ, Qiao B, et al. Risk of hepatocellular carcinoma in people with HIV in the United States, 2001-2019. J Natl Cancer Inst. (2024) 116:61–8. doi: 10.1093/jnci/djad172
2. Lee MH, Wu PF, Chen TI, Chan C, Lin HH, Huang YH, et al. Tenofovir use is associated with a decreased risk of hepatocellular carcinoma among men with HIV irrespective of coinfection status. JHEP Rep. (2022) 5:100634. doi: 10.1016/j.jhepr.2022.100634
3. Willemse S, Smit C, Sogni P, Sarcletti M, Uberti-Foppa C, Wittkop L, et al. Low compliance with hepatocellular carcinoma screening guidelines in hepatitis B/C virus co-infected HIV patients with cirrhosis. J Viral Hepat. (2019) 26:1224–8. doi: 10.1111/jvh.13146
4. Kong L, Wei G, Lv T, Jiang L, Yang J, Zhao Y, et al. Outcome of TACE treatment in HIV infected patients with hepatocellular carcinoma. Sci Rep. (2021) 12:696. doi: 10.1038/s41598-020-80311-3
5. Negri F, Missale G, Antoni AD, Porta C. Hepatocellular cancer therapy in patients with HIV infection: Disparities in cancer care, trials enrolment, and cancer-related research. Transl Oncol. (2021) 14:101153. doi: 10.1016/j.tranon.2021.101153
6. Morsica G, Bertoni C, Hasson H, Messina E, Uberti Foppa C. Case Report: Lenvatinib for the treatment of recurrent hepatocellular carcinoma in people living with HIV: a report of two cases. Front Oncol. (2023) 13:1242741. doi: 10.3389/fonc.2023.1242741
7. Merchante N, Rodríguez-Fernández M, Figueruela B, Rodríguez-Arrondo F, Revollo B, Ibarra S, et al. Impact of HIV on the survival of hepatocellular carcinoma in hepatitis C virus-infected patients. AIDS. (2020) 34:1497–507. doi: 10.1097/QAD.0000000000002578
8. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. (2018) 391:1163–73. doi: 10.1016/S0140-6736(18)30207-1
9. Kim BH, Yu SJ, Kang W, Cho SB, Park SY, Kim SU, et al. Expert consensus on the management of adverse events in patients receiving lenvatinib for hepatocellular carcinoma. J Gastroenterol Hepatol. (2022) 37:428–39. doi: 10.1111/jgh.15727
10. Piscaglia F, Ikeda K, Cheng AL, Kudo M, Ikeda M, Breder V, et al. Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study. Cancer. (2024) 130(8):1281–91. doi: 10.1002/cncr.35185
11. Guo DZ, Cheng JW, Yan JY, Huang A, Wang YP, Zhang SY, et al. Efficacy and safety of lenvatinib for preventing tumor recurrence after liver transplantation in hepatocellular carcinoma beyond the Milan criteria. Ann Transl Med. (2022) 10:1091. doi: 10.21037/atm-22-1353
12. Bang K, Casadei-Gardini A, Yoo C, Iavarone M, Ryu MH, Park SR, et al. Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation. Cancer Med. (2023) 12:2572–9. doi: 10.1002/cam4.5123
13. Han B, Ding H, Zhao S, Zhang Y, Wang J, Zhang Y, et al. Potential role of adjuvant lenvatinib in improving disease-free survival for patients with high-risk hepatitis B virus-related hepatocellular carcinoma following liver transplantation: A retrospective, case control study. Front Oncol. (2020) 10:562103. doi: 10.3389/fonc.2020.562103
14. Wang DX, Yang X, Lin JZ, Bai Y, Long JY, Yang XB, et al. Efficacy and safety of lenvatinib for patients with advanced hepatocellular carcinoma: A retrospective, real-world study conducted in China. World J Gastroenterol. (2020) 26:4465–78. doi: 10.3748/wjg.v26.i30.4465
15. Shimose S, Iwamoto H, Niizeki T, Shirono T, Noda Y, Kamachi N, et al. Clinical significance of adverse events for patients with unresectable hepatocellular carcinoma treated with lenvatinib: A multicenter retrospective study. Cancers (Basel). (2020) 12:1867. doi: 10.3390/cancers12071867
16. Sho T, Suda G, Ogawa K, Kimura M, Shimazaki T, Maehara O, et al. Early response and safety of lenvatinib for patients with advanced hepatocellular carcinoma in a real-world setting. JGH Open. (2019) 4:54–60. doi: 10.1002/jgh3.12209
17. Merchante N, Ibarra S, Revollo B, Rodríguez-Arrondo F, Merino E, Delgado-Fernández M, et al. Real-life experience with sorafenib for the treatment of hepatocellular carcinoma in HIV-infected patients. AIDS. (2017) 31:89–95. doi: 10.1097/QAD.0000000000001293
18. Massimo I, Eleonora A, Toshifumi T, Shigeo S, Goki S, Changhoon Y, et al. Incidence and predictors of esophagogastric varices bleeding in patients with hepatocellular carcinoma in lenvatinib. Liver Cancer. (2023), 1–12. doi: 10.1159/000534127
19. D'Amico G, Morabito A, D'Amico M, Pasta L, Malizia G, Rebora P, et al. New concepts on the clinical course and stratification of compensated and decompensated cirrhosis. Hepatol Int. (2018) 12:34–43. doi: 10.1007/s12072-017-9808-z
20. Jaiswal V, Hameed M, Naz S, Roy P, Deb N, Ukrani J, et al. Efficacy of lenvatinib versus sorafenib in the primary treatment of advanced hepatocellular carcinoma: A meta-analysis. JGH Open. (2023) 7:832–40. doi: 10.1002/jgh3.12999
21. Rajendran L, Ivanics T, Claasen MP, Muaddi H, Sapisochin G. The management of post-transplantation recurrence of hepatocellular carcinoma. Clin Mol Hepatol. (2022) 28:1–16. doi: 10.3350/cmh.2021.0217
22. Alshahrani AA, Hwang S, Song GW, Moon DB, Jung DH, Ahn CS, et al. Management of very late peritoneal metastasis of hepatocellular carcinoma 10 years after liver transplantation: Lessons from two cases. Ann Hepatobiliary Pancreat Surg. (2018) 22:136–43. doi: 10.14701/ahbps.2018.22.2.136
23. Guerrini GP, Berretta M, Guaraldi G, Magistri P, Esposito G, Ballarin R, et al. Liver transplantation for HCC in HIV-infected patients: long-term single-center experience. Cancers (Basel). (2021) 13:4727. doi: 10.3390/cancers13184727
24. Micali C, Russotto Y, Caci G, Ceccarelli M, Marino A, Celesia BM, et al. Loco-regional treatments for hepatocellular carcinoma in people living with HIV. Infect Dis Rep. (2022) 14:43–55. doi: 10.3390/idr14010006
25. Oshita K, Kobayashi T, Namba Y, Fukuhara S, Matsubara K, Takei D, et al. Efficacy and safety of lenvatinib-transcatheter arterial chemoembolisation sequential therapy followed by surgical resection for intermediate-stage hepatocellular carcinoma beyond Up-to-7 criteria: a study protocol for a multicentre, single-arm, prospective study. BMJ Open. (2023) 13:e073797. doi: 10.1136/bmjopen-2023-073797
26. Uldrick TS, Gonçalves PH, Abdul-Hay M, Claeys AJ, Emu B, Ernstoff MS, et al. Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer-a phase 1 study. JAMA Oncol. (2019) 5:1332–9. doi: 10.1001/jamaoncol.2019.2244
27. Xiong Y, Mo P, Yan Y, Wang S, Zhuang K, Ma Z, et al. The safety and efficacy of PD-1 inhibitors in patients with advanced cancers and HIV/AIDS in China. Front Oncol. (2023) 13:1248790. doi: 10.3389/fonc.2023.1248790
28. El Zarif T, Nassar AH, Adib E, Fitzgerald BG, Huang J, Mouhieddine TH, et al. Safety and activity of immune checkpoint Inhibitors in people living with HIV and cancer: a real-world report from the cancer therapy using checkpoint inhibitors in people living with HIV-international (CATCH-IT) consortium. J Clin Oncol. (2023) 41:3712–23. doi: 10.1200/JCO.22.02459
29. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. (2017) 389:56–66. doi: 10.1016/S0140-6736(16)32453-9
30. Zhao J, Guo Y, Feng T, Rong D, Kong X, Huang T, et al. Efficacy and safety of regorafenib in combination with immune checkpoint inhibitor therapy as second-line and third-line regimen for patients with advanced hepatocellular carcinoma: a retrospective study. J Gastrointest Oncol. (2023) 14:2549–58. doi: 10.21037/jgo-23-590
31. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. (2020) 382:1894–905. doi: 10.1056/NEJMoa1915745
Keywords: lenvatinib, hepatocellular carcinoma, recurrence, people living with HIV (PLWH), adverse events (AEs) 1
Citation: Sun C, Wen Y and Zhou J (2024) Commentary: Case Report: Lenvatinib for the treatment of recurrent hepatocellular carcinoma in people living with HIV: a report of two cases. Front. Oncol. 14:1372745. doi: 10.3389/fonc.2024.1372745
Received: 18 January 2024; Accepted: 25 March 2024;
Published: 05 April 2024.
Edited by:
Pooja Jain, Drexel University, United StatesReviewed by:
Jiang Chen, Zhejiang University, ChinaDeGaulle I. Chigbu, Salus University, United States
Copyright © 2024 Sun, Wen and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ying Wen, wenying666466@163.com; Jin Zhou, zhoujin126@126.com
†These authors have contributed equally to this work