Letters To The Editor
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 7, 2017; 23(13): 2448-2452
Published online Apr 7, 2017. doi: 10.3748/wjg.v23.i13.2448
Tumor biopsy and patient enrollment in clinical trials for advanced hepatocellular carcinoma
Lorenza Rimassa, Maria Reig, Giovanni Abbadessa, Markus Peck-Radosavljevic, William Harris, Vittorina Zagonel, Davide Pastorelli, Elena Rota Caremoli, Camillo Porta, Nevena Damjanov, Hitendra Patel, Bruno Daniele, Maria Lamar, Brian Schwartz, Terri Goldberg, Armando Santoro, Jordi Bruix
Lorenza Rimassa, Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, 20089 Rozzano, Italy
Maria Reig, Jordi Bruix, Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, 08036 Barcelona, Spain
Giovanni Abbadessa, Maria Lamar, Brian Schwartz, Clinical Development, ArQule, Inc, Burlington, MA 01803, United States
Markus Peck-Radosavljevic, Department of Gastroenterology, Hepatology, Endrocrinology, and Nephrology, Klinikum Klagenfurt am Wörthersee, 9020 Klagenfurt, Austria
William Harris, Department of Medicine, Oncology Division, University of Washington School of Medicine, Seattle, WA 98195, United States
Vittorina Zagonel, Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology-IRCCS, 35128 Padua, Italy
Davide Pastorelli, Department of Oncology, Santa Maria del Prato Hospital, 32032 Feltre, Italy
Elena Rota Caremoli, Department of Oncology, Papa Giovanni XXIII Hospital, 24125 Bergamo, Italy
Camillo Porta, Department of Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
Nevena Damjanov, Division of Gastrointestinal Oncology, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA 19104, United States
Hitendra Patel, Department of Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724, United States
Bruno Daniele, Department of Oncology, G. Rummo Hospital, Via Dell’Angelo, 82100 Benevento, Italy
Terri Goldberg, Clinical Development, Daiichi Sankyo, Edison, NJ 08837, United States
Armando Santoro, Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy
Author contributions: Rimassa L, Reig M, Abbadessa G, Santoro A and Bruix J wrote the manuscript; Peck-Radosavljevic M, Harris W, Zagonel V, Pastorelli D, Rota Caremoli E, Porta C, Damjanov N, Patel H, Daniele B, Lamar M, Schwartz B and Goldberg T contributed to the preparation, editing, and final approval of the manuscript.
Conflict-of-interest statement: Authors report no conflict of interest with the subject discussed in this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Lorenza Rimassa, Deputy Director, Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Italy. lorenza.rimassa@cancercenter.humanitas.it
Telephone: +39-2-82244573 Fax: +39-2-82244590
Received: January 20, 2017
Peer-review started: January 22, 2017
First decision: February 10, 2017
Revised: February 24, 2017
Accepted: March 15, 2017
Article in press: March 15, 2017
Published online: April 7, 2017

Abstract

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma (HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

Key Words: Liver neoplasms, Biopsy, Biomarkers, Clinical trial, Tumor

Core tip: Despite the extensive research conducted in the last two decades, still only two agents have shown positive results in phase III clinical trials for advanced hepatocellular carcinoma, and clinicians have no way to predict which patient population will benefit more. Biomarker research and well-run clinical trials require biopsies and a multidisciplinary approach to manage patients with hepatocellular carcinoma.



TO THE EDITOR

Liver cancer was estimated to be responsible for almost 746000 deaths worldwide in 2012 (WHO), with hepatocellular carcinoma (HCC) being the most common type[1]. Sorafenib, a multi-targeted tyrosine kinase inhibitor (TKI), is the only approved first-line systemic therapy for HCC[2,3]. Recently regorafenib, a similar multi-targeted TKI, was shown to benefit HCC patients who tolerated and progressed on sorafenib[4]. It is still unclear which patient sub-populations may benefit more from these drugs although interestingly, development of dermatological adverse events and AFP decrease during treatment may be associated with improved outcomes on sorafenib[5,6].

Many efforts to develop new therapies for unselected HCC populations have failed: in first-line, sunitinib[7], brivanib[8], linifanib[9] when compared to sorafenib; and erlotinib[10] and doxorubicin[11] in combination with sorafenib; in second-line, brivanib[12], everolimus[13], ramucirumab[14], and ADI-PEG 20[15]. Studies looking for alternative approaches for HCC, such as immunotherapy, are ongoing[16,17].

While for other solid tumors prognostic and predictive molecular biomarkers are already used in clinical practice, for HCC biomarker research has not produced conclusive results[18-20]. The many disappointing clinical trial failures due to excessive toxicity, lack of efficacy, study design problems, or lack of biological population enrichment, emphasize the need to identify predictive molecular biomarkers for selection of treatment in patients with HCC.

Circulating biomarker analyses from the sorafenib approval study suggested that the angiogenesis biomarkers angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF) were independent prognostic factors, while none of the tested biomarkers were predictive of sorafenib efficacy[21]. On the contrary, on the basis of positive efficacy and biomarker results in tumor MMNG HOS transforming gene (MET)-High patients in a randomized phase II study[22,23], tivantinib has been tested in two phase III studies selecting only MET-High patients, one in western countries and the other in Japan (NCT01755767, NCT02029157); while the study in the western world has recently been announced to be negative[24], results are still awaited for the Japanese study. Recently, second-line ramucirumab was shown to offer a significant survival benefit in a pre-specified subgroup of patients with elevated alpha-fetoprotein (AFP)[14] and a confirmatory phase III clinical trial is ongoing in this sub-population (NCT02435433).

Challenges of enrolling patients into clinical trials for second-line HCC

Most patients with advanced, unresectable HCC who are eligible for clinical trials with systemic therapies have a relatively short life expectancy, with rapid progression of disease, especially if they have progressed on sorafenib and have distant metastases[25,26]. To optimize timely and proper recommendations for the care of these patients, their cases should be discussed periodically by multidisciplinary teams including medical oncologists, gastroenterologists/hepatologists, surgeons, interventional radiologists, radiation oncologists, and pathologists. Such meetings would ideally take place weekly, or every two weeks: a longer delay of the proper therapeutic decision may undermine the possibilities of trial enrolment for patients.

Patients who are not followed in research centers may find it challenging to seek further treatment options, other than best supportive care, after failing standard treatments. On the other hand, many physicians have difficulties in identifying proper patients for second line clinical trials. Set up of webpages listing available clinical trials, and of inter-hospital networks to prime referrals for research studies can provide a key support to reduce the gap time for the comprehensive evaluation of these patients and speed up recruitment. Considering all this, with due exceptions, the best hospitals to involve in clinical trials for second-line HCC and to refer these patients to seem to be the larger academic centers, where HCC care is jointly pursued by at least oncologists and hepatologists.

Finally, study characteristics can make a difference in enabling trial enrolment, and involvement of active investigators from multiple relevant disciplines in the early phases of the protocol design can be beneficial to the scope.

Importance of analyzing tumor biomarkers to guide development of novel therapies

Analyzing HCC tumor specimens is essential to improve the knowledge about development, biology underpinning progression and treatment of HCC. Particularly, clarifying the tumor biology may lead to identifying biomarkers that would predict response or resistance to therapies.

Hepatology guidelines recommend that the diagnosis of HCC may be established via radiographic studies in the appropriate patient population[27], therefore not all patients with hepatic tumors have available biopsy material allowing for molecular profiling of their disease, at diagnosis. Furthermore, as tumors progress, they accumulate genetic alterations developing heterogeneity and drug resistance[28]. Studies suggest that VEGF pathway inhibition, as with sorafenib, produces a hypoxic microenvironment with oxidative stress that selects for highly aggressive, invasive tumor cells driving overexpression of proliferation factors, HCC progression, and induction of an immunosuppressive microenvironment[29,30]. Therefore, if in the future any molecular classifiers have an impact in clinical decision making, routine biopsy will become part of the standard of care. Considering the current treatment landscape, it seems rationale to biopsy patients with the purpose of including them in research studies. In the advanced disease setting, the risks associated with biopsy are minimal: seeding is rare and its consequences are irrelevant given the dismal prognosis of these patients, while bleeding is extremely rare especially if biopsy is conducted at an expert center with appropriate precautions particularly for superficial lesions. Considering the above and the general worsening of condition for many patients failing sorafenib, biopsies need to be planned ahead of time and be performed right at progression on sorafenib in order to be useful for trial enrolment.

Adequacy of tumor samples is a practical problem for clinical trials: shipment of not enough slides, or slides not containing enough tumor, causes unnecessary and significant delays to patient enrolment, particularly for patients from referring centers.

A core needle biopsy may be preferred to fine needle aspirates to provide quantitatively and qualitatively adequate material for running biological analyses on the sample. The procedure needs to take enough tumor material for at least 7-10 slides, the minimum generally needed for patient evaluation in clinical trial protocols. Slides from paraffin-embedded samples need to be unstained to allow immunohistochemistry testing. The operator performing the biopsy needs to be informed that the sample is being taken not only for diagnostic but also for biological assessments, and the pathologist needs to verify that all provided slides include sufficient tumor quantities.

A number of targeted agents are being tested in phase III clinical trials in first- or second-line HCC: nivolumab [first line, anti-programmed cell-death protein 1 (PD1) antibody], tivantinib (second line, MET inhibitor), cabozantinib (second line, VEGF-MET inhibitor), ramucirumab (second line, anti-VEGF antibody), and pembrolizumab (second line, anti-PD1 antibody). While only tivantinib (in tumor MET-High patients) and ramucirumab (in circulating AFP-High patients) are being tested in biomarker-selected patient populations, other trials are collecting tumor tissue for biomarker analyses as secondary study endpoint, emphasizing the importance of tumor tissue biopsies for patients to be enrolled in clinical trials.

In conclusion, since the approval of sorafenib in first-line, while recent data demonstrated benefit of lenvatinib (VEGFR inhibitor) in first-line[31] and regorafenib in second-line setting, ten phase III studies in HCC were negative including sunitinib, linifanib, brivanib (first and second line), ramucirumab, everolimus, ADI-PEG 20, erlotinib (in combination with sorafenib), doxorubicin (in combination with sorafenib), and tivantinib (in western patients). All these studies were conducted in unselected patient populations, except the tivantinib one.

If the research community was able to bring targeted therapies to late stage development with solid preclinical and clinical rationale to select patient populations based on the drug target, success rate might increase and adverse events would be avoided to patient populations estimated not to benefit from the experimental drug. Biological understanding of the treated population can be relevant even in trials where the target expression is not used as an entry criterion, providing key information to design subsequent target-selected studies. The historically low rates of biopsy confirmation of patients with HCC has presented a barrier to development of experimental therapeutics in this disease. With such frail patient population, multidisciplinary case discussions and inter-hospital networks can enable a seamless transition from standard care to tumor biology analysis for a clinical trial. Hopefully, as more targeted therapies are developed, the biological characteristics of tumors, including histology and more specific molecular markers, will be evaluated in the therapeutic decision process for HCC patients as currently occurs for other tumor types.

ACKNOWLEDGMENTS

We thank Hazem Hallak (CHEMC Global llc, Philadelphia, PA, United States) for his medical editorial assistance, and Kathleen Farren (ArQule) for her editorial assistance.

Footnotes

Manuscript source: Unsolicited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Italy

Peer-review report classification

Grade A (Excellent): A

Grade B (Very good): B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Gkretsi V, Varona MA S- Editor: Qi Y L- Editor: A E- Editor: Zhang FF

References
1.  Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87-108.  [PubMed]  [DOI]
2.  Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390.  [PubMed]  [DOI]
3.  Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25-34.  [PubMed]  [DOI]
4.  Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V. 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.  [PubMed]  [DOI]
5.  Reig M, Torres F, Rodriguez-Lope C, Forner A, LLarch N, Rimola J, Darnell A, Ríos J, Ayuso C, Bruix J. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol. 2014;61:318-324.  [PubMed]  [DOI]
6.  Personeni N, Bozzarelli S, Pressiani T, Rimassa L, Tronconi MC, Sclafani F, Carnaghi C, Pedicini V, Giordano L, Santoro A. Usefulness of alpha-fetoprotein response in patients treated with sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2012;57:101-107.  [PubMed]  [DOI]
7.  Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, Chung HC, Song X, Xu J, Poggi G. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31:4067-4075.  [PubMed]  [DOI]
8.  Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31:3517-3524.  [PubMed]  [DOI]
9.  Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, Kudo M, Kang YK, Chen PJ, Toh HC. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33:172-179.  [PubMed]  [DOI]
10.  Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, Bruix J, Qin S, Thuluvath PJ, Llovet JM. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33:559-566.  [PubMed]  [DOI]
11.  Abou-Alfa G, Niedzwieski D, Knox J, Kaubisch A, Posey J, Tan BR, Kavan P, Goel R, Murray JJ, Bekaii-Saab TS. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). Gastrointestinal Cancers Symposium; 2016, Jan 21-23; San Francisco, CA, USA. J Clin Oncol. 2016;34:192.  [PubMed]  [DOI]
12.  Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013;31:3509-3516.  [PubMed]  [DOI]
13.  Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, Poon RT, Blanc JF, Vogel A, Chen CL. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014;312:57-67.  [PubMed]  [DOI]
14.  Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16:859-870.  [PubMed]  [DOI]
15.  Abou-Alfa GK, Qin S, Ryoo BY, Lu SN, Yen CJ, Feng YH, Lim HY, Izzo F, Colombo M, Sarker D. Phase III randomized study of second line ADI-peg 20 (A) plus best supportive care versus placebo (P) plus best supportive care in patients (pts) with advanced hepatocellular carcinoma (HCC). ASCO Annual Meeting; 2016 June 3-6; Chicago, IL, USA. J Clin Oncol. 2016;34:4017.  [PubMed]  [DOI]
16.  El-Khoueiry AB, Sangro B, Cheung Yau T, Crocenzi TS, Hobart Welling T, Yeo W, Chopra A, Anderson J, Dela Cruz CM, Lang L. Phase I/II safety and antitumor activity of nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): Interim analysis of the CheckMate-040 dose escalation study. ASCO Annual Meeting; 2016 June 3-6; Chicago, IL, USA. J Clin Oncol. 2016;34:4012.  [PubMed]  [DOI]
17.  Gong XL, Qin SK. Progress in systemic therapy of advanced hepatocellular carcinoma. World J Gastroenterol. 2016;22:6582-6594.  [PubMed]  [DOI]
18.  Bruix J, Han KH, Gores G, Llovet JM, Mazzaferro V. Liver cancer: Approaching a personalized care. J Hepatol. 2015;62:S144-S156.  [PubMed]  [DOI]
19.  Niu ZS, Niu XJ, Wang WH. Genetic alterations in hepatocellular carcinoma: An update. World J Gastroenterol. 2016;22:9069-9095.  [PubMed]  [DOI]
20.  Scaggiante B, Kazemi M, Pozzato G, Dapas B, Farra R, Grassi M, Zanconati F, Grassi G. Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials. World J Gastroenterol. 2014;20:1268-1288.  [PubMed]  [DOI]
21.  Llovet JM, Peña CE, Lathia CD, Shan M, Meinhardt G, Bruix J. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18:2290-2300.  [PubMed]  [DOI]
22.  Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, Van Vlierberghe H, Trojan J, Kolligs FT, Weiss A. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14:55-63.  [PubMed]  [DOI]
23.  Rimassa L, Abbadessa G, Personeni N, Porta C, Borbath I, Daniele B, Salvagni S, Van Laethem JL, Van Vlierberghe H, Trojan J. Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib. Oncotarget. 2016;7:72622-72633.  [PubMed]  [DOI]
24.  ArQule, Inc. Daiichi Sankyo and ArQule Announce the Completion of the METIV-HCC Phase 3 Study of Tivantinib in Second-Line Treatment of MET-Overexpressing Hepatocellular Carcinoma.  Available from: http://investors.arqule.com/releasedetail.cfm?ReleaseID=1012374.  [PubMed]  [DOI]
25.  Reig M, Rimola J, Torres F, Darnell A, Rodriguez-Lope C, Forner A, Llarch N, Ríos J, Ayuso C, Bruix J. Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design. Hepatology. 2013;58:2023-2031.  [PubMed]  [DOI]
26.  Iavarone M, Cabibbo G, Biolato M, Della Corte C, Maida M, Barbara M, Basso M, Vavassori S, Craxì A, Grieco A. Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib. Hepatology. 2015;62:784-791.  [PubMed]  [DOI]
27.  Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020-1022.  [PubMed]  [DOI]
28.  Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883-892.  [PubMed]  [DOI]
29.  Jahangiri A, De Lay M, Miller LM, Carbonell WS, Hu YL, Lu K, Tom MW, Paquette J, Tokuyasu TA, Tsao S. Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance. Clin Cancer Res. 2013;19:1773-1783.  [PubMed]  [DOI]
30.  Ye LY, Chen W, Bai XL, Xu XY, Zhang Q, Xia XF, Sun X, Li GG, Hu QD, Fu QH. Hypoxia-Induced Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma Induces an Immunosuppressive Tumor Microenvironment to Promote Metastasis. Cancer Res. 2016;76:818-830.  [PubMed]  [DOI]
31.  Eisai Co,. Ltd. Phase III trial of anticancer agent Lenvima® as first-line treatment for unresectable hepatocellular carcinoma meets primary endpoint.  Available from: http://www.eisai.com/news/enews201706pdf.pdf.  [PubMed]  [DOI]