Title:Shadows in the current management of hepatocellularcarcinoma in Spain - An embarrassing truth

Authors:Javier Crespo García, Raúl J. Andrade

DOI: 10.17235/reed.2019.6594/2019Link: PubMed (Epub ahead of print)

Please cite this article as:Crespo García Javier, Andrade Raúl J.. Shadows in thecurrent management of hepatocellular carcinoma in Spain- An embarrassing truth. Rev Esp Enferm Dig 2019. doi:10.17235/reed.2019.6594/2019.

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EDITORIAL 6594 inglés

Shadows in the current management of hepatocellular carcinoma in Spain - An

embarrassing truth

Javier Crespo1 and Raúl J. Andrade2

1Chair of the Spanish Society of Digestive Diseases (SEPD). Chair of the Spanish

National Commission on Digestive Diseases (CND). Digestive Diseases Service. Hospital

Universitario Marqués de Valdecilla. IDIVAL. Santander, Spain. 2Chair of the Spanish

Association for the Study of the Liver (AEEH). Digestive Diseases Service. Hospital

Universitario Virgen de la Victoria. Málaga, Spain

Correspondence: Javier Crespo. Digestive Diseases Service. Hospital Universitario

Marqués de Valdecilla. Avenida Valdecilla, s/n. 39008 Santander, Spain

e-mail: Javier.crespo@scsalud.es

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related

deaths worldwide (1). Up to 80% of patients with HCC have concomitant cirrhosis as a

result of hepatitis B or C virus, alcohol abuse, or non-alcoholic steatohepatitis (2).

Unfortunately, only up to 40% of patients with HCC are diagnosed in early stages,

when therapies are available with curative intent. Therefore, many patients, likely

around 50%, must receive systemic treatment for HCC over the course of this

neoplasm (3,4). Since approval back in 2007, sorafenib has remained the only systemic

therapy that has proven effective against HCC, with repeatedly positive results (5).

Over the past two years efficacy has been established for lenvatinib (first-line) and

regorafenib, cabozantinib and ramucirumab (second-line), which means that patients

with advanced disease have a modest but consistent increase in life expectancy (6-11).

These results have led both regulatory agencies and scientific societies to authorize

and/or recommend the use of these antineoplastic drugs. As may be seen in table 1,

there is unanimity amongst regulatory agencies regarding the approval of first-line

sorafenib and lenvatinib, and second-line regorafenib and cabozantinib (12-24).

Probably because results were reported very recently, only the FDA has yet approved

the use of ramucirumab in the second line of treatment. Position statement

documents and guidelines by scientific societies are conclusive: in all cases is the use of

first-line sorafenib and lenvatinib supported, as is the use of second-line regorafenib,

cabozantinib and ramucirumab, provided the relevant information was already

available at the time of guideline publication (25-30). Lastly, the British agency NICE,

whose reports, far removed from any unscientific bias, are completely trustworthy

because of their stringency, has also issued a positive report for regorafenib and

lenvatinib, while the other drugs remain to be assessed (31,32). It is after observing

this unanimity among regulatory agencies and guidelines by scientific societies that

our first unpleasant surprise occurs: in Spain funding is only available for sorafenib.

This fact has double motivation: a) a surprising decision by the Ministry of Health to

approve the indication but not the funding of regorafenib; and b) the amazing

sluggishness of our therapeutic positioning reports (TPRs), with those related to

lenvatinib and cabozantinib still pending publication. The second, also unpleasant

surprise, namely the inequity extant in our health services, is particularly disturbing.

While in some Communities (or even hospitals) our patients with hepatocellular

carcinoma may receive second-line regorafenib, in others, actually in most of them,

our health authorities deny access to this drug based on its lack of funding despite an

approved indication. This inequity situation is even worse when considering that

access to lenvatinib and cabozantinib is for compassionate use, its authorization being

left at the discretion of each center. That is, while some patients with HCC may benefit

from the complete therapeutic armamentarium presently available, others can only

have access to sorafenib, even though there is more than enough evidence supporting

the use of other drugs when sorafenib fails to be effective or loses efficacy after a

period of time in use.

In the second part of this editorial we must denounce the present situation of HCC

management in the Basque Country. Recently, Osakidetza (the Basque Health Service)

presented the Basque Country’s Oncologic Plan, and immediately afterwards

Osakidetza’s Territorial Assistance Office ordered their tertiary hospital boards to

process all cancer drug prescriptions through Onkobide, an application to which

gastroenterology and hepatology specialists will have no access (33). At both the

Spanish Association for the Study of the Liver (AEEH) and the Spanish Society of

Digestive Diseases (SEPD) we radically reject such measure. Our rejection is based on

the following reasons:

– Cancer management cannot be thought of in isolation. Any approach to cancer

must include epidemiology; primary, secondary and tertiary prevention; natural

history of the disease; potential complications; diagnosis, prognosis, and treatment.

Explicitly, cancer management is not restricted to the administration of different

drugs in certain stages of tumor progression.

– Regarding HCC, this tumor develops in patients with liver cirrhosis in over 90%

of cases. Because of this peculiarity, the vast majority of patients with HCC develop

complications arising not from the tumor itself but from liver cirrhosis.

Gastroenterologists and hepatologists (G&H) are the specialists best qualified for

the appropriate management of these complications (34).

– The development of systemic therapy for HCC has been led by Spanish

hepatologists. Because of this relevant fact, our G&H are familiar with systemic HCC

therapy from the very start. In fact, our specialists are considered as experts in the

treatment of HCC on an international basis. Therefore, we are also obviously

qualified for the management of the potential toxicities induced by the drugs

currently approved for the treatment of HCC, and so shall we remain when it comes

to handling the newer agents to be authorized in the upcoming future.

– Our legal system (Orden SAS/2854/2009, de 9 de octubre, por la que se aprueba

y publica el programa formativo de la especialidad de Aparato Digestivo. Nº 258 de

lunes 26 de octubre de 2009. Sec. III. Pág. 89582) establishes that: “…a digestive

system specialist must have the necessary knowledge, skills, and attitudes to orient

the clinical diagnosis of patients with digestive diseases […] mostly control patients

with serious conditions (liver cirrhosis, inflammatory bowel disease, digestive

cancer)…”. Specifically and unequivocally, reference is made to the specialist’s

competence in the diagnosis and treatment of HCC. Similarly, in our neighboring

countries G&H are deemed to be competent in HCC diagnosis, staging, and

management. In this regard, the European Blue Book for digestive system diseases

may be consulted (35).

– The split in patient care established by Osakidetza between prescribing

physicians (oncologists) and physicians who treat complications for patients with

HCC (gastroenterologists) is a profound error, a poorly efficient measure that will

result in delayed care and gratuitous annoyance for patients with HCC.

– We believe that the diagnosis and treatment of patients with HCC should be

multidisciplinary, with G&H at the hub of patient care because of their being the

best qualified specialists in the holistic management of these individuals,

understanding that the underlying disease (cirrhosis) and the emerged complication

(HCC) cannot be divorced from each other.

We have no doubt whatsoever that we, G&H, are qualified to manage, in a

multidisciplinary setting, our patients with cancer, and specifically our patients with

HCC. We believe in the multidisciplinary approach to cancer, and we believe in our role

in the management of multiple tumors including HCC, where our intervention is key. In

addition to our competence and qualifications this plan disregards the law since our

current training program supports our role in the holistic management of digestive

cancer, with an emphasis on hepatocellular carcinoma.

As chairs of the AEEH, SEPD and Spanish National Commission on Digestive Diseases

(CND) we believe that for our patients to benefit from the best treatment possible,

administered by the best qualified professionals:

1. Our national health authority must approve funding for regorafenib within the

shortest possible period of time, and press for TPR completion to allow the funding

and use of lenvatinib and cabozantinib. Only in this way will the serious burden of

inequity currently overwhelming patients with HCC in our country cease to exist.

2. G&H should lead the multidisciplinary teams responsible for the diagnosis,

monitoring and treatment of patients with HCC. We ask of healthcare authorities to

revoke this clearly wrong decision in order to allow patients to receive their

treatments from their G&H, which should be obviously empowered to prescribe the

most appropriate treatment available.

ACKNOWLEDGEMENTS

Dr. Andrade and Dr. Crespo wish to thank Dr. María Varela (Hospital Universitario

Central de Asturias) and Dr. Carlos Rodríguez de Lope (Hospital Universitario Marqués

de Valdecilla) for their scientific advice.

REFERENCES

1. Yang JD, Hainaut P, Gores GJ, et al. A global view of hepatocellular carcinoma:

trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019.

2. Llovet JM, Zucman Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev

Dis Prim 2016;2:16018.

3. Varela M, Reig M, De la Mata M, et al. Tratamiento del carcinoma

hepatocelular en España. Análisis de los 705 casos en 62 centros. Med Clin (Barc)

2010;134(13):560-76. DOI: 10.1016/j.medcli.2009.10.042

4. Rodríguez de Lope C, Reig M, Matilla A, et al. Grupo de Estudio de Cáncer

Hepático (GECH). Clinical characteristics of hepatocellular carcinoma in Spain.

Comparison with the 2008-2009 period and analysis of the causes of diagnosis out of

screening programs. Analysis of 686 cases in 73 centers. Med Clin (Barc)

2017;149(2):61-71. DOI: 10.1016/j.medcle.2017.06.022

5. Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group.

Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378-90.

DOI: 10.1056/NEJMoa0708857

6. Qin S, Han KH, Ikeda K, 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(10126):1163-73. DOI: 10.1016/S0140-

6736(18)30207-1

7. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular

carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-

blind, placebo-controlled, phase 3 trial; RESORCE Investigators. Lancet

2017;389(10064):56-66. DOI: 10.1016/S0140-6736(16)32453-9

8. 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

9. Zhu AX, Park JO, Ryoo BY, et al. Ramucirumab versus placebo as second-line

treatment in patients with advanced hepatocellular carcinoma following first-line

therapy with sorafenib (REACH): a randomized, double-blind multicenter, phase 3 trial.

REACH Trial Investigators. Lancet Oncol 2015;16(7):859-70.

10. Zhu AX, Kang YK, Yen CJ, et al. REACH-2: a randomized, double-blind, placebo-

controlled phase 3 study of ramucirumab versus placebo as second-line treatment in

patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-

fetoprotein (AFP) following first-line sorafenib. J Clin Oncol 2018;36(Suppl; abstr

4003).

11. Zhu AX, Finn RS, Galle PR, et al. Ramucirumab in advanced hepatocellular

carcinoma in REACH-2: the true value of α-fetoprotein. Lancet Oncol 2019;20(4):e191.

DOI: 10.1016/S1470-2045(19)30165-2

12. European Medicines Agency. Summary of opinion (initial authorization).

Ondexxya. Disponible en: https://www.ema.europa.eu/documents/smop/chmp-post-

authorisation- summary-positive-opinion-lenvima_en.pdf

13. European Medicines Agency. Lenvima, INN-lenvatinib. Disponible en:

https://www.ema.europa.eu/documents/procedural-steps-after/lenvima- epar-

procedural-steps-taken-scientific-information-after- authorisation_en.pdf

14. U.S. Food and Drug Administration. Resources for information on approved

drugs. Disponible en:

https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm6171 85.htm

15. ZEMDRI™ Prescribing Information 1. Disponible en:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206947s007 lbl.pdf

16. European Medicines Agency. Summary of opinion (initial authorization).

Lynparza. Disponible en: https://www.ema.europa.eu/documents/smop/chmp-post-

authorisation- summary-positive-opinion-stivarga-ii-20_en.pdf

17. European Medicines Agency. Stivarga, INN-regorafenib. Disponible en:

https://www.ema.europa.eu/documents/procedural-steps-after/stivarga- epar-

procedural-steps-taken-scientific-information-after- authorisation_en.pdf

18. U.S. Food and Drug Administration. FDA approves durvalumab after

chemoradiation for unresectable stage III NSCLC. Disponible en:

https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555 548.htm

19. BRINEURA (cerliponase alfa) injection. Prescribing Information 1. Disponible en:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203085s007 lbl.pdf

20. European Medicines Agency. Summary of opinion (initial authorization).

CABOMETYX, INN-Cabozantinib. Disponible en:

https://www.ema.europa.eu/documents/smop/chmp-post-authorisation- summary-

positive-opinion-cabometyx_en.pdf

21. Comisión Europea. Decisión de ejecución de la comisión 12.11.2018 por la que

se modifica la autorización de comercialización para huso humano “CABOMETYX –

cabozantinib” concedida por la Decisión C(2016)5865(final). Bruselas; 2018. Disponible

en: http://ec.europa.eu/health/documents/community-

register/2018/20181112142721/dec_142721_es.pdf

22. European Medicines Agency. CABOMETYX, INN-Cabozantinib. Anexo 1. Ficha

técnica o resumen de las características del producto. Disponible en:

http://ec.europa.eu/health/documents/community-

register/2018/20181112142721/anx_142721_es.pdf

23. U.S. Food and Drug Administration. FDA approves cabozantinib for

hepatocellular carcinoma. Disponible en: https://www.fda.gov/drugs/fda-approves-

cabozantinib-hepatocellular- carcinoma

24. National Institute for Health and Care Excellence. Cabozantinib for previously

treated advanced hepatocellular carcinoma (terminated appraisal). 2019. Disponible

en: https://www.nice.org.uk/guidance/ta582

25. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of

hepatocellular carcinoma. Hepatology 2018;67:358-80. DOI: 10.1002/hep.29086

25. European Association for the Study of the Liver. EASL Clinical Practice

Guidelines. Management of hepatocellular carcinoma. J Hepatol 2018;69:182-236.

26. Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on

the management of hepatocellular carcinoma: a 2017 update. Hepatol Int

2017;11:317-70. DOI: 10.1007/s12072-017-9799-9

27. Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO Clinical

Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019;30:871-3.

DOI: 10.1093/annonc/mdy510

28. Forner A, Reig M, Varela M, et al. Diagnosis and treatment of hepatocellular

carcinoma. Update consensus document from the AEEH, SEOM, SERAM, SERVEI and

SETH. Med Clin (Barc) 2016;146:511.e1-511.e22. DOI: 10.1016/j.medcli.2016.01.028

29. Benson AB, D’Angelica MI, Abbott DE, et al. Guidelines insights: hepatobiliary

cancers. Version 2. 2019. J Natl Compr Canc Netw 2019;17(4):302-10. DOI:

10.6004/jnccn.2019.0019

30. National Institute for Health and Care Excellence. Final appraisal determination

- Elbasvir-grazoprevir for treating chronic hepatitis C. 2016. Disponible en:

https://www.nice.org.uk/guidance/ta551/documents/final-appraisal- determination-

document

31. National Institute for Health and Care Excellence. Final appraisal determination

- Carfilzomib for previously treated multiple myeloma. 2017. Disponible en:

https://www.nice.org.uk/guidance/ta555/documents/final-appraisal-determination-

document

32. Departamento de Salud, Gobierno Vasco. Plan Oncológico de Euskadi 2018-

2023. San Sebastián; 2018. Disponible en: https://www.euskadi.eus › plan- oncologico-

de-euskadi-2018-2023.

33. González de Frutos C, Marín Serrano E, Gómez Rubio M, et al. Formación en

ecografía de los médicos residentes de aparato digestivo: encuesta y proyecto docente

de la Asociación Española de Ecografía Digestiva. Rev Esp Enferm Dig

2019;111(10):xxx-xxx. DOI: 10.17235/reed.2019.6172/2019

34. Castro V, Cremers Tavares MI. Young GI Angle - Harmonised education: the

EBGH Blue Book. United European Gastroenterol J 2017;5:457-8. DOI:

10.1177/2050640617699747

35. Castro V, Cremers Tavares MI, Young GI Angle. Harmonised education: the

EBGH Blue Book. United European Gastroenterol J 2017;5:457-8. DOI:

10.1177/2050640617699747 

36. Acuerdos de la reunión de la Comisión Interministerial de precios de los

medicamentes. Sesión 191 de 30 de mayo de 2019. Disponible en:

https://www.mscbs.gob.es/profesionales/farmacia/pdf/ACUERDOS_DE_LA_CIPM_191

_web.pdf

Table 1. Approval of first-line sorafenib and lenvatinib use and second-line

regorafeninb and cabozantinib use by regulatory agencies. Position statement

documents and guidelines issued by scientific societies

Sorafenib Lenvatinib Regorafenib Cabozantinib Ramucirumab

Indication 1st line 1st line 2nd line after

sorafenib in

patients tolerant

to sorafenib

2nd line after

sorafenib

2nd line after

sorafenib if AFP >

400

AEMPS

approval

Yes Yes Yes Yes Not assessed

EMA

approval

Yes Yes Yes Yes Not assessed

FDA approval Yes Yes Yes Yes Yes

AEEH

position

statement

(2016)*

Yes - - - -

EASL position

statement

(2018)†

Yes Yes Yes Yes Favorable report

AASLD

position

Yes Yes Yes Yes -

statement

(2018)‡

APASL

position

statement

(2017)§

Yes - Yes - -

ESMO

position

statement

(2018)ǁ

Yes Yes Yes Yes Yes

NCCN

position

statement

(2019)¶

Yes Yes Yes Yes Yes

Therapeutic

positioning

report (TPR)

Yes Pending Yes.

Compensated

patients with

HCC, ECOG PS 0-1

and tolerant to

prior sorafenib

may be treated in

2nd line

Pending Not assessed

NHS funding Yes No, TPR

pending

No, refused by

the CIPM**

NO, TPR

pending

No

Available to

Autonomous

Communities

(ACs)

Yes Compassiona

te use.

Depending

on each AC

and/or

center

At the discretion

of each AC

Compassionate

use. Depending

on each AC

and/or center

No

*AEEH (2016): published in 2016. It includes recommendation for sorafenib. As regards

the other drugs, no clinical trial results were then available showing improved survival

(or non-inferiority). †EASL (2018): published in 2018. The ramucirumab trial was not

finished yet at the time of publication. ‡AASLD (2018): the August 2018 update includes

1st-line sorafenib and lenvatinib, and 2nd-line regorafenib and cabozantinib. The

ramucirumab trial was pending publication at the time. §APASL (2017): it includes

sorafenib (1st-line) and regorafenib (2nd-line). Results pending at the time of publication

for the other drugs. ǁESMO (2018): it includes 1st-line sorafenib and lenvatinib. 2nd-line

regorafenib, cabozantinib and ramucirumab. ¶NCCN (2019): it also includes 1st-line

sorafenib and lenvatinib and 2nd-line regorafenib, cabozantinib and ramucirumab

(these guidelines also include other options with lower evidence levels). **CIPM:

Comisión Interministerial de Precios de Medicamentos y productos sanitarios (36).