Impact of age on sorafenib outcomes in hepatocellular carcinoma: an international cohort study.
Adult
Age Factors
Aged
Aged, 80 and over
Antineoplastic Agents
/ administration & dosage
Carcinoma, Hepatocellular
/ drug therapy
Cohort Studies
Dose-Response Relationship, Drug
Female
Humans
Liver Neoplasms
/ drug therapy
Male
Middle Aged
Prognosis
Sorafenib
/ administration & dosage
Treatment Outcome
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
06
05
2020
accepted:
25
09
2020
revised:
15
09
2020
pubmed:
20
10
2020
medline:
16
4
2021
entrez:
19
10
2020
Statut:
ppublish
Résumé
There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low-dose therapy with the aim to avoid toxicities while maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) and whether a reduced starting dose impacts on OS or toxicity experienced by the elderly. In an international, multicentre cohort study, outcomes for those aged <75 or ≥75 years were determined while accounting for common prognostic factors and demographic characteristics in univariable and multivariable models. Five thousand five hundred and ninety-eight patients were recruited; 792 (14.1%) were aged ≥75 years. The elderly were more likely to have larger tumours (>7 cm) (39 vs 33%, p < 0.01) with preserved liver function (67 vs 57.7%) (p < 0.01). No difference in the median OS of those aged ≥75 years and <75 was noted (7.3 months vs 7.2 months; HR 1.00 (95% CI 0.93-1.08), p = 0.97). There was no relationship between starting dose of sorafenib 800 mg vs 400 mg/200 mg and OS between those <75 and ≥75 years. The elderly experienced a similar overall incidence of grade 2-4 sorafenib-related toxicity compared to <75 years (63.5 vs 56.7%, p = 0.11). However, the elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p < 0.01). This did not vary between different starting doses of sorafenib. Clinical outcomes in the elderly is equivalent to patients aged <75 years, independent of dose of sorafenib prescribed.
Sections du résumé
BACKGROUND
There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low-dose therapy with the aim to avoid toxicities while maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) and whether a reduced starting dose impacts on OS or toxicity experienced by the elderly.
METHODS
In an international, multicentre cohort study, outcomes for those aged <75 or ≥75 years were determined while accounting for common prognostic factors and demographic characteristics in univariable and multivariable models.
RESULTS
Five thousand five hundred and ninety-eight patients were recruited; 792 (14.1%) were aged ≥75 years. The elderly were more likely to have larger tumours (>7 cm) (39 vs 33%, p < 0.01) with preserved liver function (67 vs 57.7%) (p < 0.01). No difference in the median OS of those aged ≥75 years and <75 was noted (7.3 months vs 7.2 months; HR 1.00 (95% CI 0.93-1.08), p = 0.97). There was no relationship between starting dose of sorafenib 800 mg vs 400 mg/200 mg and OS between those <75 and ≥75 years. The elderly experienced a similar overall incidence of grade 2-4 sorafenib-related toxicity compared to <75 years (63.5 vs 56.7%, p = 0.11). However, the elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p < 0.01). This did not vary between different starting doses of sorafenib.
CONCLUSIONS
Clinical outcomes in the elderly is equivalent to patients aged <75 years, independent of dose of sorafenib prescribed.
Identifiants
pubmed: 33071284
doi: 10.1038/s41416-020-01116-9
pii: 10.1038/s41416-020-01116-9
pmc: PMC7852559
doi:
Substances chimiques
Antineoplastic Agents
0
Sorafenib
9ZOQ3TZI87
Types de publication
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
407-413Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Commentaires et corrections
Type : ErratumIn
Références
Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).
doi: 10.1002/ijc.29210
Llovet, J. M. Updated treatment approach to hepatocellular carcinoma. J. Gastroenterol. 40, 225–235 (2005).
doi: 10.1007/s00535-005-1566-3
Strumberg, D., Richly, H., Hilger, R. A., Schleucher, N., Korfee, S., Tewes, M. et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J. Clin. Oncol. 23, 965–972 (2005).
doi: 10.1200/JCO.2005.06.124
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J. F. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).
doi: 10.1056/NEJMoa0708857
Cheng, A. L., Kang, Y. K., Chen, Z., Tsao, C. J., Qin, S., Kim, J. S. et al. 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. 10, 25–34 (2009).
doi: 10.1016/S1470-2045(08)70285-7
Borzio, M., Dionigi, E., Parisi, G., Raguzzi, I. & Sacco, R. Management of hepatocellular carcinoma in the elderly. World J. Hepatol. 7, 1521–1529 (2015).
doi: 10.4254/wjh.v7.i11.1521
Bosch, F. X., Ribes, J., Cleries, R. & Diaz, M. Epidemiology of hepatocellular carcinoma. Clin. Liver Dis. 9, 191–211 (2005).
doi: 10.1016/j.cld.2004.12.009
Cancer Research UK. Liver cancer incidence statistics. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/liver-cancer/incidence (2018).
Germano, D., Tinessa, V., Barletta, E., Cannella, L. & Daniele, B. Targeted therapy for advanced hepatocellular cancer in the elderly: focus on sorafenib. Drugs Aging 30, 887–892 (2013).
doi: 10.1007/s40266-013-0124-6
Ziogas, D. C., Papadatos-Pastos, D., Thillai, K., Korantzis, I., Chowdhury, R., Suddle, A. et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: age is not a problem. Eur. J. Gastroenterol. Hepatol. 29, 48–55 (2017).
doi: 10.1097/MEG.0000000000000739
Pressiani, T., Boni, C., Rimassa, L., Labianca, R., Fagiuoli, S., Salvagni, S. et al. Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis. Ann. Oncol. 24, 406–411 (2013).
doi: 10.1093/annonc/mds343
Bruix, J., Cheng, A. L., Meinhardt, G., Nakajima, K., De Sanctis, Y. & Llovet, J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J. Hepatol. 67, 999–1008 (2017).
doi: 10.1016/j.jhep.2017.06.026
Iavarone, M., Cabibbo, G., Piscaglia, F., Zavaglia, C., Grieco, A., Villa, E. et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology 54, 2055–2063 (2011).
doi: 10.1002/hep.24644
Nishikawa, H., Takeda, H., Tsuchiya, K., Joko, K., Ogawa, C., Taniguchi, H. et al. Sorafenib therapy for BCLC stage B/C hepatocellular carcinoma; clinical outcome and safety in aged patients: a multicenter study in Japan. J. Cancer 5, 499–509 (2014).
doi: 10.7150/jca.9257
Edeline, J., Crouzet, L., Le Sourd, S., Larible, C., Brunot, A., Le Roy, F. et al. Sorafenib use in elderly patients with hepatocellular carcinoma: caution about use of platelet aggregation inhibitors. Cancer Chemother. Pharmacol. 75, 215–219 (2015).
doi: 10.1007/s00280-014-2645-z
Williet, N., Clavel, L., Bourmaud, A., Verot, C., Bouarioua, N., Roblin, X. et al. Tolerance and outcomes of sorafenib in elderly patients treated for advanced hepatocellular carcinoma. Dig. Liver Dis. 49, 1043–1049 (2017).
doi: 10.1016/j.dld.2017.06.008
Collier, J. D., Curless, R., Bassendine, M. F. & James, O. F. Clinical features and prognosis of hepatocellular carcinoma in Britain in relation to age. Age Ageing 23, 22–27 (1994).
doi: 10.1093/ageing/23.1.22
Cabibbo, G., Maida, M., Camma, C. & Craxi, A. Is the efficacy of sorafenib treatment in patients with hepatocellular carcinoma affected by age? Expert Rev. Anticancer Ther. 13, 1355–1361 (2013).
doi: 10.1586/14737140.2013.859989
Jo, M., Yasui, K., Kirishima, T., Shima, T., Niimi, T., Katayama, T. et al. Efficacy and safety of sorafenib in very elderly patients aged 80 years and older with advanced hepatocellular carcinoma. Hepatol. Res. 44, 1329–1338 (2014).
doi: 10.1111/hepr.12308
Morimoto, M., Numata, K., Kondo, M., Hidaka, H., Takada, J., Shibuya, A. et al. Higher discontinuation and lower survival rates are likely in elderly Japanese patients with advanced hepatocellular carcinoma receiving sorafenib. Hepatol. Res. 41, 296–302 (2011).
doi: 10.1111/j.1872-034X.2011.00778.x
Cox, D. R. Regression models and life-tables. J. R. Stat. Soc. Ser. B Methodol. 34, 187–220 (1972).
White, I. R. & Royston, P. Imputing missing covariate values for the Cox model. Stat. Med. 28, 1982–1998 (2009).
doi: 10.1002/sim.3618
Abbasi, J. Older patients (still) left out of cancer clinical trials. JAMA https://doi.org/10.1001/jama.2019.17016 (2019).
Brunot, A., Le Sourd, S., Pracht, M. & Edeline, J. Hepatocellular carcinoma in elderly patients: challenges and solutions. J. Hepatocell. Carcinoma 3, 9–18 (2016).
doi: 10.2147/JHC.S101448
Di Costanzo, G. G., Tortora, R., De Luca, M., Galeota Lanza, A., Lampasi, F., Tartaglione, M. T. et al. Impact of age on toxicity and efficacy of sorafenib-targeted therapy in cirrhotic patients with hepatocellular carcinoma. Med. Oncol. 30, 446 (2013).
doi: 10.1007/s12032-012-0446-y
Francini, E., Mazzaroppi, S., Fiaschi, A. I., Petrioli, R., Laera, L., Roviello, G. et al. Safety of sorafenib therapy in elderly adults with advanced hepatocellular carcinoma. J. Am. Geriatr. Soc. 62, 2204–2205 (2014).
doi: 10.1111/jgs.13091
Cantarini, M. C., Trevisani, F., Morselli-Labate, A. M., Rapaccini, G., Farinati, F., Del Poggio, P. et al. Effect of the etiology of viral cirrhosis on the survival of patients with hepatocellular carcinoma. Am. J. Gastroenterol. 101, 91–98 (2006).
doi: 10.1111/j.1572-0241.2006.00364.x
Hung, A. K. & Guy, J. Hepatocellular carcinoma in the elderly: Meta-analysis and systematic literature review. World J. Gastroenterol. 21, 12197–12210 (2015).
doi: 10.3748/wjg.v21.i42.12197
Howell, J., Pinato, D. J., Ramaswami, R., Bettinger, D., Arizumi, T., Ferrari, C. et al. On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-centre, prospective study. Aliment. Pharmacol. Ther. 45, 1146–1155 (2017).
doi: 10.1111/apt.13977
Reiss, K. A., Yu, S., Mamtani, R., Mehta, R., D’Addeo, K., Wileyto, E. P. et al. Starting dose of sorafenib for the treatment of hepatocellular carcinoma: a retrospective, multi-institutional study. J. Clin. Oncol. 35, 3575–3581 (2017).
doi: 10.1200/JCO.2017.73.8245
Reig, M., Torres, F., Rodriguez-Lope, C., Forner, A., N, L. L., Rimola, J. et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J. Hepatol. 61, 318–324 (2014).
doi: 10.1016/j.jhep.2014.03.030
Diaz-Gonzalez, A., Sanduzzi-Zamparelli, M., Sapena, V., Torres, F., N, L. L., Iserte, G. et al. Systematic review with meta-analysis: the critical role of dermatological events in patients with hepatocellular carcinoma treated with sorafenib. Aliment. Pharmacol. Ther. 49, 482–491 (2019).
doi: 10.1111/apt.15088
Tovoli, F., Ielasi, L., Casadei-Gardini, A., Granito, A., Foschi, F. G., Rovesti, G. et al. Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients. J. Hepatol. 71, 1175–1183 (2019).
doi: 10.1016/j.jhep.2019.08.015
Rimassa, L., Cicin, I., Blanc, J.-F., Klümpen, H. J., Zagonel, V., Tran, A. et al. Outcomes based on age in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC). J. Clin. Oncol. 36, 4090–4090 (2018).
doi: 10.1200/JCO.2018.36.15_suppl.4090
Moth, E. B., Kiely, B. E., Naganathan, V., Martin, A. & Blinman, P. How do oncologists make decisions about chemotherapy for their older patients with cancer? A survey of Australian oncologists. Supportive Care Cancer 26, 451–460 (2018).
doi: 10.1007/s00520-017-3843-0
Corre, R., Greillier, L., Le Caer, H., Audigier-Valette, C., Baize, N., Berard, H. et al. Use of a comprehensive geriatric assessment for the management of elderly patients with advanced non-small-cell lung cancer: the phase III randomized ESOGIA-GFPC-GECP 08-02 study. J. Clin. Oncol. 34, 1476–1483 (2016).
doi: 10.1200/JCO.2015.63.5839
Decoster, L., Kenis, C., Van Puyvelde, K., Flamaing, J., Conings, G., De Greve, J. et al. The influence of clinical assessment (including age) and geriatric assessment on treatment decisions in older patients with cancer. J. Geriatr. Oncol. 4, 235–241 (2013).
doi: 10.1016/j.jgo.2013.04.010
Food & Drug Administration & H. H. S. International Conference on Harmonisation; Guidance on E7 Studies in Support of Special Populations; Geriatrics; Questions and Answers; availability. Notice. Fed. Regist. 77, 9948–9949 (2012).
National Institutes of Health. Revision: NIH Policy and Guidelines on the Inclusion of Individuals Across the Lifespan as Participants in Research Involving Human Subjects (National Institutes of Health, Bethesda, MD, 2017).
McNamara, M. G., Slagter, A. E., Nuttall, C., Frizziero, M., Pihlak, R., Lamarca, A. et al. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur. J. Cancer 105, 1–9 (2018).
doi: 10.1016/j.ejca.2018.09.031