Sorafenib prolongs survival, but what happens to the symptoms?
Authors: Bruno M. Strebel
Journal: Journal of Hepatology (2012)

Are there opportunities for chemotherapy in the treatment of hepatocellular cancer?Journal of HepatologyVol. 56Issue 3PreviewHepatocellular cancer is a significant global health problem yet the prognosis for the majority of patients has not changed significantly over the past few decades. For patients with advanced disease, sorafenib is currently the standard of care providing a survival advantage of 2–3 months in selected patients. Cytotoxic chemotherapy has been used for over 30 years but definite evidence that it prolongs survival has been lacking. Resistance remains a significant barrier for both targeted and cytotoxic agents and an understanding of the underlying mechanisms is critical if outcomes are to be improved. Full-Text PDF Open AccessReply to: "Sorafenib prolongs survival, but what happens to the symptoms?"Journal of HepatologyVol. 57Issue 1PreviewThe main focus of our paper concerns the potential role of cytotoxic chemotherapy, which needs to be considered in the context of other standards of care [1]. As stated, the current standard of care for advanced HCC is sorafenib. An exhaustive review of the SHARP [2] and AP [3] trial data was not within the scope of our review since these have been covered extensively in previous publications. We do, however, highlight both the survival benefit and the toxicity associated with sorafenib. Survival remains the primary end point for most phase III trials and is both robust and, as Dr. Full-Text PDF Open Access A recent review published in the Journal of Hepatology discusses the opportunities for chemotherapy in hepatocellular carcinoma (HCC) [[1]Asgham U. Meyer T. Are there opportunities for chemotherapy in the treatment of hepatocellular cancer?.J Hepatol. 2012; 56: 686-695Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar]. In this review, the authors conclude that "Sorafenib is currently regarded as the standard of care in selected patients with advanced HCC based on two large randomised placebo controlled trials" [2Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.-F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (9271) Google Scholar, 3Cheng 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. 2009; 10: 25-34Abstract Full Text Full Text PDF PubMed Scopus (4552) Google Scholar]. Furthermore, the introduction suggests its use as a palliative therapeutic. But what actually defines a palliative treatment? A decent definition of palliative chemotherapy is given by V.R. Archer in 1999: "Palliative chemotherapy is defined as treatment in circumstances where the impact of intervention is insufficient to result in major survival advantage, but does affect improvement in terms of tumor-related symptoms, and where the palliation/toxicity trade-off from treatment clearly favors symptom relief" [[4]Archer V.R. Billingham L.J. Cullen M.H. Palliative chemotherapy: no longer a contradiction in terms.Oncologist. 1999; 4: 470-477PubMed Google Scholar]. Assuming sorafenib to be a palliative treatment, the data of the SHARP [[2]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. 2008; 359: 378-390Crossref PubMed Scopus (9271) Google Scholar] and the Asian Pacific Trial (APT) [[3]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. 2009; 10: 25-34Abstract Full Text Full Text PDF PubMed Scopus (4552) Google Scholar] can be used to extrapolate the medians of asymptomatic and symptomatic time of survival. In both studies, the eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less (i.e. ranging from full active: 0, to capable of self-care but unable to work: 2) [[5]Oken M.M. Creech R.H. Tormey D.C. Horton J. Davis T.E. McFadden E.T. et al.Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin Oncol. 1982; 5: 649-655Crossref PubMed Scopus (8412) Google Scholar]. It thus seems fine to assume that the patients entered the study with a preserved quality of life. Furthermore, both studies give data for the cut-off, where an asymptomatic patient changes to a symptomatic one: the time to symptomatic progression (TTSP). Both studies defined symptomatic progression (SP) as death, a decline to an ECOG performance status score of 4 (i.e. completely disabled, confined to bed, and chair) [[5]Oken M.M. Creech R.H. Tormey D.C. Horton J. Davis T.E. McFadden E.T. et al.Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin Oncol. 1982; 5: 649-655Crossref PubMed Scopus (8412) Google Scholar] or an increase of 4 points in the Hepatobiliary Symptom Index (FISH-8) questionnaire [[6]Yount S. Cella D. Webster K. Heffernan N. Chang C. Odom L. et al.Assessment of patient-reported clinical outcome in pancreatic and other hepatobiliary cancers: the FACT Hepatobiliary Symptom Index.J Pain Symptom Manage. 2002; 24: 32-44Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar]. Last but not least, both studies also report overall survival. The SHARP trial reported a median overall survival (OS) of 10.9 months vs. 7.9 months for sorafenib vs. placebo respectively (p <0.001), and a median time to symptomatic progression of 4.1 months vs. 4.9 months (p = 0.77) [[2]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. 2008; 359: 378-390Crossref PubMed Scopus (9271) Google Scholar]. The APT reported a median OS of 6.5 months vs. 4.2 months for sorafenib vs. placebo (p = 0.14), and a median TTSP of 3.5 months vs. 3.4 (p = 0.50) [[3]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. 2009; 10: 25-34Abstract Full Text Full Text PDF PubMed Scopus (4552) Google Scholar]. Assuming that patients were asymptomatic at the beginning of the study, the majority of patients remained asymptomatic until the median of TTSP was reached. Beyond this, the majority of patients was symptomatic and stayed so until the median of overall survival was reached (Fig. 1). While sorafenib definitely marks a milestone in the treatment of non-resectable HCC, both trials only show a prolongation of survival with minimal to no impact on the time to symptomatic progression (in both trials, this outcome was non-significant). Even thought sorafenib may not reflect the characteristics of an ideal "palliative drug", a patient's wish for treatment in the setting of non-curable disease should never be underestimated. For example, in 104 women with breast cancer who already had three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant treatment, the patients were asked to rate the survival benefit that would justify 6 months of such a treatment. Surprisingly, 50% of all patients would participate in another 6 months of treatment for a small 1% gain in 5 year-survival [[7]Simes R.J. Coates A.S. Patient preferences for adjuvant chemotherapy of early breast cancer: how much benefit is needed?.J Natl Cancer Inst Monogr. 2001; 30: 146-152Crossref PubMed Scopus (135) Google Scholar]. Thus, the prescribing doctor and his or her patients should be aware that while sorafenib may prolong the median survival of 2–3 months [2Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.-F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (9271) Google Scholar, 3Cheng 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. 2009; 10: 25-34Abstract Full Text Full Text PDF PubMed Scopus (4552) Google Scholar], the symptoms associated with the disease or its treatment remain untouched. For patients in whom the main desire is for a treatment "to buy them some time", sorafenib remains a good option. However, the patient must then be aware of all the possible adverse events, the possible longer symptomatic course, and the substantial costs of the treatment involved (about 2400 EUR per month). In the end, treatment deferral also remains a valid choice and accepting the natural course of a disease may indeed be the best option for some patients. This memorandum wants to point out the missing difference in TTSP and encourage clinicians to discuss both courses with their patients. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.