To the Editor: Llovet et al. (July 24 issue)1 report that theirstudy of sorafenib therapy in patients with hepatocellular carcinomashowed a higher overall incidence of treatment-related adverseevents with sorafenib than with placebo (80% vs. 52%), althoughthe difference was not noted to be significant. The availabilityof new therapies, with expected small variations in objectiveend points, has heightened awareness of the importance of theimpact of treatment on patients' overall lives.2 Besides thetraditional end points (e.g., median overall survival and timeto radiologic progression), quality of life has been acknowledgedas an important issue in cancer clinical trials and clinicalpractice.3,4 We think that an assessment of patients' qualityof life would have provided important complementary informationto be evaluated in the article.
Another concern might be the low incidence in the study of grade3 hypertension (2% in the sorafenib group vs. <1% in theplacebo group). In a recent systematic review5 of publishedclinical trials evaluating hypertension associated with sorafenib,the overall incidences of all-grade and high-grade hypertensionwere 23.4% and 5.7%, respectively.
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390. [Free Full Text]
Gunnars B, Nygren P, Glimelius B. Assessment of quality of life during chemotherapy. Acta Oncol 2001;40:175-184. [ISI][Medline]
Moinpour CM. Measuring quality of life: an emerging science. Semin Oncol 1994;21:Suppl 10:48-63. [Medline]
Yeo W, Mo FK, Koh J, et al. Quality of life is predictive of survival in patients with unresectable hepatocellular carcinoma. Ann Oncol 2006;17:1083-1089. [Free Full Text]
Wu S, Chen JJ, Kudelka A, Lu J, Zhu X. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 2008;9:117-123. [CrossRef][ISI][Medline]
To the Editor: Llovet et al. report the results of the use ofa targeted agent in a large group of patients with hepatocellularcarcinoma and relatively well-preserved liver function. Despitea very limited radiologic response rate, survival was extendedin the sorafenib group. As effective targeted therapies becomeavailable, the use of conventional end points in cancer clinicaltrials is increasingly being challenged. Furthermore, frequentlycoexisting liver disease in patients with hepatocellular cancermakes the assessment of clinical benefit difficult. The levelof alpha-fetoprotein, a useful biomarker for measuring antitumorresponse or progression in hepatocellular carcinoma, may proveto be more accurate and sensitive than conventional imagingin monitoring the response to therapy in this disease.1,2,3Llovet et al. report that in their study, the median baselinelevel of alpha-fetoprotein was one of the eight prognostic indicatorsfor survival; however, the alpha-fetoprotein response to therapyhas not been provided. It would be interesting to know whetherthe alpha-fetoprotein response or percent alteration of serialalpha-fetoprotein values correlated with the end points of diseaseprogression, survival, or both during treatment with sorafenibas compared with placebo.
Mehmet S. Copur, M.D. Saint Francis Cancer Center Grand Island, NE 68802-9804 mcopur{at}sfmc-gi.org
References
Johnson PJ. The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis 2001;5:145-159. [CrossRef][Medline]
Huo TI, Huang YH, Lui WY, et al. Selective prognostic impact of serum alpha-fetoprotein level in patients with hepatocellular carcinoma: analysis of 543 patients in a single center. Oncol Rep 2004;11:543-550. [Medline]
Díaz Sánchez A, Núñez Martinez O, Prieto Martin M, et al. Prognostic factors in patients with non-active treatment of hepatocellular carcinoma. Gastroenterol Hepatol 2007;30:441-448. [Medline]
To the Editor: Llovet et al. report that their trial showeda survival benefit for sorafenib as compared with placebo inpatients with advanced hepatocellular carcinoma, and they concludeby stating that "studies evaluating sorafenib in combinationwith other molecular targeted therapies" are needed. However,conventional chemotherapy should not be ignored in this context.Indeed, Raf signaling is implicated in doxorubicin resistancein vitro, which may be reversed by Raf inhibition,1,2 and thereis clear evidence of a benefit from the combination of chemotherapywith antiangiogenic agents in a number of other cancers.3 Furthermore,data from a randomized phase II trial investigating the additionof sorafenib to doxorubicin in patients with hepatocellularcarcinoma suggest that this is an interesting combination worthyof further study,4 particularly in an era when one expensivedrug is unattainable in many societies, let alone a combinationof two.
Daniel H. Palmer, Ph.D. University of Birmingham Birmingham B15 2TT, United Kingdom d.palmer{at}bham.ac.uk
References
Alavi A, Hood JD, Frausto R, Stupack DG, Cheresh DA. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 2003;301:94-96. [Free Full Text]
Alavi AS, Acevedo L, Min W, Cheresh DA. Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1. Cancer Res 2007;67:2766-2772. [Free Full Text]
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342. [Free Full Text]
Abou-Alfa GK, Johnson P, Knox J, et al. Final results of phase II, randomized, double-blind study of sorafenib plus doxorubicin and placebo plus doxorubicin in patients with advanced hepatocellular carcinoma. Eur J Cancer 2007;5:Suppl:259-259.
The authors reply: Spinzi and Paggi comment on the need fora quality-of-life assessment. Our trial included patient-reportedoutcomes measured through the Functional Assessment of CancerTherapy–Hepatobiliary Symptom Index 8 (FHSI8) questionnaire,and thus, their concern has already been addressed. We did notidentify differences between sorafenib and placebo in the timeto the end point of symptomatic progression. Treatment-relatedsymptoms were more frequent in the sorafenib group and appearedearly during therapy, but this was counterbalanced by the appearanceof tumor-related symptoms in the placebo group later on. Asmentioned in our report, the FHSI8 questionnaire may be inadequatefor capturing quality-of-life benefits in this setting.1 Thelow incidence of arterial hypertension is probably related tothe presence of underlying cirrhosis that induces peripheralarterial vasodilatation with arterial hypotension. Accordingly,it is inadequate to compare our data with data from populationswith preserved liver function.
We agree with Copur that there is a need to identify biomarkersas surrogates of the efficacy of sorafenib, and such studiesare under way.2 If successful, such criteria will be of majorhelp in the design of future investigations. Nevertheless, alpha-fetoproteinlevels have had limited accuracy for such purposes.1,2
Finally, Palmer proposes that priority be given to combinationsof sorafenib with chemotherapy. Proposals should have a scientificrationale and be based on efficacy data obtained in phase IIinvestigations, and, optimally, the safety profile of sorafenibshould be maintained. We think that priority should be givento molecular targeted therapies because of the available positivesignals, whereas chemotherapy has not exhibited efficacy andhas severe side effects in this study population. Obviously,as in any clinical research activity, the final answer willcome from well-designed phase III trials, and fortunately, severalof them have already been planned.
Josep M. Llovet, M.D. Institució Catalana de Recerca i Estudis Avançats 08036 Barcelona, Spain jmllovet{at}clinic.ub.es
Llovet JM, Di Bisceglie A, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698-711. [Free Full Text]
Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008;48:1312-1327. [Medline]
The editorialist replies: Palmer makes the excellent point thatmolecularly targeted agents can be effectively combined withconventional chemotherapeutic agents, particularly in contextsin which there is a strong scientific rationale for enhancementof the effects of chemotherapy by the targeted agent, as isthe case with the combination of doxorubicin with sorafenib.1As I mentioned in my editorial, "combination trials of sorafeniband similar agents with other treatment approaches and classesof agents" are eagerly anticipated.
The comment by Spinzi and Paggi highlights the importance ofquality of life as an end point in clinical trials of cancertherapy and is perhaps particularly relevant in this context,since there was no significant difference between the sorafeniband placebo groups with respect to the end point of time tosymptomatic progression. Regarding the overall low incidenceof hypertension in both groups, it is theoretically possiblethat this was due to the effects of cirrhosis on the systemiccirculation. Patients with cirrhosis typically have low or low-normalblood pressures because of peripheral vasodilatation and maybe relatively protected from sorafenib-induced hypertension.2
Copur notes the potential value of using trends in alpha-fetoproteinlevels as a marker of response to targeted therapy. This wouldbe consistent with results shown for changes in alpha-fetoproteinlevels in patients with hepatocellular carcinoma and elevatedpretreatment alpha-fetoprotein levels in response to liver transplantation,surgical resection, chemoembolization, radioembolization, orablative therapies.3,4
The editorial contained an error in the price reported for sorafenibin Korea. The correct price per month in Korea is $3,013 (U.S.dollars).
Lewis R. Roberts, M.B., Ch.B., Ph.D. Mayo Clinic Rochester,MN 55905
References
Abou-Alfa GK, Johnson P, Knox J, et al. Final results of phase II, randomized, double-blind study of sorafenib plus doxorubicin and placebo plus doxorubicin in patients with advanced hepatocellular carcinoma. Eur J Cancer 2007;5:Suppl:259-259.
Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006;43:Suppl 1:S121-S131. [CrossRef][ISI][Medline]
Xu X, Ke QH, Shao ZX, et al. The value of serum alpha-fetoprotein in predicting tumor recurrence after liver transplantation for hepatocellular carcinoma. Dig Dis Sci 2008 June 18 (Epub ahead of print).
Shirabe K, Takenaka K, Gion T, Shimada M, Fujiwara Y, Sugimachi K. Significance of alpha-fetoprotein levels for detection of early recurrence of hepatocellular carcinoma after hepatic resection. J Surg Oncol 1997;64:143-146. [CrossRef][ISI][Medline]
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