CORRESPONDENCE

Factors Predicting Response and Survival in149 Patients with Unresectable HepatocellularCarcinoma Treated by Combination Cisplatin,Interferon-alpha, Doxorubicin and5-fluorouracil Chemotherapy

I t is often difficult to decide which patients with hepatocellularcarcinoma (HCC) should be given chemotherapy, especially

when extrahepatic disease is an issue. With this dilemma in mind,we read with great interest the study by Leung et al. regardingfactors predicting survival and response to treatment in cases ofunresectable HCC treated with chemotherapy.1 These authors useda moderately toxic chemotherapy regimen of cisplatin, interferon-alpha, doxorubicin, and 5-fluorouracil (PIAF) but achieved verygood objective response and even complete remission in somecases. Positive anti-hepatitis C virus titer, absence of cirrhosis, andlow total bilirubin levels were identified as predictors of objectiveresponse. In addition, multivariate analysis revealed that earlierstage of disease, absence of cirrhosis, and absence of vascularinvolvement were associated with longer survival times. The au-thors reported two treatment-related deaths in the first 50 patientsand stated that only a select group of HCC patients showed clinicalbenefits after PIAF combination therapy. In Turkey, approximately15% of the population carries hepatitis B virus surface antigen(HbsAg), and the incidence of HCC is higher than the rates inwestern countries;2,3 thus, the predictors identified by Leung et al.are key for us in the treatment of HCC patients.

It is well known that a visible hepatic mass consistent withHCC and a serum alpha-fetoprotein level higher than 500 ng/mL inan HBsAg carrier are diagnostic for HCC, and it is acceptable toinstitute treatment without tissue diagnosis.4 However, it is gen-erally agreed that chemotherapy should only be administered topatients with histopathologically confirmed cancer.5,6 We believethat HCC should be histopathologically diagnosed before high-cost, toxic regimens such as PIAF are given, especially if treatmentresponse is to be evaluated in a trial. Systemic chemotherapy isusually not well tolerated in patients with significant underlyinghepatic dysfunction. Leung et al. reported complete pathologicresponses in resected tumor specimens from eight patients whoachieved partial remission after chemotherapy. We wonder if theseeight cases were pathologically confirmed before treatment. Itwould also be valuable to know whether the patients with sus-pected but not histopathologically diagnosed HCC had a higherresponse rate than those with histopathologically diagnosed dis-ease.

2038

© 2002 American Cancer Society

REFERENCES1. Leung WT, Tang AM, Zee B, et al. Factors predicting re-

sponse and survival in 149 patients with unresectable hep-atocellular carcinoma treated by combination cisplatin,interferon-alpha, doxorubicin and 5-fluorouracil chemo-therapy. Cancer. 2002;94:421-427.

2. Ozyilkan O, Arslan M, Ozyilkan E. Hepatitis B virus andhepatitis C virus infections in Turkish patients with hepato-cellular carcinoma. Am J Gastroenterol. 1996;91:1479-1480.

3. Ozyilkan E, Ozyilkan O, Firat D, Telatar H. Hepatitis C virusantibody in patients with primary liver cancer (hepatocel-lular carcinoma, cholangiocarcinoma, and combined hepa-tocellular-cholangiocarcinoma) in Japan. Cancer. 1994;73:2002-2003.

4. Fong Y, Kemeny N, Lawrence TS. Hepatocellular carcinoma.In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancerprinciples and practice of oncology, 6th ed. Philadelphia:Lippincott Williams & Wilkins, 2001:1164.

5. Haskell CM. Principles of cancer chemotherapy. In: HaskellCM, editor. Cancer treatment, 5th ed. Philadelphia: WBSaunders Company, 2001:81.

6. Von Hoff DD. Medical Oncology In: Weiss GR, editor. Clin-ical oncology. Appleton & Lange, 1993:89.

Zafer Akcali, M.D.Ebru Akin, M.D.

Ozgur Ozyilkan, M.D.Baskent University Faculty of Medicine

Division of Medical OncologyAnkaraTurkey

DOI 10.1002/cncr.10896

Author Reply

I agree with the authors that combination chemo-therapy cisplatin, interferon-alpha, doxorubicin,

and 5-fluorouracil (PIAF) is a moderately toxic chemo-therapy and should be given carefully to selected pa-tients. From our study, we found that patients with anabsence of cirrhosis, earlier stage disease, and betterliver function had an associated higher chance of re-sponse and longer survival.1 Our population of hepa-tocellular carcinoma (HCC) patients was mainly asso-ciated with hepatitis B (89.3%); a few patients hadhepatitis C (2.7%). We stated in the discussion that

positive anti-hepatitis C may be a favorable factor, butwe did not have enough patients and statistical powerto prove the point. This must be answered by othergroups treating mainly hepatitis C associated HCC.From our earlier studies, we accepted patients withpositive hepatitis B, alpha-fetoprotein (AFP) higherthan 500ng/mL, and radiologic evidence of hepatictumor to be diagnostic of HCC without histology. Iagree with the authors that giving a moderately toxicregimen to patients without a definitive histologic di-agnosis may be risky. The standard of practice in ourcenter at present for all clinical trials in HCC requireshistologic diagnosis, including our recent prospectiverandomized study comparing PIAF and standard sin-gle agent doxorubicin. I think this should be the trendnow for HCC trials. Among the responders, there wereonly three patients who did not have histological di-agnosis, but they all had high AFP (above 500ng/mL)that decreased after treatment together with radio-logic regression of the tumor. They all showed com-plete pathologic response from examination of theresected specimen. All except three cases who under-went surgery after PIAF had histologic diagnosis be-fore treatment.2 With the small number of patients, wewere not able to determine whether diagnosis by ra-diology and AFP level without histology are predictorsfor response or not.

REFERENCES1. Leung TW, Tang AM, Zee B, et al. Factors predicting re-

sponse and survival in 149 patients with unresectable hep-atocellular carcinoma treated by combination cisplatin,interferon-alpha, doxorubicin and 5-fluorouracil chemo-therapy. Cancer. 2002;94:421-427.

2. Lau WY, Leung TW, Lai BS, et al. Preoperative systemicchemoimmunotherapy and sequential resection for unre-sectable hepatocellular carcinoma. Ann Surg. 2001;233:236-241.

Thomas Leung, M.D.Department of Clinical Oncology

The Chinese University of Hong KongPrince of Wales Hospital

Hong Kong ChinaDOI 10.1002/cncr.10895

Correspondence 2039