Japanese Journal of Clinical Oncology

Department of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan

Chemotherapy is of limited value in the treatment of hepatocellular carcinoma (HCC), since there are no established chemotherapeutic regimens proven to be effective. The aim of the present study was to determine predictive factors for tumor response to systemic chemotherapy in HCC patients. The relationship between patients' characteristics and tumor response was examined in 147 previously untreated HCC patients receiving systemic chemotherapy. Ten patients showed partial response (PR) and none showed complete response (CR). The response rate for all single anticancer agents was less than 10% and the overall response rate was 6.8%. The response rate in patients with unilateral HCC was significantly higher than in those with bilateral HCC. However, there were no responders among patients with a performance status of 2-3, ascites, a tumor occupying more than 50% of the entire liver, tumor thrombus in the main portal trunk or a serum bilirubin level of more than 2.0 mg/dl. There was a close relationship between patients' characteristics and tumor response. It is concluded that patients with fairly advanced HCC and/or poor hepatic reserve should not be given systemic chemotherapy.

Key words: hepatocellular carcinoma - systemic chemotherapy

Introduction

Recently, two non-surgical treatments, transcatheter arterial embolization (TAE) and percutaneous ethanol injection (PEI), both having marked anti-tumor activities, have been adopted as standard treatments for hepatocellular carcinoma (HCC). However, the prognosis following these treatments remains unsatisfactory owing to post-therapeutic recurrence.

Currently, chemotherapy for HCC has limited value in clinical practice, since there are no established chemotherapeutic regimens proven to be effective against this cancer. Our clinical trials using various drugs for HCC have also yielded disappointing results (1 -6 ). In order to improve the prognosis of HCC patients, the development of a chemotherapy regimen which is truly effective against HCC is needed.

In the present retrospective study, the relationship between patients' characteristics and tumor response was analyzed in HCC patients receiving systemic chemotherapy in order to clarify factors that might help to predict the tumor response.

Patients and Methods

Patients

The present series included 147 previously untreated HCC patients. The diagnosis of HCC was confirmed by histological examination (biopsy and/or necropsy) and based on a markedly elevated level of serum [alpha]-fetoprotein (AFP) ( >= 400 ng/ml) with space-occupying lesions demonstrable by various imaging techniques, or on typical computed tomographic and/or angiographic findings. All the patients received systemic chemotherapy in phase 2 trials from April 1980 to February 1994 at the National Cancer Center Hospital, Tokyo, Japan (1 -6 ) (Table 1 ).

Before chemotherapy, all patients underwent a full clinical assessment, chest X-ray examination, complete blood count, biochemistry tests, determination of the serum AFP level and ultrasonographic and computed tomographic (CT) examinations of the abdomen.

Table 1 . Chemotherapy regimens given to 147 patients with advanced HCC

Regimen	No. of patients	No. of responders	Response rate (%)	95% Confidence limits
Tegafur	14	0	0.0	0.0-23.2
Fluorouracil	6	0	0.0	0.0-45.9
UFT	15	1	6.7	0.2-31.9
Doxorubicin	15	1	6.7	0.2-31.9
4-Epidoxorubicin	4	0	0.0	0.0-60.2
Etoposide	11	1	9.1	0.2-41.3
Mitoxantrone	19	1	5.3	0.1-26.0
Interferon-[gamma]	14	0	0.0	0.0-23.1
Cisplatin	43	4	9.3	2.6-22.1
FMP*	6	2	33.3	4.3-77.7
Total	147	10	6.8	3.3-12.2

*Fluorouracil, mitoxantrone, cisplatin.

Table 2 Tumor response to systemic chemotherapy with reference to host-related factors No. of responders/No. of patients

Characteristics	Response rate (%)	95% Confidence limits
Age
<60	5.6	1.5-13.6	4/72	N.S.
>= 60	8.0	3.0-16.6	6/75
Sex
Male	6.5	2.8-12.4	8/123	N.S.
Female	8.3	1.0-27.0	2/24
HBsAg*
(-)	7.4	3.4-13.5	9/122	N.S.
(+)	4.0	0.1-20.4	1/25
Alcohol abuse[dagger]
(-)	8.0	3.3-15.7	7/88	N.S.
(+)	5.1	1.1-14.1	3/59
Liver cirrhosis
(-)	11.4	3.8-24.6	5/44	N.S.
(+)	4.9	1.6-11.0	5/103
Total bilirubin
<2.0 mg/dl	7.7	3.8-13.7	10/130	N.S.
>= 2.0 mg/dl	0.0	0.0-19.5	0/17
Albumin
<3.5 g/dl	3.5	0.7-9.9	3/86	N.S.
>= 3.5 g/dl	11.5	4.7-22.2	7/61
Ascites
(-)	8.9	4.4-15.8	10/112	N.S.
(+)	0.0	0.0-10.0	0/35
Performance status
0, 1	9.2	4.5-16.2	10/109	N.S.
2, 3	0.0	0.0-9.3	0/38

*Hepatitis B surface antigen. ^[dagger]Ethanol intake >= 80 g/day for >= 5 yr.

Tumor Response

The response was evaluated according to the criteria of the World Health Organization (WHO) every 4 weeks after the first course of chemotherapy. Tumor response was defined as a 50% or greater reduction in the sum of the product of the two largest perpendicular diameters of all indicator lesions [i.e. a reduction of >50% for partial response (PR) and complete disappearance for complete response (CR)] lasting at least 4 weeks without the appearance of new lesions or the progression of any lesion. No change (NC) was defined as no change or up to 25% increase in tumor size 4 weeks after the first course of chemotherapy. Progressive disease (PD) was defined as a >25% increase in tumor size or the appearance of new lesions within 4 weeks after the start of treatment.

Factors Analyzed

Response rates were analyzed with reference to patients' characteristics. The variables were all binary. The chi-squared test was used to determine the significance of differences in response rates.

Results

Patients' Characteristics

The patients' characteristics are shown in Table 2 . Of the 147 patients with HCC, 123 were male and 24 were female, with a sex ratio of 5:1. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 109 patients and hepatitis B surface antigen (HBsAg) was positive in 25. Thirty-eight patients had extrahepatic metastasis and a raised level of serum AFP( >= 400 ng/ml) was found in 78.

Tumor Response

The results of the phase 2 clinical trials are shown in Table 1 (1 -6 ). None of the patients showed CR and 10 showed PR. Ninety-nine showed NC and 38 demonstrated PD. All anti-cancer agents produced a response rate of less than 10% and the overall response rate was 6.8% (95% confidence limits; range 3.3-12.2%).

Predictive Factors for Tumor Response

Table 2 shows the objective response rates with respect to host-related factors. There was no significant difference in response rate in relation to age, sex, HBsAg status or alcohol abuse. However, no patients with jaundice, ascites or a PS of 2-3 showed an objective response. With regard to tumor-related factors, patients with unilateral HCC showed a significantly higher response rate than those with bilateral HCC (Table 3 ). There were no responders among the patients with tumors occupying 50% or more of the entire liver or tumor thrombus in the main portal trunk.

Table 3 . Tumor response to systemic chemotherapy with reference to tumor-related factors

Characteristics	Response rate (%)	95% Confidence limits	No. of responders/No. of patients
No. of intrahepatic nodules
Single	3.2	0.7-9.1	3/93	N.S.
Multiple	12.0	4.5-24.3	6/50
COLSPAN=5Tumor distribution
Unilateral	10.7	4.0-21.9	6/56	p < 0.05
Bilateral	3.3	0.7-9.4	3/90
Tumor size*
<50%	10.1	5.0-17.8	10/99	N.S.
>= 50%	0.0	0.0-8.0	0/44
Tumor thrombus[dagger]
(-)	8.8	4.3-15.7	10/113	N.S.
(+)	0.0	0.0-10.6	0/33
Extrahepatic metastasis
(-)	6.4	2.6-12.8	7/109	N.S.
(+)	7.9	1.7-21.4	3/38
[alpha]-Fetoprotein
<400 ng/ml	8.7	3.3-18.0	6/69	N.S.
>= 400 ng/ml	5.1	1.4-12.6	4/78

*% of liver cross-sectional area. ^[dagger]Tumor thrombus in the main portal trunk.

Discussion

Systemic chemotherapy for HCC has limited value in clinical practice because only a small number of patients obtain meaningful palliation and because the toxicity of chemotherapy often outweighs its benefits. Therefore, patients with advanced and/or recurrent HCC are considered to be candidates only for clinical trials. However, the results of our phase 2 trials using various drugs for HCC have been disappointing; no single agent has produced a response rate of more than 10% (1 -6 ) (Table 1 ).

The present study was carried out to evaluate predictive factors for tumor response to systemic chemotherapy in 147 previously untreated patients with advanced HCC. There was a close relationship between patients' characteristics and tumor response. Patients with unilateral HCC showed a significantly higher response rate than those with bilateral HCC. However, there were no responders in the subgroup of patients who had an ECOG performance status of 2-3, a serum total bilirubin level of >= 2.0 mg/dl, ascites, tumors occupying >= 50% of the entire liver or tumor thrombus in the main portal trunk.

For appropriate evaluation of the role of chemotherapy in a given neoplastic disease, it is important to analyze the predictive factors influencing toxicity and survival, in addition to those influencing the antitumor response. With respect to toxicity, HCC patients tend to suffer more severe myelosuppression and hepatic toxicity than those with other malignant diseases, because most of them also have liver cirrhosis, which is usually associated with compromised hepatic function, thrombocytopenia and coagulopathy. However, predictive factors for toxicity were not examined in this study, since the toxicity of chemotherapy varies with the type of agents used. On the other hand, the prognosis of HCC patients with factors such as poor performance status and portal tumor thrombi has been reported to be extremely poor when systemic chemotherapy is administered (7 ); the median survival time was <4 months in patients with a performance status of 2-3, ascites, tumor occupying 50% or more of the entire liver or tumor thrombus in the main portal trunk (7 ).

There have been only a few reports concerning the predictive factors for tumor response to systemic chemotherapy for HCC. Although the response is totally unpredictable prior to chemotherapy, it is important to exclude patients unlikely to achieve a tumor response from chemotherapeutic trials. Patt et al. (8 ) reported that the serum AFP level and tumor size may help to predict the response to combination therapy with fluorouracil and recombinant interferon-[alpha]-2b. In their study, there were no responders in the subgroup of patients who had a high level of serum AFP (>50 ng/ml) and/or more than 50% liver replacement by the tumor. With respect to tumor size, their result was similar to ours. However, in our study, the serum AFP level showed no significant relationship with the response rate. Choi et al. (9 ) also reported that the serum AFP level was not correlated with response to systemic chemotherapy with adriamycin. The precise reason for this discrepancy remains unclear, although it may be due to marked regional differences in the biological characteristics of HCC.

These findings indicate that, regardless of the chemotherapy regimen used, patients with poor hepatic reserve and/or fairly advanced HCC are inappropriate candidates for clinical trials of systemic chemotherapy and should be treated with different experimental approaches or offered only systemic care to maintain their quality of life.

References

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2. Tokyo Liver Cancer Chemotherapy Study Group. Phase 2 study of co-administration of uracil and tegafur (UFT) in hepatocellular carcinoma. Jpn J Clin Oncol 1985;15:559-62.

3. Yoshida T, Okazaki N, Yoshino M, Ohkura H, Miyamoto K, Shimada Y. Phase II trial of mitoxantrone in patients with hepatocellular carcinoma.Eur J Cancer Clin Oncol 1988;24:1897-8. MEDLINE Abstract

4. Yoshino M, Okazaki N, Yoshida T, Kanda Y, Miki M, Oda H, et al. A phase II study of etoposide in patients with hepatocellular carcinoma by the Tokyo Liver Cancer Chemotherapy Study Group. Jpn J Clin Oncol 1989;19:120-2. MEDLINE Abstract

5. Yoshida T, Okazaki N, Yoshino M, Ohkura H, Shimada Y. Phase II trial of high dose recombinant gamma-interferon in advanced hepatocellular carcinoma. Eur J Cancer 1990;26:545-6. MEDLINE Abstract

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8. Patt YZ, Yoffe B, Charnsangavej C, Pazdur R, Fischer H, Cleary K, et al. Low serum alpha-fetoprotein level in patients with hepatocellular carcinoma as a predictor of response to 5-FU and interferon-alpha-2b. Cancer 1993;72:2574-82. MEDLINE Abstract

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Received 23 January 1997; accepted 12 May, 1997
For reprints and all correspondence: Shuichi Okada, Department of Internal Medicine, National Cancer Center Hospital, 1-1, Tsukiji5-chome, Chuo-ku, Tokyo, 104, Japan
Abbreviations: HCC, hepatocellular carcinoma; CR, complete response; PR, partial response; NC, no change; PD, progressive disease; AFP, [alpha]-fetoprotein; CT, computed tomography; HBsAg, hepatitis B surface antigen; PS, performance status; TAE, transcatheter arterial embolization; PEI, percutaneous ethanol injection; ECOG, Eastern Cooperative Oncology Group

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