Preliminary experience with gemcitabine and cisplatin adjuvant chemotherapy after liver transplantation for hepatocellular carcinoma

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EJSO 34 (2008) 906e910

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Preliminary experience with gemcitabine and cisplatin adjuvant chemotherapy after liver transplantation for hepatocellular carcinoma C.-B. Hsieh a, S.-J. Chou a, M.-L. Shih a, H.-C. Chu c, C.-H. Chu a, J.-C. Yu a, N.-S. Yaob,* a

Division of General Surgery, Department of Surgery, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan Department of Hematology/Oncology, Department of Internal Medicine, National Defense Medical Center, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Road, 114 Taipei, Taiwan c Division of Gastroenterology, Department of Internal Medicine, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan b

Accepted 27 November 2007 Available online 31 December 2007

Abstract Aim: Liver transplantation (LT) criteria for treatment of hepatocellular carcinoma (HCC) were refined to improved survival and disease-free rates. Adjuvant chemotherapy might eliminate disseminated tumor cells after removal of the primary liver cancer and thereby benefit LT recipients. Our purpose was to evaluate the effect of an adjuvant chemotherapy (gemcitabine and cisplatin) on outcome of patients treated with LT for HCC. Methods: Of the 99 patients who underwent liver transplantation from October 2001 through February 2006, there were 58 with HCC. Nine patients with extra-hepatic metastasis and four who died for noncancer-related reasons were excluded. Three groups (total n ¼ 45) were compared: Group A (n ¼ 15) met the Milan criteria and did not receive study chemotherapy, Group B (n ¼ 13) did not fit the Milan criteria and did not receive chemotherapy, and Group C (n ¼ 17) did not fit the Milan criteria and received gemcitabine and cisplatin. Results: The chemotherapy regimen was well tolerated. Leukopenia, the need for granulocyte colony-stimulating factor treatment, or both occurred in four patients. The disease-specific survival rates were better for groups A and C than for group B ( p ¼ 0.02) and the diseasefree survival rates were also better for groups A and C than for group B ( p ¼ 0.01). Conclusions: Systemic gemcitabine and cisplatin may improve disease-specific and disease-free survival in HCC patients who do not meet the Milan criteria after LT. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Hepatocellular carcinoma; Liver transplantation; Gemcitabine; Milan criteria; Disease-specific survival rate; Disease-free survival rate

Introduction Hepatocellular carcinoma (HCC) is the fifth most frequent malignant tumor worldwide (564,000 cases/year) and the third leading cause of death due to cancer.1,2 Complete surgical resection remains the only potentially curative therapy for this disease with the 5-year survival rates ranging from 25% to 39%.3 Unfortunately, the incidence of resectability of this tumor is low (only 3e30%).4 Tumor characteristics, such as multifocality, lymph node

* Corresponding author. Tel.: þ886 2 8792 7191; fax: þ886 2 8792 7372. E-mail address: [email protected] (N.-S. Yao). 0748-7983/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2007.11.014

metastasis, and associated cirrhosis (often hepatitis Band C-virus-related) limit its resectability.5 Liver transplantation (LT) is the only therapeutic option capable of simultaneously curing both HCC and the underlying liver disease. Several trials of LT for small HCCs have shown encouraging survival data.6e8 Attempts to define the optimal upper limits of tumor size and number as predictors for outcome after LT, however, have yielded conflicting results.6 The United Network of Organ Sharing (UNOS) has adopted the criteria proposed by the group from Milan, Italy, as selection guidelines for LT. These criteria (i.e., the Milan criteria) can be used to select patients for LT with up to three tumors (none exceeding 5 cm in diameter) and provide significant predictors of good survival after liver

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transplantation.6 The results of transplantation alone for advanced HCC are disappointing, with 5-year survival rates less than 40%.7,8 A more recent review showed only a modest improvement of the 5-year survival rate to 44% for tumors larger than 5 cm.9 Nevertheless, this finding has encouraged transplant surgeons to re-evaluate LT in advanced HCC patients and to use adjuvant therapies to control possible tumor recurrence in LT recipients. Removal of the native liver requires extensive manipulation and will likely result in intraoperative dissemination of tumor cells.10,11 In theory, adjuvant therapy could benefit patients undergoing LT by suppressing or eliminating possible tumor recurrence. Few studies have assessed the effect of adjuvant or neoadjuvant chemotherapy in patients with invasive HCC after orthotopic liver transplantation. Since each of these studies included only a small number of patients, their conclusions concerning the benefit of adjuvant chemotherapy remain controversial.12e14 Patients with advanced HCC have been treated with doxorubicin (the most frequently used drug), cisplatin, and 5-fluorouracil (5-FU). But systemic doxorubicin causes well-known complications and, more importantly, fails to improve outcome of either advanced HCC patients or LT recipients with HCC.14,15 Gemcitabine is a novel nucleoside analog that has a broad spectrum of antitumor activity. 16 Its strong activity against the growth of a human hepatocellular cancer cell line was demonstrated by Graziadei et al.17 Moreover, a recent phase II clinical study of 28 patients in Taiwan found that gemcitabine therapy achieved an 18% response rate in patients with advanced HCC.18 Gemcitabine was also found to have efficacy against HCC when combined with cisplatin (an antitumor drug that is now used routinely to treat non-small-cell lung cancer).19 The purpose of this study was to determine whether the gemcitabine/cisplatin combination improves the outcome of LT recipients with advanced HCC. Patients and methods Patient selection In total, 99 patients had liver transplants between October 2001 and February 2006. Of these, 58 patients (52 men and 6 women) had HCC and 53 underwent LT at an offshore transplant center in mainland China. Of the 58, a total of 9 with extrahepatic metastasis and 4 who died of causes other than their cancer were excluded. The included 45 were grouped into: (A) those not treated with gemcitabine/cisplatin who met the Milan criteria for LT (n ¼ 15); (B) those not treated with gemcitabine/cisplatin who did not meet the Milan criteria (n ¼ 13); and (C) those treated with gemcitabine/cisplatin who did not meet the Milan criteria. There were no inclusion or exclusion criteria for patients who did not meet the Milan criteria into

907

chemotherapy group C. It only depended on patients’ own willingness to receive chemotherapy or not after discussion with the physicians. Before study entry, all patients provided a complete medical history and underwent a physical examination, including an assessment of performance status, recent weight loss, concurrent nonmalignant diseases, and therapies. Results of laboratory studies (including complete blood count, differential count, biochemical liver and renal function tests, a-fetoprotein, cancer clinical staging, Cancer of the Liver Italian Program (CLIP) score, tumor number and size, chest radiography, and abdominal-pelvic computed tomography) were collected from the medical charts and computer database. Levels of serum hepatitis B surface antigen and serum hepatitis C virus antibody were also determined before treatment. A flow chart of this study is shown in Fig. 1. Chemotherapy protocol The therapy consisted of gemcitabine 600e800 mg/m2 (days 1, 8, and 15) delivered as an intravenous infusion over 30 min to patients in an outpatient clinic. On day 15, cisplatin 80 mg/m2 was infused in combination with the gemcitabine. One treatment course lasted 4 weeks and was repeated four times. No dose escalation was allowed. The use of anti-emetic premedication was left to the discretion of the treating physician. During treatment, patients were seen weekly by a physician for a brief history, physical examination, and toxicity assessment. A complete blood count was done before each gemcitabine treatment. Renal and liver function and a-fetoprotein level were examined every month. Measurable disease was assessed by radiography every 3 months. The side effects of chemotherapy (including leukopenia and nausea/vomiting), amount of granulocyte colony-stimulating factor (GCSF) given, adjustments to the immunosuppressant dosage, infection, and compliance were recorded. Infection was defined as fever >38.5  C requiring hospitalization. Patients were monitored regularly until death. Statistical analysis Continuous variables are expressed by means  standard deviations and differences were tested for statistical significance using the Student t-test. Categorical variables were compared using the chi-square test. Disease-free survival curves and disease-specific survival curves were constructed using the KaplaneMeier method and differences between groups were compared using the log-rank test. The triggering event for survival analysis was patient death related to cancer and that for disease-free survival was HCC recurrence. Analyses were performed using S-Plus 2000 for Windows statistical software (CANdiensten, Amsterdam,

C.-B. Hsieh et al. / EJSO 34 (2008) 906e910

908

HCC patients with liver transplantation (n= 58)

Non-cancer related mortality (n= 4) Not meeting inclusion criteria: distal metastasis (7) and lymph node metastasis (2) (n= 9)

Grouping

Group A: satisfy the Milan criteria (n= 15)

Lost to follow-up (n= 0)

Group B: do not satisfy the Milan criteria and without chemotherapy (n=13)

Lost to follow-up (n= 0)

Group C: do not satisfy the Milan criteria and with chemotherapy (n=17)

Lost to follow-up (n= 0) Incomplete chemotherapy (n= 0)

Analyzed (n= 15)

Analyzed (n= 13)

Analyzed (n= 17)

Fig. 1. Flow chart showing the grouping of patients recruited into the study.

Netherlands). Statistical significance was defined as p < 0.05. Results Demographics and clinical characteristics Table 1 shows group demographic and clinical characteristics. The mean age was 55 years, 54 years, and 52 years in groups A, B, and C, respectively ( p > 0.05). Males predominated in all three groups, along with hepatitis B virus infection; only four women were in the study. Group A patients had stage T1N0M0 tumors and satisfied the Milan criteria. The other two groups had larger tumors and did not fulfill the Milan criteria. Patients with low CLIP score met the Milan criteria; most patients with CLIP scores of 1 and 2 were in group A. Tumor size and number differed significantly between groups A, B, and C, as did clinical cancer stage and CLIP score. The mean a-fetoprotein levels of groups A, B, and C were 506, 1755, and 3490 ng/dl; because of the large standard deviations among the three groups, no statistical inference could be made.

Response to chemotherapy Seventeen patients received chemotherapy (Table 2). The side effects of gemcitabine and cisplatin included leukopenia, nausea and/or vomiting, and fatigue. Four patients had leukopenia and received the GCSF treatment. To alleviate severity of leukopenia and thereby allow completion of their adjuvant therapy, 15 of 17 patients required adjustment of their post-transplant immunosuppressive drug dosage according to the white count and transaminase level. No rejection events were observed during the dosage adjustment period and after the completion of chemotherapy, all patients’ immunosuppressive drug dosage could be adjusted back to previous level. Five patients had nausea and/or vomiting and 10 had fatigue. No treatment-related death occurred. Disease-free and -specific survival The disease-specific survival curves for the three groups are compared in Fig. 2. The 3-year survival rates of the three groups were groups C and A 78%, and group B

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Table 1 Group characteristicsa Characteristics

A

B

C

Age (years) Gender (M/F) Etiology HCC þ HBV HCC þ HCV HCC

55  8 14/1

54  11 10/3

52  10 17/0

10 3 2

10 2 1

16 0 1

Clinical stage T1N0M0 T2N0M0 T3N0M0

9 6 0

0 5 8

0 4 13

CLIP score 1 2 3 4

10 5 0 0

3 3 3 4

2 7 6 2

Tumor number Tumor size (cm) AFP ng/dl (pre-op.)

1.5  0.6 2.8  0.7 506  1644

3.0  1.0 6.3  3.6 1755  3668

3.3  1.4 8.3  4.3 3490  10954

HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; CLIP, Cancer of the Liver Italian Program; AFP, a-fetoprotein. a Data are expressed as mean  standard deviation.

32%. The p-value of the likelihood ratio test was significant at 0.02 for agreement between groups B and C. The 2-year disease-free survival rates were group A, 79%; group C, 56%; and group B, 38%. The likelihood ratio test p-value for agreement between three groups was 0.01 (Fig. 3). The median follow-up period was 19.9 months. Discussion The current treatment for HCC includes resection, arterial chemo-embolization, or systemic chemotherapy, but each modality has limited effect. The most important reason for treatment failure in HCC patients is underlying liver cirrhosis. HCC patients usually have liver cirrhosis. Liver transplantation is the only way to cure patients with both problems.

Fig. 2. Disease-specific survival curve. Group A: patients who satisfied the Milan criteria, no chemotherapy; group B: patients who did not satisfy the Milan criteria, no chemotherapy; group C: patients who did not satisfy the Milan criteria but underwent chemotherapy. The p value compares groups B and C.

between recipients of livers incidentally found to have small HCCs and recipients of livers without malignancies.20 Overall survival in carefully selected patients undergoing LT for HCC is similar to that of patients undergoing LT for nonmalignant reasons.21,22 That finding encouraged transplant surgeons to challenge objections to LT as treatment of more advanced HCC. For patients with large HCC but no extrahepatic metastasis, the recurrence rate was unacceptably high after LT and therefore they were excluded by the Milan criteria.23 However, many of such patients still receive LTs all over the world.24 Therefore, adjuvant chemotherapy is theoretically a reasonable way to eradicate possible micrometastases existing prior to LT. After LT, these patients must have adequate liver function to receive the full course of chemotherapy. However, the joint impact of post-transplant immunosuppression and systemic chemotherapy could cause severe bone marrow suppression with consequent infection problems. Both hinder the completion of chemotherapy.

Liver transplantation as treatment for HCC Attitudes toward liver transplantation as a treatment for HCC changed when no difference in survival was found Table 2 Side effects of gemcitabine and cisplatin treatment Side effects

No. of patients

Complete course Leukopenia Gr. 3&4 and GCSF Tx Leukopenia all grades/adjust Is dosage Nausea/vomiting Gr. 3&4 Fatigue Infection Gr. 3&4

17 4 15 5 10 3

GCSF Tx, granulocyte immunosuppression.

colony-stimulating

factor

treatment;

Is,

Fig. 3. Disease-free survival curve. Group A: patients who satisfied the Milan criteria, no chemotherapy; group B: patients who did not satisfy the Milan criteria, no chemotherapy; group C: patients who did not satisfy the Milan criteria, but underwent chemotherapy.

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Advantages of adjuvant gemcitabine plus cisplatin Gemcitabine results in less bone marrow suppression and fewer clinical side effects compared to other chemotherapeutic agents such as doxorubicin. Cisplatin, mainly excreted by the kidney, also causes minimal bone marrow suppression. In our study, patient compliance was good (chemotherapy completion rate, 100%) and side effects were mild, which allowed patients to complete the whole course of therapy. During the study, four patients died: one each died of acute rejection, cholangitis, and endocarditis, and one committed suicide. These deaths were not related to cancer or adjuvant chemotherapy. Thus, even though our sample size is small, the disease-specific survival rate is reliable. Conclusion In summary, although our sample size was small, those HCC patients who did not fulfill the Milan criteria, who did not have lymph node or distant metastasis, and received treatment with LT followed by systemic gemcitabine and cisplatin tended to have better disease-specific and disease-free survival than similar patients who only received LT. We suggest that gemcitabine and cisplatin chemotherapy is effective, safe, and well tolerated by recipients of LT and immunosuppressants. With only a few patients in our study, it is not possible to make definitive conclusions, but the survival advantage demonstrated is worthy of more detailed exploration. A larger and randomized clinical trial with longer follow-up to confirm the significance of our findings is warranted. Conflict of interest There is no proprietary, financial, professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in or the review of, the manuscript.

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