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10.1245/s10434-006-9004-1
Annals of Surgical Oncology 13:1329-1337 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Postresectional Adjuvant Intraportal Chemotherapy in Patients with Hepatocellular Carcinoma: A Case-Control Study

Gar-Yang Chau, MD, MPH1,2, Wing-Yiu Lui, MD1,2, Shyh-Haw Tsay, MD2,3, Yee Chao, MD, PhD2,4, Kuang-Liang King, MD1,2 and Chew-Wun Wu, MD, FACS1,2

1 Department of Surgery, Taipei Veterans General Hospital, 201 Shih-pai Road, Section 2, Shih-pai, Taipei, Taiwan 112
2 School of Medicine, National Yang-Ming University, 155 Li-Nong Street, Section 2, Peitou, Taipei, Taiwan 112
3 Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
4 Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan

Correspondence: Address correspondence and reprint requests to: Gar-Yang Chau, MD, MPH; E-mail: gychau{at}vghtpe.gov.tw


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The postresectional tumor recurrence rate is high in patients with hepatocellular carcinoma (HCC). Tumor portal venous invasion is the most important factor related to recurrence. Adjuvant intraportal infusion chemotherapy (IPIC) was used in HCC patients to improve the outcomes.

Methods: Between June 1998 and May 1999, 28 HCC patients (IPIC group) underwent postresectional IPIC daily for 2 days with 5-fluorouracil (650 mg/m2), leucovorin (45 mg/m2), doxorubicin (10 mg/m2), and cisplatin (20 mg/m2). Treatment was repeated every 3 weeks for six cycles. Patient outcomes were compared with those of 66 matched HCC patients (control group) who underwent hepatectomy without adjuvant therapy.

Results: The IPIC group received an average of 5.2 cycles of chemotherapy, starting 5 to 24 days after surgery. The most frequent IPIC-related adverse events were upper abdominal pain, vomiting, and myelosuppression. Five-year disease-free and overall survival rates for the IPIC group were 44.6% and 60.7%, respectively. Subgroup analysis of patients with tumor-node-metastasis stage I and II disease identified significantly lower recurrence rates for the IPIC group (33.3%) than the control group (65.0%; P = .025). For patients with stage I and II disease, 5-year disease-free and overall survival rates for the IPIC group (70.6% and 83.3%, respectively) were significantly higher than those of the control group (33.4% and 46.9%, respectively; P < .05). Patients with stage III disease do not benefit from IPIC.

Conclusions: Postoperative IPIC benefits HCC patients with tumor-node-metastasis stage I and II disease. The survival advantages demonstrated justify a selection of patients for future trials.

Key Words: Hepatocellular carcinoma • Hepatic resection • Tumor recurrence • Adjuvant chemotherapy • Intraportal infusion


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatocellular carcinoma (HCC) is a common malignancy worldwide and has been difficult to treat successfully.1 Although surgical resection offers HCC patients a chance for a cure, the postresectional tumor recurrence rate is high, with a cumulative 5-year tumor recurrence rate ranging from 40% to 80%.2,3 To improve long-term outcome for HCC patients after potentially curative resection, effective measures in reducing recurrence risk are mandatory.

Presently, tumor vascular invasion to the portal venous system—macroscopic, microscopic, or both—is regarded as one of the most important factors related to recurrence after hepatic resection for HCC.4–6 Many efforts to reduce the recurrence risk after HCC resection have been tried, including various regimens of postsurgical systemic or hepatic artery chemotherapy.7 Encouraging results of reduced recurrence have been noted in patients who are given adjuvant systemic chemotherapy after liver transplantation.8,9 However, studies evaluating the effect of adjuvant chemotherapy on prevention of postresectional HCC recurrence have shown divergent results.7

After HCC resection, the hepatic remnant is the most common site of tumor recurrence and is involved at diagnosis in 68% to 96% of patients.10,11 Tumor recurrence occurs mostly within the first 2 years after hepatic resection.11 Hepatic transarterial chemotherapy has been shown to be effective for locoregional treatment of inoperable or recurrent HCC.12,13 The effect of hepatic transarterial chemotherapy used as postoperative adjuvant therapy has been diverse.14 Recent studies have shown that it may not reduce intrahepatic recurrence after hepatic resection.15,16 In HCC, the frequency of tumor microscopic vascular invasion is high, even in patients with resectable disease.17 These small or microscopic tumor emboli may exist before surgery and/or result from tumor dissemination during surgical manipulation. Intra-arterial chemotherapy cannot eradicate tumor cells in portal tracts. The rationale for continuous intraportal infusion chemotherapy (IPIC) is that direct infusion of cytotoxic agents into the portal vein early after HCC resection increases drug exposure of microscopic tumor emboli in the portal venules, thus achieving maximal tumor cell death.

In our institution, a combination regimen of 5-fluorouracil, leucovorin, cisplatin, and doxorubicin was used in a preliminary study to assess the feasibility and safety of IPIC. This study reports the results of the first 28 patients who underwent the protocol of postoperative adjuvant IPIC, after a median follow-up of 74 months. Additionally, these outcomes were compared with those of 66 HCC patients who underwent hepatic resection without adjuvant therapy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between June 1998 and May 1999, HCC patients with resectable tumors were recruited for postoperative adjuvant intraportal chemotherapy at Taipei Veterans General Hospital, Taipei, Taiwan. The protocol was approved by the institutional review board. Informed consent was obtained from each patient. Entry criteria were that the patients underwent curative resection, had a Child-Pugh class A hepatic status, and were free of extrahepatic disease. Patients with a history of tumor biopsy, transcatheter arterial chemoembolization, and chemotherapy or alcohol injection were excluded. Patients with regional lymph node involvement, preoperative tumor rupture, or tumor involvement of adjacent tissue (including the diaphragm or adrenal glands discovered at the time of operation) were also excluded.

Preoperative liver function evaluations included serum biochemistry, prothrombin time, and measurement of the indocyanine green retention value at 15 minutes. Preoperative imaging studies included chest X-ray, abdominal ultrasonography, hepatic arteriography (including computed tomographic angiography portography), and magnetic resonance imaging.

Surgery
Operations were performed according to standard procedures as previously described.18–20 Intraoperative ultrasonography was routinely performed. The hepatic parenchyma was transected with either a small Kelley clamp (tissue-fracture technique) or an ultrasound dissector under intermittent inflow occlusion.20 Intraoperative cholangiography was performed routinely. All operative procedures were performed without concomitant thoracotomy. Two closed-suction drains were placed in the perihepatic space before the abdomen was closed.

Pathologic Examination and Laboratory Analysis
After surgery, the macroscopic and microscopic features of the tumor, including size, number, capsular formation, and vascular invasion, were recorded. Tumor grade was assessed by using the grading scheme of Edmondson and Steiner.21 Patients were classified according to the American Joint Committee on Cancer/Union Internationale Contre le Cancer tumor-node-metastasis staging system.22

Techniques of Intraportal Chemotherapy
Immediately after hepatic resection and intraoperative pathologic documentation of the resected HCC, a 6.6F radio-opaque catheter (Bard Port; C. R. Bard Inc., Salt Lake City, UT) was inserted into the left gastric vein (coronary vein) along the margin of the lesser curvature of the stomach, passing antegrade to the junction of the left gastric vein and splenic vein. The catheter was then attached to an injection port implanted subcutaneously over the right anterior chest wall. After surgery, adjuvant chemotherapy was initiated when patients resumed oral intake and were free of significant ascites with adequate hepatic and renal function (total bilirubin value < 3.0 mg/dL, prothrombin time < 1.3 times control, and creatinine level < 2.0 mg/dL). Patients were also required to have an adequate blood count (white blood cell count > 3,000/ µL and platelet count > 80,000/µL) and no sign of infection. Before chemotherapy, a catheter portogram with injection of 60% meglumine sodium amidotrizoate was obtained to check the position and patency of the catheter and the distribution of the infusion.

One course of intraportal infusion therapy consisted of daily administration of 5-fluorouracil (650 mg/m2 of body surface for 24 hours on days 1 and 2), leucovorin (45 mg/m2 of body surface for 24 hours on days 1 and 2), doxorubicin (10 mg/m2 of body surface for 10 minutes on days 1 and 2), and cisplatin (20 mg/ m2 of body surface for 6 hours on days 1 and 2). Metoclopramide and dexamethasone were administered before chemotherapy to control nausea and vomiting. Complete blood counts and liver and renal function tests were performed before each cycle. Treatment was repeated every 3 weeks or delayed for 1 to 2 weeks until the white blood cell count was > 3,000/µL and the platelet count was > 80,000/µL. The maximum number of treatment cycles was 6.

During the study period, 31 consecutive patients were enrolled to undergo the protocol with initially successful IPIC catheterization after hepatic resection. One patient did not undergo chemotherapy as a result of persistently high postsurgical serum bilirubin levels. Two patients declined chemotherapy. These 3 patients were excluded from the study, leaving 28 patients for further evaluation. For comparison, 66 HCC patients who underwent liver resection between March 1997 and February 2000 with no adjuvant therapy (control group) were selected consecutively from a computer database. All patients in this control group underwent curative surgery. The control group patients were matched for age, sex, liver function, and tumor stage with IPIC group patients and had no contraindications to IPIC. Data were collected prospectively and analyzed retrospectively.

Follow-Up
After completing chemotherapy regimens, patients were followed up every 2 months with measurements of serum alfa fetoprotein, ultrasonography, and/or computed tomography or magnetic resonance imaging. Serum alfa fetoprotein positivity indicated observation of newly increased alfa fetoprotein values in patients with initially alfa fetoprotein–positive tumors. When recurrence was indicated by any examination, hepatic angiography was performed to confirm recurrence. For cases with tumor recurrence, the further treatment modalities applied were repeated resection, transcatheter arterial embolization, percutaneous alcohol injection, and chemotherapy.

Statistical Analysis
Statistical analysis was performed with SPSS (SPSS Inc., Chicago, IL). Student’s t-test was used to compare continuous variables, and {chi}2 and Fisher’s exact test were used to compare discrete variables. Survival rates were calculated with the Kaplan-Meier method,23 and survival curves were compared by using the log-rank test. Data are expressed as mean (SD). P < .05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Tables 1Go and 2Go list patient characteristics for patients in both groups. No significant differences were noted between groups. No patient with HCC of the fibrolamellar variant was encountered in the IPIC or control group.


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  		TABLE 1. Clinical characteristics and operative procedures performed on IPIC and control group patients
 

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  		TABLE 2. Pathologic factors of IPIC and control group patients
 
Morbidity and Mortality
The surgical factors (Table 3Go) were not significantly different between groups. One patient who received one course of IPIC died 2 months after surgery as a result of gastritis with bleeding and hepatic failure. No patient in the control group died of postoperative complications. There was no increase in the incidence of intra-abdominal sepsis or intra-abdominal bleeding in the IPIC group.


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  		TABLE 3. Surgical factors of IPIC and control group patients
 
Adjuvant therapy began on postoperative days 5 to 24. Patients received an average of 5.2 cycles of chemotherapy. Twenty-one patients completed the six-course treatment. Chemotherapy was discontinued prematurely because of gastritis in one patient (3.6%), tumor recurrence in two (7.1%), catheter occlusion in two (7.1%), an increased serum bilirubin level in one (3.6%), and drug extravasation in one (3.6%).

Adverse Events Related to Chemotherapy
Twenty patients (71.4%) experienced adverse events during IPIC treatment (Table 4Go). The most frequent adverse events were mild-to-moderate upper abdominal pain, malaise, nausea and vomiting, and myelosuppression. No patient experienced severe chemical hepatitis or regional hepatic toxicity. Complications related to the portal catheter were extravasation of chemotherapy agents at the subcutaneous port site with resultant tissue necrosis in one patient and catheter occlusion during treatment in two patients.


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  		TABLE 4. Morbidities associated with intraportal infusion chemotherapy
 
Recurrence and Survival
The median follow-up of surviving patients was 74 months (range, 60–81 months) in the IPIC group and 73 months (range, 47–86 months) in the control group. During follow-up, there were 16 recurrences (57.1%) in the IPIC group and 48 recurrences (72.7%) in the control group (P = .138). The respective 1-, 3-, and 5-year disease-free survival rates were 66.9%, 48.3%, and 44.6% for patients in the IPIC group (Fig. 1Go) and 67.5%, 39.2%, and 33.6% in the control group (P = .478). The respective 1-, 3-, and 5-year overall survival rates were 85.7%, 64.3%, and 60.7% for patients in the IPIC group (Fig. 1Go) and 86.4%, 65.2%, and 45.0% in the control group (P = .338). There was a trend toward better overall and disease-free survival in the IPIC group than in the control group. When analysis was restricted to patients with tumor-node-metastasis stage I and II disease, the tumor recurrence rate was significantly lower in the IPIC group (33.3%; 6 of 18) than in the control group (65.0%; 26 of 40; P = .025), and the respective 1-, 3-, and 5-year disease-free survival rates were significantly better in the IPIC group (88.2%, 76.5%, and 70.6%) compared with those in the control group (71.9%, 42.5%, and 33.4%; P = .019; Fig. 2Go). The respective 1-, 3-, and 5-year overall survival rates were also significantly better in the IPIC group (94.4%, 83.3%, and 83.3%) compared with those in the control group (92.5%, 77.5%, and 46.9%; P = .029; Fig. 3Go). For patients with tumor-node-metastasis stage III disease, there was no difference in tumor recurrence and disease-free and overall survival among patients in the IPIC group compared with those in the control group. The tumor recurrence rate was 100% (10 of 10) in the IPIC group and 84.6% (22 of 26) in the control group (P = .188). The respective 1-, 3-, and 5-year disease-free survival rates were 30.0%, .0%, and .0% for patients in the IPIC group and 53.9%, 17.1%, and 12.8% in the control group (P = .160). The respective 1-, 3-, and 5-year overall survival rates were 76.9%, 46.2%, and 34.6% for patients in the IPIC group and 70.0%, 30.0%, and 20.0% in the control group (P = .295).


Figure 1
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  		FIG. 1. Disease-free and overall survival rates of patients undergoing intraportal infusion chemotherapy.

 

Figure 2
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  		FIG. 2. Disease-free survival rates of the intraportal infusion chemotherapy group and the control group patients with tumor-node-metastasis (TNM) stage I and II disease. The log-rank test found statistically significant differences between groups.

 

Figure 3
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  		FIG. 3. Overall survival rates of the intraportal infusion chemotherapy group and the control group patients with tumor-node-metastasis (TNM) stage I and II disease. The log-rank test found statistically significant differences between groups.

 
At the time of this study analysis, 14 patients (50.0%) in the IPIC group and 41 patients (62.1%) in the control group had died. The major cause of death was progressive recurrent tumors (12 patients in the IPIC group and 38 in the control group). Sites of recurrence and the outcomes of patients with recurrence are summarized in Table 5Go.


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  		TABLE 5. Outcomes of IPIC group and control group patients stratified according to tumor stage
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The role of adjuvant therapy after hepatic resection for HCC patients has not been well established. This is the first study that evaluated the efficacy of adjuvant chemotherapy with cytotoxic agents delivered directly into the portal vein of HCC patients with complete follow-up data. The main result of this study is that HCC patients with tumor-node-metastasis stage I or II disease benefit from IPIC. Tumor recurrence rates and survival rates of the IPIC group were significantly better than those of the control group.

Locoregional chemotherapy of the liver, using either the intrahepatic arterial or intraportal route, is an alternative to systemic chemotherapy in the management of malignant hepatic tumors. Intrahepatic arterial chemotherapy has been extensively investigated in both the adjuvant and palliative settings.12–16 In most published series,14–16,24–28 common toxicities of chemotherapy of either the intrahepatic arterial route or the intraportal route were similar and included gastrointestinal symptoms (mucositis, nausea and vomiting, and diarrhea), chemical hepatitis, and bone marrow toxicity. Severe hepatic injury with hepatic failure was rarely encountered. Despite of its safety, recent studies indicated that adjuvant hepatic transarterial chemotherapy failed to show a benefit in improving the survival of HCC patients after hepatic resection.15,16

The common disappointing results of adjuvant chemotherapy via systemic or intra-arterial routes in HCC patients resulted in the use of intraportal vein infusion as the delivery strategy in this study. Intra-portal chemotherapy has been tried to provide the advantages of increased survival after colorectal resection.26,27 In 1987, Elias et al.28 showed the potential feasibility of early adjuvant intraportal chemotherapy after curative hepatectomy for colorectal liver metastases. Our prospective trial of IPIC in HCC patients after curative resection used a case-control analysis comparing long-term outcomes of patients with or without IPIC. The two groups compared underwent surgery within a 3-year period. Patients in the two groups were matched for age, sex, liver function status, and tumor stage. There was no significant difference between the two groups in follow-up time or in the main risk factors of tumor recurrence and death.

The chemotherapeutic agents used in this study have been widely used in palliative treatment for patients with inoperable HCC and have been used as adjuvant therapy for HCC patients after liver transplantation.8,9,29–31 In this study, the therapeutic regimens were administered early, 5 to 24 days after surgery. Hepatitis B virus carriers made up 89.3% of the IPIC group and 75.8% of the control group, whereas hepatitis C antibody positivity in the IPIC group was 10.7% and was 18.2% in the control group. Patients with hepatitis B and C chronic infection may have hepatitis reactivation due to cytotoxic chemotherapy.32,33 Hepatitis B virus reactivation after a single session of transarterial chemoembolization in patients with HCC has been reported.34 Increased baseline alanine aminotransferase, hepatitis B virus e antigen positivity, male sex, young age, and highly immunosuppressive treatment are risk factors for hepatitis B virus reactivation.32,33 In our study, early intraportal chemotherapy after hepatic resection was not associated with a morbidity of severe hepatic dysfunction or hepatitis virus reactivation; this was because of the lower drug dosages used in this regimen compared with those used in systemic chemotherapy for patients with advanced HCC, because most of our patients had a good liver function reserve, and because therapy was given as a continuous infusion.

Intraportal chemotherapy is designed to achieve high intraportal drug concentrations, with consequent destruction of early-phase tumor deposits and microscopic tumor emboli within the portal tracts. This treatment modality is expected to be most effective in eradicating residual microscopic disease in the liver after cancer resection. The clinical benefit after adjuvant IPIC treatment, then, is likely limited to a select group of patients with relatively early-stage HCC, and this may explain findings that adjuvant IPIC significantly benefits survival for the subgroup of patients with tumor-node-metastasis stage I and II disease. In patients with stage III disease, there is a probability of intrahepatic and/or extrahepatic tumor metastases not detected by preoperative imaging studies. IPIC presents challenges in having a favorable effect on the complete eradication of residual disease in these patients. In addition, as reported by Lai et al.15 and Ono et al.,35 adjuvant transarterial and systemic chemotherapy in patients with advanced-stage HCCs compromised patient survival after hepatic resection. This phenomenon may be due to chemotherapy, or, in case of destroying only the subpopulation of drug-sensitive tumor cells in patients with advanced-stage disease, the treatment could stimulate the proliferation of tumor cells with a higher malignant potential.15

Although IPIC-related adverse events existed, most patients tolerated the treatment well, and the survival benefit of IPIC demonstrated by this study was remarkable in patients with tumor-node-metastasis stage I and II disease. The long median follow-up of IPIC group patients (74 months) implies a low risk of underestimating tumor recurrence in this series. In our series, patients with recurrent disease were treated with a multitude of therapies, including repeated resection, transcatheter arterial embolization, percutaneous alcohol injection, and chemotherapy. This may confound the long-term survival of the patients, but its effect was apparently limited to the survival after recurrence. In our study, adjuvant IPIC was seen to prolong both disease-free and overall survival and to decrease tumor recurrence. The survival advantages demonstrated in this study justify a selection of patients for further trials. Criteria essential for patient selection are patients with tumor-node-metastasis stage I or II disease with good liver function reserve. Special attention should be paid to exclude patients from IPIC with tumors involving a major branch of the portal or hepatic vein(s), patients with multiple tumors and tumors > 5 cm (patients with tumor-node-metastasis stage III disease), and patients undergoing noncurative resection (including patients with an unclear surgical margin).

In conclusion, this study confirmed the feasibility and safety of IPIC delivered early after hepatic resection for HCC patients. In patients with tumor-node-metastasis stage I and II disease, improvement in the frequency of both recurrence and survival was noted. Consequently, further prospective randomized trials are warranted to verify these findings.


   ACKNOWLEDGMENTS
 
Supported by a grant from Taipei Veterans General Hospital (93-VGHTPE-237).

Received for publication November 11, 2005. Accepted for publication January 30, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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