Survival benefits of intra-arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis

Methods and materials: Between January 1995 and January 2001, a total of 102 patients with advanced HCC with portal vein thrombosis were enrolled and divided into three groups: group 1 ( n = 24) was managed with only supportive care, group 2 ( n = 25) received systemic combination chemotherapy and group 3 ( n = 52) received intra-arterial infusion chemotherapy with 5-fluorouracil + cisplatin via implanted chemoport. Results: One-year survival rates were 0, 4, 21% and median survivals were 2, 4, 6 months in groups 1, 2, 3, respectively ( p = 0.003). When we divide group 3 patients into long-term (more than 8 months) or short-term survivors, long-term survivor had significantly low level of serum AST ( p = 0.032) and alkaline phosphatase ( p = 0.033). Especially, all female patients ( n = 9) survived more than 8 months ( p = 0.000). Other favorable prognostic factors for survival were cirrhosis of Child-Pugh class A ( p = 0.003), only one major branch involvement of the portal vein by tumor ( p = 0.005), presence of enhancement of tumor portion in arterial phase of CT scan ( p = 0.044), presence of enhancement of non-tumor portion in portal phase of CT scan ( p = 0.029). Conclusions: Intra-arterial infusion chemotherapy achieved favorable results in advanced HCC with portal vein thrombosis and showed better survival in selected patients. Keywords Hepatocellular carcinoma Portal vein Tumor thrombosis Arterial infusion chemotherapy 1 Introduction Advanced hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) has a poor prognosis [1] . The majority of patients with advanced HCC live no longer than 6 months from the day of initial diagnosis [1] . The only curative treatment for HCC is surgical resection [2] ; however, most patients have unresectable HCC at the time of diagnosis because of advanced tumor stage and/or poor hepatic reserve function [2,3] . Treatment modalities, which have been used for unresectable HCC include systemic chemotherapy, intra-arterial (IA) chemotherapy, tumor embolization and a combination of the above [4–7] . But there is not yet an effective standard therapy for advanced HCC. The liver has a dual blood supply with the portal vein supplying 80% of blood to the normal liver. By contrast, the hepatic artery provides at least 80% of the blood supply to the HCC [8] . With the advent of spiral computed tomography (CT), it is now possible to image the entire liver during the hepatic arterial-dominant phase of enhancement. HCC is a hypervascular tumor and the direct IA infusion of chemotherapeutic agents with or without hepatic artery occlusion has resulted in improved tumor response rates compared with systemic chemotherapy [9] . HCC with increased vascularity, as determined on angiography, have also been shown to be more responsive to treatment with transarterial chemoembolization (TACE) [10] . PVT in main branch is contraindication for TACE for fear of hepatic failure [5,11] . IA infusion chemotherapy via implanted port delivery system was reported to have antitumor effect and minimize the risk of hepatic failure [12,13] . At present, for those with advanced HCC, IA infusion chemotherapy is the main treatment modality [12,13] . Therefore, we compared therapeutic efficacies and survival in patients with advanced HCC with PVT (TNM stage IVa) according to treatment modalities, and analyzed the prognostic factors, which influenced survival in patients who underwent IA infusion chemotherapy. 2 Materials and methods 2.1 Subjects Between January 1995 and January 2001, a total of 102 patients with advanced HCC with PVT (TNM stage IVa) admitted at Ajou University Hospital, were retrospectively reviewed. All fulfilled standard criteria for the diagnosis of HCC are as follows: either a serum alpha-fetoprotein (AFP) level of greater than 400 ng/ml in a patient known to have cirrhosis with hepatic mass demonstrated on either ultrasonography (US) or CT and/or diagnostic histology. All the enrolled patients had advanced HCC with PVT confirmed by US, CT or angiography. Exclusion criteria included extrahepatic metastasis, age of more than 75 years old, performance status on the ECOG scale of more than 2, and liver cirrhosis of Child-Pugh class C. We classified patients into three groups according to the treatment modalities. Group 1 (24 patients; 17 men, 7 women, mean age 57.40 years) patients were managed with only conservative care. The patients left untreated for whatever reasons were included in group 1. Group 2 (25 patients; 19 men, 6 women, mean age 50.68 years) patients were treated with systemic intravenous chemotherapy of 5-fluorouracil (5-FU, Choong-wae, Seoul, Korea) and doxorubicin hydrochloride (adriamycin; Il-dong, Seoul, Korea) and mitomycin-C (Kyowa Hakko Kogyo, Tokyo, Japan) or 5-FU and etoposide (Bristol-Myers Squibb, NY, USA) and cisplatin (cDDP; Il-dong, Seoul, Korea). Group 3 (53 patients; 45 men, 8 women, mean age 50.32 years) patients received IA infusion chemotherapy with 5-FU (250 mg for 5 days) and cisplatin (10 mg for 5 days) via implanted chemoport. Group 3 was further subclassified into patients who had survived more than 8 months (long-term survivor) and those who had survived less than 8 months (short-term survivor). 2.2 Intra-arterial chemotherapy methods In group 3, celiac angiography was performed by the Seldinger technique. After the detection of HCC and its feeding artery, the intra-arterial catheter was placed in the proper hepatic artery under fluoroscopic control. After the catheter was connected to the injection port, the device was implanted in a subcutaneous pocket in the right iliac fossa. One course of chemotherapy consisted of the daily administration of cisplatin (10 mg on days 1–5) and by 5-FU (250 mg on days 1–5). Using a automatic injector, the cisplatin and 5-FU were infused continuously for 1 and 5 h, respectively. This procedure was repeated at 4 weeks intervals for as long as it was tolerable to patients. Mean cycles of IA infusion chemotherapy were three cycles (1–11 cycles). 2.3 Analysis of prognostic factors, response rate and survival Prognostic factors selected as being likely to influence survival were age, gender, tumor size, type of tumor, PVT, bilobular involvement, Child-Pugh classification, serum total bilirubin, albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), AFP levels and response to treatment. Serum AFP value was monitored in those patients with a serum AFP value before chemotherapy exceeding 20 ng/ml. Response rates, survival rates, side effects and toxicities with respect to treatment were compared. Each individual HCC lesion can vary in the degree of vascularity (enhancement) during the hepatic arterial phase during CT scanning. Triple phase CT scans obtained before initial IA infusion chemotherapy and 8 weeks after treatments. The protocols of CT scan were as follows. A total of 120 ml of contrast media was injected intravenously with power injector at rate of 2–3 ml/s. Arterial phase, portal venous phase and late venous phase were obtained at 30, 60 s and 2 min after the start of injection, respectively. The predominant enhancement patterns during the hepatic arterial phase of lesion were classified as follows: grade I, good enhancement; grade II, moderate enhancement; group III, poor enhancement. The grade of enhancement of HCC on dynamic CT was determined by consensus agreement of two experienced gastrointestinal radiologists. Remaining liver enhancement in arterial and portal phase was classified as same manner. Extent of PVT was divided according to radiologic findings as follows: left portal vein (LPV), right portal vein (RPV), both PV, main trunk involvement. Tumors were classified into three types (nodular, massive and diffuse type) according to Eggel [14] by abdominal US, CT and angiography. The tumor reduction rate was determined by comparing the CT results obtained at identical scanning levels of the maximum tumor diameter before and after the therapy. We measured the largest transverse and longitudinal diameters of the tumor and multiplied these parameters to obtain tumor volume. The tumor volume was defined as the longest tumor diameter and by its summation in the case of multiple tumors. Tumor responses to chemotherapy were defined as follows [15] : complete response (CR), disappearance of tumor; partial response (PR), a reduction greater than 50%; moderate response (MR), a reduction of 25–50%; no change (NC), a change less than 25%; progressive disease (PD), an increase greater than 25% or the appearance of new lesion. All cases were followed up every month or every 2 months with laboratory tests of serum AFP and US examinations, and every 3 or 6 months with CT scans. 3 Statistics Chi-square test, t -test were used for the analysis of clinical characteristics and prognostic factors. The parameters that have been suggested to influence the prognosis were subjected to univariate analysis. These parameters were age, gender, tumor type, tumor volume, serum AFP at the time of diagnosis, enhancement pattern during arterial and portal phase on CT. The Kaplan–Meier method was used to analyze cumulative survival. Statistical difference, in all analyses, was accepted when the p -value was lower than 0.05. 4 Results 4.1 Clinical characteristics A total of 102 patients were enrolled in this study. Twenty-four patients received only conservative treatment (group 1), 25 received systemic intravenous chemotherapy (group 2) and 53 patients had IA infusion chemotherapy (group 3). Table 1 showed baseline demographic findings of enrolled patients. As reflected Table 1 , three groups were identical with regard to age, sex, etiology of liver disease and degree of liver function impairment (Child class). 4.2 Survival analysis according to treatment modalities IA infusion chemotherapy is more effective treatment modality than systemic chemotherapy in advanced HCC patients. Survival time was significantly improved for the patients treated with IA infusion chemotherapy ( Fig. 1 ). The median survival time of IA infusion chemotherapy group was significantly longer than those of conservative treatment group or systemic chemotherapy group. One-year survival rates were 0, 4, 21% and median survivals were 2, 4, 6 months in groups 1, 2, 3, respectively ( p = 0.003) ( Fig. 1 ). 4.3 Therapeutic response and survival in IA chemotherapy group For all IA infusion chemotherapy group patients, the 2, 4, 6, 8, 10, 12 and 18 months survival rates were 81.1, 64.2, 41.5, 33.6, 25.7, 21.0 and 18.2%, respectively. When we divide IA chemotherapy group patients into long-term survivors (patients who survived more than 8 months) or short-term survivors (less than 8 months), 19 patients (35.8%) were long-term survivor and 34 patients (64.2%) were short-term survivor. Table 2 and Fig. 2 showed therapeutic responses and survival time in at 3 and 8 months. Responder (CR + PR + MR) had a significant longer survival time compared with non-responder (NR + PD) at 3 and 8 months. In other words, tumor response after chemotherapy significantly affected survival. 4.4 Prognostic factors influencing survival in IA chemotherapy group Table 3 demonstrated clinical factors influencing survival in IA chemotherapy group. Female sex, Child class A cirrhosis, low AST levels and low ALP levels were favorable prognostic factors. Especially, all female patients ( n = 9) survived more than 8 months, and had a longer survival than male patients ( p = 0.000). Table 4 summarizes the radiologic factors influencing the patient survival in IA infusion chemotherapy group. Nodular type tumor ( p = 0.004) and only one major branch involvement of the portal vein by tumor ( p = 0.005) were favorable prognostic factors. And the survival rate was significantly higher in patients with good or moderate tumor enhancement in arterial phase compared with poor enhancement ( p = 0.044). And good enhancement in non-tumor portion during portal phase on spiral CT was also favorable prognostic factor ( p = 0.029). 4.5 Complications of IA infusion chemotherapy Fever, anorexia, abdominal pain and an elevation of ALT (to more than twice the normal level) were observed in descending order of frequency. The side effect rate was similar between IA chemotherapy and systemic chemotherapy groups (47.1% versus 52.0%, respectively). However, these side effects were transient and tolerable, and self-limiting in 1 week. They were managed successfully by conservative treatment. Four patients in systemic chemotherapy group had myelosuppression. In two of them, their blood counts recovered within 2 weeks and they could continue systemic chemotherapy. And two patients were withdrawn from systemic chemotherapy. None of the patients showed serious side effects more than grade III in IA chemotherapy group. Most patients received IA or systemic chemotherapy died from hepatic failure caused by tumor progression, and this is the most common factor contributing to withdrawal from IA or systemic chemotherapy. There were two patients each with sepsis and chemoport occlusion and one patient with infection. The occluded or infected chemoports were removed and new chemoports were re-introduced in two mentioned patients. After administering antibiotics and conservative management, infection was controlled and these patients received IA chemotherapy without further complication. 5 Discussion HCC has a poor prognosis, which is influenced by the development of tumor thrombosis of the portal vein [16] . HCC with major vascular invasion is not good candidate for surgery [2] . For unresectable advanced HCC, TACE has been most widely performed as a treatment for patients with advanced HCC [4–8,11] . In contrast to the responses for systemic chemotherapy via intravenous route, many investigators have reported that IA chemotherapy has a response rates more than 40% [9,11,12,17,18] . The principle underlying this concept is that, whereas approximately 80% of the oxygen-carrying blood to the normal liver is delivered via the portal vein, but HCC derives their blood supply from an arterial supply [8] . But, advanced HCC with PVT has been considered a contraindication for TACE because of deterioration of hepatic function [11] . The IA infusion chemotherapy is known to be relatively safe in advanced HCC with PVT [12,13] . The progress of an implantable drug delivery system enables the repeated arterial infusion of chemotherapeutic agents to patients with HCC [19] . For this purpose, several anticancer agents, such as doxorubicin, epirubicin, mitomycin C, cisplatin and 5-FU, are used singly or in combination [20–23] . Doxorubicin has been the most active and widely used single cytotoxic agent for the treatment of malignant tumors including HCC. However, in case of HCC, the response rate is less than 20%, and only 5% of cases show complete response [23] . The IA infusion of cisplatin has also been evaluated as treatment for HCC [24,25] . With IA cisplatin infusion, a response rate (CR + PR) of 20–50% was quoted and a median survival period of 5–15 months. Cisplatin, therefore, seemed to be more effective than other anticancer agents. Furthermore, cisplatin can amplify the effect of 5-FU in addition to its own effect; therefore, synergistic effect can be expected when combined with 5-FU [26] . There has been few selective studies of advanced HCC with PVT [17] . By selecting only patients with advanced HCC with PVT, we attempted to compare the efficacies of IA infusion chemotherapy with systemic chemotherapy or conservative management. In our present study, 1-year survival rate and median survival were found to be higher in IA infusion chemotherapy group than in systemic chemotherapy or supportive care groups. Because the HCC is nourished mainly by hepatic artery, the administration of anticancer agents into the hepatic artery is thought to be more effective than intravenous treatment. Furthermore, IA infusion of chemotherapeutic agents has the benefit of increasing the local concentration of drugs and reducing side effects compared with systemic chemotherapy. Therefore, IA infusion with 5-FU and cisplatin may be useful in treating patients with advanced HCC with PVT. We investigated that the factors to predict which patients with advanced HCC would obtain the most benefit from IA infusion chemotherapy. The patient sex, Child class, AST and alkaline phosphatase, tumor type, PVT extent and tumor responses at 3 or 8 months after chemotherapy were significant prognostic factors. Among these, tumor responses at 3 months after chemotherapy might be useful in deciding whether to continue anticancer treatment. Recent advances in spiral CT systems have enhanced the usefulness of CT examination in diagnosis and treatment of HCC [10] . Typical classical HCCs are hyperdense in the arterial-dominant phase of dynamic CT and become hypodense in the portal-dominant phases [8] . Hypovascular HCC showed an inferior response to TACE when compared with hypervascular HCC [27] . Recent studies reported that the degree of tumor vascularity has been correlated with improved patient survival [10] . In this study, using tri-phasic CT before the initial treatment, we found that patients with a good to moderate enhancement pattern HCC during arterial phase showed better survival than poorly enhancement pattern HCC. The hypervascular lesions may still have a treatment delivery advantage compared with other hypovascular lesions. These findings imply that arterial phase CT enhancement findings before treatment may confer a prognostic information. Our results correlate well with those of Yamashita et al. who found better response and survival rates for patients with hypervascular tumors as determined on angiography [27] . In addition, portal phase enhancement of non-tumor portion was also correlated with patient survival. This findings may imply that portal blood supply to non-tumor portion indirectly reflect the reserved hepatic function after IA chemotherapy. This investigation suggests the potentially valuable role of tri-phasic CT in the prediction of treatment response and survival after IA infusion chemotherapy. A prospective study with more patients is needed to further evaluate the impact of tumor vascularity, as determined by hepatic arterial phase spiral CT, on response to IA infusion chemotherapy. Interestingly, HCC with both portal vein or main portal vein trunk involvement was a poor prognostic indicator, but bilobular tumor was not significant. This result means that current TNM staging cannot predict outcome of treatment with advanced HCC patients. In this study, we have shown that even in TNM stage IVa HCC, there could be important prognostic factors other than the TNM stage, and that treatment based upon these prognostic factors might prolong survival time. In conclusion, IA infusion of 5-FU and cisplatin achieved favorable results in advanced HCC with PVT, and increased survival in selected patients. Between long- and short-term survivors in the IA infusion chemotherapy group, the significant prognostic factors were patient sex, Child class, AST and alkaline phosphatase, tumor type, PVT extent, arterial phase enhancement pattern of tumor, portal phase enhancement pattern of remaining liver parenchyma. 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