Abstract
Background/Aim: The aim of this retrospective study was to clarify the effectiveness of chemotherapy with gemcitabine combined with low-dose 5-fluorouracil and cisplatin (GFP) for advanced biliary carcinoma after hepatectomy. Patients and Methods: Sixty-two patients had biliary carcinoma with lymph node metastasis, intrahepatic metastasis or positive surgical margins, including intrahepatic cholangiocarcinoma (IHC, n=25), hilar cholangiocarcinoma (HC, n=14), and gallbladder cancer (GBC, n=23). Twenty-eight patients (IHC; n=9, HC; n=8, GBC; n=11) received adjuvant GFP chemotherapy. Results: We found no significant difference in clinicopathological factors in patients treated with or without adjuvant GFP chemotherapy. Overall, survival in the adjuvant GFP group was significantly better than that in the non-adjuvant GFP group (3-year survival: 61.9% vs. 8.8%, p<0.001), as was relapse-free survival. Conclusion: Adjuvant GFP chemotherapy after hepatectomy may be a promising option for improving surgical outcomes in patients with advanced biliary carcinoma.
Biliary carcinoma, which includes intrahepatic cholangiocarcinoma (IHCC), hilar cholangiocarcinoma (HC) and gallbladder carcinoma (GBC), may be a relatively uncommon malignancy in Western countries, but is one of the most lethal digestive tract tumours because of metastasis or invasion of the tumour directly into adjacent organs at diagnosis. In Japan, the incidence of biliary carcinoma has markedly increased over the past several decades. Vital statistics in 2013 in Japan showed that biliary carcinoma was the sixth leading cause of carcinoma deaths with an incidence of over 22 per 100,000 and a mortality rate of ~15 per 100,000 (1). Complete surgical resection provides the only chance of survival. Many surgeons have advocated aggressive surgery, including major hepatectomy, extended lymph node (LN) dissection and combined vascular resection for improving surgical outcomes (2-8). However, despite aggressive liver surgery, the prognosis after surgery remains unsatisfactory, with 5-year survival rates of 19-35% for HC (5-8), 32-53% for GBC (9-11) and 23-29% for IHCC (12-14). Moreover, several investigators have indicated that LN metastasis, intrahepatic metastasis and positive surgical margins in the bile duct are poor prognostic factors (12-15). Even with aggressive surgical resection, tumour relapse frequently occurs immediately after surgery, particularly in patients with poor prognostic factors. Nevertheless, no standard treatment before or after surgery has been established, even in patients with biliary carcinoma with high risk factors of recurrence. Therefore, a multidisciplinary strategy including adjuvant therapy is desirable before or after surgery, at least for those patients with poor prognostic factors.
For unresectable biliary carcinoma, gemcitabine alone has been regarded as the key antitumour agent (17); recently, gemcitabine combined with cisplatin became the new standard regimen based on the results of the ABC-02 trial (18). In Japan, several investigators have reported the efficacy of gemcitabine plus S-1, an oral anticancer drug consisting of tegafur as a prodrug of 5-fluorouracil (5-FU), 5-chloro-2,4-dihydroxypyridine and potassium oxonate, in advanced biliary carcinoma (18-21). However, adjuvant treatment after surgery has shown little impact on this malignancy, and combinations of effective chemotherapeutic agents and regimens have not been established. With the exception of periampullary carcinoma, only one randomized control trial has demonstrated the efficacy of the combination adjuvant therapy of mitomycin C and 5-FU for GBC (22). Most recently, a retrospective study on adjuvant therapy with gemcitabine plus S-1 chemotherapy after aggressive surgery significantly improved prognosis, with 57% survival at 5 years after surgery (23, 24).
In our institution, gemcitabine combined with low-dose 5-FU and cisplatin chemotherapy (GFP) for unresectable biliary carcinoma was introduced in 2004 (25, 26). We further applied this regimen as adjuvant treatment after surgery for advanced biliary carcinoma, particularly in patients with LN metastasis, intrahepatic metastasis and a positive surgical margin. In this retrospective study, we investigated the clinical impact of adjuvant GFP chemotherapy after hepatectomy for advanced biliary carcinoma.
Patients and Methods
Study design and patient selection. Our sample included 62 patients with advanced biliary carcinoma, including patients with IHCC (n=25), HC (n=14), and GBC (n=23) admitted to our institution from 1995 to 2012, who had at least one or more of the following: LN metastasis, intrahepatic metastasis and microscopic positive surgical margins of the bile duct. All patients were pathologically diagnosed as having biliary carcinoma after hepatectomy, and final staging and curability were defined according to the seven edition of the tumour-node-metastasis classification system for malignant tumours published by the Union for International Cancer Control (UICC) (27). We introduced adjuvant GFP therapy for such patients in 2004. The eligibility criteria for adjuvant GFP chemotherapy were as follows: i) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1; ii) adequate bone marrow function (white blood cell count of at least 3,000/mm3, platelet count of at least 100,000/mm3, haemoglobin level >10.0 g/dl); iii) aspartate aminotransferase/alanine aminotransferase (AST/ALT) no more than 3.0 times the upper limit of normal, total bilirubin of 1.5 mg/dl or less; iv) serum creatinine of 1.5 mg/dl or less; and v) written informed consent. Consequently, 28 patients with advanced biliary carcinoma (IHCC; n=9, HC; n=8, GBC; n=11) received postoperative adjuvant chemotherapy with GFP, and were divided into two groups based on the administration or not of adjuvant GFP chemotherapy (adjuvant GFP group and non-adjuvant GFP group). The clinicopathological characteristics, including prognosis and tumour relapse, were compared with those not having postoperative adjuvant chemotherapy. None had received prior chemotherapy or irradiation before surgical resection. The toxicity of adjuvant GFP chemotherapy was also analysed. Adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (CTCAE V4.0; available from URL: http://ctep.cancer.gov/reporting/ctc.html). Tumour markers and chest-abdominal computed tomographic (CT) scans were examined every 3 months during the first year after surgery. From the second year, tumour markers were examined every 3 months, and chest-abdominal CT every 6 months. In principle, the duration of surveillance was 5 years after surgery. The mean follow-up period was 31.9 months (range=4.6-90.4 months) for the adjuvant GFP group and 23.1 months (range=5.5-143.6 months) for the non-adjuvant GFP group.
Adjuvant GFP therapy protocol. The GFP regimen was a single 4-week course of treatment that included a triple combination of agents namely gemcitabine, 5-FU, and cisplatin. Gemcitabine (1,000 mg/m2) was diluted with 100-ml normal saline and administered intravenously over 30 minutes on days 1, 8, 15 and 22. Cisplatin at 3 mg/m2/day and 5-FU at 300 mg/m2/day were given peripherally on days 1 to 5, 8 to 12, 15 to 19 and 22 to 26, followed by a 2-week withdrawal from chemotherapy. Induction therapy with two cycles of GFP therapy started within at least 4 months of hepatectomy for patients meeting the eligibility criteria. In patients with positive surgical margins, outpatient therapy was continued with one dose every 2 weeks of gemcitabine and cisplatin intravenously, and one dose 5 days each week of oral tegafur/uracil (300 mg). Chemotherapy was terminated for unacceptable toxicity, or by patient request. After tumour relapse, patients were able to receive second-line chemotherapy including radiotherapy at their physician's discretion.
Statistical analysis. All statistical analysis was performed using statistical software (JMP 8.0.1; SAS, Cary, NC, USA). Relationships for clinicopathological variables between the adjuvant GFP group and the non GFP group were analysed with the Chi-square and Mann–Whitney U-test. Survival curves were calculated using the Kaplan–Meier method and compared using the log-rank test. Statistical significance was defined as p<0.05.
Results
Clinical and tumour characteristics. Table I shows clinical and tumour characteristics of patients who received or did not receive adjuvant GFP chemotherapy. In the adjuvant GFP group, age tended to be higher and the proportion of males a little lower. Otherwise, there was no significant difference in tumour location between the two groups. LN metastasis occurred in 67.8% of the adjuvant GFP group and in 73.5% of the non-adjuvant group. Intrahepatic metastasis was observed in 28.6% of the adjuvant GFP group and 32.4% of the non-adjuvant group. Positive microscopically resected margins of the bile duct were present in 35.7% of the adjuvant GFP group and 20.6% of the non-adjuvant GFP group. The incidence of LN metastasis, intrahepatic metastasis and positive margins was not statistically different between the two groups. Union for International Cancer Control (UICC) primary tumour factor and UICC stage did not differ between the two groups. There was also no significant difference in serum CA19-9 levels between the two groups.
Operative procedures. The extent of hepatectomy did not significantly differ between the two groups. Overall, hepatic lobectomy was performed in 67.9% of the adjuvant GFP group and 58.8% of the non-adjuvant GFP group. An extra-hepatic bile duct resection was performed in 57.1% of the adjuvant GFP group and 70.5% of the non-adjuvant GFP group. While the induction of systemic regional LN dissection was equivalent for the two groups, para-aortic LN dissection in the adjuvant GFP group was significantly infrequent compared with that in the non-adjuvant GFP group (17.9% vs. 55.9%, respectively, p=0.002) (Table I).
Patient characteristics.
Survival outcomes. Overall survival curves for both groups are shown in Figure 1. The 3- and 5-year overall survival rates were 61.4% and 44.2% in the adjuvant GFP group, and 8.8% and 5.9% in the non-adjuvant GFP group, respectively. Adjuvant GFP chemotherapy significantly prolonged surgical outcomes in advanced biliary carcinoma after hepatectomy (p<0.0001). Additionally, no significant prognostic factors were observed for these patients except for the administration of adjuvant GFP therapy.
Primary tumour relapse site with and without adjuvant gemcitabine combined with low-dose 5-fluorouracil and cisplatin (GFP) therapy after hepatectomy.
In relapse-free survival, the adjuvant GFP group had a significantly better prognosis compared with the non-adjuvant GFP group (p=0.034) (Figure 2). Twenty-two out of 28 patients (78.6%) in the adjuvant GFP group and 31 out of 34 patients (91.1%) in the non-adjuvant GFP group experienced relapse after hepatectomy (Table II). Adjuvant GFP chemotherapy tended to reduce the tumour relapse rate (p=0.1609) and significantly inhibited hepatic recurrence after hepatectomy (p=0.0172).
Toxicity. Adjuvant GFP chemotherapy was introduced at a mean of 58 days following hepatectomy (range=25-117 days). All patients were evaluated for toxicity, and toxicities were observed during treatment. Adjuvant GFP chemotherapy was generally well tolerated and there were no treatment-related deaths. CTCAE grade 3 or 4 hematological toxicities included leucopenia in 14 patients (50%), thrombocytopenia in 13 patients (46.4%) and anaemia in four patients (14.2%). No patient with grade 3 or 4 neutropenia had febrile episodes. No CTCAE grade 3 or 4 non-hematological toxicities were observed.
Discussion
Biliary carcinoma has a poorer prognosis than other digestive malignancies because of metastasis or direct invasion into adjacent organs at diagnosis. Especially in patients with LN metastasis, intrahepatic metastasis and positive surgical margins of the bile duct, even aggressive surgical treatment might not Improve surgical outcomes (12-16). Our retrospective study investigated the possibility of using adjuvant chemotherapy after hepatectomy for advanced biliary carcinomas. We found that adjuvant GFP chemotherapy for patients with LN metastasis, intrahepatic metastasis and positive surgical margins had improved surgical outcomes, with a 44.2% 5-year survival rate after hepatectomy, and had acceptable toxicity. Although the tumour relapse rate remained high despite induction with adjuvant GFP chemotherapy, relapse-free survival also improved significantly with this strategy.
Overall survival curves of patients according to the administration or not of adjuvant low-dose 5-fluorouracil and cisplatin (GFP) chemotherapy after hepatectomy.
Relapse-free survival curves of patients according to the administration or not of adjuvant low-dose 5-fluorouracil and cisplatin (GFP) chemotherapy after hepatectomy.
Results of adjuvant chemotherapy after surgery for biliary carcinoma.
Gemcitabine-based chemotherapy is the standard anticancer agent for unresectable biliary carcinoma, and gemcitabine combined with cisplatin therapy has recently been used as first-line treatment in clinical settings because of the results of the ABC-02 trial (18). Likewise, several investigators have reported use of various adjuvant treatments after surgery, but the optimal multidisciplinary treatment has not yet been established. One meta-analysis revealed that chemotherapy or chemoradiotherapy had a statistically greater benefit than radiotherapy alone (32). It has also been reported that remote organ metastasis is more frequently observed than locoregional recurrence of biliary carcinoma after surgery (28-31). Therefore, adjuvant treatment with systemic chemotherapy might have some advantage in the regulation of recurrences after drastic local treatment such as surgery as compared with local radiotherapy. To our knowledge only one randomized control study has reported the efficacy of adjuvant therapy in biliary carcinoma, with the exception of adjuvant therapy for periampullary carcinoma. Takada et al. demonstrated that patients with GBC receiving adjuvant therapy consisting of mitomycin C and 5-FU after surgery had an improved overall survival (22). Some have recommended adjuvant chemotherapy and chemoradiotherapy after surgery for biliary carcinoma, as shown in Table III (21, 24, 33-42). However, the results of adjuvant external-beam radiation therapy with concurrent 5-FU treatment were unsatisfactory, with a 5-year survival rate of less than 40% (38-42). Therefore, it is still unclear whether adjuvant chemoradiotherapy based on 5-FU offers improved survival for patients with biliary carcinoma. Recently, gemcitabine-based adjuvant chemotherapy has been applied in this setting. Adjuvant gemcitabine alone was expected to improve the prognosis of patients with GBC after non-curative resections (34). Another study recommended that adjuvant gemcitabine alone might be effective in selected patients with either stage III biliary carcinoma or IHCC (33). Furthermore, adjuvant gemcitabine and S-1 combination chemotherapy has been introduced for its synergistic antitumour effect, and the regimen provided the best clinical impact for patients with UICC stage IIA/B biliary carcinoma, with a 57% survival rate at 5 years after aggressive surgery. More recently, Kainuma et al. investigated the feasibility and efficacy of gemcitabine combined with cisplatin for patients with biliary tract cancer after R0 resection of hepatectomy or pancreatodudenectomy in a single-arm phase II trial. In the near future, other gemcitabine-based combination chemotherapies such as gemcitabine combined with cisplatin, which was the first standard regimen for unresectable biliary carcinoma, might be tried as adjuvant treatment.
Many investigators have not defined clear indicators for adjuvant treatment after surgery. In the one randomized trial mentioned above, the criteria for inclusion may have been too broad (R0/1 resection and stage II-IV) and thus the trial failed to show any clinical significance for adjuvant chemotherapy for extrahepatic biliary carcinoma. However, several investigators have noted that adjuvant therapy may be of value for particular indications. Glazer et al. indicated that neither neoadjuvant nor adjuvant chemotherapy for biliary carcinoma rescued patients with adequate negative margins (>1 cm) after surgery (43). Nakamura et al. also recommended adjuvant gemcitabine treatment for GBC only after non-curative resection (34). In a sub-group analysis, Yamanaka et al. suggested that the survival benefits were possibly modified by LN metastasis, stage III, IHCC, and poorly differentiated tumour, although survival probabilities with adjuvant chemotherapy in the analysis of all patients did not prove favourable (33). Other reports have indicated that the benefits of adjuvant chemotherapy were more likely to be found in patients who had high-risk features, including high level of lymphovascular invasion, LN metastasis, advanced stage, pT4 stage and R1 resection (44-46). Murakami et al. enrolled selected patients with UICC stage IIA/B biliary carcinoma as candidates for adjuvant gemcitabine plus S-1 chemotherapy after aggressive surgery (20). Two molecular biomarkers have been identified in clinical studies as being able to prove the efficacy of gemcitabine-based chemotherapy (47, 48). Murakami et al. suggested that combined analysis of intratumoural human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase subunit 1 (RRM1) that are highly expressed was more useful for predicting the results of adjuvant gemcitabine-based chemotherapy after surgery in patients with biliary carcinoma. In the future, we might have to consider these predictive biomarkers for gemcitabine-based chemotherapy, as well as for indications for adjuvant chemotherapy after surgery.
In our trials, gemcitabine combined with low-dose 5-FU and cisplatin was introduced for biliary carcinoma. The combination of gemcitabine and cisplatin has been explored in several studies because the combination appears to be synergistic, based on laboratory data (49-52). Favourable results with GFP chemotherapy for unresectable biliary carcinoma have been reported in a pilot study (25,26). Subsequently, this regimen was applied in adjuvant settings for hepatectomized patients with LN metastasis, intrahepatic metastasis and positive surgical margins of the bile duct, because even aggressive surgery has not improved surgical outcomes in patients with these prognostic factors. We showed favourable outcomes with acceptable toxicity. However, in our series, the 5-year survival rate was about 44%, a little lower than that for adjuvant gemcitabine plus S-1 chemotherapy. The difference in survival rate may be due to there being more advanced cases in our study (UICC stage III and IV). The limitations of our study are its retrospective design and small number of patients. The mean follow-up period was comparatively shorter in the adjuvant GFP group, therefore our results might be immature. Hence, the adjuvant GFP chemotherapy regimen warrants further detailed evaluation, using a well-designed randomized prospective investigation that includes biological activity as a stratification strategy.
In conclusion, our trial indicated that a regimen of gemcitabine combined with low-dose 5-FU and cisplatin is an active therapeutic option as adjuvant chemotherapy after hepatectomy for patients with LN metastasis, intrahepatic metastasis and positive surgical margins of bile duct in biliary tract carcinoma. While a randomized controlled trial with a larger number of patients is required to confirm the efficacy of adjuvant chemotherapy after surgery of biliary carcinoma, adjuvant GFP chemotherapy after surgery may be a promising option for improving surgical outcomes of patients with advanced biliary cancers.
Footnotes
This article is freely accessible online.
- Received May 24, 2017.
- Revision received June 13, 2017.
- Accepted June 14, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
