A phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) in advanced biliary tract carcinoma

This study protocol was approved by the Kochi Municipal Central Hospital, Japan and written informed consent was obtained from all the patients. The patients were required to have unresectable locally advanced or metastatic disease of the biliary-tract or gallbladder advanced carcinoma with measurable lesions on a computed tomography (CT) scan. Other eligibility criteria included an age 18 years or more, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, estimated life expectancy of 12 weeks or more, adequate bone marrow function (leukocyte count > 3,500/μl, neutrophil count > 1,500/μl, and platelet count > 100,000/μl), bilirubin < 5.0 mg/dl, transaminases and alkaline phosphatase < 6 times upper limit of normal, and normal renal function tests (creatine level < 1.5 mg/dl, or creatinine clearance > 60 ml/min). No previous chemotherapy was permitted within 2 weeks. Radiotherapy and stenting to decompress the biliary tract was permitted. Patients with other clinically significant laboratory abnormalities, uncontrolled infection, concurrent severe medical problems unrelated to malignancy that would expose the patient to extreme risk, patients receiving another investigational drug within 30 days prior to study or receiving concurrent hormonal therapy, immunotherapy and those pregnant or lactating were excluded from the study. The study was conducted according to the Good Clinical Practices and the Declaration of Helsinki as amended in Hong Kong (1989).

All patients were admitted to the hospital for about 10 days for a pretreatment evaluation, the first cycle treatment, and observation for adverse effects. If the degree of toxicity was within Grade 0–2, a second cycle of treatment or more were continued on an outpatient basis.

A pretreatment evaluation included complete medical history, physical examination, evaluation of performance status, urinalysis, chest radiograph, and diagnostic studies assessment such as CT scan. When the patient meets the eligibility criteria, central venous catheter system with a heparin coated catheter (Anthron PU catheter; TORAY™ and a port (Celcite brachial; TORAY™ or Vital port mini; COOK™) is implanted according to the method of Hata et al [19] prior to treatment.

The treatment plan involved the administration of 5-FU (160 mg/m²/day) was continuously infused over 24 hours using a disposable infusion pump (7-day Infuser; Baxter™) and CDDP (3–6 mg/m²/day) diluted with normal serine was infused for half an hour. Hydration was not needed. These doses were determined based on our experience of the previous LFP therapy for hepatocellular carcinoma [15]. The administration schedule consisted of 5-FU for 7 consecutive days and CDDP twice a week (day 1 and day 4) for each of four weeks as one treatment course. The treatment schedule and CV catheter system was depicted on figure 1. Unless an exacerbation of the symptoms was observed, multiple courses of treatment were administered. When more than a grade 3 adverse effect was observed, a CDDP infusion was omitted and observed. If this omission was ineffective, 5-FU was also omitted. In case of hemoglobin < 8.0 g/dl, platelet count < 50,000/μl neutrophil count < 1,000/μl, blood transfusion of concentrated red blood cells (RBCs) or platelets, or granulocyte-stimulating factor (G-CSF) was applied.

We do not increase the dose of the anti-cancer agent during the chemotherapy protocol, even if the toxicity is low.

Complete blood counts twice a week and biochemical examinations were weekly carried out. Toxicity was evaluated based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC) ver.3. The response was classified based on the Response Evaluation Criteria in Solid Tumors Guidelines (RECIST criteria) [20], taking into account the measurement of the longest diameter only for all target lesions: complete response (CR)-the disappearance of all target lesions; partial response (PR)-at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; progressive disease (PD) -at least a 20% increase in the sum of the longest diameter of target lesions, taking as referenve the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions; no change (NC)-neither sufficient shrinkage to quality for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started. Patients with a CR, a PR, an NC, or a PD required a confirmatory disease assessment at least one month later. Target lesions were evaluated by a plain and enhanced CT scan and plain chest X-ray for each course.

We used the Stat View J 5.0 software package (Abacus Concepts, Stat View. Abacus Concepts, Inc., Berkeley, CA, 1992–1998) for the statistical analysis. The time to Treatment Failure and the overall Survival Cumulative were obtained by the Kaplan-Meier method. The disease-free survival was compared by the Log rank test among the groups. Prognostic variables were evaluated by Cox's multivariate proportional hazard model. We defined the risk factors for LFP therapy for biliary tract malignancies in our study as significant factors based on both the Cox's and Kaplan-Meier's. A p value of less than 0.05 was considered to be statistically significant.

From February 1996 to December 2003, 42 patients were enrolled into the present study, and all were evaluable for efficacy and toxicity analyses. They consisted of 24 males and 18 females. The mean age was 66.5(47–79). The number of patients with BDca and GBca were 27 and 15, respectively. Twenty-six patients who were initially diagnosed to have biliary tract malignancies were not eligible for surgery because of locally advanced disease and/or metastasis (locally advanced). Another 16 patients had local recurrence and/or distant metastasis after surgery (postoperative recurrence). Disease extension was such that 11 patients (BDca: 7, GBca: 4), had only primary or local recurrence patients had only metastatic disease (BDca: 9, GBca: 5), another 17 patients (BDca:11, GBca: 6) had both diseases. Four patients had previously undergone chemotherapy, including such treatments as CDDP + VP-16, 5-FU + mitomycin C + farmorubicin, adriamycin + 5-FU. Two of 4 patients experienced surgery before these chemotherapy (i.e. postoperative recurrence). Seven of BDca patients had palliative radiotherapy. Three of these seven underwent surgery before radiation (i.e. postoperative recurrence). There were some differences between BDca and GBca on age, and serum tumor marker levels (CEA and CA19-9), but neither was statistically significant. The patient characteristics are enumerated in Table 1.

The overall response rate (RR) was 42.9% (95% confidence interval C.I.: 27.7–59.0) with CR 0, PR 18, NC 13, PD 11, and clinical benefit was 73.8% (95% C.I.: 58.0–86.2). Patients with a PR, an NC or a PD required a confirmatory disease assessment at least two months later.

One GBca patient who got PR, could receive curative resection. The RR of primary lesion or locally advanced lesion was 50.0% (95% C.I.: 30.6–69.4), and the RR of metastatic lesions was 32.3%. Various RRs were demonstrated in Table 2. The responses of meatastatic lesions were as such; liver (CR:0, PR:6, NC:0, PD:3), lung (CR:0, PR:1 NC:3, PD:0), lymph node (CR:0, PR:3, NC: 6, PD2), miscellaneous (CR:0, PR: 2, NC: 2, PD: 1). There was no significant difference in terms of anti tumor effects against both malignant neoplasms. The overall MST was 225 days. The median TTF was 107 days. Figure 2 Shows the BDca a longer MST and TTF than did GBca (234 vs 150, 117 vs 85, respectively), but neither difference was statistically significant.

As shown in Table 3, neither any treatment related death nor grade 4 toxicity occurred. Overall, the most common toxicity was anemia occurring in 26.2% of patients followed by nausea (19.0%). The most frequent grade 3 toxicity was appetite loss (14.3%). The occurrence of ascites and jaundice may be partly because of the outcome of the disease progression.

An analysis of a Cox proportional hazard model showed that no significant factor was found prognostic factors for either the overall survival or TTF (Table 4). However, the patients with LFP courses ≧2 had both a longer overall survival and TTF than those with LFP courses < 2 as depicted in Figure 3. The distribution of the patients with LFP courses ≧2 was (PR/NC/PD = 16/8/3), while that of those with LFP courses ≤2 was (PR/NC/PD = 2/5/8).

The difference between the inpatient-basis and the outpatient-basis or home treatment of this therapy in respect to cost is shown in Table 5. This was calculated based on the assumption that one patient received one-month treatment of this LFP therapy covered by Japanese National Health Insurance. The cost for outpatient-basis/home LFP therapy was approximately equivalent to 996 U.S. dollars which was about one-sixth less than the cost on an inpatient-basis.