Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial

G. V. Kornek1,*, B. Schuell1, F. Laengle2, T. Gruenberger2, M. Penz3, K. Karall4, D. Depisch4, F. Lang5 and W. Scheithauer1

1 Division of Clinical Oncology, Department of Internal Medicine I, 2 Department of Surgery, and 3 Division of Gastroenterology & Hepatology, Department of Internal Medicine IV, Vienna University Hospital, Vienna; 4 Department of Surgery, Wr Neustadt General Hospital, Wr Neustadt; 5 Department of Surgery, Neunkirchen General Hospital, Neunkirchen, Austria

Received 2 August 2003; revised 22 October 2003; accepted 16 December 2003


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

Patients with advanced biliary tract carcinoma face a particularly dismal prognosis, and no standard palliative chemotherapy has yet been defined. Among several different single agents, mitomycin C and, more recently, the oral fluoropyrimidine capecitabine and the nucleoside analogue gemcitabine, have been reported to exert antitumour activity. In view of a potential drug synergy, the present randomised phase II trial was initiated. The aim was to investigate the therapeutic efficacy and tolerance of mitomycin C (MMC) in combination with gemcitabine (GEM) or capecitabine (CAPE) in previously untreated patients with advanced biliary tract cancer.

Patients and methods:

A total of 51 patients were entered in this study and randomly allocated to treatment with MMC 8 mg/m2 on day 1 in combination with GEM 2000 mg/m2 on days 1 and 15 every 4 weeks, or MMC 8 mg/m2 on day 1 plus CAPE 2000 mg/m2/day on days 1–14, every 4 weeks. In both arms, chemotherapy was administered for a total of 6 months unless progressive disease occurred earlier.

Results:

Pretreatment characteristics were well balanced between the two treatment arms. The overall independent review committee-confirmed response rate among those treated with MMC + GEM was 20% (five of 25) compared with 31% (eight of 26) among those treated with MMC + CAPE. Similarly, median progression-free survival (PFS; 4.2 versus 5.3 months) and median overall survival (OS; 6.7 versus 9.25 months) tended to be superior in the latter combination arm. Chemotherapy was fairly well tolerated in both arms, with a comparably low rate of only grade 1 and 2 non-haematological adverse reactions. Also, only four (17%) patients in both treatment arms experienced grade 3 leukocytopenia, and three (13%) and four (17%) had grade 3 thrombocytopenia in the MMC + GEM and MMC + CAPE arm, respectively.

Conclusions:

The results of this study indicate that both combination regimens are feasible, tolerable and clinically active. The MMC + CAPE arm, however, seems to be superior in terms of response rate, PFS and OS, and should therefore be selected for further clinical investigation in advanced biliary tract cancer.

Key words: advanced biliary tract cancer, capecitabine, chemotherapy, gemcitabine, mitomycin C


    Introduction
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Adenocarcinoma of the biliary tract, which accounts for ~4% of all malignant neoplasms of the gastrointestinal tract, remains a major challenge to surgical, medical and radiation oncologists [1, 2]. Unfortunately, the large majority of these tumours are not resectable at the time of diagnosis, and patients with advanced disease face a particularly dismal prognosis [2].

The role of non-surgical treatment remains a matter of debate, and has been thought to be largely ineffective, if not detrimental, in patients with advanced disease. However, in a randomised trial, Glimelius et al. [3] demonstrated that the administration of a 5-fluorouracil (5-FU)-based chemotherapy can improve survival and quality of life in patients with pancreatico-biliary tract cancer. Despite these data, no standard chemotherapy regimen for advanced disease has been established [4].

Mitomycin C (MMC) seems to be active as a single agent, and when combined with 5-FU response rates of 20–30%, with a median survival of ~8 months, have been reported [49]. Capecitabine (CAPE), a new orally administrable, selectively tumour-activated fluoropyrimidine, has shown activity in several solid tumours, including colorectal and breast cancer [1012]. Preliminary phase I/II trials and case reports suggest activity in biliary tract carcinoma [13, 14]. Sawada et al. [15] demonstrated that MMC increases the levels of thymidine phosphorylase (dThdPase) significantly, which is an essential enzyme for the activation of CAPE and its intermediate metabolite (5'-dFUrd) to 5-FU in tumours, and of tumour necrosis factor-{alpha}, which is an up-regulator of dThdPase. These findings were confirmed by Saeki and Takashima [16], who described additive effects of CAPE combined with MMC, and prompted us to investigate this combination (MMC + CAPE) in advanced biliary tract cancer.

Gemcitabine (GEM) is among several other new anticancer drugs currently being investigated in advanced biliary tract cancer [1725]. Apart from its favourable toxicity profile, this nucleoside analogue has demonstrated activity in many solid tumours and constitutes the standard regimen in patients with advanced pancreatic adenocarcinoma [26]. In view of the histogenetic affinity between the pancreas and the biliary tract, and several case reports describing the efficacy of GEM in advanced biliary tract carcinoma, a number of phase II trials have been undertaken [1725]. We have recently published our series investigating biweekly high-dose GEM in advanced cholangiocellular carcinoma, which resulted in an overall response rate of 22% and a median overall survival (OS) of 11.5 months [21]. Aung et al. [27] demonstrated a marked synergic activity of GEM and MMC when used concurrently in human colon carcinoma cell lines, and concluded that the chemosensitizing effect of GEM may be beneficial in the treatment of tumours that are sensitive to MMC. Klapdor et al. [28] investigated this combination (intra-arterial and intravenous administration of both agents) in the treatment of advanced pancreatic carcinoma and observed an objective response rate of 40% and normalization of tumour markers in 80%.

Based on this background information, we initiated a randomised phase II trial investigating the efficacy and tolerance of two potentially synergic MMC combination regimens in patients with previously untreated advanced biliary tract cancer.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
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Patient selection
Patient eligible for the study were required to have histologically or cytologically ascertained, non-resectable metastatic adenocarcinoma of the biliary tract. Further inclusion criteria were bidimensionally measurable disease, age between 19 and 75 years, and an anticipated life expectancy of at least 3 months. Furthermore, patients were required to have a baseline WHO performance status of at least 2, and to have adequate renal (serum creatinine level <1.5 mg/dl), liver (total bilirubin level <2 mg/dl and transaminase levels less than twice the upper limits of normal) and bone marrow (leukocyte count ≥4000/µl, absolute neutrophil count ≥2000/µl and platelet count ≥100 000/µl) function. A minimum of 3 weeks was required to have elapsed in cases of prior abdominal exploration or palliative surgery. Patients with other serious or uncontrolled concurrent medical illness or with central nervous system metastases were not eligible for treatment, nor were those who had undergone any prior palliative chemotherapy. Before study entry, informed consent was obtained from all patients according to institutional regulations.

Randomisation procedures
Before randomisation, patient eligibility was confirmed by a protocol-specific check list. After signing informed consent documents, patients were stratified according to WHO performance status (0–1 versus 2), number of metastatic sites (single versus multiple) and primary tumour site (gallbladder versus cholangiocellular carcinoma). Patients were then assigned to one treatment regimen by the central office located at the University of Vienna.

Treatment protocol
Chemotherapy consisted of MMC 8 mg/m2 given as an intravenous bolus injection on day 1 in combination with GEM 2000 mg/m2 given as a 30-min infusion on days 1 and 15, every 4 weeks (arm A, MMC + GEM), or MMC 8 mg/m2 in combination with CAPE 2000 mg/m2/day given orally in equally divided two daily doses ~12 h apart, from days 1–14, every 4 weeks (arm B, MMC + CAPE). CAPE was supplied as film-coated tablets in two dose strengths: 150 and 500 mg, which were not to be split, and were taken orally with water within 30 min after ingestion of food. Compliance with the oral medication regimen was assessed by tablet counts at each clinical visit. Treatment was continued in patients achieving objective response or stable disease until a total of six courses. Dexamethasone and 5-HT3 antagonists were routinely given only on the day of intravenous cytotoxic drug administration.

Toxicity and dosage modification guidelines
Adverse reactions were evaluated according to WHO criteria. Chemotherapeutic drug doses were reduced by 25% in subsequent cycles if the lowest white blood cell count (absolute neutrophil count) was <1000/µl (500/µl), the lowest platelet count was <50 000/µl or if any severe (WHO grade ≥3) non-haematological toxicity was observed in the previous cycle. Treatment could be delayed for up to 2 weeks until adverse reaction resolved or improved to at least grade 1. Any patient who required >2 weeks for recovery of treatment-related toxicity was taken off study.

Pretreatment and follow-up evaluation
Pretreatment evaluation included a complete medical history, physical examination, ECG and routine laboratory studies. The latter consisted of a complete blood count (CBC) with platelet and leukocyte differential count, and an 18-function biochemical profile. Imaging procedures included chest X-ray and computed tomography of the abdomen. CBCs and differential counts were determined weekly, and complete biochemical profiles were assessed before each treatment cycle. Objective tumour assessments were performed every 2 months until progression.

Study objectives and assessment of objective response
The primary study end point was objective response rate according to WHO standard criteria [29]. In case of partial remission (PR) or complete remission (CR), a second assessment 4 weeks later was required for confirmation of response; all tumour measurements were reviewed and confirmed by an independent panel of radiologists (independent review committee). Secondary efficacy end points included progression-free survival (PFS), OS and treatment tolerance.

Sample size and statistical considerations
Simon’s two-stage minimax design [30] was used to determine the number of patients to be included in this phase II study. With a 5% alpha risk and a 20% beta risk, we determined a first-stage response probability of 10% (which, if true, implied discontinuing the trial) and a minimal rate of efficacy of 30% (which, if true, implied moving on to the second stage of the trial). The number of patients to be included in each arm was calculated to be 15 for the first stage and an additional 10 for the second stage. After the inclusion of 25 patients in each arm, the observation of five or fewer patients with objective response allowed a conclusion of insufficient treatment efficacy. Differences in distribution of patients between the two arms of the trial were evaluated with the {chi}2-test [31]. The exact binominal confidence interval (CI) was applied to estimate the response rates. PFS and OS were examined using the Kaplan–Meier product-limit method [32].


    Results
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
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Patient population
A total of 51 patients from four institutions were entered in this trial between March 2000 and September 2001. Table 1 lists demographic data, baseline disease characteristics and prior surgical procedures for all patients. The two groups were well balanced for potential prognostic factors. As expected, most patients were elderly (median age 67 years), almost two-thirds of the study population were female and the majority had multiple intra-abdominal sites of metastases. Four patients in arm A (MMC + GEM) and seven in arm B (MMC + CAPE) had undergone palliative surgery for biliary decompression, and five (arm A) and six (arm B) patients had received endoscopic stenting to relieve obstructive jaundice before study entry. Only two patients in each treatment group had undergone prior potential curative surgery, with disease recurrence after 23 or 5 months (arm A) and 23 or 4 months (arm B), respectively.


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Table 1. Pretreatment characteristics
 
Most patients had an impaired performance status at baseline. A WHO performance status of 1 or 2 was recorded in 18 patients in both treatment groups.

Treatment summary
Of the 51 patients enrolled, 47 (92%) patients received at least one course of the allocated treatment, ~80% completed 12 weeks of therapy, and 32% (arm A) and 42% (arm B) of the patients completed the planned treatment period of 24 weeks. Two patients in each arm did not receive the treatment as scheduled due to rapid disease progression with concomitant impairment of liver function. They were rated as treatment failures according to the intention-to-treat analysis, but were not evaluable for toxicity.

In arm A, treatment was stopped early in one patient because of cardiac decompensation that was considered unrelated to treatment; in all other patients the reason for treatment discontinuation was progressive disease. Both treatment groups adhered closely to the planned dosage regimens. For patients treated with MMC + GEM, the mean dose intensity (1.96 mg/m2/week for MMC and 977 mg/m2/week for GEM) corresponded to 97.7% of the scheduled dose, and the mean duration of therapy was 3.9 months. For patients treated with MMC + CAPE, the mean dose of both agents (1.89 mg/m2/week for MMC and 6615 mg/m2/week for CAPE) corresponded to 94.5% of the scheduled dose, and the mean duration of treatment was 4.9 months.

Antitumour efficacy
Independent review committee-confirmed objective treatment responses, PFS and OS data are summarized in Table 2. In arm A, there were no CRs, while five patients (20%; 95% CI 8.9% to 39.1%) had a PR lasting for a median of 6 months (range 3–16); nine additional patients (36%) had stable disease (median duration 6.5 months; range 3.5–10) and 11 patients (44%) progressed during treatment. The median PFS was 4.2 months (range 1–18) and the median OS was 6.7 months (range 1–22+), with five patients currently alive.


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Table 2. Summary of treatment results
 
In arm B, eight patients achieved a PR (31%; 95% CI 16.5% to 49.9%) that lasted for a median duration of 7.5 months (range 3–13). Nine patients had a stabilization of disease (34.5%; median duration 5.5 months; range 4.5–11) and the remaining nine patients were rated progressive (34.5%). The median PFS was 5.35 months (range 1–16) and the median OS was 9.25 months (range 1.5–24+), with eight patients currently alive.

Toxicity
In arm A (MMC + GEM), toxicity was recorded in 23 patients, who received a total of 97 treatment courses, with a median of four courses (range zero to six) per patient. In arm B (MMC + CAPE), side effects were recorded in 24 patients, who received a total of 127 courses, with a median of five courses (range one to six) per patient. Two patients in each treatment arms, who did not receive the treatment as scheduled due to rapid disease progression with concomitant impairment of liver function before therapy was initiated, were not evaluable for toxicity assessment. Overall, the data suggest that both chemotherapeutic drug regimens were well tolerated throughout the study. The most frequently encountered toxicity was myelosuppression, although grade 3 leukocytopenia and neutropenia occurred in only four (17%) and three (13%) patients, respectively, in arm A (MMC + GEM), and four (17%) and four patients, respectively, in arm B (MMC + CAPE). There was no serious infection in either treatment group. Thrombocytopenia was observed more frequently in arm B (65% versus 28% in arm A), and was grade 3 in seven patients (17% versus 13% in arm A). Drug-related symptomatic toxicity was equally distributed between the two treatment arms, and included universally minor (grades 1 or 2) nausea/emesis (44% versus 42%), diarrhoea (28% in both arms), fatigue (36% versus 42%) and elevated liver functional parameters (40% versus 54%); the latter, frequent adverse reaction, however, is likely to be partially related to progression of the tumour, which was located in the liver in >80% of our patients in both treatment groups. Alopecia (28% versus 12%) and fever in the absence of infection (20% versus 8%) occurred more commonly in the GEM than in the CAPE combination arm, and in the latter treatment group only, four patients experienced grade 1 or 2 hand–foot syndrome.

In the MMC + GEM arm, three patients had a treatment delay of 1 week at some time during therapy, and the total number of delayed courses was four (4.1%). The reason for delayed courses were leukocytopenia in two, and infection and nausea in one patient. In the MMC + CAPE arm, treatment delays were required in 10 patients over 16 (12.6%) courses for thrombocytopenia (13 cycles), leukocytopenia (two cycles) and personal reasons (one cycle).

Dose reductions for adverse reactions were required in only two patients in the MMC + GEM arm (for thrombocytopenia) and in four in the MMC + CAPE arm (for grade 3 thrombocytopenia).


    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The present randomised phase II trial was initiated in response to the lack of activity of established anticancer chemotherapeutic drugs in advanced biliary tract malignancies, the urgent need for such therapy, and because preclinical data suggest a potentially synergic activity between MMC and GEM and MMC and CAPE [15, 16, 27]. In both treatment arms, an identical dose regimen of MMC (8 mg/m2, given as an intravenous bolus injection) was used. In arm A, the antitumour antibiotic was combined with biweekly high-dose GEM, which showed superior activity compared with a standard dose regimen (1000 mg/m2 on days 1, 8 and 15, every 4 weeks) in a previous phase II trial [19]. Therapy in arm B consisted of MMC and CAPE, given at a dose of 2000 mg/m2 on days 1–14, every 3 weeks.

The results of this trial suggest feasibility, an acceptable level of antitumour activity and a fairly good tolerance of both regimens. According to the primary study end point, the observed objective response rates, however, MMC + CAPE was identified as the ‘winning’ arm, with eight of 26 responding patients (31%). Similarly, median PFS (4.2 versus 5.3 months) and median OS (6.7 versus 9.25 months) tended to be superior to those in the MMC + GEM comparator arm. As previously demonstrated in colorectal cancer, the concept of MMC-induced up-regulation of intratumoural expression of thymidine phosphorylase resulting in enhanced antitumour activity of co-administered CAPE may thus also be of clinical relevance in advanced biliary tract malignancies [15, 16, 33]. As it concerns the other treatment arm, in view of the previously reported fairly good activity of GEM alone [19, 20, 25], the combination with MMC does not appear to hold its promise of synergic anticancer drug activity. Because of the small number of patients and the possibility that the biweekly GEM administration schedule used in this study may not be optimal for combinability with MMC, data must be interpreted with caution.

As far as it concerns toxicity, both combination regimens were very well tolerated, with grade 3 haematological adverse events in only five (MMC + GEM) and four (MMC + CAPE) patients, respectively. Subjective toxicities consisted mainly of nausea and emesis, which were rated minor or moderate in all cases and could be controlled easily by additional antiemetic drugs. Increased liver enzymes were noted in approximately half of our patients, and can be explained partially by the progression of the tumour, which was located in the liver in more than two-thirds of all patients.

While our therapeutic results obtained with MMC + CAPE seem to be at least comparable to other, previously reported MMC-containing regimens [49], potential advantages of this combination are its excellent tolerance and the fact that CAPE can be safely administered in patients with elevated serum bilirubin levels, which is often seen in advanced biliary tract carcinomas [10].

In conclusion, our data suggest feasibility of treating advanced biliary tract cancer with both MMC + GEM and MMC + CAPE. A superior response activity was noted with the latter combination, which resulted in abrogation of progressive disease (PR + stable disease) in two-thirds of all patients, and a promising PFS and OS. In view of the dire need to improve our therapeutic armentarium in this dreadful disease, further evaluation of this combination, which has also shown an excellent therapeutic index when used as first-line treatment in metastatic colorectal cancer, seems warranted [33].


    FOOTNOTES
 
* Correspondence to: Dr G. V. Kornek, Division of Clinical Oncology, Department of Internal Medicine I, Vienna University Hospital, Waehringer Guertel 18–20, A-1090 Vienna, Austria. Tel: +43-1-40400; Fax: +43–1-45462; E-mail: gabriela.kornek{at}akh-wien.ac.at Back


    REFERENCES
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
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