1 Division of Oncology, Department of Internal Medicine I, Vienna University Medical School, Vienna; 2 Department of Surgery, Wiener Neustadt General Hospital, Wiener Neustadt; 3 Department of Internal Medicine, Kirchdorf General Hospital, Kirchdorf a.d. Krems; 4 Department of Surgery, Neunkirchen General Hospital, Neunkirchen, Austria
Received 27 May 2002; revised 9 August 2002; accepted 9 September 2002
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Abstract |
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Gemcitabine is an active antitumor agent in the treatment of advanced pancreatic cancer, and has shown potential synergistic activity with the oral fluoropyrimidine capecitabine in previous phase I/II trials. Based on this background and in order to define the therapeutic potential and tolerance of this combination more precisely, the present randomized multicenter phase II trial was initiated.
Patients and methods:
We prospectively randomized 83 patients to treatment with biweekly gemcitabine 2200 mg/m2 given as a 30 min intravenous infusion on day 1, or the same treatment plus oral capecitabine 2500 mg/m2 given from days 1 to 7. In both arms, chemotherapy was administered for a duration of 6 months unless there was prior evidence of progressive disease. The efficacy of the two treatment arms was evaluated according to standard criteria, i.e. objective response, progression-free survival (PFS) and overall survival (OS), as well as by analysis of clinical benefit response.
Results:
The overall objective response rate among the 42 patients treated with gemcitabine alone was 14% compared with 7/41 (17%) among those treated with the combination arm. Similar to response rates, there was no apparent difference between the two groups in terms of median PFS (4.0 versus 5.1 months) and median OS (8.2 versus 9.5 months) in the gemcitabine and combination arm, respectively. Of 61 patients with tumor-related symptoms, who were considered evaluable for clinical benefit response, 10/30 (33%) and 15/31 (48.4%) experienced significant palliation in the gemcitabine and combination arm, respectively. Chemotherapy was well tolerated in both arms with only four versus six patients experiencing WHO grade 3 symptoms. Apart from the occurrence of handfoot syndrome in 10 patients, no major increase in incidence and/or degree of adverse reactions was noted in the combination arm.
Conclusions:
Results of this trial suggest a fairly good therapeutic index for the combination of biweekly high-dose gemcitabine and capecitabine for the treatment of advanced pancreatic cancer. Despite a somewhat superior clinical benefit response rate, no advantage over single-agent gemcitabine, however, was noted in terms of objective efficacy parameters.
Key words: capecitabine, chemotherapy, gemcitabine, pancreatic cancer
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Introduction |
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Although in a recently published randomized trial the novel cytidine analog gemcitabine was shown to be more effective than 5-fluorouracil (5-FU), the reported objective response rate was only 5.4%. Similarly, there was only a modest survival advantage (5.65 versus 4.41 months), and only one out of four patients (23.8%) experienced clinical benefit [3]. Further improvements in the therapeutic management of patients with advanced pancreatic cancer are certainly warranted, and might by achieved by modification of the administration schedule as suggested by Temporo et al. [4], or by dose intensification: preclinical studies evaluating the in vitro activity of gemcitabine against human tumor colony forming units taken directly from patients and grown in soft agar [5], as well as studies with various established human tumor cell lines including those of pancreatic cancer origin [68], have suggested a doseresponse relationship. This observation has been confirmed in the clinical setting in patients with advanced non-small-cell lung cancer [915], and is supported by a recently published trial involving 43 patients with advanced pancreatic cancer: the objective response rate was 21%, a clinical benefit was noted in 44% and the median survival time was 8.8 months [16]. Despite realization of a rather high-dose intensity with biweekly administration of gemcitabine 2200 mg/m2, treatment was fairly well tolerated with only a few patients experiencing gastrointestinal and/or other subjective toxicities.
Another possibility to enhance the antitumor potential of gemcitabine may be to combine it with other active cytotoxic drugs. Encouraging phase II data in patients with this common and fatal malignancy have been reported for its combination with cisplatin [17, 18], bolus and continuous 5-FU plus or minus leucovorin [1923], epirubicin [24], docetaxel [2531], irinotecan [32], oxaliplatin [33] and more complex polychemotherapy drug combinations [34]. Objective response rates as high as 51% and median survival times 10 months have been reported in some of these studies; the effect of these combination regimens in terms of clinical benefit and/or quality of life has only been occasionally determined, however, and in view of the occurrence of severe adverse events in
50% of patients, who frequently present in poor general condition, any superiority over gemcitabine monotherapy remains uncertain.
An alternative, potentially attractive combination partner for gemcitabine in pancreatic cancer is the oral 5-FU prodrug capecitabine. Objective response activity (in 4/42 assessable patients) and clinically significant beneficial effects on tumor-related symptoms [in 10/42 (24%) patients] have been described in a recently published phase II trial [35]. Furthermore, preclinical studies suggest positive interactions [36, 37], both drugs are well tolerated and their overlapping toxicity is expected to be low. In fact, preliminary data in the form of two recently reported phase I/II trials [38, 39] and a retrospective patient series [40] suggest a promising therapeutic index for this particular combination in advanced pancreatic cancer.
The present multicenter randomized phase II study was initiated to investigate the feasibility and therapeutic index of a biweekly high-dose gemcitabine regimen in combination with capecitabine versus gemcitabine alone in previously untreated patients with advanced pancreatic adenocarcinoma. The antitumor efficacy was assessed by conventional measures, i.e. objective response, progression-free survival (PFS) and overall survival, as well as by clinical benefit response analysis as previously described [3].
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Patients and methods |
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Randomization procedures
Before randomization, patient eligibility was confirmed by a protocol-specific check list. After signing informed consent documents, and a 27 days pain stabilization lead-in period in symptomatic patients (that aimed to provide adequate pain control and to establish baseline measures for clinical benefit response assessment), patients were stratified according to Karnofsky performance status (score 90100% versus 5080%) and prior adjuvant treatment (chemotherapy and/or radiation therapy versus no prior treatment). Patients were then assigned to one treatment regimen by the central office located at the University in Vienna.
Treatment protocol
Chemotherapy consisted of biweekly gemcitabine 2200 mg/m2 diluted in 250 ml normal saline administered as a 30 min intravenous (i.v.) infusion on day 1 (arm A) or the same regimen plus oral capecitabine 2500 mg/m2/day given orally in equally divided two daily doses approximately 12 h apart from days 1 to 7 (arm B). The latter drug was supplied as film-coated tablets in two dose strengths, 150 mg and 500 mg, which were not to be split and taken orally with water within 30 min after the ingestion of food. Compliance with the oral medication regimen was assessed by tablet counts at each clinical visit. Treatment courses were repeated every 2 weeks and continued in patients achieving objective response or stable disease until a total of 12 courses (6 months) had been administered. Ondansetron 8 mg was routinely given only on the day of i.v. chemotherapeutic drug administration.
Toxicity and dosage modification guidelines
Adverse reactions were evaluated according to World Health Organization (WHO) criteria [41]. Chemotherapeutic drug doses were reduced by 25% in subsequent cycles if the lowest WBC (absolute neutrophil) count was <1000/µl (500/µl), the lowest platelet count was <50 000/µl, or if any severe (WHO grade 3) non-hematological toxicity was observed in the previous cycle. Treatment could be delayed for up to 2 weeks until adverse effects resolved or at least improved to grade 1. Any patient who required more than 2 weeks for recovery of treatment-related toxicity was taken off the 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 leucocyte differential count, and an 18-function biochemical profile. Imaging procedures included chest X-ray and computed tomography of the abdomen. Complete blood counts and differential counts were determined weekly and complete biochemical profiles were assessed before each treatment cycle. Objective tumor assessments were performed at the end of every four cycles during chemotherapy and every 2 months after discontinuation of treatment.
Study objectives and assessment of objective/clinical benefit response
The primary study end point was PFS. Secondary objective study end points included overall survival and response rate, which was assessed every 2 months using WHO standard criteria. In cases of partial response (PR) or complete response (CR), a second assessment 4 weeks later was required for confirmation of response; all tumor measurements were reviewed and confirmed by an independent panel of radiologists and oncologists (IRC). In addition to these objective study end points, clinical benefit was evaluated in symptomatic patients as previously described [3].
Sample size and statistical considerations
The primary end point of this study was PFS, which was calculated from the time of the first infusion to disease progression or death. Data from our previous phase II trial investigating biweekly high-dose gemcitabine monotherapy in advanced pancreatic cancer suggest a median PFS of approximately 5 months. We wanted to test the hypothesis that using the experimental combination arm with capecitabine, 75% of patients would be progression-free 5 months after the start of treatment. It was calculated that 41 evaluable patients would have to be recruited to yield a 90% power of detection with an alpha error of 0.05 [42]. Differences in distribution of patients between the two arms of the trial were evaluated with the
2 test [43]. The exact binomial confidence interval was applied to estimate the response rates. Progression-free and overall survival rates were examined with the KaplanMeier product-limit method [44].
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Results |
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Treatment summary
Of the 83 patients enrolled, 79 (95%) received at least one dose of the allocated treatment, approximately two-thirds completed 12 weeks of therapy, and 43% completed the planned treatment period of 24 weeks. In both arms, treatment was stopped early in only one patient for adverse reactions; in all other patients the reason for treatment discontinuation was progressive disease, including three cases with tumor complications while still receiving chemotherapy who required palliative endoscopic or surgical intervention (one biliary and two intestinal obstructions). Both treatment groups adhered closely to the planned dosage regimens. For patients treated with gemcitabine alone, the mean dose intensity (1073 mg/m2/wk) corresponded to 97.5% of the scheduled dose and the mean duration of treatment was 4.3 months. For patients treated with gemcitabine plus capecitabine, the mean dose of both drugs (1067 mg/m2/week and 8380 mg/m2/week, respectively) corresponded to 95.8% of the scheduled dose and the mean duration of treatment was 4.6 months.
Antitumor efficacy
Treatment responses, PFS and overall survival data are summarized in Table 2. The overall response rates according to the IRC assessment were comparable between the two groups: 14.3% [95% confidence interval (CI) 5.4% to 28.5%] with gemcitabine versus 17.1% (95% CI 7.2% to 32.0%) with gemcitabine plus capecitabine. In both treatment groups, all responses were partial, occurred within 3 months of therapy and their median duration was superimposable (5.5 versus 5.8 months). Disease stabilization was noted in 18 (43%) and 23 (56%) additional patients, lasting for a median duration of 4.5 versus 5.2 months for the gemcitabine and gemcitabine plus capecitabine groups, respectively.
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Toxicity
In the gemcitabine arm, toxicity was recorded in 39 patients, who received a median of nine courses (range 312; 362 courses were analyzed). In the experimental capecitabine combination arm, toxicity was recorded in 40 patients, who received a median of 12 courses (range 212; 380 courses were analyzed). Side-effects associated with treatment are listed in Table 4. Overall, data suggest that both chemotherapeutic drug regimens were well tolerated throughout the study. The most frequently encountered toxicity was myelosuppression, though grade 3 leukopenia/neutropenia occurred in only three and four patients in arms A and B, respectively. There were no serious infections in either treatment group and grade 3 or 4 thrombocytopenia was not observed. As listed in Table 4, drug-related symptomatic toxicity was also generally mild in both treatment groups. Gastrointestinal symptoms, specifically stomatitis (5.1% versus 25%) and diarrhea (20.5% versus 35%) tended to be more frequently observed in the combination arm, though symptoms were severe in only three patients in the latter arm. The only other adverse reaction that was more commonly noted in the experimental combination arm was handfoot syndrome, but again, only one patient required a dose attenuation because of severe (grade 3) symptoms. Other symptomatic toxicities were equally distributed between the two treatment groups, and included universally minor (grades 1 or 2) nausea/emesis (51% versus 53%), constipation (10% versus 10%), fatigue (46% versus 48%), alopecia (13% versus 23%), fever in the absence of infection (16% versus 10%), skin rash (9% versus 5%) and transient elevations in liver functional parameters (46% versus 43%).
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Dose reductions for adverse reactions were required in only two patients in the gemcitabine group (for skin toxicity and grade 3 thrombocytopenia) and in three cases in the gemcitabine plus capecitabine group (for diarrhea plus or minus stomatitis in two patients and handfoot syndrome in one patient). Adverse reactions led to treatment discontinuation in only one patient in each group because of persisting drug-related fever plus skin toxicity and stomatitis plus diarrhea despite dose adjustments.
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Discussion |
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In the experimental combination arm, feasibility, an encouraging antitumor effectiveness and a fairly good tolerance were noted. IRC-confirmed objective responses occurred in 17% (95% CI 7.2% to 28.5%) of the 41 evaluable patients. With an additional 56% of patients experiencing stable disease (for a median duration of 5.2 months), this combination regimen resulted in abrogation of progression of this aggressive tumor in 73% of patients. Furthermore, almost half of the patients with symptomatic disease (48.3%) experienced clinically significant and sustained improvements in pain, analgesic consumption and/or Karnofsky performance score, and the median PFS (5.1 months) and overall survival (9.5 months) seem equally encouraging. As opposed to several other (e.g. platinum- or taxane-based) potentially effective gemcitabine combination regimens, the clinical beneficial effects of biweekly high-dose gemcitabine plus capecitabine were not negated by frequent or severe clinically relevant treatment-related toxicities. In fact, grade 3 adverse events requiring dose adjustments occurred in only six patients and there were no treatment-related deaths.
Despite these encouraging treatment results in the experimental combination arm, it must be emphasized that compared with the biweekly high-dose gemcitabine monotherapy arm, no statistically significant improvement in objective or subjective response parameters was detectable. In the control arm, in agreement with our previous phase II investigation, 14% partial responses, 33% clinical benefit responses and a median PFS and OS of 4 and 8.2 months, respectively, were observed. As previously described, tolerance of treatment in the control arm was remarkable, and at least with respect to gastrointestinal side-effects and handfoot syndrome, it was superior than in the capecitabine combination arm. Although a cost-effectiveness analysis has not been included in the present trial, it seems very likely that this aspect would implicate another advantage in favor of gemcitabine monotherapy.
The lack of a significant difference between the two treatment groups might be explained by the small number of patients accrued in this randomized phase II investigation and/or our overoptimistic expectations with respect to the potential effectiveness of the combination arm with capecitabine in improving PFS. Similarly, use of a biweekly high-dose gemcitabine regimen might have been suboptimal when in combination with capecitabine, as might have been the case for the once every other week administration schedule of the oral 5-FU prodrug when combined with gemcitabine. Compared with other studies, however, a much higher dose intensity could be realized for both chemotherapeutic drugs (e.g. compared with the recommended dose of Herrmann et al. [38], the dose intensity of gemcitabine was 165% and that of capecitabine 144%), and as it concerns the latter hypothetical objection, preclinical studies in human tumor xenografts indicate that inhibition of tumor growth depends on the total dose of capecitabine but not on its administration schedule [45].
In conclusion, we were able to demonstrate feasibility, activity and tolerance of combined gemcitabine plus capecitabine in patients with metastatic pancreatic adenocarcinoma, a combination which apart from its potential drug synergism appeared particularly attractive because of the simplicity of concomitant administration without the need of indwelling vascular devices or pumps and the different and mild toxicity profile of each drug. Disappointingly, but in agreement with two other recently reported randomized trials comparing gemcitabine with or without bolus or continuous infusional 5-FU [46, 47], we were unable to demonstrate a clear superiority compared with the (biweekly high-dose) gemcitabine control arm. Since a supraadditive effect of the two compounds can not be ruled out entirely due to the sample size and a different drug dose/administration schedule used in our trial, additional randomized phase III studies such as that initiated recently by the Swiss Group for Clinical Cancer Research (SAKK) and Central European Cooperative Oncology Group (CECOG) seem justified. Still, the above-described results, which are in line with the disappointing study outcome of the randomized studies of Berlin et al. [46] and Di Costanzo et al. [47], raise certain doubts that fluoropyrimidine-based drug combinations will be significantly more effective than gemcitabine monotherapy. Even when gemcitabine was not used, it has never been demonstrated that combination chemotherapy was superior to 5-FU alone [48]. Despite the fact that no polychemotherapy regimen has yet reached the level of an evidence-based standard treatment [48], further clinical research efforts including combination testing with other conventional anticancer drugs and/or biologicals are encouraged as there continues to be a dire need to improve our therapeutic arsenal for advanced pancreatic cancer.
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Acknowledgements |
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Footnotes |
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References |
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