Departments and Units of Medical Oncology, Parma, Bergamo, Pesaro, Treviglio (BG), Milan, Taormina (ME) and Urbino (PU), Italy
Received 13 May 2002; revised 5 August 2002; accepted 9 September 2002
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Abstract |
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This phase II study was initiated to determine the activity and toxicity of a combination of gemcitabine (GEM) and cisplatin (CDDP) in patients with pancreatic cancer.
Patients and methods:
CDDP 35 mg/m2 was given as a 30-min infusion and GEM 1000 mg/m2 as a 30-min infusion. Both drugs were administered once weekly for 2 consecutive weeks out of every 3 weeks to chemonaive patients with locally advanced or metastatic pancreatic cancer.
Results:
Forty-five advanced pancreatic cancer patients received this regimen for a total of 180 cycles of chemotherapy. One complete and four partial responses have been observed for an overall response rate of 9% (95% confidence interval 10% to 11%). Twenty-one patients (46%) had stable disease and 19 progressed on therapy. The median time to progression was 3.6 months, with a median survival of 5.6 months. A clinical benefit was obtained in nine of 37 patients (24%). Side-effects were mainly represented by hematological toxicity. Grade 3/4 WHO toxicities included neutropenia (6% of the patients) and thrombocytopenia (11%). The dose of GEM and CDDP was reduced in 14 patients (31%) and treatment was delayed in 10 patients (22%).
Conclusions:
Our results in terms of response rate, clinical benefit and survival do not support an advantage for the combination of GEM and CDDP given by this schedule.
Key words: intensive chemotherapy, palliation, pancreatic cancer
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Introduction |
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Several chemotherapeutic regimens have been tested with limited impact on patient outcome. However, the development of new drugs and the introduction of innovative end points of treatment have led to a cautious optimism for the use of chemotherapy for advanced disease [2].
Gemcitabine (GEM) is the most investigated new drug in pancreatic cancer. It showed a very favorable toxicity profile and demonstrated activity, also reducing symptoms caused by the cancer [3, 4]. Although this first step appears to be promising, combinations with other drugs could potentially add to the efficacy of GEM. Several studies assessed the feasibility and activity of a combination of GEM with 5-fluorouracil, docetaxel and epidoxorubicin, produced conflicting results [510]. Over the past 2 years there has been a development with the use of GEM plus cisplatin (CDDP) in the treatment of patients with several types of oncological disease [1113]. The choice for such a combination of drug therapy was based on theoretical considerations and results of laboratory experiments indicating synergy between the two drugs [14]. In addition, the two drugs have no overlapping dose-limiting toxicities, facilitating their use in combination. In pancreatic cancer, phase II clinical trials investigating this combination at the dose of 1000 mg/m2 for GEM on day 1, 8 and 15, and 50 mg/m2 for CDDP on day 1 and 15 every 4 weeks, seem to be promising with a response rates of 1525% and a median survival of 78 months [14, 15]. However, most of the patients treated with this combination experienced moderate to severe toxicity. Since advanced pancreatic cancer patients generally present a poor performance status and do not tolerate aggressive chemotherapy well, we modified the schedule of GEM/CDDP in order to treat a wider number of patients by reducing the single dose of CDDP (from 50 to 35 mg/m2) but maintaining a similar dose intensity (25 versus 23.3 mg/m2/week).
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Patients and methods |
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Informed consent was obtained from all participants after the nature of the study had been fully explained, and the protocol was approved by the institutional review board.
The chemotherapeutic regimen consisted of an administration of CDDP 35 mg/m2 as a 30-min infusion in 250 ml normal saline with adequate prehydration accompanied by adequate urinary output, and GEM 1000 mg/m2 as a 30-min infusion in 250 ml normal saline. Both drugs were administered once weekly for 2 consecutive weeks out of every 3 weeks. Treatment with GEM and CDDP continued until there was evidence of disease progression or until there was significant clinical deterioration because of tumor-related symptoms.
As antiemetic regimen, all patients received dexamethasone 20 mg in 50 ml saline given as an intravenous infusion over 15 min, 45 min before CDDP, and ondansetron 8 mg made up to 50 ml saline as an intravenous infusion over 15 min.
Doses of both drugs were reduced for toxicity the day of treatment as follows: 50% in patients with an absolute neutrophil count of 500900/mm3 or with a platelet count of 50 00074 000/mm3. For patients with grade 3/4 non-hematological toxicity (exluding nephrotoxicity), doses were reduced 50% for those with grade 3 non-hematological toxicity (except nausea/emesis and alopecia), and doses were held for those with grade 4 non-hematological toxicity (except nausea/vomiting and alopecia). The dose of CDDP was reduced and appropriate hydration measures were implemented if the serum creatinine level was 1.62.0 x upper limit of normal.
Tumor response was classified according to WHO criteria and documented by two investigations at least 6 weeks apart. Disease status for patients was assessed every 6 weeks [16]. In addition to objective response, the clinical benefit measurement was assessed prospectively. It derived from measurements of three common debilitating signs or symptoms present in most patients with advanced pancreatic cancer: pain, functional impairment and weight loss.
Pain assessment comprised separate measures of both pain intensity and analgesic consumption. Each patient was categorized as positive, negative or stable for these two pain-related outcomes, as previously reported [17].
Karnofsky performance status (KPS) was determined by two independent observers at baseline and on a weekly basis thereafter. In cases where the scores differed, the lower of the two scores was used.
Clinical benefit response was determined by both pain assessment classification and KPS. A patient was considered to be a clinical benefit non-responder by the primary measures of response if either pain or KPS was classified as negative. Barring this occurrence, if either the pain or performance status measures were positive a patient was identified as a clinical benefit responder. If pain and performance status were both stable, then the secondary measure of weight change was used to determine clinical benefit. A patients weight was recorded once at baseline and weekly thereafter. Patients who were stable on pain assessment and performance status were considered to be clinical benefit responders if they experienced a positive change in weight. Patients were categorized as clinical benefit non-responders if they were stable on the primary measures and experienced a non-positive change in weight [17].
This was a multi-institutional phase II study; the primary objective was to determine the response rate and the toxicity of this regimen. Secondary objectives were to measure the clinical benefit and survival.
According to the optimal two-stage phase II design by Simon, an early termination of the study was required if no responses were seen in the first 18 patients. If two responses were seen in the first 18 patients enrolled, then an accrual of 45 patients was set to ensure that at least 43 eligible patients were enrolled. A response rate of 25% was determined as a worthy goal on the basis of findings from other trials with GEM and CDDP. If the true response rate was 25% then there was an 80% chance that the treatment would be considered worthy of further investigation [18].
The 95% exact confidence interval (CI) for response was calculated. Survival time was calculated from the onset of chemotherapy.
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Results |
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Clinical benefit
Nine of 37 patients (24%) were classified as positive in the pain category. In four patients both pain and KPS improved while in the other five there was an improvement in pain with no worsening of performance status. Therefore these patients were classified as clinical benefit responders by their primary measures. With regard to the secondary measure of clinical benefit, three patients had a positive weight change. All of them had already been categorized as clinical benefit responders by primary measures. The other six patients achieving a clinical benefit had stable weight.
Toxicity
Side-effects were mainly represented by hematological toxicity (Table 2). Grade 3/4 WHO toxicities included neutropenia (4% of the patients) and thrombocytopenia (11%). The dose of GEM and CDDP was reduced in 14 patients (31%) and treatment was delayed in 10 patients (22%).
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Discussion |
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In pancreatic cancer a GEM (1000 mg/m2) 4-week cycle was used with CDDP (50 mg/m2) given every 2 weeks [14, 15]. This combination appeared to have greater activity than single-agent GEM as suggested by the preliminary results of a randomized trial [21], even if most patients experienced significant toxicity resulting in frequent dose reductions or omissions. Since most pancreatic cancer patients present at diagnosis with a poor performance status, this GEM/CDDP schedule could not be appropriate for them. In order to develop a safer schedule, we planned to give GEM (1000 mg/m2) and CDDP (35 mg/m2) weekly for 2 consecutive weeks out of every 3 weeks. This choice depends on a previous experience in lung cancer where a weekly schedule regimen was used but with a 3-week cycle followed by 1 week of rest [22]. Since day 15 administration was often omitted because of hematological toxicity we decided to omit this administration giving GEM and CDDP for 2 weeks every 3 weeks. This weekly administration of both drugs might determine a more favorable toxicity profile and furthermore many biological and clinical arguments are strongly in favor of rapidly repeated regimens in several cancer types [23]. This regimen was well-tolerated, toxicity being generally mild (Table 2). Nevertheless, in spite of this good tolerance the activity seemed to be really disappointing.
We registered a response rate of 9% and a clinical benefit was achieved in only 24% of patients. Also the median survival was not improved in comparison with GEM alone: 5.4 versus 5.1 months.
These disappointing results may be due to our schedule with the CDDP repeated early in the treatment course (eighth day). Sheperd et al. [19] in fact reported that a GEM and CDDP schedule may influence activity in advanced non-small-cell lung cancer, with the weekly schedule obtaining the worst results. The administration of CDDP after a loading dose of GEM (second day) or later in the treatment course (fifteenth day) seemed to be associated with the most favorable therapeutic index.
However, in spite of the used schedules, the trials investigating this combination in pancreatic cancer gave overall conflicting results since the present study and the study of Heinemann et al. [15] reported a response rate of 9% and 11%, respectively, while trials by Colucci et al. [24] and Philip et al. [14] found an activity of 26%. Furthermore, the results from the trial of Colucci et al. do not help us to understand the real value of this combination in pancreatic cancer because of the statistical design (a phase II randomized study) and the sample size (
50 patients per arm). We really need the results of a well-conducted phase III randomized trial to define the efficacy and the role of such a combination in pancreatic cancer.
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Footnotes |
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References |
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