Phase II study of cisplatin, gemcitabine and 5-fluorouracil in advanced pancreatic cancer

A. Novarino1, I. Chiappino1,*, G. F. Bertelli2, A. Heouaine3, G. Ritorto1, A. Addeo1, G. Bellone4, M. Merlano3 and O. Bertetto1

1 Oncologia Medica, Centro Oncologico Ematologico Subalpino, Azienda Ospedaliera Molinette, Torino, Italy; 2 South West Wales Cancer Institute, Singleton Hospital, Swansea, UK; 3 Oncologia Medica, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy; 4 Dipartimento di Fisiopatologia Clinica,Università di Torino, Torino, Italy

Received 4 August 2003; revised 7 November 2003; accepted 19 December 2003


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

The aim of this study was to determine the activity of the combination of cisplatin, gemcitabine and 5-fluorouracil (5-FU) as therapy for metastatic or locally advanced inoperable pancreatic adenocarcinoma.

Patients and methods:

Patients with histologically proven advanced or metastatic pancreatic adenocarcinoma received first-line chemotherapy comprising cisplatin (20 mg/m2 on days 1, 8, 15, 22, 29 and 36), gemcitabine (1000 mg/m2 on days 1, 8, 29 and 36) and 5-FU (200 mg/m2 as continuous infusion on days 1–42) every 56 days.

Results:

A total of 34 patients were studied. Eighty courses were administered (median two courses per patient). Among 32 patients evaluable for response, two patients had a complete response and four a partial response for an overall response rate of 19% (95% confidence interval 7% to 36%). Thirteen patients had stable disease (40%) and 13 progressed. Median progression-free survival was 4.7 months, median survival 9.0 months and 26% of patients achieved 1-year survival. Ten of 25 patients (40%) with pain at presentation had a sustained reduction of analgesic consumption. The principal grade 3/4 toxicities were neutropenia, thrombocytopenia, anaemia and mucositis, occurring in 24%, 21%, 9% and 3% of patients.

Conclusion:

This schedule seems well tolerated and active in pancreatic cancer and worthwhile of further evaluation.

Key words: chemotherapy, cisplatin, 5-fluorouracil, gemcitabine, pancreatic cancer, phase II study


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Pancreatic cancer accounts for ~2% of all new cancer diagnoses, but has an all-stage 5-year survival rate of <5%, which has basically remained unchanged during the last 30 years [1]. Cure can be achieved only if the primary tumour can be radically resected, but ~80% of patients affected with carcinoma of exocrine pancreas present with unresectable disease due to metastases or local extension.

Until recently pancreatic cancer was considered a chemotherapy-resistant tumour and no standard treatment was recommended. Two phase III studies in the last decade demonstrated an improvement in overall survival without impairing quality of life with 5-fluorouracil (5-FU)-based regimens [2, 3]. However, single-agent 5-FU therapy in randomised studies showed a response rate of 0–7% and median survival of <5 months [4, 5].

On the basis of a randomised trial comparing gemcitabine with 5-FU, which highlighted the superiority of gemcitabine in terms of median and 1-year survival (5.6 months and 18% versus 4.4 months and 2% with 5-FU), but not in terms of objective response, gemcitabine has been largely accepted as first-line therapy for advanced disease. In the above trial, gemcitabine was better than 5-FU also for a composite end point, defined clinical benefit response, developed to quantify the impact of therapy on symptoms typically associated with progressive pancreatic cancer. Due to the difficulty in evaluation of response in pancreatic cancer, a combination of pain intensity, analgesic consumption, performance status and weight was chosen as a surrogate parameter; clinical benefit rate was 23.8–27% with gemcitabine, significantly greater than with 5-FU (4.8%) [5, 6].

Due to its activity and its favourable toxicity profile gemcitabine has been largely evaluated in combination with other drugs. Several attempts at developing more efficacious chemotherapy regimens have been carried out with the combination of gemcitabine with 5-FU [7, 8], cisplatin [9, 10], docetaxel [11, 12], irinotecan [13, 14] and epirubicin [15] with conflicting outcomes. However, most of these two-drug regimens have not yielded results very different from those obtained with gemcitabine alone. Preclinical studies have shown a synergistic or at least additive activity of gemcitabine combination with both cisplatin [16] and fluoropirymidines [17, 18]. An overall response rate of 21% in pancreatic carcinoma with cisplatin [19] and infusional 5-FU [20] used as monotherapy has been reported.

The aim of this study was to evaluate the activity and the toxicity profile of a combination of cisplatin, gemcitabine and infusional 5-FU in the treatment of locally advanced or metastatic pancreatic cancer.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patients with locally advanced or metastatic, histologically confirmed, pancreatic adenocarcinoma and no prior chemotherapy were eligible for the study. Other eligibility criteria were measurable or assessable disease not previously irradiated, age >18 years, Zubrod performance status grade ≤2, expected survival >12 weeks, adequate liver, kidney and bone marrow function. Patients with prior malignancy were ineligible for the study, with the exception of skin basal-cell carcinoma, cervix carcinoma in situ or other cancer for which the patient was disease-free for at least 5 years. Other exclusion criteria were prior chemotherapy, radiation therapy within the previous 4 weeks, serious ongoing infection or co-morbidity. Pregnant or breast-feeding women were ineligible, and fertile participants had to agree to practice contraception. All participating patients were required to give informed consent before entering the study and the procedures followed were in accordance with the Helsinki Declaration.

The pretreatment evaluation consisted of a complete medical history and physical examination, blood counts, chemistry profile with hepatic and renal function test and computed tomography scans to document disease extent. Follow-up studies included weekly blood counts, medical history, physical examination and chemistry profile before each course of treatment. Disease status was assessed every 8 weeks. Response evaluation was carried out according to the World Health Organization criteria: complete response (CR) was defined as the complete disappearance of all assessable disease for at least 4 weeks, partial response (PR) indicated a decrease of at least 50% in the sum of the products of the bidimensional diameters of measurable lesions for at least 4 weeks, stable disease (SD) was defined as the decrease of <50% or the increase of <25% in tumour size, and progressive disease (PD) an increase of at least 25% or appearance of new neoplastic lesion(s). Toxicity was assessed weekly and adverse events were graded according to the standard National Cancer Institute common toxicity criteria (NCI CTC).

Every course of therapy lasted 56 days. Cisplatin 20 mg/m2 was delivered as a 30-min infusion in 250 ml of normal saline, with adequate prehydration accompanied by adequate urinary output, on days 1, 8, 15, 22, 29 and 36. Gemcitabine 1000 mg/m2 was given as a 30-min infusion in 250 ml of normal saline on days 1, 8, 29 and 36. 5-FU 200 mg/m2 was supplied as continuous infusion on days 1–42. Antiemetic regimen consisted of dexamethasone 8 mg in 100 ml normal saline as a 15-min intravenous infusion and ondansetron 8 mg in 100 ml normal saline as a 15-min intravenous infusion. The treatment was delayed until recovery in case of haematological toxicity equal or exceeding NCI CTC grade 2. In case of haematological toxicity grade 3 or 4 the subsequent dose of cisplatin and gemcitabine was decreased by 25%. In case of hand–foot syndrome 5-FU was suspended until recovery. Patients were allowed to remain on treatment provided there was no evidence of progressive disease. Patients with intolerable toxicity could be removed from the protocol. Performance status, pain and disease-related symptoms, analgesic consumption and weight were recorded at study entry and re-evaluated weekly thereafter.

According to a Simon two-stage phase II optimal design [21] for a goal of 30% true response rate with an {alpha} and ß error probability of 0.05 and 0.20, respectively, an accrual of at least 29 patients evaluable for response was planned. An early termination of the study was required if no response was seen in the first 10 patients. If one or more patients responded, additional patients would be accrued, to have a final set of 29 evaluable patients. If five or more responses were observed the conclusion would be that the regimen is promising.

The 95% confidence interval (CI) for response was calculated. Overall survival and progression-free survival were estimated on an intent to treat basis from the start of therapy, with the Kaplan–Meier method of analysis and the 95% Andersen CI.


    Results
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Between November 1999 and January 2003, 34 patients were accrued to the study. Their baseline characteristics are shown in Table 1. No patient had received any prior chemotherapy.


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Table 1. Patients characteristics
 
A total of 80 cycles of chemotherapy were completed. Two patients started the therapy but did not complete the first cycle before early death due to advanced disease and did not have their disease reassessed, so they have been evaluated for toxicity only. Thirty-two patients were evaluable for tumour response. Thirteen patients (40%) had progressive disease during chemotherapy. Two complete and four partial responses have been observed for an overall response rate of 19% (95% CI 7–36%), while 13 patients (40%) had stable disease. Tumour growth stabilisation (the sum of complete and partial remission and stable disease) was achieved in 59% of patients. The median response duration was 3.8 months. All responses were after one or two courses of therapy, thereafter no more tumour shrinkage was registered. Six patients had stable disease for ≥3.8 months and five patients had stable disease for >4.6 months. Median progression-free survival was 4.7 months (95% CI 1.7–7.5 months) and median survival was 9.0 months (95% CI 5.0–12.7 months). One-year survival was 26%.

Among 25 patients with pain at presentation, 11 (44%) had sustained analgesic consumption reduction, without worsening in performance status or weight loss. Haematological and non-haematological toxicity is shown in Table 2.


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Table 2. Patients with maximum toxicity
 
Toxic effects of NCI CTC grade 3–4 were neutropenia (24%), thrombocytopenia (21%), anaemia (9%) and mucositis (3%). One patient had thrombocytosis. There were no neutropenic fevers. Two patients had hand–foot syndrome. No case of neurotoxicity was observed. During the treatment three patients had a catheter-related venous thrombosis and one had a splenic infarction. The dose of gemcitabine and cisplatin had to be reduced in 13 patients (38%).


    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Pancreatic adenocarcinoma remains one of the leading causes of cancer death. Gemcitabine in phase II trials had a low measurable antitumour efficacy with a median objective response rate of 10% (range 6.3–14.3%) and a median survival of 5.6–6.3 months [22, 23].

In vitro synergistic cytotoxicity of gemcitabine and cisplatin have been observed; adequate repair of DNA damage caused by cisplatin was prevented by gemcitabine [16]. Moreover, 5-FU metabolites may inhibit deoxycytidine monophosphate deaminase, an enzyme responsible for inactivation of gemcitabine monophosphate [17, 18].

A synergistic or at least additive effect among cisplatin, 5-FU and gemcitabine has been suggested by some, but not all clinical studies evaluating different combinations. Combination of cisplatin and 5-FU has been shown [24] to induce a better overall response rate (12% versus 0%) than 5-FU alone and an amelioration of 1-year progression-free survival (10% versus 0%) and 1-year overall survival (17% versus 9%).

Several clinical trials of gemcitabine and 5-FU in combination used widely different 5-FU administration methods, from bolus injection, to 24–48 h infusion, to protracted infusion over several weeks, rendering it difficult to make a definitive judgment about the efficacy of this combination, as reviewed by Oettle and Riess [25] and by Heinemann [26]. Although there are some promising results, especially with infusional 5-FU in small phase I–II trials [2729], the combination of gemcitabine with bolus 5-FU in a randomised trial [7] failed to improve overall survival in comparison to gemcitabine alone (6.7 versus 5.4 months), showing only a significant advantage in terms of progression-free survival (3.4 versus 2.2 months).

The role of combination gemcitabine and cisplatin, although promising greater activity than gemcitabine alone, has still to be determined. A schedule of bimonthly cisplatin with weekly gemcitabine in a phase II study [30] produced an objective response rate of 11.4%, with a median survival of 8.2 months and a 1-year survival of 27%. Preliminary results of a randomised trial [31] suggested an improvement of gemcitabine efficacy by the addition of cisplatin, albeit the frequent dose reductions and omissions due to the haematological toxicity of the schedule. In a phase II study of weekly gemcitabine and cisplatin for two consecutive weeks every 3 weeks, however, the response rate was 9% and the median survival 5.4 months [10]. These results have been explained as a consequence of the weekly administration of cisplatin, probably less synergistic with gemcitabine than when supplied on day 2 or 15 [32].

The overall response rate obtained in our study is more promising than those reported in studies with gemcitabine alone, but for pancreatic cancer this could be a poor surrogate end point. The associated desmoplastic reaction can induce overestimation of the tumour mass, while associated pathological changes in the pancreas, such as chronic pancreatitis or cyst, and the location of the pancreas complicate radiographical interpretation of changes. The most interesting result of our study, albeit preliminary, is the 1-year survival, suggesting that efforts must be made to improve such a combination schedule, to reduce toxicity. In patients affected with locally advanced or metastatic pancreatic carcinoma, for the merely palliative intention of the treatment, special attention should be paid to the side-effects and the toxicity profile. Such a three-drug combination is worthwhile of further study and modification of timing of administration, to render it less toxic. A study by Krep et al. [33] on the different toxicity profiles of four sequences of administration of cisplatin and gemcitabine showed that leucopenia was schedule-dependent and more severe when cisplatin preceded gemcitabine, and that gemcitabine 24 h before cisplatin has the more manageable toxicity.

A true measure of the benefits from a chemotherapy regimen in advanced pancreatic adenocarcinoma can only come from phase III study, to compare it to the current standard of care, gemcitabine alone, with survival and quality of life as the critical end points.


    FOOTNOTES
 
* Correspondence to: Dr I. Chiappino, A.O. San Giovanni Battista, via Pincipessa Felicita di Savoia 13, c.so Bramante 88, 10100 Torino, Italy. Tel: +39-011-660-4038; Fax: +39-011-660-4038; E-mail: ichiapp{at}tin.it Back


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 ABSTRACT
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 Patients and methods
 Results
 Discussion
 REFERENCES
 
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