1 Department of Medical Oncology, VU University Medical Centre, Amsterdam; 2 Department of Internal Medicine, De Heel-Zaans Medisch Centrum, Zaandam, The Netherlands
Received 20 August 2003; revised 14 November 2003; accepted 19 December 2003
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ABSTRACT |
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This phase II study was performed to determine the efficacy and toxicity of cisplatin and gemcitabine in patients with advanced gastric cancer.
Patients and methods:
Forty chemo-naïve patients with measurable locoregionally advanced or metastatic gastric cancer were included; the median patient age was 53 years (range 3571). Cisplatin was administered at a dose of 50 mg/m2, given in 1 h intravenously (i.v.) on days 1 and 8, followed after 24 h by gemcitabine at a dose of 800 mg/m2 given in 30 min i.v. on days 2, 9 and 16, every 28 days.
Results:
A median number of four therapy cycles were given (range 28). Myelosuppresion was the most important toxicity. Grade 34 thrombopenia was observed in 19 patients (48%) and grade 34 leukopenia was observed in 23 (58%). Myelotoxicity was cumulative and caused omission of gemcitabine on day 16 in 55% of cycles. Non-haematological toxicity consisted mainly of grade 12 nausea and vomiting. Objective responses were observed in 30% of patients including two complete remissions and 10 partial remissions. Median survival was 11 months (range 327+).
Conclusions:
This cisplatingemcitabine regimen had moderate efficacy in patients with advanced gastric cancer, with manageable toxicity. Further studies with this combination may be warranted.
Key words: advanced gastric cancer, cisplatin, gemcitabine
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Introduction |
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Cisplatin has some activity as a single agent in advanced gastric cancer and in a variety of other solid tumours, including head and neck cancer, ovarian cancer and lung cancer [35]. The principal mechanism of action of cisplatin is the formation of DNAplatinum adducts: DNADNA cross-links, both intra- and interstrand [6] and the binding of cisplatin to two adjacent guanine moieties on the same DNA strand (pt-GG) is the most abundant lesion (~62%) [7]. Gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) is a deoxycytidine analogue with activity as a single agent and in combination therapy against several chemotherapy-resistant tumours, including pancreas and non-small-cell lung cancer [8]. However, gemcitabine has no significant anti-tumour activity as a single agent in gastric cancer [910]. Gemcitabine acts by incorporation of its triphosphate (dFdCTP) into DNA, subsequently leading to inhibition of DNA replication and repair. Several self-potentiating mechanisms have been described [1113], enhancing the incorporation of dFdCTP into DNA and possibly also into RNA.
Preclinical studies have shown additive and synergistic effects of gemcitabine and cisplatin in combination. Gemcitabine may increase the formation of DNAplatinum adducts, while cisplatin may increase the incorporation of gemcitabine into DNA [8, 1315]. It has been shown that this synergistic interaction is related to a decrease in repair of DNAPt adducts [16]. This combination has shown significant activity in a number of tumour types and has become a standard regimen in advanced non-small-cell lung cancer [5] and bladder cancer.
We performed a schedule finding study, comparing four alternating sequences with a 4 h and a 24 h interval between cisplatin and gemcitabine [1718]. Based on the results of that study, we selected the schedule with cisplatin given at 50 mg/m2 on days 1 and 8, followed after 24 h by gemcitabine given at 800 mg/m2 on days 2 and 9 for the present phase II study in advanced gastric patients. With this regimen we observed two partial responses and three patients with stable disease out of six patients with advanced gastric cancer.
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Patients and methods |
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Patients
All eligible patients met the following criteria: histologically or cytologically confirmed gastric adenocarcinoma; measurable disease on a computed tomography (CT) scan; age 18 and
75 years; WHO performance status
2; and a life expectancy
3 months. Adequate haematological, renal and liver function tests were required, defined respectively as white blood cell count (WBC)
4 x 109/l, absolute neutrophil count (ANC)
2 x 109/l, platelets
100 x 109/l, bilirubin
25 µmol/l, aspartate aminotransferase (ASAT)/alanine aminotransferase (ALAT) within 2 x the upper normal limit, creatinine
120 µmol/l or creatinine clearance
60 ml/min. No prior chemotherapy was allowed and patients with signs of cardiac failure or rhythm disturbances requiring medication or signs of brain metastases or leptomeningeal disease were excluded. No patients with poor medical risks because of non-malignant disease or uncontrolled infection were allowed onto the study.
This study was approved by the institutional ethics committee of both participating hospitals, and all patients gave informed consent.
Assessments and treatment
Pre-treatment evaluation included history, physical examination and tumour assessment. A chest film, an abdominal CT scan and an electrocardiogram (ECG) were performed, as well as laboratory studies. Cisplatin was administered at a dose of 50 mg/m2 by intravenous (i.v.) infusion over 1 h on days 1 and 8. Gemcitabine was administered at a dose of 800 mg/m2 by i.v. infusion over 30 min on days 2, 9 and 16. Gemcitabine was administered 24 h after cisplatin. Cycles were repeated every 4 weeks.
Before cisplatin treatment, patients received i.v. hydration with 1000 ml saline plus 20 mmol potassium chloride and 2 g magnesium sulfate over 2 h. After cisplatin infusion, 4000 ml saline plus 80 mmol potassium chloride and 8 g magnesium sulfate were given over 24 h. Prophylactic i.v. anti-emetics, ondansetron 8 mg and dexamethason 8 mg, were administered twice on the day of cisplatin infusion. No prophylactic use of colony stimulating factors was allowed.
Toxicities were graded using National Cancer Institutecommon toxicity criteria [19]. Treatment was delayed if leukopenia grade 3 and/or thrombocytopenia grade
2 occurred, for a maximum of 2 weeks. Gemcitabine on day 16 was given only if WBC
2 x 109/l, ANC
0.75 x 109/l and platelets
60 x 109/l. Before recycling, bone marrow recovery and creatinine
165 µmol/l, or creatinine clearance
40 ml/min were required. Patients went off study if the treatment delay was >2 weeks. Dose adaptations were not performed. Treatment was discontinued in case of disease progression, unacceptable toxicity or the patient wished to stop the treatment. Six cycles were given to responding patients and patients with stable disease when feasible.
Response to treatment was defined according to the World Health Organization (WHO) criteria and response assessment was every two cycles [20]. To qualify for response assessment, patients had to complete at least two cycles of treatment. Duration of response was defined as time from documentation of the response to documentation of disease progression. Time to progression (TTP) was defined as time from start of treatment to documentation of disease progression. Survival was defined as time from the start of treatment until death.
Statistical analysis
A response rate of 20% was targeted and initially 14 patients were accrued in a two-step design. If the response rate was
20%, then the probability of obtaining no responses in 14 patients would be <0.005. If there were more responses, in the first 14 patients, additional patients were added up to a total of 40 patients. This sample size allows the determination of response rate with a standard error <0.10 [21]. Statistical analyses were performed using the computer program SPSS (Chicago, IL).
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Results |
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Discussion |
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Although gemcitabine administered as a single agent did not show activity in advanced gastric cancer [910], combination with cisplatin has been shown to be additive or even synergistic in several preclinical models [8, 1315]. This was the rationale for testing this combination in advanced gastric cancer. The results of our study are similar to other combinations based on 5-fluorouracil (5-FU) and cisplatin. Lacave et al. treated 56 patients with advanced gastric cancer with cisplatin, 100 mg/m2 (by i.v. continuous infusion over 24 h) and 5-FU 1000 mg/m2/day (by 5-day continuous infusion), every 4 weeks. The response rate was 41% and the median survival in this study was 10.6 months. Leucopenia and thrombocytopenia were mild, nausea and vomiting were common [24]. A similar study was carried out by Rougier et al. Cycles were administered every 4 weeks and consisted of 5-FU 1000 mg/m2/day as 5 days continuous infusion with cisplatin given at 100 mg/m2 on day 2. In this study, 87 patients were entered with a response rate of 43% and a median survival of 9 months. Toxicity was acceptable, although three patients died of sepsis as a consequence of severe neutropenia [25]. Mochizuki et al. reported a study of 49 patients with advanced gastric cancer in which 5-FU was given at a dose of 370 mg/m2 (days 15, i.v. 24 h infusion); leucovorin at a dose of 30 mg (days 15, i.v. bolus); and etoposide and cisplatin both at 70 mg/m2 (days 7 and 21, i.v. 2 h) which was repeated every 5 weeks. The overall response rate was 40.8% and the median survival time was 12.6 months [26].
A relatively small randomised study compared a two-drug non-cisplatin-based regimen to the same combination with the addition of cisplatin in 122 patients with advanced gastric cancer. Epirubicin combined with 5-FU (FE) was compared with epirubicin, 5-FU and cisplatin (FEP). Response rates were 28.6% and 42.6% in the FE and FEP arms, respectively, and survival was significantly longer in the FEP arm (7.1 versus 9.6 months, respectively) to the cost of some additional toxicity [27].
Another randomised study compared ECF with the older standard FAMTX in 274 patients with advanced oesophagogastric cancer [28]. The ECF regimen consisted of 5-FU continuous i.v. infusion at a dose of 200 mg/m2 per day using a portable pump for up to 6 months, epirubicin (50 mg/m2 i.v.) and cisplatin (60 mg/m2 i.v.) were given every 3 weeks for a maximum of eight cycles. The overall response rate was 45% with ECF and 21% with FAMTX. Toxicity was tolerable and there were only three toxic deaths. The median survival was 8.9 months with ECF and 5.7 months with FAMTX. Both response rate and survival were significantly better in the ECF arm [28]. However, an important disadvantage of the ECF regimen is the need for a portable pump for a prolonged time.
The introduction of novel agents, such as docetaxel, in the treatment of advanced gastric cancer has been attempted in several studies. Mitachi et al. conducted a study without 5-FU, docetaxel and cisplatin. Docetaxel was given at a dosage of 60 mg/m2 and cisplatin at a dosage of 80 mg/m2. The treatment was repeated every 34 weeks until disease progression or unacceptable toxicity. Grade 3 or 4 leucopenia and neutropenia were observed in 71.4% and 82.1% of patients, respectively. Non-haematological toxicities were not severe. The response rate was 25% and median survival was 9.7 months [29]. This and other studies underline the difficulties in identifying novel agents with activity in this disease and the increased toxicity of regimens with more than two agents.
The combination of cisplatin and gemcitabine tested in this study is active and is similar to other cisplatin-based regimens. It may be possible to build on this combination with the addition of agents with non-overlapping side-effects. In this respect, the 3-weekly regimen is to be preferred over the 4-weekly regimen as tested in the present study. New approaches are required which may consist of combination chemotherapy with biologicals, such as angiogenesis inhibitors [30]. Recently, the use of Bevacizumab (anti-VEGF recombinant antibody) in combination with chemotherapy has provided a significant increase in survival in patients with advanced colorectal cancer over chemotherapy alone [31].
In conclusion, this study confirms the activity of the cisplatingemcitabine combination regimen in gastric cancer patients also, but the employed schedule appears to be not easily manageable.
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FOOTNOTES |
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