Phase II trial of cisplatin and gemcitabine in patients with advanced gastric cancer

S. M. De Lange1, C. J. van Groeningen1, J. R. Kroep1, A. Van Bochove2, J. F. Snijders1, G. J. Peters1, H. M. Pinedo1 and G. Giaccone1,*

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


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

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 35–71). 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 2–8). Myelosuppresion was the most important toxicity. Grade 3–4 thrombopenia was observed in 19 patients (48%) and grade 3–4 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 1–2 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 3–27+).

Conclusions:

This cisplatin–gemcitabine 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


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The prognosis of patients with gastric cancer is relatively poor even after complete resection, with 5-year survival rates ranging from 20% to 40%, due to the fact that many patients already have advanced disease at diagnosis [1]. The results obtained with chemotherapy in patients with locally advanced or metastatic gastric cancer are disappointing. Combination chemotherapy, particularly cisplatin-based regimens, results in higher response rates than single-agent chemotherapy, with response rates ranging from 25% to 50% [2]. Responses are, however, usually partial and of short duration, and toxicity is substantial with some of the combination chemotherapy regimens.

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 DNA–platinum adducts: DNA–DNA 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 DNA–platinum 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 DNA–Pt 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.


    Patients and methods
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The aim of this phase II study was to assess the efficacy and toxicity of cisplatin and gemcitabine in patients with advanced or metastatic gastric cancer.

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 Institute–common 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).


    Results
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patients were accrued at two institutions from August 1998 to May 2001. Table 1 shows the characteristics of the 40 patients who participated in the study. The median WHO performance status was 1. Thirty-seven patients (93%) had metastatic disease with lymph nodes and the liver being the main metastatic sites. Three patients had an unresectable primary tumour without metastases. Prior gastrectomy had been performed in six patients, and two patients had prior radiotherapy for bone metastasis. All patients were evaluable for response.


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Table 1. Patient characteristics
 
Thirteen patients (35%) received all the planned six cycles. One patient with a partial remission received eight cycles. A total of 177 cycles were administered, with a median of four cycles per patient (range 2–8) (Table 2). Treatment was not continued up to six cycles because of progressive disease (12 patients), stable disease without symptomatic improvement (two patients) or toxicity (seven patients). In one patient this was because of neurotoxicity, in two patients because of nephrotoxicity, in two patients because of thrombocytopenia, in another patient because of severe nausea and vomiting, and in the last patient because of persistent leukopenia. The other reasons for treatment discontinuation were surgery in two patients, two patients refused further treatment after two and five cycles, respectively, and the last two patients because both stopped after four cycles after achieving complete remission.


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Table 2. Cycles
 
Toxicity
All patients were evaluable for toxicity. Myelosuppression was the most frequently occurring side-effect. Table 3 shows the haematological toxicity for the first two cycles and of all delivered cycles. Grade 3 and 4 leucopenia was observed in 23 patients (58%), and grade 3 or 4 thrombocytopenia was observed in 19 (48%).


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Table 3. Haematological toxicity during the first two cycles and overall toxicity
 
Gemcitabine administration on day 16 was omitted in 55% of the cycles due to myelotoxicity. Anaemia occurred frequently and was treated with erythropoietin, red blood cell transfusions or both in 85% of patients. Myelosuppression was cumulative for leucocytes (Figure 1) with day 16 values decreasing from 2.6 ± 0.2 (mean ± SEM) in the first cycle to 2.0 ± 0.2 in the sixth cycle (P = 0.009), and for platelets (Figure 2) with day 16 values decreasing from 125 ± 10 in the first cycle to 45 ± 6 in the sixth cycle (P = 0.0009).



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Figure 1. Accumulation of leucopenia during cisplatin–gemcitabine treatment (mean of all patients ± SEM) for the days 1, 8, 16 and 22 of treatment cycles one to six. Filled circle, cycle 1; open circle, cycle 2; filled triangle, cycle 3; open triangle, cycle 4; filled square, cycle 5; open square, cycle 6. WBC, white blood cell count.

 


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Figure 2. Accumulation of thrombocytopenia during cisplatin–gemcitabine treatment (mean of all patients ± SEM) for the days 1, 8, 16 and 22 of treatment cycles one to six. Filled circle, cycle 1; open circle, cycle 2; filled triangle, cycle 3; open triangle, cycle 4; filled square, cycle 5; open square, cycle 6.

 
Non-haematological toxicity was mostly mild to moderate with only three cases of grade 3 or 4 toxicity (Table 4). Non-haematological toxicity consisted mainly of grade 1 or 2 nausea and vomiting. Four patients developed mild renal disturbances. There were eight patients with moderate to severe liver toxicities; one patient with liver metastases had a grade 3 toxicity, probably not therapy related. The onset of peripheral neuropathy and hearing loss was observed after a median of three cycles. Eight patients developed grade 2 hearing loss and only one patient developed grade 2 peripheral neuropathy.


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Table 4. Overall non-haematological toxicities
 
Responses
All patients were evaluable for response. Two patients had complete remission and 10 patients had partial remission for an overall objective response rate of 30% (95% confidence intervals 15.8% to 44.2%). Responses were observed after a median of two cycles. Twenty-four patients had stable disease, and six patients had progressive disease at the time of the first evaluation. The median duration of response was 5 months and the median time to progression was 7 months. Thirty-five patients died, 34 patients because of malignant disease, and one patient because of a perforation leading to sepsis which occurred during endoscopy. The median survival was 11 months (range 3–27+) (Figure 3). The median survival of responders was 8 months. There was a significant difference in survival between non-progressors and patients with progressive disease (11 versus 4 months; P < 0.00001). There was no difference between survival of responders and patients with stable disease.



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Figure 3. Kaplan–Meier plot of survival of patients with advanced gastric cancer treated with cisplatin and gemcitabine.

 

    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
In patients with unresectable gastric cancer the combination of cisplatin and gemcitabine resulted in a 30% objective response rate, with three complete remissions and a median response duration of 5 months. The toxicity of this regimen was manageable with myelosuppression as the most important toxicity. Myelotoxicity was cumulative and required omission of gemcitabine administration on day 16 in over 50% of cycles. Three-weekly schedules have been investigated, mainly in advanced NSCLC, and appear to preserve activity and have reduced toxicity compared with the schedule employed in this study [2223].

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 1–5, i.v. 24 h infusion); leucovorin at a dose of 30 mg (days 1–5, 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 3–4 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 cisplatin–gemcitabine combination regimen in gastric cancer patients also, but the employed schedule appears to be not easily manageable.


    FOOTNOTES
 
* Correspondence to: Dr G. Giaccone, Department of Medical Oncology, VU Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel: +31-20-4444321; Fax: +31-20-4444079; E-mail: G.Giaccone{at}vumc.nl Back


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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
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