Phase II study of oxaliplatin, 5-fluorouracil and leucovorin in previously platinum-treated patients with advanced gastric cancer

D. Y. Kim, J. H. Kim, S.-H. Lee, T. Y. Kim, D. S. Heo+, Y.-J. Bang and N. K. Kim

Department of Internal Medicine, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

Received 3 June 2002; revised 23 September 2002; accepted 22 October 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
Background:

Oxaliplatin shows preclinical activity in many cancer cell lines that are resistant to cisplatin, and also has synergism with 5-fluorouracil (5-FU). We undertook this study to evaluate the efficacy and toxicities of a combined oxaliplatin, 5-FU and leucovorin (LV) continuous infusion regimen in patients with advanced gastric cancer who progressed during or after treatment with 5-FU and platinum compounds.

Patients and methods:

Twenty-six patients with advanced gastric cancer, whose disease progressed while receiving, or after discontinuing, chemotherapy with a 5-FU and platinum regimen, were enrolled in this study. Treatment comprised oxaliplatin (85 mg/m2 on day 1) as a 2-h infusion followed by bolus 5-FU (400 mg/m2 on day 1), and 48-h infusion of 5-FU 2.4–3.0 g/m2 concurrently with LV 150 mg/m2. Cycles were repeated at 2-week intervals.

Results:

Of the 23 evaluable patients, there were six partial responses (response rate 26%). All responding patients were among those who entered into this trial immediately after failure of previous chemotherapy with 5-FU and cisplatin. The median time to progression was 4.3 months and the median overall survival was 7.3 months. The most common hematologic toxicity was grade 1–2 anemia in 39 cycles (39%). No grade 4 leukopenia or thrombocytopenia were observed. The most common non-hematologic toxicity was nausea/vomiting (33%). Peripheral neuropathy of grade 1 or 2 was noted (27%), but there was no grade 3 or 4 neurotoxicity.

Conclusions:

This phase II study of oxaliplatin, 5-FU and LV continuous infusion showed activity in previously platinum-treated patients with advanced gastric cancer, with acceptable toxicities.

Key words: advanced gastric cancer, 5-fluorouracil, leucovorin, oxaliplatin, phase II study, platinum compounds


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
5-Fluorouracil (5-FU) and cisplatin combination chemotherapy is one of the most effective regimens in advanced gastric cancer, with a response rate of approximately 30–50% [1, 2]. However, chemotherapy in cases refractory to 5-FU and cisplatin remains a challenge.

Oxaliplatin is a third-generation cisplatin analog with a 1,2-diaminocyclohexane (DACH) carrier ligand. Its main mode of action is mediated by the formation of DACH-platinum adducts [3]. Oxaliplatin has demonstrated additive or synergistic activities with 5-FU, even in 5-FU-resistant cell lines [4]. Moreover, it has also shown activity in many tumor cell lines resistant to cisplatin [5].

The biochemical modulation of 5-FU by leucovorin (LV) is an established fact. Several studies have confirmed that biochemical modulation of 5-FU by LV confers a superior response rate to 5-FU alone in advanced gastric cancer [6]. However, the most effective dosage of LV has not been determined, though it has been demonstrated that the effective modulation of 5-FU by LV is a function of the length of exposure to LV [7]. The active metabolite appeared to have a longer half-life after constant infusion than after i.v. bolus injection, and a larger apparent distribution was obtained by the constant infusion of LV [7].

Based on these findings, an oxaliplatin, 5-FU and LV (FOLFOX) regimen was tried in patients having colorectal cancer refractory to 5-FU-based chemotherapy [8]. Also, this regimen was suggested to be active with a 50% objective response rate in gastric cancer patients [9].

In this study, the authors devised a bimonthly regimen of oxaliplatin, 5-FU and LV continuous infusion (OFL-CI) chemotherapy based on the FOLFOX trial in colorectal cancer and LV pharmacokinetics. A single-center phase II study of the OFL-CI regimen was conducted in previously platinum-treated patients with advanced gastric cancer.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
Eligibility
The eligibility criteria were: histologically confirmed adenocarcinoma of the stomach; previous treatment with 5-FU and platinum compounds; bidimensionally measurable lesions; no central nervous system metastases; no second malignancy; no active infection; Eastern Cooperative Oncology Group (ECOG) performance status 0–2; and age <70 years. The protocol was approved by IRB and informed consent was obtained from all patients.

Chemotherapy
Chemotherapy consisted of oxaliplatin (85 mg/m2 on day 1) as a 2-h infusion followed by a 5-FU bolus (400 mg/m2 on day 1), and 48-h infusion of 5-FU 2.4–3.0 g/m2 concurrently with LV 150 mg/m2, without mixing. Cycles were repeated at 2-week intervals. During the first cycle, patients received 2.4 g/m2/48 h of continuous 5-FU, which was increased to 2.7 g/m2/48 h for the second cycle if the maximal toxicity was below WHO grade 2. If the maximum toxicity remained below WHO grade 2 in the second cycle, the dose of continuous 5-FU infusion was increased to 3.0 g/m2/48 h in the third cycle and this was maintained in subsequent cycles. This regimen was administered until progression.

Treatment delays and dose modifications were based on complete blood cell counts taken on the day of the planned next treatment. When thrombocytopenia or neutropenia grade >=2 developed, treatment was delayed by 1 week (maximum of 2 weeks). Any patient requiring more than 2 weeks for recovery of adverse reactions was removed from the study. Peripheral neuropathy was graded according to the oxaliplatin-specific scale [10]. An oxaliplatin dose of 85 mg/m2 was maintained throughout the cycles unless there were grade 2 peripheral neuropathies. If grade 2 or greater peripheral neuropathy persisted between cycles, the treatment was discontinued regardless of response.

Study parameters
Physical examination including a neurological examination and complete blood counts were performed before the first treatment cycle. Pretreatment evaluation also included biochemical analyses, chest X-ray, and CT scans to define the extent of the disease. Complete blood cell counts with differential counts and serum biochemistry analyses were repeated at each treatment cycle. Tumor responses were evaluated by physical examination as well as necessary imaging studies. Subjective symptoms, physical examination results, performance status and all adverse reactions were recorded before each treatment cycle. CT scans were repeated every two cycles.

Complete response was defined as the complete disappearance of all measurable lesions for at least 4 weeks without the appearance of new lesions, while partial response was defined as a decrease of at least 50% in the sum of the products of the largest perpendicular diameters of measurable lesions for at least 4 weeks. Stable disease was defined as a decrease of <50% or an increase of the disease of <25%, and progressive disease was defined as an increase of at least 25% of this product sum or the appearance of a new neoplastic lesion. Therapy was continued until disease progression or the occurrence of non-tolerable toxicity.

Statistical analysis
Survival times were calculated from the start of the study treatment until death. Progression-free survival (PFS) was calculated from the first day of the chemotherapy until the date of progression. PFS and overall survival curves were obtained using the Kaplan–Meier method. Response duration was calculated from the date of response confirmation to the date of disease progression.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
Patient characteristics
From March 2000 to February 2002, 26 patients were enrolled in this study. The patients’ characteristics are shown in Table 1. Median age of the patients was 60 years, and the majority of the study population were male (21 out of 26). Nineteen patients had an ECOG performance status of 2. The predominant site of metastases was the liver. Previous therapy consisted of 5-FU and cisplatin regimen in 23 patients, and 5-FU and heptaplatin in three patients.


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Table 1. Patient characteristics
 
Twenty patients entered into the clinical trial immediately after failure of previous platinum-containing chemotherapy, while six patients had a treatment-free period after discontinuing platinum-containing chemotherapy. Median time from last platinum-containing chemotherapy to this trial was 5.7 weeks. The median number of cycles administered was four (range 1–12 cycles). Median delivered dose intensity of 5-FU was 2.8 g/m2/cycle.

Twenty-six patients were evaluable for toxicity and 23 patients for response. One patient could not be evaluated for response because of follow-up loss after the second cycle of chemotherapy, and one patient refused further chemotherapy after the first cycle. Response evaluation was not possible in an additional one patient, who experienced tumor lysis syndrome, which developed 48 h after the first cycle of OFL-CI. He died 6 days after chemotherapy, despite intensive therapeutic interventions.

Objective tumor responses
The response rate in evaluable patients was 26% (six out of 23 partial responses). Median duration of these responses was 5.2 months. All responding patients are among those who entered into this trial immediately after failure of previous chemotherapy. One patient who initially responded to prior chemotherapy but progressed, had another response with this regimen. Two patients (9%) had stable disease and 15 patients (65%) had tumor progression (Table 2). One patient in partial response received palliative bypass surgery. Fifteen patients stopped treatment due to progressive disease. Grade 2 neuropathy prevented further treatment in one patient in stable disease. Among six responders, one patient stopped treatment because of disease progression after four cycles. Other patients are still in remission after 6–10 cycles.


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Table 2. Response rates of patients
 
Toxicity
The incidence of the main toxicities per cycle is summarized in Table 3. A total of 100 cycles were evaluated. The most common hematological toxicity was grade 1–2 anemia, which was observed in 39 cycles (39%). Leukopenia was mild, and occurred in 16% of cycles as grade 1 or 2. Grade 1 thrombocytopenia occurred in 5% of cycles. No grade 4 leukopenia and/or thrombocytopenia were observed. Grade 1 neuropathy, paresthesia with decreased deep-stendon reflexes, occurred in five patients (19%). Severe paresthesia with mild motor weakness (grade 2 neuropathy) occurred in two patients (8%). No patients experienced grade 3 or 4 neurological toxicity.


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Table 3. Incidence of hematological and non-hematological toxicities
 
Survival
The median PFS was 4.3 months, and median overall survival was 7.3 months from the start of chemotherapy (Figures 1 and 2).



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Figure 1. Progression-free survival of eligible patients receiving oxaliplatin, 5-fluorouracil and leucovorin continuous infusion.

 


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Figure 2. Overall survival of eligible patients receiving oxaliplatin, 5-fluorouracil and leucovorin continuous infusion.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
This study assessed the clinical efficacy and toxicity of oxaliplatin in combination with bimonthly OFL-CI in previously platinum-treated patients with advanced gastric cancer.

A combination of 5-FU and platinum compounds is commonly used as first-line treatment in advanced gastric cancer, and has a response rate of 30–50% [1, 2]. Systemic chemotherapy is effective in newly diagnosed advanced gastric cancer. However, second-line chemotherapy in advanced gastric cancer patients who have progressed after first-line chemotherapy remains a challenge. Recently, second-line chemotherapeutic agents, such as taxanes [11] or irinotecan [12] have been tried in previously treated advanced gastric cancer patients and the response rate with single agents was 5% and 16%, respectively.

Oxaliplatin, 5-FU and LV combination chemotherapy is accepted in patients refractory to 5-FU and LV in colorectal cancer. These combination regimens, based on bimonthly schedules, are called FOLFOX regimens, and are applied at various doses and schedules. Up to the present, FOLFOX2 to FOLFOX6 trials have been performed in colorectal cancer, and the response rate is reported to be 20–46% [8, 1315]. Recently, oxaliplatin in combination with 5-FU and LV (FOLFOX6) was tried as first-line treatment in advanced or metastatic gastric cancer patients and showed an objective response rate of 50%, which included a 4% complete response [9].

We administered oxaliplatin, 5-FU and LV as a second-line chemotherapy to advanced gastric cancer patients who progressed after chemotherapy with 5-FU in combination with platinum compounds. Cisplatin and heptaplatin were used as platinum compounds. Heptaplatin is a new platinum derivative with antitumor activity in various cell lines, including several cisplatin-resistant tumor cell lines, and is less nephrotoxic than cisplatin [16].

In this trial, six of 23 evaluable patients achieved an objective response. Median response duration was 5.2 months. Interestingly, all responding patients are among those who entered into this trial immediately after failure of previous chemotherapy. We believe that oxaliplatin as well as infusional LV had a role in efficacy, because prior 5-FU chemotherapy had been carried out without LV.

In the present study, no grade 4 hematological toxicities were observed. The most common hematological toxicity was grade 1–2 anemia in 39 cycles (39%). Grade 1 leukopenia developed in 13% of the administered cycles, and grade 2 leukopenia and thrombocytopenia occurred in 3% and 4%, respectively. Hematological toxicities were the main reason for cycle postponement, but there was no episode of admission due to febrile neutropenia.

In the various FOLFOX trials, neurotoxicity was the most common side-effect, which led to treatment discontinuation, but the neurotoxicity occurred at a relatively low level in the present study. This may be due to a relatively low cumulative dose of oxaliplatin (median 340 mg/m2) in this series, because neuropathy is reported especially with cumulative doses >540 mg/m2 [17]. However, this may have contributed to the wide variability of interpatient susceptibility to oxaliplatin-induced sensory neuropathy. Severe diarrhea and stomatitis were rare side-effects. Nausea and vomiting were the most common among the non-hematological toxicities, and most of these were grade 1.

Our regimen (OFL-CI) has significant effects as a palliative chemotherapeutic regimen for advanced gastric cancer patients who are refractory to first-line platinum-containing regimen, because of encouraging response and mild toxicities. A phase III randomized trial is being planned to determine whether this current regimen has a role in improvement of survival as well as quality of life as a second-line treatment for advanced gastric cancer patients.


    Conclusions
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
The results of our study suggest that OFL-CI regimen has activity in previously platinum-treated patients with advanced gastric cancer, and that it has acceptable toxicity.


    Acknowledgements
 
This work was supported by KOSEF through SRC-MTRC.


    Footnotes
 
+ Correspondence to: Dr D. S. Heo, Department of Internal Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, Korea. Tel: +82-2-760-2857; Fax: +82-2-742-6689; E-mail: heo1013{at}plaza.snu.ac.kr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
 References
 
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