© 2004 European Society for Medical Oncology
Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study
1 Catholic University of Sacred Heart, Rome, Italy; 2 Szt Margarit Hospital, Budapest, Hungary; 3 III Med. Klinik, Munich, Germany; 4 All Union CRC, Moscow, Russia; 5 Estonian Oncology Center, Tallin, Estonia; 6 Hielkoskopie Centrum, Poznan, Poland; 7 Moscow Oncological Center, Moscow, Russia; 8 Aventis Pharma, Antony; 9 Institut Claudius Regaud, Toulouse, France
* Correspondence to: Dr C. Barone, Medical Oncology, Catholic University of the Sacred Heart, Largo Francesco Vito, 1.00168 Rome, Italy. Tel: +39-06-3015-4844; Fax: +39-06-3017-334; Email: carlobarone{at}rm.unicatt.it
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Abstract |
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Background: To identify the most effective of two combinations, irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) and irinotecan/cisplatin, in the treatment of advanced gastric cancer, for investigation in a phase III trial.
Patients and methods: Patients were randomized to receive irinotecan [80 mg/m2 intravenously (i.v.)], FA (500 mg/m2 i.v.) and a 22-h infusion of 5-FU (2000 mg/m2 i.v.), weekly for 6 weeks with a 1-week rest, or irinotecan (200 mg/m2 i.v.) and cisplatin (60 mg/m2 i.v.), on day 1 for 3 weeks.
Results: A total of 115 patients were eligible for analysis in the per-protocol population. The overall response rate in the irinotecan/5-FU/FA arm (n=59) was 42.4%, with a complete response rate of 5.1%. Corresponding figures for the irinotecan/cisplatin arm (n=56) were 32.1% and 1.8%, respectively. The median time to progression was 6.5 months (irinotecan/5-FU/FA) and 4.2 months (irinotecan/cisplatin) (P < 0.0001), with median survival times of 10.7 and 6.9 months, respectively (P=0.0018). The major toxicity was grade 3/4 neutropenia, which was more pronounced with irinotecan/cisplatin than with irinotecan/5-FU/FA (65.7% versus 27%). Diarrhea was the main grade 3/4 non-hematological toxicity with both irinotecan/5-FU/FA (27.0%) and irinotecan/cisplatin (18.1%).
Conclusions: Both combinations were active, with acceptable safety profiles. Irinotecan/5-FU/FA was selected as the most effective combination for investigation in a phase III trial in advanced gastric cancer.
Key words: advanced gastric cancer, cisplatin, 5-FU/FA, irinotecan, phase II
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Gastric cancer is the second most frequent cancer worldwide [1
], and management of this disease is a challenge for oncologists. In early and locally advanced cancer, surgery remains the mainstay of curative treatment, but relapse is common. The majority of patients present with advanced disease, and the prognosis for such patients is poor.
Despite a number of years of controversy, the weight of evidence now supports the use of chemotherapy to improve outcome in both advanced [2–4] and resectable [5] disease. Adjuvant therapy may be particularly useful for patients with resected disease and poor prognostic factors [6, 7]. Established agents showing activity in gastric cancer include 5-fluorouracil (5-FU), cisplatin, methotrexate, doxorubicin, epirubicin and mitomycin [8]. Although 5-FU was for many years the standard treatment choice for advanced cancer, attempts to improve response rates led to the use of combination therapy. The combination of 5-FU, doxorubicin and mitomycin (FAM) was used widely until 5-FU, doxorubicin and high-dose methotrexate (FAMTX) was shown to be superior, in terms of both response rate and survival [9]. Subsequently, a randomized trial showed that the cisplatin-based combination of etoposide, doxorubicin and cisplatin (EAP), which had produced promising results in a number of small studies, was no more effective than FAMTX, and led to significantly greater toxicity [10]. More recently, a randomized trial in patients with previously untreated advanced esophagogastric cancer demonstrated that the cisplatin-based combination of epirubicin and cisplatin coupled with protracted venous infusion of 5-FU (ECF) was associated with improved response rates (46% versus 21%; P=0.00003) and 2-year survival rates (14% versus 5%; P=0.03) compared with FAMTX [11]. The superiority of a combination of cisplatin, epirubicin and bolus 5-FU/FA (PELF) over FAMTX has also been suggested in another randomized trial in advanced gastric cancer [12]. However, a randomized phase III trial showed that there were no significant differences in response rate and survival rate between three cisplatin- and non-cisplatin-containing regimens [etoposide, leucovorin, 5-FU (ELF), infusional 5-FU plus cisplatin (FUP) and FAMTX] [13]. Furthermore, all three combinations demonstrated only modest activity in advanced gastric cancer, with median survival times of <9 months. These trials highlight the urgent need for novel strategies to improve the outcome of patients with advanced gastric disease.
Although improvements in outcome have been made with chemotherapy, sustained responses are still elusive, and ways to improve the outcome of patients with gastric cancer are constantly being sought. In addition to novel combinations of established agents, the use of newer agents, such as irinotecan (CPT-11, Campto®; Aventis Pharma, Antony, France), is under investigation [14]. Irinotecan is a semi-synthetic, water-soluble derivative of the plant alkaloid camptothecin. Following conversion to its active metabolite, SN-38, irinotecan acts by inhibiting DNA topoisomerase-I, thereby interfering with DNA replication and cell division. Single-agent irinotecan after 5-FU failure has been shown to prolong the survival of patients with metastatic colorectal cancer [15, 16], and irinotecan in combination with infusional or bolus 5-FU [5-FU/folinic acid (FA)] is now standard first-line therapy for this disease [17, 18]. In early phase trials in advanced gastric cancer, single-agent irinotecan demonstrated efficacy in both first- and second-line treatment settings [19–22]. The unique activity of irinotecan means that it can be combined effectively with other chemotherapeutic agents without cross-resistance, and promising activity in esophagogastric malignancies has been shown for irinotecan in combination with a number of agents, most notably cisplatin [23–26] and 5-FU [27–29].
In view of the results of previous studies with irinotecan in gastric cancer, and the benefits of irinotecan/5-FU/FA in colorectal cancer, a phase II/III study to evaluate the efficacy of an irinotecan-based combination in advanced gastric cancer was designed. This paper reports the results of the phase II part of the study in which the efficacy and tolerability of two test arms, irinotecan/continuous infusion 5-FU (5-FU/FA) [18] and irinotecan/cisplatin [30], were compared in order to select the most effective combination for investigation in a subsequent phase III study.
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Patients and methods |
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This randomized phase II study was conducted at 41 centers in 13 European countries and Israel, Lebanon, Turkey and South Africa, between January 1999 and April 2000. The study was conducted in accordance with the Declaration of Helsinki, and with the approval of independent ethics committees at each center.
Patient selection and randomization
Patients aged 18–75 years, with histologically confirmed metastatic gastric or esophageal–gastric junction adenocarcinoma and measurable and/or evaluable metastatic disease (locally recurrent disease was acceptable if there was at least one measurable lymph node) were eligible for inclusion in the study. Other inclusion criteria included: Karnofsky performance status >70%; satisfactory hematopoietic (hemoglobin 
10 g/dl; neutrophils 2 x 109/l; platelets 100 x 109/l), renal [creatinine 
1.25x the upper normal limit (UNL) or 120 µmol/l] and hepatic [total bilirubin 1.5x UNL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5x UNL; alkaline phosphatase 5x UNL] function; prothrombin time 0.5x the lower normal value; no previous palliative chemotherapy (previous adjuvant and/or neo-adjuvant chemotherapy were allowed provided a 12-month interval had elapsed since the end of therapy); a period of at least 6 weeks since radiotherapy and 3 weeks since surgery; and provision of written informed consent.
Exclusion criteria were: cancer other than adenocarcinoma; previous treatment with camptothecins; previous receipt of a cumulative dose of cisplatin >300 mg/m2 (adjuvant or neoadjuvant); bowel obstruction or subobstruction; history of inflammatory enteropathy or extensive intestinal resection; symptomatic peripheral neuropathy National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) grade 2; symptomatic or history of brain metastasis; active uncontrolled infection; active disseminated intravascular coagulation; previous or concurrent other malignancy, except non-melanoma skin cancer or in situ cervix carcinoma curatively treated; any severe medical conditions (e.g. myocardial infarction in the last 6 months); pregnant or lactating patients; and concurrent treatment with any other anticancer therapy. To be eligible for inclusion, a patient should have had no major protocol deviations from the inclusion and exclusion criteria.
In this study, a minimization method was used to stratify randomization according to: center, liver and/or peritoneal metastases (yes versus no), prior gastrectomy (yes versus no) and disease type (measurable versus evaluable only lesions).
Treatment
Patients were randomized to one of the following two treatment arms: irinotecan/5-FU/FA or irinotecan/cisplatin. Treatment in the irinotecan/5-FU/FA arm consisted of a 30-min infusion of irinotecan [80 mg/m2 intravenously (i.v.)] and a 2-h infusion of FA (500 mg/m2 i.v.), followed immediately by a 22-h infusion of 5-FU (2000 mg/m2 i.v.), once weekly for 6 weeks (on days 1, 8, 15, 22, 29 and 36) followed by a 1-week rest. Cycles were repeated every 7 weeks. Treatment in the irinotecan/cisplatin arm consisted of irinotecan (200 mg/m2 i.v.) administered first as a 30-min infusion on day 1, followed on the same day by hyperhydration (1 l normal saline during the first hour), then a 4-h infusion of cisplatin (60 mg/m2 i.v.) followed by 1.5 l normal saline over 3 h. Cycles were repeated every 3 weeks. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. No further antitumor therapy was to be given after the end of treatment until disease progression was documented, unless requested by the patient or deemed necessary by the investigator. Further chemotherapy with taxanes or camptothecins was not recommended.
Management of vomiting and diarrhea
Pre-chemotherapy antiemetic medication was mandatory for both arms and comprised ondansetron (8 mg i.v.) and dexamethasone (20 mg i.v.). The use of metoclopramide was at the discretion of the investigator. Diarrhea was treated promptly.
At the first liquid stool or abnormal bowel movement, patients had to receive loperamide orally (4 mg initial dose and then 2 mg every 2 h for at least 12 h and up to 12 h after the last liquid stool, without exceeding a total treatment duration of 48 h). Oral rehydration with large volumes of water and electrolytes was to be prescribed during the whole diarrhea episode. Diarrhea persisting for >48 h, despite loperamide, required hospitalization, broad-spectrum antibiotic treatment (fluoroquinolone) and replacement of loperamide by another antidiarrheal agent. Oral fluoroquinolones were also administered for any grade 4 diarrhea, diarrhea with concomitant grade 3/4 neutropenia without fever, and diarrhea with fever. Concomitant diarrhea and vomiting, fever or Karnofsky performance status <70% required hospitalization for i.v. rehydration.
Dose modification for toxicity
In the case of neutropenia (absolute neutrophil count <1.5 x 109/l) or thrombocytopenia (platelets <100 x 109/l) or diarrhea grade >1, treatment was delayed by 1–2 weeks, followed by dose reduction if the condition persisted. In all arms, dose reduction was applied to any toxicity grade >2 if medically appropriate (except for alopecia and anemia). Dose reductions were mandatory in the following cases: a second episode of isolated febrile neutropenia or grade 3/4 neutropenia lasting >7 days, despite granulocyte colony-stimulating factor (G-CSF) (dose reduction of irinotecan); grade 4 diarrhea, diarrhea with concomitant grade 3/4 neutropenia without fever, and diarrhea with fever or infection (dose reduction of irinotecan and/or 5-FU); grade 3 stomatitis lasting >48 h (5-FU dose reduction); grade 2 peripheral neuropathy (cisplatin dose reduction). A maximum of two dose reductions were allowed, as follows: irinotecan/5-FU/FA (irinotecan 80 then 65 then 50 mg/m2; 5-FU 2000 then 1750 then 1500 mg/m2); irinotecan/cisplatin (irinotecan 200 then 175 then 150 mg/m2; cisplatin 60 then 50, then 40 mg/m2). Patients with grade 3 peripheral neuropathy or ototoxicity stopped treatment.
Treatment assessment
Patients were evaluable for response if they had received at least five infusions (irinotecan/5-FU/FA) or two cycles (irinotecan/cisplatin) and had a tumor assessment performed at least 5 weeks (irinotecan/5-FU/FA) or 4 weeks (irinotecan/cisplatin) from the start of treatment and before any further antitumor therapy. Tumor response was assessed every 8 weeks (56 days) during therapy, irrespective of the treatment cycle duration, until disease progression. This 8-week treatment period was a means of assessing the 6-weekly cycle (every 7 weeks) (irinotecan/5-FU/FA) and the 3-week cycle (irinotecan/cisplatin) over the same period of time, thereby helping to avoid bias. Response was recorded according to World Health Organization (WHO) criteria. Patients who had disease progression were followed every 3 months until death. Patients who finished treatment but who had not progressed were followed every 8 weeks after the end of treatment until documented progression and every 3 months thereafter. An external response review committee reviewed radiological and clinical documentation for all patients in the study. All adverse events were evaluated and graded according to NCIC CTG criteria.
Statistical analysis
The main aim of the study was to select the better of the two irinotecan-based combination treatment arms. This was assessed using the primary end point of complete response (CR). Assuming a true CR rate difference of 10% between the two test arms, 30 evaluable patients per test arm were necessary to ensure a 90% probability to rank correctly the two test arms on efficacy, according to their observed CR rate. With this rationale, the test arm with the highest observed CR rate would be identified as the most efficacious test arm. However, this efficacy did not in itself determine the optimal test arm, but rather provided one input into an overall benefit–risk analysis of the efficacy and safety of the test arms. Secondary end points included safety, time to progression (TTP) and overall survival (OS). Accrual was continued during analysis.
The response rate was calculated for both the full analysis and per-protocol populations. The full analysis population was defined as the population of all treated patients analyzed according to the randomization arm; the per-protocol population was defined as all randomized and treated patients who were eligible and evaluable for response and who had no major protocol deviations. TTP and OS were estimated by the Kaplan–Meier method and the two arms were compared using a two-sided log-rank test with an 
error of 5%.
An independent data monitoring committee (IDMC) selected the best test arm, based on guidelines issued at the time of protocol writing and agreed by the IDMC. The final decision was made independently of the sponsor.
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Results |
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Patient characteristics
A total of 148 patients were randomized between January 1999 and April 2000: 75 in the irinotecan/5-FU/FA arm and 73 in the irinotecan/cisplatin arm (Figure 1). Altogether, 130 (88%) patients were eligible (89% in the irinotecan/cisplatin arm and 87% in the irinotecan/5-FU/FA arm). Among the 18 patients (12%) who were not eligible, this was due mainly to non-measurable metastatic disease (n=11), but also to abnormal blood chemistry (n=5), current other cancer (n=1) or local recurrence without measurable lymph nodes (n=1). Twenty-three patients were not evaluable for response, 11 receiving irinotecan/cisplatin and 12 receiving irinotecan/5-FU/FA, either because of early treatment discontinuation [n=5 (two deaths unrelated to treatment, two treatment-related adverse events and one major protocol violation) and n=4 (one death unrelated to treatment, one non-treatment-related adverse event and two treatment-related adverse events), respectively], non-evaluable target (n=2 and 6, respectively), or because the response was not properly assessed (n=4 and 2, respectively).
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Patient characteristics at baseline are shown in Table 1. The most frequent site of primary disease in both the irinotecan/5-FU/FA and the irinotecan/cisplatin arms was the stomach antrum and body (82.4% and 68.1%). One-third (33.8%) of patients receiving irinotecan/5-FU/FA and 27.8% of those receiving irinotecan/cisplatin had at least three organs involved. Nearly half of the patients in each arm had a relatively poor Karnofsky performance status (80%) (48.6% and 47.2%, respectively). Patient characteristics were generally similar in the two arms (Table 1). However, an imbalance was observed, particularly in gender distribution (77% male in irinotecan/5-FU/FA arm versus 64% in irinotecan/cisplatin arm) and sites of disease (junction plus fundus, 16% versus 32%, respectively).
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Study treatment data
The median treatment duration was 17 weeks (range 2–80) in the irinotecan/5-FU/FA arm and 16 weeks (range 3–40) in the irinotecan/cisplatin arm. The median relative dose intensity was 0.84 for irinotecan and 0.83 for 5-FU in the irinotecan/5-FU/FA arm, and 0.94 for irinotecan and 0.93 for cisplatin in the irinotecan/cisplatin arm.
Dose reduction and/or delay
Dose reduction was required for at least one infusion in 48.6% of patients treated with irinotecan/5-FU/FA compared with 22.2% of those receiving irinotecan/cisplatin. Corresponding figures for at least one infusion delay were 79.7% and 55.6%.
The primary reason for treatment dose reduction and/or delay in the irinotecan/cisplatin arm was neutropenia (8.3%/25% of all patients). In the irinotecan/5-FU/FA arm, diarrhea was the primary reason for treatment dose reduction and/or delay (16.2%/29.7% of all patients).
Treatment discontinuation
During the first cycle (irinotecan/5-FU/FA) or first two cycles (irinotecan/cisplatin), two patients (2.7% of the treated population) receiving irinotecan/5-FU/FA and two (2.8%) receiving irinotecan/cisplatin discontinued treatment due to toxicity or toxic death, and five (6.8%) and none, respectively, discontinued due to withdrawal of consent. Overall, the main reasons for study discontinuation in the irinotecan/5-FU/FA and irinotecan/cisplatin arms, respectively, were: progressive disease (54.1% versus 58.3%), adverse events unrelated to the study drug (6.8% versus 6.9%), toxicity (8.1% versus 5.6%), patient consent withdrawn (17.6% versus 8.3%) and death (6.8% versus 11.1%). Similar numbers of patients in both arms died due to malignant disease (2.7% versus 2.8%). There was one toxic death during the study, in the irinotecan/5-FU/FA arm; this was due to grade 4 diarrhea with concomitant grade 4 neutropenia, which was not managed properly.
Over one-third (34.2%) of all patients treated over both arms received additional therapy following discontinuation of study treatment.
Efficacy
The per-protocol population most accurately reflects the effects of treatment in patients meeting the eligibility criteria and was therefore considered the most useful indicator of treatment efficacy in this study. Analysis of restricted populations is not uncommon in this disease [31]. For completeness, results for the full analysis population are also presented here.
In the per-protocol population, the overall response rate was 42.4% in the irinotecan/5-FU/FA arm and 32.1% in the irinotecan/cisplatin arm (Table 2). The number of CRs achieved were three (5.1%) and one (1.8%), respectively. The response rate followed a similar trend in the full analysis population (Table 2). The median duration of response in the per-protocol population was 9.9 months (range 4+ to 14.6) in the irinotecan/5-FU/FA arm and 6.6 months (range 2.8–8.5) in the irinotecan/cisplatin arm.
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The median TTP was significantly longer in the irinotecan/5-FU/FA arm, 6.5 months [95% confidence interval (CI) 5.59–8.51] compared with 4.2 months (95% CI 3.42–5.45) in the irinotecan/cisplatin arm (P <0.0001) (Figure 2). The median OS was also significantly longer in the irinotecan/5-FU/FA arm than in the irinotecan/cisplatin arm: 10.7 months (95% CI 8.02–14.62) versus 6.9 months (95% CI 5.55–8.67) (P=0.0018) (Figure 3). Estimated 1-year survival rates were 44.9% and 25.3% for the irinotecan/5-FU/FA and irinotecan/cisplatin arms, respectively.
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Safety data
The major hematological and non-hematological toxicities are summarized in Table 3. Neutropenia was the most common hematological toxicity in both arms. Grade 3/4 neutropenia was observed in more patients in the irinotecan/cisplatin arm (65.7% of patients) than in the irinotecan/5-FU/FA arm (25.7%).
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Diarrhea was the main grade 3/4 non-hematological toxicity in both arms. The incidence of diarrhea was slightly higher in the irinotecan/5-FU/FA arm (27% of patients) than in the irinotecan/cisplatin arm (18.1%). Other non-hematological toxicities included asthenia and infection in the irinotecan/cisplatin arm, and anorexia in the irinotecan/5-FU/FA arm. Over half of the patients in the irinotecan/5-FU/FA and irinotecan/cisplatin arms reported at least one serious adverse event (52.7% and 55.6%): 31.1% and 31.9% of patients, respectively, had at least one study drug-related serious adverse event. Diarrhea was the most frequent study drug-related serious adverse event in both the irinotecan/5-FU/FA arm (24.3%; 18.9% grade 3/4) and the irinotecan/cisplatin arm (19.4%; 11.1% grade 3/4).
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Despite the number of combination regimens that have been investigated for the treatment of advanced gastric cancer over the past 10 years or more, no one regimen has consistently demonstrated clinically relevant improvements over the others [8
]. In clinical practice, cisplatin-based regimens, such as ECF, are commonly used. However, results from trials investigating the benefits of adding cisplatin to 5-FU-based regimens are equivocal [10, 11, 32], casting doubt over the contribution of cisplatin to the treatment of metastatic gastric cancer. Irinotecan has established efficacy, alone and in combination with other agents, in the treatment of metastatic colorectal cancer [15–18]. It has shown single-agent activity in metastatic gastric cancer when administered as both first- [33] and second-line [19] therapy. In this study, combinations of irinotecan with 5-FU/FA or cisplatin demonstrated efficacy in the treatment of metastatic gastric cancer. The response rate with irinotecan/5-FU/FA was higher than that with irinotecan/cisplatin (42.4% versus 32.1% in the per-protocol population), and there were three CRs in the irinotecan/5-FU/FA arm and one in the irinotecan/cisplatin arm. The response rate seen with irinotecan/5-FU/FA was the same as that in a recently reported randomized phase II study with bolus and infusional 5-FU (400 mg/m2 i.v. followed by 22-h continuous infusion of 600 mg/m2) [34] and is higher than the 22% reported for irinotecan in combination with bolus 5-FU/FA in patients with previously untreated metastatic or advanced gastric cancer [28]. It was noted that 21% of patients were not evaluable for response in this study. Although this figure may seem high compared with studies in other gastrointestinal cancers, such as colorectal cancer, it is similar to that seen in other gastric cancer studies [35–37] and reflects both the poor status of these patients and the difficulties in evaluating the disease and its response to treatment. Furthermore, the proportion of patients excluded from the per-protocol population was balanced between the two arms (irinotecan/5-FU/FA 21% and irinotecan/cisplatin 23%).
The present study was not powered to detect survival differences between the treatment arms. However, the available data indicate that patients in the irinotecan/5-FU/FA arm had a longer median TTP (6.5 versus 4.2 months; P <0.0001) and median OS (10.7 versus 6.9 months; P=0.0018) than those in the irinotecan/cisplatin arm. These survival data are similar to those observed with irinotecan in combination with bolus and infusional 5-FU/FA (11.3 months) [34] in patients with previously untreated disease, and compare favorably with those reported with irinotecan in combination with bolus 5-FU (median 7.6 months) [28]. OS with irinotecan/5-FU/FA was also higher than that reported with ECF (median 8.7 months) [11] and PELF (7.7 months) [12] in previously untreated advanced disease. The findings are particularly encouraging in view of the fact that >91% of the patients in each arm of the present study had metastatic disease. The relative proportion of patients with metastatic, compared with locally advanced, gastric cancer will have an impact on treatment outcome, as locally advanced gastric disease is associated with a better prognosis than metastatic disease. It is interesting to note that in the study comparing FAMTX, ELF and FUP, 84% of the patients had metastatic disease and 16% had locally advanced disease.
Overall, both combinations investigated in the present study were reasonably well tolerated. Myelotoxicity was substantially higher in the irinotecan/cisplatin arm than in the irinotecan/5-FU/FA arm (grade 3/4 neutropenia 65.7% versus 25.7%). The incidence of gastrointestinal side-effects was similar between the two groups, with only a slightly higher incidence of grade 3/4 diarrhea in the irinotecan/5-FU/FA arm (25.7% versus 18.1%). Compared with the combination of irinotecan and bolus administration of 5-FU [28], continuous infusion of 5-FU was associated with a similar incidence of diarrhea but a lower incidence of neutropenia. The incidence of grade 3/4 diarrhea in the irinotecan/5-FU/FA arm was similar to that seen with irinotecan in combination with bolus and infusional 5-FU in metastatic gastric cancer (22%) [34]. There was a greater incidence of dose reduction and/or delay in the irinotecan/5-FU/FA arm due to weekly administration. It is of note that the improved efficacy was achieved in the irinotecan/5-FU/FA arm despite these dose reductions/delays.
In conclusion, this study confirms the activity of irinotecan in combination with cisplatin and with infusional 5-FU/FA in the treatment of advanced gastric cancer. The difference in the CR rates (per-protocol population) between the two arms did not reach the hypothesized 10%. However, the overall per-protocol response rate was 42.4% for irinotecan/5-FU/FA and 32.1% for irinotecan/cisplatin. In addition, the secondary end points of TTP and OS were significantly in favour of irinotecan/5-FU/FA, and the safety was also better with this regimen. Therefore, according to the guidelines set out prior to commencement of the study, an independent committee selected the irinotecan/5-FU/FA arm as the best combination for investigation in a phase III trial in advanced gastric cancer on the first 60 patients randomized to each arm. These findings were confirmed by the results on the total population of 148 patients. The combination of irinotecan/5-FU/FA represents a real alternative for the treatment of advanced gastric cancer to the use of cisplatin-based regimens. The results of the phase III trial comparing this combination with cisplatin/5-FU are awaited.
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Acknowledgements |
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We thank the following for their participation: I. Chernozemski (Bulgaria); P. Kellokumpu (Finland); M. Ducreux, D. Khayat, M. Ychou (France); C. Aul, M. Clemens, A. Harstrick, C. H. Koehne, K. Mross, P. Preusser (Germany); V. Georgoulias (Greece); M. Dank, M. Wenczl (Hungary); R. Catane, P. Rath (Israel); E. Bajetta, C. Iacono (Italy); M. Ghosn (Lebanon); M. Nowaski, T. Popiela (Poland); J. Cronje, B. Rapoport (South Africa); A. Carrato, J. R. Germa Lluch, B. Massuti, G. Perez Manga (Spain); B. Glimelius, H. Starkhammar (Sweden); M. Bos, R. Jansen (The Netherlands); and F. Aykan (Turkey). This study was sponsored by an educational grant from Aventis Pharma International S.A.
Received for publication April 22, 2004. Revision received July 14, 2004. Accepted for publication July 14, 2004.
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References |
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