Japanese Journal of Clinical Oncology Advance Access originally published online on September 1, 2005
Japanese Journal of Clinical Oncology 2005 35(9):520-525; doi:10.1093/jjco/hyi148
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© 2005 Foundation for Promotion of Cancer Research
Phase I Study of S-1 Combined with Irinotecan (CPT-11) in Patients with Advanced Gastric Cancer (OGSG 0002)
1 Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, 2 Department of Gastroenterology, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka, 3 Department of Surgery, Osaka National Hospital, Osaka, 4 Department of Surgery, Sakai Municipal Hospital, Sakai, Osaka and 5 Japan Society for Cancer Chemotherapy, Osaka, Japan
For reprints and all correspondence: Hiroya Takiuchi, Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku Cho, Takatsuki, Osaka, 569-8686, Japan. E-mail: in2028{at}poh.osaka-med.ac.jp
Received April 13, 2005; accepted July 26, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: A dose-escalation study of irinotecan (CPT-11) combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD) and dose-limiting toxicities (DLTs) in advanced gastric cancer.
Methods: S-1 was administered orally at 80 mg/m2/day for 21 consecutive days followed by a 2 week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at an initial dose of 40 mg/m2/day, stepping up to 60, 80, 100 or 120 mg/m2/day depending on the DLT. Courses were repeated every 5 weeks, unless disease progression or severe toxicity was observed. At a level of the RD, five patients were added to conduct a pharmacokinetic (PK) study.
Results: A total of 24 patients were entered in this study. The MTD of CPT-11 was considered to be 100 mg/m2, because 50% of the patients (3/6) developed DLTs, diarrhea and rash. Therefore, the RD of CPT-11 was set at the dose immediately below 80 mg/m2. The overall response rate (RR) by the criteria of the Japanese Research Society of Gastric Cancer was 58.3% (14/24) and the RR at the RD was 66.7% (6/9), suggesting promising clinical efficacy. There were no significant differences between the PK parameters of S-1 on days 10 and 15.
Conclusions: S-1 with CPT-11 can be combined safely without CPT-11 effect on S-1 PK data and holds promise as an effective regimen for advanced gastric cancer.
Key Words: S-1 • irinotecan • combination chemotherapy • pharmacokinetics
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Unresectable advanced or recurrent gastric cancer still has a poor prognosis and chemotherapy is the only reasonable therapeutic option for these patients (1–3). Consequently, many combination regimens based on 5-fluorouracil (5-FU) have been studied clinically to further improve the objective response rate (RR) and survival for unresectable advanced gastric cancer. The additive survival advantage yielded by these combination therapies appears to be marginal, however, thus no standard regimen has yet been established (4–8). Thus, there is a need to develop new agents and combination regimens to achieve greater survival benefit in unresectable advanced or recurrent gastric cancer.
The new oral fluoropyrimidine S-1 has been commercially available for patients with gastric cancer in Japan since 1999. S-1 consists of tegafur (FT) and two modulators, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (OXO), at a molar ratio of 1:0.4:1 (9). CDHP is a reversible competitive inhibitor of dihydropyrimidine dehydrogenase, which is an enzyme for 5-FU degradation. Therefore, CDHP with FT is expected to yield prolonged 5-FU concentration in serum and tumor tissue. OXO is a reversible competitive inhibitor of orotate phosphoribosyltransferase (OPRT), which is an enzyme for 5-FU phosphoribosylation in the gastrointestinal mucosa. It is reported that OXO ameliorates gastrointestinal toxicity of FT by decreasing 5-fluorodeoxyuridine monophosphate production in the gastrointestinal mucosa (10). In two late phase II clinical studies for advanced gastric cancer in Japan, the RR of S-1 as a single agent was 44.6% (45/101), with a low incidence of grade 3 or 4 toxicities (11–12). The median survival time (MST), 1 year survival rate and 2 year survival rate were 244 days, 37 and 17%, respectively. These results warrant further investigation with combination chemotherapy with S-1 for advanced gastric cancer.
Irinotecan (CPT-11) has shown clinical activity against many gastrointestinal neoplasms. A Japanese phase II study of CPT-11 as single agent drug in advanced gastric cancer reported an RR of 23% (13). Most single agent responses are short-lived and have no associated survival benefit. Combination chemotherapy may offer a survival advantage in the treatment of advanced gastric cancer. Fortunately, CPT-11 have been safely and effectively combined with other agents in the treatment of gastrointestinal malignancies. In addition, combinations of CPT-11 with 5-FU and leucovorin have shown promising activity not only in metastatic colorectal cancer but also in advanced or recurrent gastric cancer (14–16). Therefore, we performed a phase I study to evaluate the tolerability, clinical efficacy and serum concentration of 5-FU by giving a combination of S-1 with CPT-11 for patients with advanced gastric cancer.
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PATIENTS AND METHODS |
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ELIGIBILITY CRITERIA
Before entry, tumor size was determined by chest or gastrointestinal X-ray film, endoscopic examination of the upper gastrointestinal tract, computed tomographic (CT) scan of the abdomen, barium enema and bone scintigram. A complete blood cell count, liver and renal function test, and urinalysis were performed within 7 days before entry. The eligibility criteria were as follows: age 20–75 years; histologically proven unresectable locally advanced or metastatic gastric adenocarcinoma; no previous chemotherapy, except adjuvant chemotherapy >30 days before entry; adequate organ function, defined as hemoglobin >8 g/dl, leukocyte count >4000–12 000/mm3, platelet count >100 000/mm3, serum bilirubin level <1.5mg/dl, serum transaminase (aspartate aminotransferase and alanine aminotransferase) <100/UI, alkaline phosphatase < twice the upperlimit of the normal range (ULN) of each hospital, serum creatinine level less than the ULN of each hospital; Eastern Cooperative Oncology performance status 0–1; expected survival period >3 months; and written informed consent from the patients. Patients with symptomatic brain metastases were not eligible. This study was approved by the ethics committees in each institution.
TREATMENT AND DOSE-ESCALATION SCHEDULE
S-1 dose was made up to 40, 50 and 60 mg, b.i.d. according to body surface area for 21 consecutive days and CPT-11 was diluted in 500 ml physiological saline, and administered as a 90 min i.v. infusion on days 1 and 15. The starting dose of CPT-11 was 40 mg/m2 (level 1), which was increased in 20 mg/m2 increments to 120 mg/m2 unless the maximum-tolerated dose (MTD) was achieved. No intrapatient dose-escalation was allowed. At least three patients were treated at each dose level. If one of three patients at a given dose developed any dose-limiting toxicity (DLT), three or more patients were entered at the same dose. Before proceeding to the next dose level, all previously treated patients had received at least one course.
This treatment course was repeated every 5 weeks with an allowance for a delay in treatment if toxicity was observed. The next course was started only for patients whose organ biological parameters had been maintained at levels satisfying the eligibility criteria, except for the leukocyte count (>3000/mm3) and with no disease progression observed. Prophylactic administration of antiemetic medication (HT3 antagonist and corticosteroid) at standard doses was routinely used when CPT-11 was administered to prevent nausea and vomiting. The treatment was repeated unless disease progression or severe toxicity was observed.
EVALUATION
A complete blood cell count, liver and renal function test, and urinalysis were assessed at least once a week during the first course, and every other week afterwards. Before each course, additional examinations were performed to evaluate sites. The National Cancer Institute common toxicity criteria version 2.0 was applied to evaluate the toxicity of this therapy during each course. DLTs were defined as grade 4 neutropenia lasting >3 days, grade 4 thrombocytopenia, any febrile grade 3 or 4 (severe) hematological toxicity or grade 3 non-hematological toxicity (except nausea and vomiting) during the first course. More than 7 days of rest following S-1 and the discontinuation of the second administration of CPT-11 during the first course were also categorized as DLT. The MTD was defined as the dose at which 
33% patients experienced DLTs during the first course. The recommended dose (RD) is also defined as the dose one level under MTD.
Lesions noted at baseline and 1 week after each course were measured or evaluated by CT, magnetic resonance imaging, gastroendoscopy and upper gastrointestinal radiography. Objective responses were classified according to not only response evaluation criteria in solid tumors (RECIST) criteria but also criteria for response assessment of chemotherapy for gastric carcinoma established by the Japanese Research Society of Gastric Cancer. The survival period was calculated from the start of treatment to death or the latest followed-up day. The eligibility and suitability for assessment and the objective response to the treatment were reviewed extramurally.
PHARMACOKINETICS
At a level of RD, five patients were added to conduct a pharmacokinetic (PK) study. The serum concentrations of 5-FU, FT, CDHP and OXO on days 10 and 15 during the first course were measured in order to evaluate if any possible metabolic interactions between components of S-1 and CPT-11 were seen in this combination therapy. Whole blood samples were taken before and 1, 2, 4, 6 and 8 h after S-1 administration on days 10 and 15 during the first course. Each peripheral blood sample (6 ml) was collected into a tube, stored for 30 min at room temperature and centrifuged at 3000 rpm for 10 min. The serum was stored at –20°C until the measurement of the S-1 component. The PK parameters were compared between patients treated with S-1 alone on day 10, and combined with CPT-11 on day 15 by Student's paired t-test.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Between July 2000 and May 2002, 24 patients were enrolled from three participating centers. Among 24 patients, 19 patients were entered into the phase I portion and the next five patients were entered into the PK study at the RD level, and the toxicities and efficacy were analyzed. The demographic characteristics of the patients were listed in Table 1. Toxicity was evaluated in all patients, regardless of course and objective response evaluation (Table 1). Among the 24 patients, 20 patients had metastatic lesions and four patients only had primary gastric lesion. Histological evaluation revealed six cases to be intestinal type and 18 cases to be diffuse type. The median number of courses per patient was 4 (range 1–6) at level 1, 3 (range 2–5) at level 2, 4 (range 1–12) at level 3 and 2.5 (range 2–4) at level 4. The median duration of therapy per patient was 112 days (range 92–189) at level 1, 82 days (range 66–172) at level 2, 182 days (range 15–467) at level 3 and 83 days (range 50–119) at level 4. Additionally, S-1 oral compliance was 95.1% during four courses at level 3.
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DETERMINATION OF MTD
At level 1, one patient developed grade 3 appetite loss during the first course, but the other two patients in the same cohort showed no DLT. An additional three patients were enrolled for safety evaluation, but no other patients developed a DLT at 40 mg/m2 of CPT-11. Three patients were assigned to receive dose level 2 and four patients were assigned to receive dose level 3. No DLT was observed at either level 2 or 3. However, at dose level 4, three of six patients exhibited DLTs in the first course, one of whom had grade 3 diarrhea and the other two patients had grade 3 rash and skipped the second administration of CPT-11 on day 15 because of delayed resolution of grade 2 leukopenia (Table 2). Consequently, dose level 4 was declared to be the MTD, and level 3 as the RD for the phase II study.
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EFFICACY
A total of 24 patients were evaluated to determine the confirmed RR at each level. At level 3, nine patients including five patients for the PK study were treated with the RD of 80 mg/m2 CPT-11. The RRs at levels 1 and 2 by RECIST criteria were 0% (0/2) and 50.0% (1/2), respectively. The RRs at the RD (level 3) and the MTD (level 4) by RECIST criteria were 55.5% (5/9) and 80.0% (4/5), respectively. The overall RR by RECIST criteria was 55.5% (10/18). The RRs at levels 1 and 2 by the criteria of the Japanese Research Society of Gastric Cancer were both 33.3% (2/6 and 1/3, respectively). The RRs at the RD (level 3) and the MTD (level 4) were 66.7% (6/9) and 83.3% (5/6), respectively (Table 3). The overall RR by the criteria of the Japanese Research Society of Gastric Cancer was 58.3% (14/24). The MST of all eligible patients was 425 days (95% confidence interval = 211–481) and 1 and 2 year survival rates were 56.5 and 20.7%, respectively. The median duration of follow-up for surviving patients was 23.9 months (range 18.8–36.6).
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PHARMACOKINETICS
Plasma PK analysis was performed on samples obtained from five patients during the first course for the S-1 components and serum concentration of 5-FU at the RD (Table 4). There were no significant differences between the PK parameters of S-1 and the serum concentration of 5-FU on days 10 and 15 (Fig. 1).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The purpose of this study was 2-fold—to determine the safety, effectiveness and tolerability of the combination of S-1 and CPT-11 in advanced gastric cancer, and also to determine whether a phase II study of this combination was warranted. Two late phase II studies of S-1 as a single agent in advanced gastric cancer conducted in Japan in 1998 and 2000 obtained RRs of 40% (20/50) and 49% (25/51), respectively (11–12). Combined analysis of the results of these two studies showed the MST, 1 year survival rate and 2 year survival rate to be 244 days, 37 and 17%, respectively, while toxicities were generally mild. Major toxicities of grade 3 or more were leukopenia 2%, neutropenia 4%, thrombocytopenia 2%, anemia 5% and diarrhea 2%. The results of these two pivotal phase II studies suggested that S-1 is one of the most active single agents for advanced gastric cancer and is even comparable to conventional combination therapies. There are several ongoing combination studies of S-1 with another agent with a different action mechanism aimed at obtaining better antitumor efficacy and longer survival (17–18).
CPT-11 has been employed in combination with CDDP in Japan. After a dose finding phase I/II study, a phase II study of this combination obtained an RR of 48% (21/44), and in particular, the MST of 322 days for chemotherapy-naive patients appeared to be promising (19). Based on these results, the Japan Clinical Oncology Group has initiated a randomized trial comparing 5-FU alone with the combination of CPT-11 and CDDP, and with S-1 alone. Another randomized trial testing the combination of CPT-11 and CDDP was conducted in Europe. In a randomized phase II study the combination of CPT-11 and CDDP was compared with the combination of CPT-11 and 5-FU/LV (14). The RR and MST of patients receiving the combination of CPT-11 and 5-FU/LV were 42.4% and 10.8 months. The combination of CPT-11 and CDDP was less effective, with an RR of 32.1% and MST of 6.9 months. These results underline the potential of the combination of CPT-11 and 5-FU/LV regimen for the treatment of advanced gastric cancer. In addition, oral agents such as S-1 are more convenient for patients and obtained greater compliance (20). From that point of view, it would be ideal if S-1 could be used instead of 5-FU/LV. We planned the present phase I study to test the safety and the efficacy of the combination of CPT-11 and S-1 as an alternative to CPT-11 and 5-FU/LV combination as an outpatient regimen.
As most toxicities of S-1 in two late phase II studies appeared at 4 weeks of consecutive S-1 administration, a phase I/II study of S-1 with CDDP was conducted in which S-1 was to be administered daily for three consecutive weeks, i.e. 1 week less than the period at which toxicities such as leucopenia appeared. This combination study showed a high RR of 74% with acceptable toxicity (18). Based on these data, we also used S-1 to be administered daily for three consecutive weeks in the present study. CPT-11 was administered bi-weekly on days 1 and 15 of the 21 day consecutive S-1 administration. In this phase I study, the dosage of S-1 was the standard dose (80 mg/m2/day) used in Japan, while the CPT-11 dose was escalated from 40 mg/m2 at level 1 to 100 mg/m2 at level 4. DLTs were observed in three of six patients at level 4, which was defined as the MTD. DLTs consisted of grade 3 diarrhea, skin rash and delayed resolution of myelosuppression. Diarrhea is a common toxicity with not only CPT-11 but also S-1, but grade 3 skin rash is uncommon. The incidence of skin rash was 10.9% (total) and 4.0% (grade 2) by S-1 single therapy. It suggests that in combination with CPT-11 might be increased a little. The RD of CPT-11 combined with S-1 was the level 3 dose of 80 mg/m2 according to the protocol conditions. Moreover, six (66.7%) of nine patients at level 3 obtained partial response, suggesting promising antitumor efficacy at this dosage of CPT-11 combined with S-1.
The PK results of the S-1 components in the present combined study were similar to the results obtained from a previous single-agent therapy study (21). The serum concentration of 5-FU with S-1 administration has been reported to be as high as that by continuous 5-FU infusion (21–22). Additionally, it was reported that the PK analysis of CPT-11 in this combination showed no change in any PK parameter as compared with the expected values for CPT-11 as a single agent (23). In this phase I study, tri-weekly schedule with the combination of CPT-11 and S-1 also held the promise of being a safe and effective treatment for advanced gastric cancer (23).
In summary, our phase I trial showed that the combination of S-1 and CPT-11 is effective and well tolerated with acceptable toxicity. Even though the present study is only limited in scope, a further phase II study to confirm the efficacy and safety of combination therapy of S-1 with CPT-11 is warranted.
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Acknowledgments |
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The authors are indebted to Prof. J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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