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Japanese Journal of Clinical Oncology Advance Access originally published online on November 6, 2008
Japanese Journal of Clinical Oncology 2008 38(12):810-815; doi:10.1093/jjco/hyn109
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© The Author (2008). Published by Oxford University Press. All rights reserved

Irinotecan Plus Cisplatin Therapy and S-1 Plus Cisplatin Therapy for Advanced or Recurrent Gastric Cancer in a Single Institution

Koji Nakashima, Shuichi Hironaka, Narikazu Boku, Yusuke Onozawa, Akira Fukutomi, Kentaro Yamazaki, Hirofumi Yasui, Keisei Taku, Takashi Kojima and Nozomu Machida

Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan

For reprints and all correspondence: Shuichi Hironaka, Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi Sunto-gun, Shizuoka 411-8777, Japan. E-mail: s.hironaka{at}scchr.jp

Received June 5, 2008; accepted September 15, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Background: From the results of the JCOG9912 and SPIRITS trials, S-1 plus cisplatin (CDDP) therapy (SP) has been recognized as the standard chemotherapy for advanced gastric cancer in Japan. However, in their subsets of patients with the target lesion, irinotecan (CPT-11) plus CDDP therapy (IP) resulted in longer survival than 5-fluorouracil alone while SP exhibited a survival similar to S-1 alone. The objective of this study was to clarify the safety and efficacy of these two regimens.

Methods: Forty-four patients were treated with IP and 32 with SP between September 2002 and July 2006 at Shizuoka Cancer Center. In IP, 70 mg/m2 CPT-11 was administered on Days 1 and 15, 80 mg/m2 CDDP on Day 1, repeated every 4 weeks. In SP, 40–60 mg S-1 depending on the patient’s body surface area was given orally twice daily for 21 days and 60 mg/m2 CDDP intravenously on Day 8, repeated every 5 weeks.

Results: The response rate, progression-free survival and median survival were 47% (17 of 36), 170 and 444 days in IP, and 80% (21 of 26), 235 and 469 days in SP. In patients with target lesions, those were 47%, 170 and 431 days in IP, and 80%, 235 and 442 days in SP. The incidence of Grade 3 or 4 toxicity was similar in both groups, but patient refusal of treatment was more frequent for IP than for SP.

Conclusions: Our results demonstrate a better efficacy and feasibility of SP than IP for advanced gastric cancer patients, with or without a target lesion.

Key Words: gastric cancer • irinotecan • cisplatin • S-1


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Gastric cancer is one of the most frequently occurring malignancies in the world (1). Despite early detection and curative resections, gastric cancer remains the second most common cause of cancer-related death in Japan. For patients with unresectable or recurrent gastric cancer, the main therapeutic option is palliative chemotherapy. 5-fluorouracil (5-FU)- based chemotherapy is widely used for advanced gastric cancer and has been shown to have a survival benefit compared with the best supportive care (2). However, there has been no world-wide consensus about a standard chemotherapy regimen.

Recently, two Phase III studies were reported from Japan (3,4). One was the JCOG9912 trial, which revealed that S-1 alone demonstrated non-inferiority to 5-FU alone and that irinotecan (CPT-11) plus cisplatin (CDDP) therapy failed to demonstrate superiority to 5-FU alone for overall survival. The trial concluded that S-1 alone should be considered for standard chemotherapy of advanced gastric cancer. Another trial was the SPIRITS, which investigated the superiority of S-1 plus CDDP to S-1 alone. The trial found that S-1 plus CDDP was significantly superior to S-1 alone (P = 0.037) for overall survival. Generally, S-1 plus CDDP has been recognized as the standard chemotherapy for advanced or recurrent gastric cancer in Japan.

However, in the subset analysis of patients having the target lesion for JCOG9912, the response rates of 5-FU, CPT-11 plus CDDP and S-1 were 9, 38 and 28%, respectively, and their median survival times (MST) were 9.0, 12.1 and 10.5 months (3). These results suggest that therapy with CPT-11 plus CDDP might be more effective than S-1 or 5-FU alone for patients with the target lesions. On the other hand, in the subset analysis of patients having the target lesion of the SPIRITS trial, the hazard ratio of S-1 plus CDDP to S-1 alone was higher than 1.0 (4). These results posed a question of which regimen, CPT-11 plus CDDP or S-1 plus CDDP, are more suitable for patients with the target lesions. There was no direct comparison between CPT-11 plus CDDP and S-1 plus CDDP for advanced gastric cancer. The objective of this study was to clarify the safety and efficacy of these two regimens.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 References
 
Patients
The subjects in this study were 76 patients treated between September 2002 and July 2006 at the Shizuoka Cancer Center. Among them, 44 patients were treated with CPT-11 plus CDDP (IP group), and 32 patients were treated with S-1 plus CDDP (SP group). The subjects were recruited according to the following selection criteria: histologically proven gastric adenocarcinoma; Eastern Cooperative Oncology Group (ECOG) performance status 0–2; age 20–75 years; no prior chemotherapy or radiation therapy; adequate bone marrow (WBC count ≥3000/µl and ≤12 000, platelet count ≥100 000/µl), liver (serum bilirubin level ≤1.5 mg/dl and serum transaminase level ≤99 IU/l), and renal function (serum creatinine level≤1.5 mg/dl); no other active malignancy; sufficient oral intake; and the provision of written informed consent. These criteria are almost the same as those of the JCOG9912 and SPIRITS trials. The reasons for exclusion were adenocarcinoma with neuroendocrine carcinoma components in six, brain metastasis in one, and severe liver dysfunction in one from the IP group, and ages older than 75 years in two, performance status 3 in two, adenocarcinoma with neuroendocrine carcinoma components in two, brain metastasis in one, combination with radiotherapy in one, another active malignancy in four, severe liver dysfunction in four, massive pleural effusion and/or ascites in five, dyspnea due to lymphangitis carcinomatosa in two, insufficient oral intake in five, heart failure in one and an old cerebral infarction in one from the SP group. Thus, the subjects of this retrospective study were 44 patients in the IP group and 32 in the SP group.

Treatment Schedule
In the IP group, CPT-11 (70 mg/m2) was administered by intravenous infusion for 90 min, and after a 2 h interval, CDDP (80 mg/m2) was administered over 2 h with adequate hydration on Day 1. The same dose of CPT-11 was administered on Day 15. This treatment was repeated every 4 weeks. In the SP group, S-1 was orally administered at a dose not exceeding 40 mg/m2 based on the patient’s body surface area (BSA): BSA <1.25 m2, 40 mg; 1.25 m2 ≤ BSA < 1.5 m2, 50 mg; and BSA ≥ 1.5 m2, 60 mg. S-1 was administered twice daily for 21 consecutive days and CDDP (60 mg/m2) was administered intravenously with adequate hydration on Day 8. This treatment was repeated every 5 weeks. Both treatments were repeated until disease progression, unacceptable toxicity or patient refusal.

Evaluation
Laboratory data and patients' conditions were assessed at least every 2 weeks and prior to infusion of anti-tumor agents. The response and toxicities were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) and Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The target lesion was defined as a measurable lesion 1 cm or larger in diameter detected by CT scan with 5 mm slice. Patients were assessed for response every 1 to 2 months as a rule in both treatment groups. The disease progression was evaluated according to RECIST. The survival time was calculated from the date of chemotherapy initiation to the date of all-cause death or the latest follow-up with the Kaplan–Meier method. Progression-free survival (PFS) was calculated from the start of chemotherapy to the first day of disease progression. If chemotherapy was discontinued for any reason other than progressive disease, PFS was counted to the day of disease progression during the subsequent therapy.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 References
 
Patient Characteristics
Characteristics of the subjects are listed in Table 1. The median age was 63 and 60 years in the IP and SP group, respectively. For the IP and SP groups, 42 (95%) and 31 (97%) patients had a performance status of 0–1, 21 (48%) and 15 (47%) had an intestinal type of adenocarcinoma, and 22 (52%) and 22 (69%) had multiple metastatic sites, respectively. Thirty-six patients (82%) in the IP group and 26 (81%) in the SP group had target lesions. In the subset with target lesions, the median age was 63 and 60 years, 34 (94%) and 26 (100%) had a performance status of 0–1, 19 (56%) and 14 (54%) had an intestinal type of adenocarcinoma and 21 (58%) and 20 (77%) had multiple metastatic sites, respectively.


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  		Table 1. Patient characteristics

 
Treatment Results
Table 2 summarizes the results of treatment. The total number of treatment courses was 226 in the IP group and 172 in the SP group. The median number of treatment courses was 4.5 (range, 1–14 courses) in the IP group and 5.5 (range, 1–10 courses) in the SP group. In the IP group, the dose intensity of CPT-11 was 29.6 mg/m2 per week and the intensity of CDDP was 18.1 mg/m2 per week, which corresponded to 85 and 91% of the planned doses, respectively. In the SP group, the dose intensity of S-1 was 309 mg/m2 per week and the intensity of CDDP was 11.1 mg/m2 per week, which corresponded to 92 and 93% of the planned doses, respectively.


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  		Table 2. Treatment results

 
The reasons for treatment failure in the IP group were disease progression in 34 patients (77%), unacceptable toxicity in one (2%), patient refusal related to toxicity in seven (16%) and surgery in two (5%). The reasons for treatment discontinuation in the SP group were disease progression in 29 patients (91%), severe toxicity in one (3%) and patient refusal related to toxicity in two (6%). The incidence of a patient’s refusal related to toxicity seemed to be higher in IP than in SP.

Response and Survival
Thirty-six patients (82%) in the IP group and 26 (81%) in the SP group with target lesions were assessed for their response. The response rates (RRs) were 47% [17 of 36, 95% confidence interval (CI) 30.9–63.5] and 80% (21 of 26, 95% CI 65.6–95.9) in the IP and SP groups, respectively (Table 3). Figure 1 shows the overall survival (OS) and PFS curves of both groups. The MST and PFS of the IP group were 444 and 170 days, and those of the SP group were 469 and 235 days, respectively. Figure 2 shows the OS and PFS of the subset of patients with the target lesion. The MST and PFS of the IP group were 431 and 170 days, respectively, and for the SP group they were 442 and 235 days, respectively. Between the IP and SP groups, there were no obvious differences in the pattern of progressive disease. From these results, while the OS was comparable in both groups, the RR and PFS seemed to be longer in the SP group compared with the IP group, when observing either all patients or the subset with target lesions.


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  		Table 3. Response rate

 

Figure 1
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  		Figure 1. Overall survival curve and progression-free survival (PFS) curve. The median survival time (MST) and PFS were 444 and 170 days in the group receiving irinotecan plus cisplatin (IP) and 469 and 235 days in the group receiving S-1 plus cisplatin (SP), respectively. OS, overall survival.

 

Figure 2
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  		Figure 2. In patients with target lesions, the MST and PFS were 431 and 170 days in the group receiving IP and 442 and 235 days in the group receiving SP, respectively.

 
Adverse Reactions
The adverse events observed in both groups are listed in Table 4. In the IP group, Grade 3 or 4 neutropenia was observed in 15 patients (36%), anemia in 19 (39%), and Grade 3 febrile neutropenia was observed in two (5%). In the SP group, Grade 3 or 4 neutropenia was observed in nine patients (28%), anemia in 10 (31%), thrombocytopenia in four (13%), and Grade 3 febrile neutropenia was observed in two (6%). In both groups, the incidence of either Grade 3 or 4 non-hematological toxicity was <12%. The common non-hematological toxicities in the IP group were anorexia (11%), fatigue (7%) and diarrhea (5%); those in the SP group were anorexia (9%) and nausea (6%). No treatment-related deaths occurred in either group. While the toxicity profiles were different between the groups, there seemed to be no remarkable difference in the incidence of severe toxicity.


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  		Table 4. Adverse events

 
Subsequent Chemotherapy
Table 5 shows the second-line chemotherapy for both groups. In the IP group, 38 patients (86%) received second-line chemotherapy after failure of the IP regimen. Twenty-one patients (58%) were treated with S-1 alone and nine patients (25%) were treated with weekly paclitaxel. In the SP group, 26 patients (90%) received second-line chemotherapy, 16 (62%) were administered a CPT-11-based regimen (10, CPT-11 plus mitomycin C; 3, CPT-11 alone; 3, FOLFIRI) and seven (27%) received weekly paclitaxel. Therefore, more than half of the patients were treated by a crossover treatment strategy between S-1 and CPT-11.


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  		Table 5. Second-line chemotherapy

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
References
 
Until the release of the results of the JCOG9912 and SPIRITS trials at the annual meeting of the American Society of Clinical Oncology in 2007, there was no standard chemotherapy for advanced gastric cancer in Japan. In this study, patients were treated between September 2002 and July 2006, at that time, the treatment for each patient was decided by the patient’s choice or randomization after explaining about the JCOG9912 (randomization of 5-FU alone, CPT-11 plus CDDP or S-1 alone) trial. If a patient refused to participate in the JCOG9912 trial, we explained another treatment option including S-1 plus CDDP therapy. Therefore, the medical oncologists had no specific selection criteria for both regimens, and they might have had little impact on the patient’s treatment decision.

In the previous studies, it was reported that the RR, MST and PFS of IP therapy were 38–58%, 9–12.3 and 3.7–6 months (3,5,6) and 51–74%, 10.9–13 and 4.8–6 months for SP therapy (4,7,8). These reports suggest that the SP is slightly more effective than the IP regimen. In this retrospective study, the overall survival of the IP and SP groups were very similar despite the higher RR and longer PFS of the SP group compared with the IP group. Furthermore, in the subset with target lesions, the SP group also exhibited a higher RR and slightly better PFS than the IP group. Although there was a little difference in patient backgrounds between the IP and SP groups such as the rate of PS 0 and one metastatic organ site that was in favor of the IP regimen, the SP group showed better MST and PFS than the IP group. Because our study was retrospective and small, we have too many limitations to draw conclusions from these results; however, we could find no superiority of the IP regimen to SP regimen from our results.

In the subsequent chemotherapy, >85% of the patients in both groups received second-line chemotherapy and more than half of them had the crossover treatment strategy between S-1 and CPT-11. Survival data of both groups in our study were better than previous reports (3,4). In colon cancer, it is considered to be important for the prolongation of survival to use all three active drugs, 5-FU, CPT-11 and oxaliplatin during the whole treatment course (9). Similarly, the subsequent treatment may have some impact on the overall survival of patients with advanced gastric cancer.

The incidence of patients' refusal for further treatment was higher in the IP group than the SP group. Although the incidence of Grade 3 or 4 toxicity was similar in both groups, the toxicity profile differed between them. The incidence of Grade 2 nausea, anorexia and diarrhea was observed to be 41, 39 and 9%, respectively, in the IP group and 6, 22 and 6% in the SP group. These differences in the incidence of mild symptomatic toxicities might cause patients' refusal of treatment. Thus, SP seems more feasible than IP.

In conclusion, our results demonstrate a better efficacy and feasibility of SP than IP for advanced gastric cancer patients, with or without a target lesion. The presence or absence of a target lesion cannot be used to choose between the IP and SP chemotherapy regimens.

Conflict of interest statement

None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 References
 
1 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin (2005) 55:74–108.[Abstract/Free Full Text]

2 Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M. Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer (1993) 72:37–41.[CrossRef][Web of Science][Medline]

3 Boku N, Yamamoto S, Shirao K, Doi T, Sawaki A, Koizumi W, et al. Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912). Proc ASCO (2007) 25:18S.

4 Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol (2008) 9:215–21.[CrossRef][Web of Science][Medline]

5 Boku N, Ohtsu A, Shimada Y, Shirao K, Seki S, Saito H, et al. Phase II study of a combination of irinotecan and cisplatin against metastatic gastric cancer. J Clin Oncol (1999) 17:319–23.[Abstract/Free Full Text]

6 Ajani JA, Baker J, Pisters PW, Ho L, Mansfield PF, Feig BW, et al. CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophageal junction carcinoma: results of a phase II study. Cancer (2002) 94:641–6.[CrossRef][Web of Science][Medline]

7 Koizumi W, Tanabe S, Saigenji K, Ohtsu A, Boku N, Nagashima F, et al. Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer. Br J Cancer (2003) 89:2207–12.[CrossRef][Web of Science][Medline]

8 Ajani JA, Lee FC, Singh DA, Haller DG, Lenz HJ, Benson AB 3rd, et al. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol (2006) 24:663–7.[Abstract/Free Full Text]

9 Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol (2004) 22:1209–14.[Abstract/Free Full Text]


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This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
38/12/810    most recent
hyn109v1
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