Lung Cancer 63 (2009) 68–71

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Lung Cancer

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Phase II study of combination chemotherapy with S-1 and weekly cisplatin inpatients with previously untreated advanced non-small cell lung cancer

Yuichi Ozawaa, Naoki Inuia,b,∗, Tateaki Naitoha, Kazumasa Yasudaa, Masaharu Nagayamaa,Toshihiro Shirai a, Hideki Suganumaa, Masato Fujii a, Hirotoshi Nakamuraa,Takafumi Sudaa, Kingo Chidaa

a The Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Japanb Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Japan

a r t i c l e i n f o

Article history:Received 21 February 2008Received in revised form 10 April 2008Accepted 17 April 2008

Keywords:CisplatinDosage regimenNon-small cell lung cancerOutpatientPhase II study

a b s t r a c t

We aimed to evaluate the efficacy and safety of combination chemotherapy with S-1 and low-dose weeklycisplatin in patients with advanced non-small cell lung cancer (NSCLC). In this phase II trial, previouslyuntreated patients with stage IIIB/IV NSCLC were treated with oral administration of S-1 at 80 mg/m2

for 21 days and three consecutive weekly low doses of cisplatin (25 mg/m2) followed by a 2-week restperiod. Twenty-six patients were eligible for the assessment of efficacy and safety. Six partial responseswere observed with an overall response rate of 23.1% (95% confidence interval: 12.3–31.6%). The mediansurvival time and median progression-free survival were 13.4 months and 5.4 months, respectively. Grade3/4 hematologic toxicities were observed in 9 patients (34.6%), including one grade 4 neutropenia andthrombocytopenia. As for non-hematologic adverse reactions, although grade 3 events were observedin 4 patients (15.3%), no severe renal toxicity or vomiting was found. S-1 and weekly low-dose cisplatin

S-1 combination chemotherapy in patients with advanced NSCLC showed an acceptable response rate, overallsurvival time, and toxicity. Because this regimen can be performed in an outpatient setting, it might bean alternative useful and convenient option. Further investigations with a large population are required

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. Introduction

Lung cancer is a leading cause of cancer mortality in manyountries [1]. Combination chemotherapy with platinum agentsnd new-generation non-platinum antitumor agents are currentlysed for chemotherapy of non-small cell lung cancer (NSCLC),lthough the outcomes are far from acceptable [2]. S-1 (TS-1®;aiho Pharmaceutical Co. Ltd., Tokyo, Japan) is a new oral anti-ancer fluoropyrimidine agent that contains the 5-fluorouracil5-FU) prodrug tegaful and two enzyme inhibitors, 5-chloro-2,4-ihydroxypyridine (CDHP) and potassium oxonate [3]. Since CDHP

nhibits dihydropyrimidine dehydrogenase activity and potassiumxonate suppresses pyrimidine phosphoribosyl transferase activity,ral S-1 administration can generate a higher concentration of 5-FUhan protracted intravenous injection of 5-FU, without increasing

∗ Corresponding author at: Hamamatsu University School of Medicine, 1-20-1andayama, Hamamatsu 431-3192, Japan. Tel.: +81 53 435 2263;

ax: +81 53 435 2386.E-mail address: inui@hama-med.ac.jp (N. Inui).

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169-5002/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.lungcan.2008.04.007

© 2008 Elsevier Ireland Ltd. All rights reserved.

he incidence of adverse events in the gastrointestinal tract [4,5].n a phase II trial in Japan and our study, which involved monother-py with S-1 at 80 mg/m2/day for 28 days followed by a 2-weekest period in chemo-naive advanced NSCLC patients, the overallesponse rate was 22–26% and the median survival time (MST)as 10.2 months [6,7]. Since cisplatin has a synergistic antitumor

ffect with 5-FU [8,9], S-1 is usually used with cisplatin. Combi-ation chemotherapy with S-1 (80 mg/m2, from day 1 to day 21)nd cisplatin (60 mg/m2 on day 8, every 5 weeks) resulted in aesponse rate of 47% and a MST of 11 months and provided com-arable efficacy with currently used combination chemotherapyith platinum agents [2,11]. On the other hand, the intravenous

njection of cisplatin requires hospital admission for hydration torevent renal damage induced by cisplatin, which unfortunatelyegates the advantage and the convenience of S-1 as an orallydministered drug in enabling outpatient treatment. The quality

f life and convenience of treatment have been emphasized evenn cancer chemotherapy. Outpatient chemotherapy, based on theremise that it has almost the same efficacy as standard regimens,

s one of the options for treatment. To improve the tolerability ofegimens containing cisplatin, many trials administering cisplatin

Cancer 63 (2009) 68–71 69

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Table 1Patient characteristics

No. 26Sex, male/female 20/6Age, year (range) 66 (47–73)

Performance statusa

0 221 4

Histologic typeAdenocarcinoma 15Squamous cell carcinoma 8Non-small-cell carcinoma 3

StageIIIB 7IV 19

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Y. Ozawa et al. / Lung

n a weekly schedule or in divided doses, have been conducted12–14]. A phase I study of S-1 and weekly cisplatin for metastaticastric cancer was feasible and promising with a high response raten an outpatient setting [15,16]. In the present study, we conductedphase II study with oral administration of S-1 for 21 days and threeonsecutive weekly low doses of cisplatin followed by 2 weeks restn patients with advanced NSCLC, and determined the efficacy andafety of this regimen.

. Patients and methods

.1. Patient eligibility

All patients with histologically or cytologically confirmed stageIIB (without indication of radiotherapy) or IV NSCLC were eli-ible if they were from 20 to 75 years of age, had no previousreatment and an Eastern Cooperative Oncology Group (ECOG) per-ormance status of 0 or 1. Additional eligibility criteria includeddequate bone marrow, liver and renal functions (leukocyte countf 4000–12,000/�L and an absolute granulocyte count of morehan 2000/�L; platelet count ≥100,000/�L; hemoglobin >9.0 g/dL;erum bilirubin <1.5 mg/dL; serum aspartate aminotransferase andlanine aminotransferase <100 IU/L; normal serum creatinine levelr creatinine clearance ≥50 mL/min). Since S-1 is in tablet form,atients were required to be able to swallow. For staging, a com-uted tomography scan of the thorax and abdomen, either aomputed tomography scan or magnetic resonance image of therain, and a radioisotopic bone scan were carried out. Patients werexcluded if they had severe complications or a concomitant malig-ancy. The protocol was approved by our Institutional Review Boardnd each patient gave written informed consent.

.2. Treatment schedule

Patients received S-1 orally 40 mg/m2 twice a day after mealsn days 1–21. The dose of S-1 was determined according to bodyurface area (BSA) and renal function. In patients with creatininelearance >80 mL/min: with a BSA <1.25 m2, 40 mg twice a day wasiven; with a BSA of 1.25–1.5 m2, 50 mg twice a day was given;nd with a BSA >1.5 m2, 60 mg twice a day was given. In patientsith creatinine clearance <80 mL/min but >50 mL/min: with BSA

1.25 m2, 25 mg twice a day was given; with a BSA of 1.25–1.5 m2,0 mg twice a day was given; and with a BSA >1.5 m2, 50 mg twiceday was given. A low dose of cisplatin (25 mg/m2) was adminis-

ered intravenously on days 7, 14 and 21. An antiemetic agent coulde administered at the discretion of each patient’s physician. Thereatment regimen was repeated every 5 weeks until disease pro-ression or unacceptable toxicity occurred. A leukocyte count of3000/�L, an absolute granulocyte count of ≥2000/�L, and thentry eligibility criteria regarding organ functions had to be sat-sfied to start the next cycle. Doses were adjusted according toematologic and non-hematologic toxicity. The dose of S-1 and cis-latin was reduced by one level (20 mg per day of S-1 and 25% of theose of cisplatin) in patients with grade 3 or more hematologic oron-hematologic toxicity during any cycle of administration. If weonfirmed the recovery from such toxicities at a reduced dose, thedministration at the reduced dose was continued. If a rest periodf ≥4 weeks was required, the patient was withdrawn from thetudy.

.3. Evaluation of response and toxicity

Patients who received more than one cycle were included in thessessment of efficacy and toxicity. Chest X-ray, complete bloodount, and blood chemistry analyses were repeated at least once a

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alues are expressed as number or median.a Performance status was according to the Eastern Cooperative Oncology Group

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eek. The response was assessed based on chest computed tomog-aphy scan findings that initially had been used to define the extentf the tumor. The response was evaluated using the Responsevaluation Criteria in Solid Tumors. Adverse events were gradedccording to the National Cancer Institute Common Toxicity Criteriaersion 3.0.

.4. Statistical analysis

The minimum number of patients to be enrolled in this studyas defined as 19, with the assumption that the 95% confidence

nterval would be 10% under the conditions of an ˛ error of 0.05 (oneided) and a ˇ error of 0.1, assuming an expected response rate of0%. According to this, we aimed for 25 patients to take dropout intoonsideration. The differences between categorized groups wereompared by the �2-test. The overall survival, which was defineds the time from diagnosis to death from any cause or when lastnown to be alive, was estimated by the Kaplan–Meier method ofnivariate analysis. All values were analyzed using StatView 5.0rogram for Windows (SAS Institute Inc., Cary, NC). All statisticalests were two sided, and values of p < 0.05 were considered tondicate statistical significance.

. Results

.1. Patient characteristics

Between June 2005 and May 2006, 27 patients were enrolled inhis study. All but one of the patients were assessable for efficacynd safety. One patient was excluded as ineligible since he had noteen treated because of massive hemoptysis after enrollment. Theharacteristics of 26 assessable patients are listed in Table 1. Twentyatients (77%) were male and 6 patients (23%) were female. Mediange was 66 years, with a range of 47–73 years. All patients hadood performance status (ECOG 0 or 1). Seven patients (27%) hadtage IIIB and 19 patients had stage IV NSCLC. The predominantistological type was adenocarcinoma (58%). The median follow-uperiod was 9.1 months.

.2. Efficacy

Among evaluable patients, no complete response was observednd 6 patients had a partial response (PR), yielding an overallesponse rate of 23.1% (95% confidence interval: 12.3–31.6%). Histo-ogically, a PR was observed in 3/15 (20.0%) with adenocarcinomand 2/8 (25.0%) with squamous cell carcinoma. The response rates

70 Y. Ozawa et al. / Lung Cancer 63 (2009) 68–71

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Table 2Maximum hematologic and non-hematologic toxicity grades associated with S-1and weekly cisplatin

Toxicity Grade Grade 3–4 (%)

1 2 3 4

HematologicalLeukopenia 4 6 2 1 11.5Neutropenia 3 6 3 1 15.4Anemia 11 6 4 0 15.4Thrombocytopenia 6 3 3 1 15.4

Non-hematologicalBilirubin 1 1 0 0 0Creatinine 3 3 0 0 0Anorexia 7 4 1 0 3.8Nausea 6 3 0 0 0Vomiting 3 2 0 0 0Diarrhea 2 6 2 0 7.7Fatigue 3 2 2 0 7.7

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ig. 1. Overall survival of the 26 treated patients was calculated according to theaplan–Meier method. The median survival time was 13.4 months, and the 1-yearnd 2-year survival rates were 52.0% and 34.6%, respectively.

bserved in stage IIIB and stage IV patients were 28.6% and 21.1%,espectively. The median response duration was 4.9 months. Ashown in Fig. 1, the MST was 13.4 months, and the 1-year and 2-ear survival rates were 52.0% and 34.6%, respectively. The medianrogression-free survival was 5.4 months (Fig. 2).

.3. Safety

The major adverse events are shown in Table 2. The hematolog-cal adverse events reaching grade 3/4 were anemia, neutropenia,nd thrombocytopenia in 4 patients (15.4%). Of these events, gradeneutropenia and thrombocytopenia was observed in one patient

3.8%). Febrile neutropenia was rare. The non-hematological gradetoxicities were anorexia in 1 patient, diarrhea in 2 patients, and

atigue in 2 patients. No grade 3/4 renal toxicity or vomiting wasbserved. There was no irreversible toxicity or death in this studyhat was considered to be related to treatment.

.4. Compliance

Most patients were treated at the outpatient clinic, except forhe first cycle. A range of 1–9 cycles was administered. Six patients

eceived only one cycle and no response was observed in theseatients. The reasons they were given only one cycle of treatmentere progressive disease in 3 patients and adverse events in 3atients. The adverse events consisted of grade 3/4 leukopenia andeutropenia in 2 patients and grade 3 diarrhea in 1 patient. Of the

ig. 2. Progression-free survival of the 26 treated patients was calculated accordingo the Kaplan–Meier method. The median progression-free survival time was 5.4

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ther 20 patients, 8 patients received 2 cycles, 5 patients receivedcycles, and 7 patients received 4 or more cycles. A total of 70

ycles were given to 26 patients. The dose was reduced in 6 patientsecause of adverse events including grade 3 or 4 hematologicaldverse events.

. Discussion

This is the first phase II study designed to explore the efficacynd safety of the combination regimen of S-1 with weekly cisplatinor the treatment of chemotherapy-naïve patients with stage IIIBr IV NSCLC. Although combination chemotherapy of S-1 with cis-latin every 5 weeks has higher activity against NSCLC than singledministration of S-1 [6,9], the necessity for hospitalization for cis-latin administration weakens the benefit of S-1 as oral medication.or the purpose of outpatient chemotherapy with S-1 and cisplatin,e administered low doses of cisplatin on a weekly schedule.

The treatment regimen of this study was determined from pre-iously reported phase I trials of metastatic gastric cancer [15,16].n these trials, the dose of S-1 was almost fixed (70–80 mg/m2)nd cisplatin was increased from 10 or 15 to 20 or 25 mg/m2/week,espectively. Few dose limiting toxicities were observed even withhe maximum dose in each trial, and the maximum toleratedose was not strictly determined. Weekly cisplatin at a dose of0–25 mg/m2/week was recommended when it was combinedith daily administration of S-1 from day 1 to day 21, followed byweeks rest, and we fixed the dose of cisplatin at 25 mg/m2/weekn days 7, 14 and 21.

In standard regimens using platinum agents and new-eneration non-platinum antitumor agents for NSCLC, the MSTas been reported to be 7–9 months [2,11]. A phase II trial of-1 with administration of cisplatin every 5 weeks showed anST of 11 months [10]. In the present study, the MST of 13.4onths was promisingly long as compared with previous stud-

es despite a relatively low response rate [10]. The reason for thisissociation may be explained by the high rate of stable disease58.3%), which extended the disease control rate to 76.9%. Fur-hermore, additional chemotherapy might contribute the favorableurvival. Eighteen (69%) and 10 patients (38%) received second-

nd third-line chemotherapy, respectively. As second-line treat-ent, 5 patients received single non-platinum antitumor agent

nd the others used platinum-based double chemotherapy regi-ens. Regarding epidermal growth factor receptor tyrosine kinase

nhibitor, 5 adenocarcinoma patients received gefitinib as second-

Y. Ozawa et al. / Lung Canc

Table 3Combination chemotherapy with S-1 and cisplatin for advanced non-small cell lungcancer

Current study Five-weekly cisplatinwith S-1 (10)

EfficacyOverall response rate (%) 23.1 47Median survival months 13.4 111-year survival rate (%) 52.0 45

Toxicities (grade 3 or 4)Hematological

Leukopenia (%) 11.5 6Neutropenia (%) 15.4 29Anemia (%) 15.4 22Thrombocytopenia (%) 15.4 2

Non-hematologicalCreatinine (%) 0 2Anorexia (%) 3.8 13Vomiting (%) 0 7Diarrhea (%) 7.7 7

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[15] Hyodo I, Nishina T, Moriwaki T, Endo S, Terao T, Hirao K, et al. A phase I study of S-1 combined with weekly cisplatin for metastatic gastric cancer in an outpatient

urrent study uses the regimen of oral S-1 (80 mg/m2, from day 1 to day 21) andntravenously administered cisplatin (25 mg/m2, on days 7, 14 and 21). Five-weeklyisplatin with S-1 means the regimen that S-1 (80 mg/m2, from day 1 to day 21) andisplatin (60 mg/m2 on day 8, every 5 weeks) (10).

r third-line chemotherapy and 2 patients had a PR. As expected, noevere (grade 3 or 4) renal toxicity or vomiting was observed in thistudy, regardless of cisplatin being administered intravenously inhe outpatient department. In a phase II study of S-1 and 5-weeklyisplatin, about 2% of patients experienced severe renal toxicity10]. Using the S-1 and weekly cisplatin regimen, we can reducehe requirement for hospitalization for high dose hydration andvoid the occurrence of renal failure. As for hematological toxic-ties, only one (3.8%) grade 4 neutropenia and thrombocytopeniaas observed without any severe anemia. These results were com-arable to those in the S-1 and 5-weekly cisplatin regimen (Table 3)10], in which the incidence of adverse events was lower than thetandard chemotherapy for NSCLC. In addition to S-1, consecu-ive weekly administration of docetaxel and cisplatin was reportedo reduce myelosuppression in the treatment of NSCLC patients12]. Taken together, these data suggest that S-1 and weekly cis-latin chemotherapy can be an alternative therapeutic regimen fordvanced NSCLC. Also, with a low incidence of renal toxicity and noecessity for massive hydration, this therapy may be also applicable

n the treatment of aged patients.In conclusion, S-1 and weekly low-dose cisplatin combination

hemotherapy is effective for the treatment of NSCLC. The compar-tively low toxicity of weekly low-dose cisplatin enables treatment

s an outpatient.

onflict of interest

All authors declare no actual or potential conflicts of interest.

[

er 63 (2009) 68–71 71

cknowledgment

N.I was supported by a grant-in-aid for scientific research20590536) from Japan Society for the Promotion of Science.

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