Purpose: To evaluate the efficacy and toxicity of combination therapy with the oral fluoropyrimidine formulation S-1 and irinotecan for patients with advanced NSCLC.

Experimental Design: Chemotherapy-naive patients with advanced NSCLC were treated with i.v. irinotecan (150 mg/m2) on day 1 and with oral S-1 (80 mg/m2) on days 1 to 14 every 3 weeks.

Results: Fifty-six patients (median age, 63 years; range, 40-74 years) received a total of 286 treatment cycles (median, 5; range, 1-15). No complete responses and 16 partial responses were observed, giving an overall response rate of 28.6% [95% confidence interval (95% CI), 17.3-42.2%]. Twenty-four patients (42.9%) had stable disease and 12 patients (21.4%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 71.4% (95% CI, 57.8-82.7%). Median progression-free survival was 4.9 months (95% CI, 4.0-6.4 months), whereas median overall survival was 15 months. Hematologic toxicities of grade 3 or 4 included neutropenia (25%), thrombocytopenia (3.6%), and anemia (3.6%), with febrile neutropenia being observed in four patients (7.1%). The most common nonhematologic toxicities of grade 3 or 4 included anorexia (14.3%), fatigue (8.9%), and diarrhea (8.9%). There were no deaths attributed to treatment.

Conclusions: The combination of S-1 and irinotecan is a potential alternative option with a favorable toxicity profile for the treatment of advanced NSCLC. This nonplatinum regimen warrants further evaluation in randomized trials.

Translational Relevance

Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. The dismal outlook for patients with advanced NSCLC treated with available therapies has prompted a search for new and more effective chemotherapeutic agents and combination regimens. S-1 is a new oral fluorinated pyrimidine formulation that combines tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate and has been found to exhibit marked antitumor activity in recent clinical trials with cancer patients, including those with NSCLC. We have now examined the therapeutic efficacy and toxicity of the combination of S-1 and irinotecan in chemotherapy-naive patients with advanced NSCLC. We found this drug combination to be active, with a response rate of 28.6%, median progression-free survival of 4.9 months, and median overall survival of 15 months, values that compare favorably with those reported for phase III studies of standard platinum-based doublet chemotherapy. Furthermore, toxicities were manageable, and in most instances, treatment could be continued in the outpatient setting. Our data indicate that the combination of S-1 and irinotecan is a promising alternative for treatment of advanced NSCLC. This nonplatinum regimen warrants further evaluation in randomized trials.

Non–small cell lung cancer (NSCLC) is the leading cause of death related to cancer worldwide (1). Platinum-based chemotherapy is the standard first-line treatment for advanced NSCLC based on the moderate improvement in survival and quality of life it confers compared with best supportive care alone (24). The poor outlook even for patients with advanced NSCLC who receive such treatment has prompted a search for new chemotherapeutic agents and combination regimens.

S-1 is an oral fluorinated pyrimidine formulation that combines tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate in a molar ratio of 1:0.4:1 (5). Tegafur is a prodrug that generates 5-fluorouracil (5-FU) in blood largely as a result of its metabolism by cytochrome P450 in the liver. CDHP increases the plasma concentration of 5-FU through competitive inhibition of dihydropyrimidine dehydrogenase, which catalyzes 5-FU catabolism (6). CDHP also attenuates the cardiotoxic and neurotoxic effects of 5-FU by reducing the production of fluoro-β-alanine, the main catabolite of 5-FU (7, 8). Oxonate reduces the gastrointestinal toxicity of 5-FU. After its oral administration, oxonate becomes distributed selectively to the small and large intestine, where it inhibits the phosphorylation of 5-FU to fluoropyrimidine monophosphate catalyzed by orotate phosphoribosyltransferase within gastrointestinal mucosal cells, thereby reducing the incidence of diarrhea (9). In a phase II trial of S-1 as a single agent for treatment of advanced NSCLC, a response rate of 22% and a median survival time of 10.2 months were obtained in 59 patients without prior chemotherapy (10). Few severe gastrointestinal or hematologic adverse events were reported (10). Moreover, a phase II trial of S-1 plus cisplatin in advanced NSCLC patients revealed a response rate of 47% and a median survival time of 11 months (11).

Irinotecan is an inhibitor of DNA topoisomerase I. It has shown activity as a single agent in first-line chemotherapy for advanced NSCLC (12). Weekly administration of irinotecan (100 mg/m2) for 3 weeks followed by 1 week of rest yielded a response rate of 20.5% and a median survival time of 10.6 months in 132 patients with advanced NSCLC (13).

S-1 and irinotecan have both shown single-agent activity against a wide range of solid tumors, including NSCLC, and the combination of these two agents has manifested synergistic effects in tumor xenograft models in vivo (14). A phase I study examined administration of irinotecan at a dose of 150 mg/m2 on day 1 and of S-1 at 80 mg/m2 per day from days 1 to 14 of a 21-day cycle (15); it found no difference in pharmacokinetic variables for the two drugs relative to the expected values for S-1 or irinotecan administered as single agents. A subsequent phase II study in patients with advanced colorectal cancer showed that this combination was well tolerated and had marked antitumor activity (16). The safety or effectiveness of the combination of S-1 and irinotecan in patients with advanced NSCLC has not previously been reported.

We now present the results of a multicenter phase II trial of S-1 in combination with irinotecan for patients with previously untreated advanced NSCLC. The aims of this study were to determine the objective tumor response rate, overall and progression-free survival, and toxicity profile for such treatment.

Patient eligibility. The criteria for patient eligibility included a diagnosis of NSCLC confirmed either histologically or cytologically, clinical stage IV or IIIB (including only patients with no indications for curative radiotherapy, such as those with malignant pleural effusion, pleural dissemination, malignant pericardial effusion, metastatic lesions in the same lobe of the primary lesion, or involvement of contralateral mediastinal or hilar lymph nodes), measurable disease, no prior chemotherapy, an age range of 20 to 74 y, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a projected life expectancy of at least 3 mo. Other eligibility criteria for organ function included a leukocyte count of ≥3,000/mm3, a neutrophil count of ≥1,500/mm3, a platelet count of ≥100,000/μL, a serum bilirubin concentration of ≤1.5 mg/dL, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of ≤2.5 times the upper normal limit, a normal serum creatinine level, and either a partial pressure of arterial oxygen of ≥65 torr or a peripheral oxygen saturation of ≥92%. Main exclusion criteria included active concomitant of any malignancy, symptomatic brain metastasis, interstitial pneumonia, watery diarrhea, obstructive bowel disease, heart failure, uncontrolled diabetes mellitus, active infection, and a past history of drug allergy. Written informed consent was obtained from all patients, and the study protocol was approved by the institutional ethics committee of each of the participating institutions.

Study design and treatment. This was a multicenter, open-label, single-arm, phase II study. The primary end point of the study was the response rate, which determined the sample size. We chose a 35% response rate as a desirable target level and a 20% response rate as uninteresting with an α error of 0.05 and a power of 0.8, resulting in a requirement for 50 patients. Allowing for a patient ineligibility rate of 10%, we planned to enroll 55 patients.

Each treatment cycle consisted of the oral administration of S-1 (40 mg/m2) twice daily for 2 wk, with a 90-min i.v. infusion of irinotecan (150 mg/m2) on day 1 followed by a drug-free interval of 1 wk. S-1 was available as capsules containing 20 or 25 mg of tegafur. Patients were assigned based on body surface area to receive one of the following oral doses of S-1 twice daily: 40 mg (body surface area < 1.25 m2), 50 mg (1.25 ≤ body surface area < 1.50 m2), or 60 mg (body surface area ≥ 1.50 m2). Courses of treatment were repeated every 21 d until the occurrence of tumor progression or unacceptable toxicity, refusal of the patient, or a decision by the physician to stop treatment.

If laboratory variables changed after the start of treatment so that they no longer met the eligibility criteria for the study, subsequent courses of treatment were withheld until the abnormality had resolved. If the abnormality had not resolved within 43 d, the patient was excluded from the study. The doses of both S-1 and irinotecan were reduced in the event of any of the following toxicities during the previous treatment cycle: neutropenia of grade 4 for >7 d, febrile neutropenia, thrombocytopenia of grade ≥4, and nonhematologic toxicity of grade ≥3. S-1 was reduced in subsequent courses from 60, 50, or 40 mg twice daily to 50, 40, and 25 mg twice daily, respectively. The dose of irinotecan was reduced by 25 mg/m2 for subsequent courses. Once lowered, the doses of S-1 and irinotecan were not increased.

Evaluation. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (17). Tumors were measured by computed tomography within 2 wk before the first cycle of treatment and then every 4 wk. Patients were evaluable for response if they had a baseline exam and at least one follow-up exam and had received at least one cycle of treatment. A central radiological review was done to determine the eligibility of patients and the response to treatment. Response was confirmed at least 4 wk (for a complete or partial response) or 6 wk (for stable disease) after it was first documented. Progression-free survival was defined as the time from registration until objective tumor progression or death. Patients whose disease had not progressed at the time of discontinuation of the study treatment continued to be assessed until progression was documented. If a patient died without documentation of disease progression, the patients was considered to have had tumor progression at the time of death, unless there was sufficient documented evidence to conclude otherwise. Overall survival was defined as the time from registration until death from any cause. Progression-free and overall survival as well as the 1-y survival rate were estimated by the Kaplan-Meier method.

Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (version 3). All patients who received one dose of chemotherapy were assessable for toxicity. A clinical and laboratory assessment was done at least every 2 wk.

Patient characteristics. Between February and June 2006, a total of 59 patients were enrolled in the study at the 14 participating centers. Three patients did not receive treatment: one patient withdrew her consent, and two patients had a fall before treatment onset that resulted in a reduction in performance status. These three patients were thus not included in the analysis. The remaining 56 patients (46 men and 10 women) were eligible for the current analysis and their characteristics are summarized in Table 1. Their median age was 63 years, with a range of 40 to 74 years. Histologic analysis revealed that 30 patients (54%) had adenocarcinoma and 21 patients (38%) had squamous cell carcinoma. Forty patients (71%) had stage IV disease and the other 16 patients had stage IIIB disease (including 12 patients with malignant pleural effusion).

Table 1.

Characteristics of the 56 eligible patients

CharacteristicNo. patients
Median age, y (range) 63 (40-74) 
Sex  
    Male 46 (82%) 
    Female 10 (18%) 
Performance status (ECOG)  
    0 20 (36%) 
    1 36 (64%) 
Stage  
    IIIB 16 (29%) 
    IV 40 (71%) 
Histology  
    Adenocarcinoma 30 (54%) 
    Squamous cell carcinoma 21 (38%) 
    Adenosquamous cell carcinoma 1 (1.8%) 
    Large cell carcinoma 1 (1.8%) 
    NSCLC, not specified 3 (5.4%) 
CharacteristicNo. patients
Median age, y (range) 63 (40-74) 
Sex  
    Male 46 (82%) 
    Female 10 (18%) 
Performance status (ECOG)  
    0 20 (36%) 
    1 36 (64%) 
Stage  
    IIIB 16 (29%) 
    IV 40 (71%) 
Histology  
    Adenocarcinoma 30 (54%) 
    Squamous cell carcinoma 21 (38%) 
    Adenosquamous cell carcinoma 1 (1.8%) 
    Large cell carcinoma 1 (1.8%) 
    NSCLC, not specified 3 (5.4%) 

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

Treatment administered. Patients received a median of five cycles of treatment (range, 1-15), with 37 patients (66%) completing at least four cycles. Overall, 286 cycles of chemotherapy were delivered. The mean relative dose intensities of S-1 and irinotecan were 91% and 98%, respectively. Dose reductions were uncommon and were necessary according to the study protocol in only eight cycles (2.8% of total cycles) because of diarrhea in three patients, anorexia in two patients, vomiting in two patients, and an increase in serum ALT and AST levels in one patient. Treatment administration was delayed for at least 1 week because of toxicity in 12 cycles (4.2% of total cycles); the major causes of delayed administration were insufficient bone marrow function (six cycles with a leukocyte count of <3,000/mm3 and one cycle with a platelet count of <100,000/μL) and nonhematologic toxicity (two cycles with fever in the absence of neutropenia, two cycles with an increase in serum ALT and AST levels, and one cycle with diarrhea).

Response and survival. Four patients were not evaluable for response: three patients withdrew from the study after one treatment cycle and one patient did not have a measurable target lesion. There were 16 partial responses and no complete responses, yielding an overall response rate of 28.6% (Table 2). Twenty-four patients (42.9%) had stable disease, yielding an overall disease control rate (complete response + partial response + stable disease) of 71.4% [95% confidence interval (95% CI), 57.8-82.7%]. Twelve patients (21.4%) had progressive disease as the best response.

Table 2.

Overall response rate (Response Evaluation Criteria in Solid Tumors criteria) by independent radiologic assessment

ResponseNo. patients (%)
Complete response 0 (0) 
Partial response 16 (28.6) 
Overall response 16 (28.6; 95% CI, 17.3-42.2) 
Stable disease 24 (42.9) 
Disease progression 12 (21.4) 
Not evaluable 4 (7.1%) 
ResponseNo. patients (%)
Complete response 0 (0) 
Partial response 16 (28.6) 
Overall response 16 (28.6; 95% CI, 17.3-42.2) 
Stable disease 24 (42.9) 
Disease progression 12 (21.4) 
Not evaluable 4 (7.1%) 

All 56 treated patients were assessable for progression-free survival and overall survival. With a median follow-up time of 14.9 months (range, 1.4-20.1 months), 25 patients were still alive. The progression-free survival curve is shown in Fig. 1; the median progression-free survival was 4.9 months (95% CI, 4.0-6.4 months). The curve for overall survival is shown in Fig. 2; the median overall survival time was 15 months (95% CI could not be estimated) and the 1-year survival rate was 63% (95% CI, 50-75%). No correlation was apparent between overall survival and sex, age, histology, disease stage, or smoking status.

Fig. 1.

Kaplan-Meier analysis of progression-free survival for all 56 treated patients.

Fig. 1.

Kaplan-Meier analysis of progression-free survival for all 56 treated patients.

Close modal
Fig. 2.

Kaplan-Meier analysis of overall survival for all 56 treated patients.

Fig. 2.

Kaplan-Meier analysis of overall survival for all 56 treated patients.

Close modal

Toxicity. The adverse events observed for all 56 treated patients are summarized in Table 3. The most frequently observed hematologic toxicity of grade 3 or 4 was neutropenia (14 cases, 25%). Four patients (7.1%) developed febrile neutropenia. Anemia or thrombocytopenia of grade 3 or 4 was less frequent, each occurring in 3.6% of patients. Nonhematologic toxicities were generally mild in intensity. The most common nonhematologic toxicities of grade 3 or 4 were anorexia (14.3%), fatigue (8.9%), diarrhea (8.9%), vomiting (3.6%), and an increase in serum ALT or AST levels (3.6%). Treatment was discontinued because of toxicity in only two of the 56 patients (3.6%): in one patient because of pneumonitis (grade 3) and in the other because of prolonged anorexia (grade 3) and fatigue (grade 3). The patient with pneumonitis developed fever with hypoxemia after the fourth course of treatment. A computed tomographic scan of the chest revealed new ground-glass opacities distributed diffusely in both lungs. The patient responded well to steroid therapy and improved. No treatment-related deaths were observed.

Table 3.

Toxicity for all 56 treated patients according to the National Cancer Institute Common Toxicity Criteria (version 3)

ToxicityGrade
Grade ≥3 (%)
1234
Leukopenia 10 8.9 
Neutropenia 12 25.0 
Anemia 31 19 3.6 
Thrombocytopenia 23 3.6 
Febrile neutropenia NA NA 7.1 
Anorexia 25 10 14.3 
Fatigue 18 12 8.9 
Diarrhea 12 11 8.9 
Nausea 27 11 1.8 
Vomiting 12 3.6 
Stomatitis 
Rash 
Hyperbilirubinemia 12 
Elevation of AST/ALT 18 3.6 
Elevation of creatinine 
Pneumonitis 1.8 
ToxicityGrade
Grade ≥3 (%)
1234
Leukopenia 10 8.9 
Neutropenia 12 25.0 
Anemia 31 19 3.6 
Thrombocytopenia 23 3.6 
Febrile neutropenia NA NA 7.1 
Anorexia 25 10 14.3 
Fatigue 18 12 8.9 
Diarrhea 12 11 8.9 
Nausea 27 11 1.8 
Vomiting 12 3.6 
Stomatitis 
Rash 
Hyperbilirubinemia 12 
Elevation of AST/ALT 18 3.6 
Elevation of creatinine 
Pneumonitis 1.8 

Abbreviation: NA, not applicable.

Platinum-based doublet chemotherapy is the standard of care for most patients with advanced NSCLC (24). However, there continues to be reluctance on the part of both patients and treating physicians to accept the toxicity of platinum-based therapy given the associated small gain in survival. Active therapies with improved toxicity profiles are clearly needed in this setting. Since the introduction of active third-generation agents (docetaxel, paclitaxel, gemcitabine, vinorelbine, and irinotecan), many clinical trials have been undertaken to evaluate nonplatinum regimens based on these drugs in the hope that platinum analogues could be eliminated from the treatment of advanced NSCLC. A recent meta-analysis showed that these newer nonplatinum regimens are valid options for the treatment of advanced NSCLC because of their shown activity and good toxicity profiles (18). Currently, however, there is no single best treatment regimen for advanced NSCLC.

As first-line chemotherapy for advanced NSCLC, the oral fluoropyrimidine formulation S-1 administered as a single agent showed a response rate of 22% and a median survival time of 10.2 months with toxicities that were generally mild (10). Combinations of S-1 with other active agents with a different mechanism of action are being investigated with the aim of achieving a greater clinical benefit. Irinotecan and fluoropyrimidines were shown not to induce cross-resistance in both experimental and clinical settings (19). Preclinical studies have also found that the combination of irinotecan and 5-FU has antitumor activities that are additive to synergistic (20). Furthermore, a possible molecular mechanism for synergistic cytotoxicity of S-1 and irinotecan has been suggested by the observation that irinotecan reduces thymidylate synthetase activity in tumor xenografts and thereby facilitates the antitumor effect of S-1 (14). Recent phase II studies have shown that combination treatment with S-1 and irinotecan is highly active with acceptable toxicity in patients with advanced colorectal cancer or gastric cancer (16, 21). However, the activity of this combination in patients with NSCLC has not previously been documented.

We have now assessed the efficacy and safety of combined treatment with S-1 and irinotecan in patients with previously untreated advanced NSCLC. We found the combination to be active, with a response rate of 28.6%, median progression-free survival of 4.9 months, median overall survival of 15 months, and 1-year survival rate of 63%. Previous phase III studies of platinum-based doublets for the treatment of advanced NSCLC showed response rates of 17% to 33%, a median time to progression or progression-free survival of 3 to 5 months, and a median overall survival time of 7 to 14 months (2225). Although there are limitations to comparisons of the results from different studies, the efficacy data in our study compare favorably with those reported in these previous phase III studies of platinum-based doublets.

The S-1-irinotecan regimen was well tolerated in the patients of the present study. With regard to hematologic toxicity, neutropenia of grade 3 or 4 occurred in only 25% of all treated patients without the prophylactic administration of granulocyte colony-stimulating factor. Anemia and thrombocytopenia of grade 3 or 4 were each observed in only two patients (3.6%). These results compare favorably with the toxicity profiles reported for platinum-based combinations in previous studies with NSCLC patients, in which higher frequencies of neutropenia (∼80%), anemia (∼20%), and thrombocytopenia (∼23%) of grade 3 or 4 were observed (2224). The only nonhematologic toxicity of grade 3 or 4 encountered in >10% of patients in the present study was anorexia (14.3%). Although irinotecan and S-1 have each been shown to increase the frequency of severe diarrhea, the incidence of diarrhea of grade 3 in the present study was only 8.9%, consistent with the findings of a recent phase II study of the combination of S-1 and irinotecan administered according to the same doses and schedule in patients with advanced colorectal cancer (16). Thus, both hematologic and nonhematologic toxicities were generally manageable, and in most instances, treatment could be continued in an outpatient setting, resulting in a median of five treatment courses (range, 1-15).

In conclusion, we have presented the results of the first plhase II study of the combination of S-1 and irinotecan for the treatment of chemotherapy-naive patients with advanced NSCLC. This regimen yielded a response rate, progression-free survival, and overall survival similar to or better than those previously reported for platinum-based regimens. In addition, this regimen was well tolerated and could be administered in an outpatient setting. Given its efficacy and favorable toxicity profile, the combination of S-1 and irinotecan is a promising alternative for treatment of advanced NSCLC and a feasible nonplatinum option to which molecularly targeted agents can be added. The chemotherapy regimens of S-1 plus platinum derivatives have been studied (11). We are currently conducting a randomized phase III trial comparing carboplatin/S-1 with carboplatin/paclitaxel for chemonaive advanced NSCLC. We firmly believe that further trials comparing S-1 plus irinotecan with platinum-based doublet chemotherapy (perhaps carboplatin/S-1) are warranted.

No potential conflicts of interest were disclosed.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We thank Koichi Hosoda for data management and Professor J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript.

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