- Email: [email protected]
Phase II study of S-1 monotherapy in platinum-refractory, advanced non-small cell lung cancer
Lung Cancer 74 (2011) 85–88
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Phase II study of S-1 monotherapy in platinum-refractory, advanced non-small cell lung cancer Takayuki Shiroyama a,∗ , Kiyoshi Komuta a , Fumio Imamura b , Tomonori Hirashima c , Takashi Kijima d , Isao Tachibana d , Ichiro Kawase d a
Department of Respiratory Medicine, Osaka Police Hospital, 10-31 Kitayama-chou, Tennoji-ku, Osaka 543-0035, Japan Department of Pulmonary Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka, Japan d Department of Respiratory, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan b c
a r t i c l e
i n f o
Article history: Received 8 October 2010 Received in revised form 14 January 2011 Accepted 23 January 2011 Keywords: Lung cancer Second line Platinum-refractory S-1 monotherapy Ambulatory setting Oral medication
a b s t r a c t Objective: The aim of this study was to evaluate the efficacy and toxicity of a novel oral 5-fluorouracil formulation (S-1) as second-line therapy after platinum agent chemotherapy for advanced non-small cell lung cancer (NSCLC). Methods: S-1 was administered orally at a dose of 80 mg/m2 for 28 days, followed by 14 days of rest (1 cycle); treatment was repeated until disease progression, unacceptable toxicity, or patient refusal. Results: Of the 46 patients enrolled in this study, 44 were evaluable. Six patients (14%) exhibited a partial response and 28 (64%) showed stable disease. Disease-control rate was 77.3% (34/44) (95% CI, 64.9–89.7%). The overall response rate was 14% (6/44) (95% CI, 3.5–23.8%). Median progression-free survival was 4.2 months. The median survival time was 16.4 months, and the one-year survival rate 60.3%. Grade 3/4 hematological toxicities were minor. All of those adverse reactions were tolerable and reversible. Conclusion: This study demonstrated the efficacy of S-1 monotherapy as second-line treatment for advanced NSCLC. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the most common cancer worldwide, with an estimated 1.2 million new cases globally (12.3% of all cases of cancer) and 1.1 million deaths (17.8% of all cancer deaths) in 2000 [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all cases of lung cancer. For chemotherapy-naive patients with good performance status (PS) at a stage of IIIB (with pleural effusion) or IV, platinum-based chemotherapy offers a modest survival advantage over best supportive care (BSC) alone [2–4]. To improve outcome, however, there is a need for novel regimens. A recent phase III clinical study of conventional second-line therapies reported median survival times (MST) of approximately 6–8 months for docetaxel, gefitinib, and erlotinib [5–8]. On the other hand, in Japanese trials targeting this population have showed more favorable MST of approximately 12–17 months [9,10]. Doublet chemotherapy as second-line treatment for advanced NSCLC significantly elevates response rate and prolongs progression-free survival (PFS), but it is more toxic and
∗ Corresponding author. Tel.: +81 6 6771 6051. E-mail address: [email protected] (T. Shiroyama). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.01.017
does not improve overall survival rate compared to single-agent treatment [11]. S-1 is a novel, orally administered drug that is a combination of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and oteracil potassium (Oxo) in a 1:0.4:1 molar concentration ratio [12]. CDHP is a competitive inhibitor of dihydropyrimidine dehydrogenase, which is involved in the degradation of 5-FU, and acts to maintain efficacious concentrations of 5-FU in plasma and tumor tissues. Oxo, a competitive inhibitor of orotate phosphoribosyltransferase, inhibits the phosphorylation of 5-FU in the gastrointestinal tract, reducing the serious gastrointestinal toxicity associated with 5-FU. The antitumor effect of S-1 has already been demonstrated in a variety of solid tumors such as advanced gastric cancer [13,14], colorectal cancer [15], head and neck cancer [16,17], breast cancer [18], pancreatic cancer [19,20] and biliary tract cancer [21]. A recent phase II study of S-1 for chemo-naive, advanced NSCLC patients yielded promising results, with a response rate of 22.0%, MST of 10.2 months and favorable toxicity profile [22]. S-1 has exhibited promising activity against several tumors. Moreover, treatment with it can be administered on an outpatient basis. Oral agents such as S-1, which feature few adverse events, are appealing in the 2nd or 3rd line setting when patients are in less favorable condition.
86
T. Shiroyama et al. / Lung Cancer 74 (2011) 85–88
We therefore conducted a prospective study to evaluate the efficacy and feasibility of S-1 monotherapy in patients with progressive, advanced NSCLC under platinum-based, first line chemotherapy. 2. Patients and methods 2.1. Patient eligibility Patients were required to meet the following eligibility criteria: histologically confirmed NSCLC; at least one measurable lesion; prior platinum-based treatment; Eastern Cooperative Oncology Group performance status of 0–1; age ≥20 years, adequate organ function, defined as a leukocyte count of 3500–12,000 mm3 , neutrophil count of more than 2000 mm3 , platelet count of more than 100,000 mm3 , hemoglobin level of more than 9.0 g/dl, a serum total bilirubin level within 2.0 times the ULN, and serum creatinine level not exceeding the ULN; partial pressure of arterial oxygen ≥60 mm Hg, and an estimated life expectancy of at least 3 months. The exclusion criteria were as follows: pregnancy, serious concomitant disease (brain metastasis, active infection, severe heart disease or uncontrolled diabetes mellitus), concomitant malignancy, pleural effusion requiring treatment, symptomatic cerebral involvement, and obvious interstitial pneumonia or pulmonary fibrosis on chest radiography. All patients gave written informed consent prior to enrollment in the study, and the protocol was approved by the Institutional Ethics Committee of each participating institution. 2.2. Study treatment The initial doses of S-1 were assigned on the basis of body surface area (BSA). Accordingly, the patients received one of the following oral doses divided in two and administered daily after meals: 80 mg for patients with BSA < 1.25 m2 , 100 mg for BSA ≥ 1.25 and <1.50 m2 , and 120 mg for BSA ≥ 1.50 m2 . One therapy cycle comprised the administration of single-agent S-1 for 28 consecutive days followed by 14 days of no treatment. This schedule was repeated every 6 weeks until the occurrence of disease progression, unacceptable toxicities, or patient refusal. In the absence of evidence of disease progression, patients were allowed to continue S-1 treatment. A dose reduction of 20 mg/day was recommended if ≥grade 3 hematological or non-hematological toxicity occurred in the previous cycle; dose re-escalation was not allowed. Patients who required more than 4 weeks of rest for recovery from any toxicity other than nausea, vomiting, or anemia, or who required a dose reduction >20 mg/day, were withdrawn from the study.
Table 1 Patient characteristics (n = 44). Characteristic Sex Male Female Age, years Median Range ECOG performance status 0 1 Stage IIIB IV Histology-no. (%) Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Others First line therapy Carboplatin/paclitaxel Carboplatin/gemcitabine Carboplatin/vinorelbine Carboplatin/docetaxel Cisplatin/docetaxel Response of first line therapy PR SD PD NE
No. of patients
%
35 9
79.5 20.5
64 47–79 13 31
29.5 70.5
15 29
34.1 65.9
30 11 1 2
68.2 25.0 2.3 4.5
33 5 3 2 1
75.0 11.4 6.8 2.3 4.5
15 6 13 10
34.2 13.6 29.5 22.7
2.4. Study design and statistical analysis This was a phase II single-arm trial. The primary endpoint was evaluation of the activity, defined as the disease control rate at 8 weeks, of S-1 as a single agent in patients with NSCLC. Disease control rate (DCR) was defined as the percentage of patients without disease progression (CR, PR, or SD) and still on treatment at 8 weeks. DCR was confirmed and sustained 8 weeks or longer. Secondary endpoints included PFS, OS, and safety. PFS was defined as the time from the first day of administration of the study drug to disease progression or death for toxicity or disease progression. OS was defined as the time from the first day of study drug administration to death or last contact. The primary endpoint of the trial was the DCR (CR + PR + SD according to RECIST criteria) at 8 weeks. The target sample size was 45 patients. Given a threshold DCR of 40% and expected DCR of 60%, the required sample size was estimated to be 39 patients, with ˛ = 0.05 and power ˇ = 0.8. 3. Results
2.3. Evaluation of response and toxicity
3.1. Patients
Before entering the study, all patients provided a detailed medical history and underwent a complete physical examination, complete blood cell count, serum chemistry examination, chest computed tomography scan (CT), determination of weight and height, and determination of ECOG PS. A CT scan was performed for tumor assessment within 14 days of initiation of study treatment and was repeated every 1–2 months. Physical examination, symptom evaluation, and routine blood tests and biochemistry blood examination were performed every 2 weeks during the treatment. Objective response was evaluated every 2 months. Ratings of complete response, partial response (PR), stable disease (SD), progressive disease (PD) or not evaluated (NE) were made according to RECIST version 1.0. Toxicity was evaluated every 2 weeks according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
From June 2005 to May 2007, 46 patients were enrolled. Of these 46 patients, one was found to be ineligible because of 3rd line treatment, and one other patient withdrew consent. Thus, 44 patients remained in the analysis. A total of 43 patients had received carboplatin-based chemotherapy, and one patient had received cisplatin-based chemotherapy. Of these 44 patients, one had exhibited CR, 14 PR, 6 SD, and 23 PD. The baseline characteristics of these patients and their tumors are in listed in Table 1. 3.2. Treatments The 44 patients received a total of 70 cycles of chemotherapy, with a median number of cycles of two (range, 1–7). The dose of S-1 was reduced in 2 patients because of either grade 3 diarrhea
T. Shiroyama et al. / Lung Cancer 74 (2011) 85–88 Table 3 Hematologic and non-hematologic toxicities.
Table 2 Patient characteristics in relation to the response. Response rate n (%) (2nd line) CR PR SD PD NE Response rate Disease control rate
87
0 6 (13.6) 28 (63.6) 5 (11.3) 5 (11.3) 13.6 (95% CI, 5.0–20.0%) 77.3 (95% CI, 64.9–89.7%)
Adverse event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 3/4 (%)
Leukopenia Neutropenia Anemia Diarrhea Amylase Pulmonary fibrosis
1 2 5 0 0 0
1 1 1 2 0 0
2 2 2 1 1 0
0 0 0 0 0 1
4.5 4.5 4.5 2.3 2.3 2.3
3.4. Safety All patients were assessed for toxicities, which are listed in Table 3. No grade 4 or more severe hematological toxicities were observed; grade 3 events included two episodes each (4.5%) of leucopenia, neutropenia, and anemia. Non-hematological toxicities included one episode each (2.3%) of grade 3 diarrhea, grade 3 anorexia, grade 3 increase in amylase, and grade 4 interstitial pneumonia, each of which recovered with appropriate treatment. The most common hematological and non-hematological toxicities were mild or moderate. There were no treatment-related deaths directly attributable to S-1 chemotherapy. 4. Discussion
Fig. 1. Overall survival of patient treated with S-1 monotherapy after failure of firstline (platinum-base therapy) treatment.
and abnormal amylase level. The median relative dose intensity for the entire study population was 97.3%, indicating that patient compliance with S-1 chemotherapy was good.
3.3. Efficacy A total of 44 patients were evaluable for response. Six patients achieved PR, resulting in an overall response rate (RR) of 13.6% (95% CI, 5.0–20%). Twenty-eight patients had SD, yielding an overall DCR of 77.3% (95% CI, 64.9–89.7%). The RR and DCR were evaluated separately from those for the previous first-line chemotherapy (Table 2). At the time of median follow-up interval of 18 months, 20 patients were still alive and censored; MST was calculated for all 44 patients, and OS was 16.4 months, the one-year survival rate 60.3%, and PFS 4.2 months The Kaplan–Meier survival curve is shown in Figs. 1 and 2.
Fig. 2. Progression-free survival of patient treated with S-1 monotherapy after failure of first-line (platinum-base therapy) treatment.
Recently, docetaxel has been demonstrated to be useful as second-line therapy for non-small cell lung cancer (NSCLC). Pemetrexed was then found to yield a response rate, overall survival, and PFS similar to those for docetaxel while producing many fewer adverse events; it has therefore been approved as a regimen for second-line therapy in Europe and the United States. Moreover, EGFR-TKI also became a treatment option for second-line therapy for NSCLC, based on the results of comparative studies with docetaxel and BSC. However, it was also reported that pemetrexed was ineffective against squamous cell carcinoma and that EGFR-TKI exhibited only poor efficacy in a group without EGFR gene mutation (exon 19, exon 21) [23–26]. In addition, the combination chemotherapy using two agents exhibited a better response rate and longer PFS than single-agent chemotherapy. On the other hand, since combination chemotherapy produced more toxicity and did not yield prolongation of overall survival compared with single-agent chemotherapy, single-agent chemotherapy has been recognized as effective as second-line therapy. It has also been reported that response rate with second-line or later chemotherapy worsens each time compared with first-line chemotherapy (first 20.9%, second 16.3%, third 2.3%, fourth 0.0%). Therefore, less toxic and highly tolerable singleagent therapy which can be administered on an outpatient basis without impairing QOL, in addition to demonstrating high response rate, is required [27]. Since it was shown in Phase II studies of S-1 in untreated advanced NSCLC that S-1 has a 22.0% anti-tumor effect with low frequency of serious adverse reactions, the present study was conducted to evaluate the efficacy and safety of S-1 in patients with NSCLC previously treated with platinum-based therapy. The median age of eligible subjects in our study was 64 years, and 70% of them had adenocarcinoma. Of the total of 44 evaluable patients, 6 (14%) were responsive to the treatment. Disease control was achieved in 34 patients (77.3%). Grade 3 or more severe toxicities were infrequently observed, including two episodes each (4.5%) of leucopenia, neutropenia, and anemia as hematological toxicities, and one episode each (2.3%) of diarrhea, nausea/vomiting, anorexia, increase in amylase, and interstitial pneumonia as nonhematological toxicities. Throughout all courses in this study, a total of 16% of the patients discontinued, while 4.5% of them was because of violation of discontinuation criteria. Dose inten-
88
T. Shiroyama et al. / Lung Cancer 74 (2011) 85–88
sity exhibited a good percentage of 97.3%, however, change of treatment schedule to two-week dosing followed by one-week wash-out and dose adjustment should be considered in some cases. The major treatment category (inpatient/outpatient) was outpatient therapy, suggesting that this treatment can be safely administered in an ambulatory setting as well. OS, one-year survival rate, and PFS with this treatment were 16.4 months, 57%, and 4.2 months, respectively, suggesting that approximately the same results as obtained with other monotherapies can be achieved with S-1 [28]. On the other hand, Yamamoto et al. reported S-1 may be no difference in efficacy according to histological type [29]. Therefore, we compared squamous cell carcinoma with non-squamous cell carcinoma of PFS (Non-sq;3.6M, Sq: 4.6M) and OS (Non-sq;13.6M, Sq: 17.6M), and no significant differences were observed. However, the patient number of the present study is too little to evaluate the histological deviation in the responders to S-1. In conclusion, S-1 monotherapy appeared to be effective and highly tolerable as second-line therapy in patients with advanced/recurrent NSCLC previously treated with platinumbased therapy. This therapy could be an option for patients wishing to be treated by oral medication or in an ambulatory setting. Conflicts of interest statement None declared. References [1] Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533–43. [2] Stephens R, Fairlamb D, Gower N, Maslove L, Milroy R, Napp V, et al. The Big Lung Trial (BLT): determining the value of cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC): preliminary results in the supportive care setting. Proc Am Soc Clin Oncol 2002;21:291a (abstr 1161). [3] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer—a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 1995;311:899–909. [4] Grilli R, Oxman A, Julian J. Chemotherapy for advanced non-small cell lung cancer: how much benefit is enough? J Clin Oncol 1993;11:1866–72. [5] Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinumbased chemotherapy. J Clin Oncol 2000;18:2095–103. [6] Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354–62. [7] Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer to gefitinib. Lancet 2008;372:1809–18. [8] Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Eng J Med 2005;353:123–32. [9] Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K, et al. Phase III study V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol 2008;26:4244–52.
[10] Ohe Y, Ichinose Y, Nakagawa K, Tamura T, Kubota K, Yamamoto N, et al. Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res 2008;14:4206–12. [11] Di Maio M, Chiodini P, Georqoulias V, Hatzidaki D, Takeda K, Wachters FM, et al. Meta-analysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2009;27:1836–43. [12] Shirasaka T, Shimamoto Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, et al. Development of a novel form of 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor-selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996;7:548–57. [13] Sugimachi K, Maehara Y, Horikoshi N, Shimada Y, Sakata Y, Mitachi Y, et al. An early phase II study of oral S-1 a newly developed 5-fluorouracil derivative for advanced and recurrent gastrointestinal cancers. Oncology 1999;57: 202–10. [14] Koizumi W, Kurihara M, Nakano S, Hasegawa K. Phase II study of S-1, a novel oral derivative of 5-fluorouracil in advanced gastric cancer. Oncology 2000;58:191–7. [15] Ohtsu A, Baba H, Sakata Y, Mitachi Y, Horikoshi N, Sugimachi K, et al. Phase II study of S-1, a novel oral fluoropyrimidine derivative, in patients with metastatic colorectal carcinoma. Br J Cancer 2000;83:141–5. [16] Inuyama M, Kida A, Tsukuda M, Kohno N, Satake B. Early phase II study of S1 in patients with advanced head and neck cancer. Jpn J Cancer Chemother 1998;25:1151–8. [17] Inuyama M, Kida A, Tsukuda M, Kohno N, Satake B. Late phase II study of S1 in patients with advanced head and neck cancer. Jpn J Cancer Chemother 2001;28:1381–90. [18] Saeki T, Takashima S, Sano M, Horikoshi N, Miura S, Shimizu S, et al. A phase II study of S-1 in patients with metastatic breast cancer—A Japanese Trial by the S-1 Cooperative Study Group, Breast Cancer Working Group. Breast Cancer 2004;11:194–202. [19] Saeki T, Takashima S, Sano M, Horikoshi N, Miura S, Shimizu S, et al. A late phase II clinical study of S-1 in patients with progressed, refractory breast cancer. Jpn J Cancer Chemother 2004;31:539–47. [20] Ueno H, Okusaka T, Ikeda M, Takezako Y, Morizane C. An early phase II study of S-1 in patients with metastatic pancreatic cancer. Oncology 2005;68: 171–8. [21] Ueno H, Okusaka T, Ikeda M, Takezako Y, Morizane. Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer 2004;91:1769–74. [22] Kawahara M, Furuse K, Segawa Y, Yoshimori K, Matsui K, Kudoh S, et al. Phase II study of S-1 a novel oral fluorouracil in advanced non-small-cell lung cancer. Br J Cancer 2001;85:939–43. [23] Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–97. [24] Scagliotti GV, Parkih P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-smallcell lung cancer. J Clin Oncol 2008;26:3543–51. [25] Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Eng J Med 2009;361:947–57. [26] Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin docetaxel in patients with non-small lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol 2010;11:121–8. [27] Massarelli E, Andre F, Liu DD, Lee JJ, Wolf M, Fandi A, et al. A retrospective analysis of the outcome of patients who have received two prior chemotherapy regimens including platinum and docetaxel for recurrent non-small-cell lung cancer. Lung Cancer 2003;39:55–61. [28] Totani Y, Saito Y, Hayashi M, Tada T, Kohashi Y, Mieno Y, et al. A phase II study of S-1 monotherapy as second-line treatment for advanced non-small cell lung cancer. Cancer Chemother Pharmacol 2009;64:1181–5. [29] Yamamoto N, Yamanaka T, Ichinose Y, Kubota K, Sakai H, Genma A, et al. Pooled analysis of S-1 trials in non-small cell lung cancer according to histological type. Anticancer Res 2010;30:2985–90.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Phase II study of S-1 monotherapy in platinum-refractory, advanced non-small cell lung cancer Takayuki Shiroyama a,∗ , Kiyoshi Komuta a , Fumio Imamura b , Tomonori Hirashima c , Takashi Kijima d , Isao Tachibana d , Ichiro Kawase d a
Department of Respiratory Medicine, Osaka Police Hospital, 10-31 Kitayama-chou, Tennoji-ku, Osaka 543-0035, Japan Department of Pulmonary Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka, Japan d Department of Respiratory, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan b c
a r t i c l e
i n f o
Article history: Received 8 October 2010 Received in revised form 14 January 2011 Accepted 23 January 2011 Keywords: Lung cancer Second line Platinum-refractory S-1 monotherapy Ambulatory setting Oral medication
a b s t r a c t Objective: The aim of this study was to evaluate the efficacy and toxicity of a novel oral 5-fluorouracil formulation (S-1) as second-line therapy after platinum agent chemotherapy for advanced non-small cell lung cancer (NSCLC). Methods: S-1 was administered orally at a dose of 80 mg/m2 for 28 days, followed by 14 days of rest (1 cycle); treatment was repeated until disease progression, unacceptable toxicity, or patient refusal. Results: Of the 46 patients enrolled in this study, 44 were evaluable. Six patients (14%) exhibited a partial response and 28 (64%) showed stable disease. Disease-control rate was 77.3% (34/44) (95% CI, 64.9–89.7%). The overall response rate was 14% (6/44) (95% CI, 3.5–23.8%). Median progression-free survival was 4.2 months. The median survival time was 16.4 months, and the one-year survival rate 60.3%. Grade 3/4 hematological toxicities were minor. All of those adverse reactions were tolerable and reversible. Conclusion: This study demonstrated the efficacy of S-1 monotherapy as second-line treatment for advanced NSCLC. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is the most common cancer worldwide, with an estimated 1.2 million new cases globally (12.3% of all cases of cancer) and 1.1 million deaths (17.8% of all cancer deaths) in 2000 [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all cases of lung cancer. For chemotherapy-naive patients with good performance status (PS) at a stage of IIIB (with pleural effusion) or IV, platinum-based chemotherapy offers a modest survival advantage over best supportive care (BSC) alone [2–4]. To improve outcome, however, there is a need for novel regimens. A recent phase III clinical study of conventional second-line therapies reported median survival times (MST) of approximately 6–8 months for docetaxel, gefitinib, and erlotinib [5–8]. On the other hand, in Japanese trials targeting this population have showed more favorable MST of approximately 12–17 months [9,10]. Doublet chemotherapy as second-line treatment for advanced NSCLC significantly elevates response rate and prolongs progression-free survival (PFS), but it is more toxic and
∗ Corresponding author. Tel.: +81 6 6771 6051. E-mail address: [email protected] (T. Shiroyama). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.01.017
does not improve overall survival rate compared to single-agent treatment [11]. S-1 is a novel, orally administered drug that is a combination of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and oteracil potassium (Oxo) in a 1:0.4:1 molar concentration ratio [12]. CDHP is a competitive inhibitor of dihydropyrimidine dehydrogenase, which is involved in the degradation of 5-FU, and acts to maintain efficacious concentrations of 5-FU in plasma and tumor tissues. Oxo, a competitive inhibitor of orotate phosphoribosyltransferase, inhibits the phosphorylation of 5-FU in the gastrointestinal tract, reducing the serious gastrointestinal toxicity associated with 5-FU. The antitumor effect of S-1 has already been demonstrated in a variety of solid tumors such as advanced gastric cancer [13,14], colorectal cancer [15], head and neck cancer [16,17], breast cancer [18], pancreatic cancer [19,20] and biliary tract cancer [21]. A recent phase II study of S-1 for chemo-naive, advanced NSCLC patients yielded promising results, with a response rate of 22.0%, MST of 10.2 months and favorable toxicity profile [22]. S-1 has exhibited promising activity against several tumors. Moreover, treatment with it can be administered on an outpatient basis. Oral agents such as S-1, which feature few adverse events, are appealing in the 2nd or 3rd line setting when patients are in less favorable condition.
86
T. Shiroyama et al. / Lung Cancer 74 (2011) 85–88
We therefore conducted a prospective study to evaluate the efficacy and feasibility of S-1 monotherapy in patients with progressive, advanced NSCLC under platinum-based, first line chemotherapy. 2. Patients and methods 2.1. Patient eligibility Patients were required to meet the following eligibility criteria: histologically confirmed NSCLC; at least one measurable lesion; prior platinum-based treatment; Eastern Cooperative Oncology Group performance status of 0–1; age ≥20 years, adequate organ function, defined as a leukocyte count of 3500–12,000 mm3 , neutrophil count of more than 2000 mm3 , platelet count of more than 100,000 mm3 , hemoglobin level of more than 9.0 g/dl, a serum total bilirubin level within 2.0 times the ULN, and serum creatinine level not exceeding the ULN; partial pressure of arterial oxygen ≥60 mm Hg, and an estimated life expectancy of at least 3 months. The exclusion criteria were as follows: pregnancy, serious concomitant disease (brain metastasis, active infection, severe heart disease or uncontrolled diabetes mellitus), concomitant malignancy, pleural effusion requiring treatment, symptomatic cerebral involvement, and obvious interstitial pneumonia or pulmonary fibrosis on chest radiography. All patients gave written informed consent prior to enrollment in the study, and the protocol was approved by the Institutional Ethics Committee of each participating institution. 2.2. Study treatment The initial doses of S-1 were assigned on the basis of body surface area (BSA). Accordingly, the patients received one of the following oral doses divided in two and administered daily after meals: 80 mg for patients with BSA < 1.25 m2 , 100 mg for BSA ≥ 1.25 and <1.50 m2 , and 120 mg for BSA ≥ 1.50 m2 . One therapy cycle comprised the administration of single-agent S-1 for 28 consecutive days followed by 14 days of no treatment. This schedule was repeated every 6 weeks until the occurrence of disease progression, unacceptable toxicities, or patient refusal. In the absence of evidence of disease progression, patients were allowed to continue S-1 treatment. A dose reduction of 20 mg/day was recommended if ≥grade 3 hematological or non-hematological toxicity occurred in the previous cycle; dose re-escalation was not allowed. Patients who required more than 4 weeks of rest for recovery from any toxicity other than nausea, vomiting, or anemia, or who required a dose reduction >20 mg/day, were withdrawn from the study.
Table 1 Patient characteristics (n = 44). Characteristic Sex Male Female Age, years Median Range ECOG performance status 0 1 Stage IIIB IV Histology-no. (%) Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Others First line therapy Carboplatin/paclitaxel Carboplatin/gemcitabine Carboplatin/vinorelbine Carboplatin/docetaxel Cisplatin/docetaxel Response of first line therapy PR SD PD NE
No. of patients
%
35 9
79.5 20.5
64 47–79 13 31
29.5 70.5
15 29
34.1 65.9
30 11 1 2
68.2 25.0 2.3 4.5
33 5 3 2 1
75.0 11.4 6.8 2.3 4.5
15 6 13 10
34.2 13.6 29.5 22.7
2.4. Study design and statistical analysis This was a phase II single-arm trial. The primary endpoint was evaluation of the activity, defined as the disease control rate at 8 weeks, of S-1 as a single agent in patients with NSCLC. Disease control rate (DCR) was defined as the percentage of patients without disease progression (CR, PR, or SD) and still on treatment at 8 weeks. DCR was confirmed and sustained 8 weeks or longer. Secondary endpoints included PFS, OS, and safety. PFS was defined as the time from the first day of administration of the study drug to disease progression or death for toxicity or disease progression. OS was defined as the time from the first day of study drug administration to death or last contact. The primary endpoint of the trial was the DCR (CR + PR + SD according to RECIST criteria) at 8 weeks. The target sample size was 45 patients. Given a threshold DCR of 40% and expected DCR of 60%, the required sample size was estimated to be 39 patients, with ˛ = 0.05 and power ˇ = 0.8. 3. Results
2.3. Evaluation of response and toxicity
3.1. Patients
Before entering the study, all patients provided a detailed medical history and underwent a complete physical examination, complete blood cell count, serum chemistry examination, chest computed tomography scan (CT), determination of weight and height, and determination of ECOG PS. A CT scan was performed for tumor assessment within 14 days of initiation of study treatment and was repeated every 1–2 months. Physical examination, symptom evaluation, and routine blood tests and biochemistry blood examination were performed every 2 weeks during the treatment. Objective response was evaluated every 2 months. Ratings of complete response, partial response (PR), stable disease (SD), progressive disease (PD) or not evaluated (NE) were made according to RECIST version 1.0. Toxicity was evaluated every 2 weeks according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
From June 2005 to May 2007, 46 patients were enrolled. Of these 46 patients, one was found to be ineligible because of 3rd line treatment, and one other patient withdrew consent. Thus, 44 patients remained in the analysis. A total of 43 patients had received carboplatin-based chemotherapy, and one patient had received cisplatin-based chemotherapy. Of these 44 patients, one had exhibited CR, 14 PR, 6 SD, and 23 PD. The baseline characteristics of these patients and their tumors are in listed in Table 1. 3.2. Treatments The 44 patients received a total of 70 cycles of chemotherapy, with a median number of cycles of two (range, 1–7). The dose of S-1 was reduced in 2 patients because of either grade 3 diarrhea
T. Shiroyama et al. / Lung Cancer 74 (2011) 85–88 Table 3 Hematologic and non-hematologic toxicities.
Table 2 Patient characteristics in relation to the response. Response rate n (%) (2nd line) CR PR SD PD NE Response rate Disease control rate
87
0 6 (13.6) 28 (63.6) 5 (11.3) 5 (11.3) 13.6 (95% CI, 5.0–20.0%) 77.3 (95% CI, 64.9–89.7%)
Adverse event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 3/4 (%)
Leukopenia Neutropenia Anemia Diarrhea Amylase Pulmonary fibrosis
1 2 5 0 0 0
1 1 1 2 0 0
2 2 2 1 1 0
0 0 0 0 0 1
4.5 4.5 4.5 2.3 2.3 2.3
3.4. Safety All patients were assessed for toxicities, which are listed in Table 3. No grade 4 or more severe hematological toxicities were observed; grade 3 events included two episodes each (4.5%) of leucopenia, neutropenia, and anemia. Non-hematological toxicities included one episode each (2.3%) of grade 3 diarrhea, grade 3 anorexia, grade 3 increase in amylase, and grade 4 interstitial pneumonia, each of which recovered with appropriate treatment. The most common hematological and non-hematological toxicities were mild or moderate. There were no treatment-related deaths directly attributable to S-1 chemotherapy. 4. Discussion
Fig. 1. Overall survival of patient treated with S-1 monotherapy after failure of firstline (platinum-base therapy) treatment.
and abnormal amylase level. The median relative dose intensity for the entire study population was 97.3%, indicating that patient compliance with S-1 chemotherapy was good.
3.3. Efficacy A total of 44 patients were evaluable for response. Six patients achieved PR, resulting in an overall response rate (RR) of 13.6% (95% CI, 5.0–20%). Twenty-eight patients had SD, yielding an overall DCR of 77.3% (95% CI, 64.9–89.7%). The RR and DCR were evaluated separately from those for the previous first-line chemotherapy (Table 2). At the time of median follow-up interval of 18 months, 20 patients were still alive and censored; MST was calculated for all 44 patients, and OS was 16.4 months, the one-year survival rate 60.3%, and PFS 4.2 months The Kaplan–Meier survival curve is shown in Figs. 1 and 2.
Fig. 2. Progression-free survival of patient treated with S-1 monotherapy after failure of first-line (platinum-base therapy) treatment.
Recently, docetaxel has been demonstrated to be useful as second-line therapy for non-small cell lung cancer (NSCLC). Pemetrexed was then found to yield a response rate, overall survival, and PFS similar to those for docetaxel while producing many fewer adverse events; it has therefore been approved as a regimen for second-line therapy in Europe and the United States. Moreover, EGFR-TKI also became a treatment option for second-line therapy for NSCLC, based on the results of comparative studies with docetaxel and BSC. However, it was also reported that pemetrexed was ineffective against squamous cell carcinoma and that EGFR-TKI exhibited only poor efficacy in a group without EGFR gene mutation (exon 19, exon 21) [23–26]. In addition, the combination chemotherapy using two agents exhibited a better response rate and longer PFS than single-agent chemotherapy. On the other hand, since combination chemotherapy produced more toxicity and did not yield prolongation of overall survival compared with single-agent chemotherapy, single-agent chemotherapy has been recognized as effective as second-line therapy. It has also been reported that response rate with second-line or later chemotherapy worsens each time compared with first-line chemotherapy (first 20.9%, second 16.3%, third 2.3%, fourth 0.0%). Therefore, less toxic and highly tolerable singleagent therapy which can be administered on an outpatient basis without impairing QOL, in addition to demonstrating high response rate, is required [27]. Since it was shown in Phase II studies of S-1 in untreated advanced NSCLC that S-1 has a 22.0% anti-tumor effect with low frequency of serious adverse reactions, the present study was conducted to evaluate the efficacy and safety of S-1 in patients with NSCLC previously treated with platinum-based therapy. The median age of eligible subjects in our study was 64 years, and 70% of them had adenocarcinoma. Of the total of 44 evaluable patients, 6 (14%) were responsive to the treatment. Disease control was achieved in 34 patients (77.3%). Grade 3 or more severe toxicities were infrequently observed, including two episodes each (4.5%) of leucopenia, neutropenia, and anemia as hematological toxicities, and one episode each (2.3%) of diarrhea, nausea/vomiting, anorexia, increase in amylase, and interstitial pneumonia as nonhematological toxicities. Throughout all courses in this study, a total of 16% of the patients discontinued, while 4.5% of them was because of violation of discontinuation criteria. Dose inten-
88
T. Shiroyama et al. / Lung Cancer 74 (2011) 85–88
sity exhibited a good percentage of 97.3%, however, change of treatment schedule to two-week dosing followed by one-week wash-out and dose adjustment should be considered in some cases. The major treatment category (inpatient/outpatient) was outpatient therapy, suggesting that this treatment can be safely administered in an ambulatory setting as well. OS, one-year survival rate, and PFS with this treatment were 16.4 months, 57%, and 4.2 months, respectively, suggesting that approximately the same results as obtained with other monotherapies can be achieved with S-1 [28]. On the other hand, Yamamoto et al. reported S-1 may be no difference in efficacy according to histological type [29]. Therefore, we compared squamous cell carcinoma with non-squamous cell carcinoma of PFS (Non-sq;3.6M, Sq: 4.6M) and OS (Non-sq;13.6M, Sq: 17.6M), and no significant differences were observed. However, the patient number of the present study is too little to evaluate the histological deviation in the responders to S-1. In conclusion, S-1 monotherapy appeared to be effective and highly tolerable as second-line therapy in patients with advanced/recurrent NSCLC previously treated with platinumbased therapy. This therapy could be an option for patients wishing to be treated by oral medication or in an ambulatory setting. Conflicts of interest statement None declared. References [1] Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533–43. [2] Stephens R, Fairlamb D, Gower N, Maslove L, Milroy R, Napp V, et al. The Big Lung Trial (BLT): determining the value of cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC): preliminary results in the supportive care setting. Proc Am Soc Clin Oncol 2002;21:291a (abstr 1161). [3] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer—a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 1995;311:899–909. [4] Grilli R, Oxman A, Julian J. Chemotherapy for advanced non-small cell lung cancer: how much benefit is enough? J Clin Oncol 1993;11:1866–72. [5] Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinumbased chemotherapy. J Clin Oncol 2000;18:2095–103. [6] Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354–62. [7] Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer to gefitinib. Lancet 2008;372:1809–18. [8] Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Eng J Med 2005;353:123–32. [9] Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K, et al. Phase III study V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol 2008;26:4244–52.
[10] Ohe Y, Ichinose Y, Nakagawa K, Tamura T, Kubota K, Yamamoto N, et al. Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res 2008;14:4206–12. [11] Di Maio M, Chiodini P, Georqoulias V, Hatzidaki D, Takeda K, Wachters FM, et al. Meta-analysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 2009;27:1836–43. [12] Shirasaka T, Shimamoto Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, et al. Development of a novel form of 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor-selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996;7:548–57. [13] Sugimachi K, Maehara Y, Horikoshi N, Shimada Y, Sakata Y, Mitachi Y, et al. An early phase II study of oral S-1 a newly developed 5-fluorouracil derivative for advanced and recurrent gastrointestinal cancers. Oncology 1999;57: 202–10. [14] Koizumi W, Kurihara M, Nakano S, Hasegawa K. Phase II study of S-1, a novel oral derivative of 5-fluorouracil in advanced gastric cancer. Oncology 2000;58:191–7. [15] Ohtsu A, Baba H, Sakata Y, Mitachi Y, Horikoshi N, Sugimachi K, et al. Phase II study of S-1, a novel oral fluoropyrimidine derivative, in patients with metastatic colorectal carcinoma. Br J Cancer 2000;83:141–5. [16] Inuyama M, Kida A, Tsukuda M, Kohno N, Satake B. Early phase II study of S1 in patients with advanced head and neck cancer. Jpn J Cancer Chemother 1998;25:1151–8. [17] Inuyama M, Kida A, Tsukuda M, Kohno N, Satake B. Late phase II study of S1 in patients with advanced head and neck cancer. Jpn J Cancer Chemother 2001;28:1381–90. [18] Saeki T, Takashima S, Sano M, Horikoshi N, Miura S, Shimizu S, et al. A phase II study of S-1 in patients with metastatic breast cancer—A Japanese Trial by the S-1 Cooperative Study Group, Breast Cancer Working Group. Breast Cancer 2004;11:194–202. [19] Saeki T, Takashima S, Sano M, Horikoshi N, Miura S, Shimizu S, et al. A late phase II clinical study of S-1 in patients with progressed, refractory breast cancer. Jpn J Cancer Chemother 2004;31:539–47. [20] Ueno H, Okusaka T, Ikeda M, Takezako Y, Morizane C. An early phase II study of S-1 in patients with metastatic pancreatic cancer. Oncology 2005;68: 171–8. [21] Ueno H, Okusaka T, Ikeda M, Takezako Y, Morizane. Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer 2004;91:1769–74. [22] Kawahara M, Furuse K, Segawa Y, Yoshimori K, Matsui K, Kudoh S, et al. Phase II study of S-1 a novel oral fluorouracil in advanced non-small-cell lung cancer. Br J Cancer 2001;85:939–43. [23] Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–97. [24] Scagliotti GV, Parkih P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-smallcell lung cancer. J Clin Oncol 2008;26:3543–51. [25] Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Eng J Med 2009;361:947–57. [26] Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin docetaxel in patients with non-small lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomized phase 3 trial. Lancet Oncol 2010;11:121–8. [27] Massarelli E, Andre F, Liu DD, Lee JJ, Wolf M, Fandi A, et al. A retrospective analysis of the outcome of patients who have received two prior chemotherapy regimens including platinum and docetaxel for recurrent non-small-cell lung cancer. Lung Cancer 2003;39:55–61. [28] Totani Y, Saito Y, Hayashi M, Tada T, Kohashi Y, Mieno Y, et al. A phase II study of S-1 monotherapy as second-line treatment for advanced non-small cell lung cancer. Cancer Chemother Pharmacol 2009;64:1181–5. [29] Yamamoto N, Yamanaka T, Ichinose Y, Kubota K, Sakai H, Genma A, et al. Pooled analysis of S-1 trials in non-small cell lung cancer according to histological type. Anticancer Res 2010;30:2985–90.