ANTICANCER RESEARCH 26: 2265-2268 (2006)

Phase I Study of S-1 and Nedaplatin for Patients with Recurrence of Head and Neck Cancer

TAKESHI KODAIRA, NOBUKAZU FUWA, HIROYUKI TACHIBANA and SATOSHI HIDANO

Department of Therapeutic Radiation Oncology, Aichi Cancer Center Hospital, 464-8681 Nagoya, Aichi, Japan

Abstract. A phase I study of chemotherapy was planned with toxicity, oral chemotherapeutic agents have been rigorously S-1 and nedaplatin to find the optimal dose for patients with tested in Japan. Recently the oral fluorouracil prodrugs recurrent head and neck cancer. Materials and Methods: Oral showed promising results for several solid tumors including administration of S-1 (days 1-14) and intravenous nedaplatin SCCHN (3). Oral administration of UFT (tegafur and uracil (day 8) were tested for patients with recurrent head and neck in a 1:4 molar concentration) showed a significant survival cancer in a phase-I setting. The dose of S-1 was fixed and the advantage in lung (4) and breast cancer (5). dose of nedaplatin was escalated from 80 mg/m2, with an S-1 (Taiho Pahrmaceutical Co., Ltd., Tokyo, Japan) is an increase of 10 mg/m2 per step, to find the maximum tolerated oral anticancer agent (tegafur, gimeracil and oteracil dose. Results: Nine patients were recruited in this trial. The potassium at a molar ratio 1:0.4:1) based on the biochemical maximum tolerated dose (MTD) of nedaplatin was 90 mg/m2. modulation of 5FU (6). S-1 is thought to be potentially At this dose level, dose-limiting toxicity (DLT) was observed more active than 5FU, and several clinical reports have in two out of three patients. One experienced grade 4 suggested encouraging clinical results in chemotherapy for thrombocytopenia and febrile grade 3 neutropenia, while the SCCHN (7, 8). other suffered myelosuppression causing more than a two-week Nedaplatin (NDP) is a platinum complex also developed delay of the second chemotherapy cycle. Myelosuppression was in Japan, and believed to be an active agent for SCCHN (9). the DLT of this regimen. Conclusion: The recommended This agent is thought to have an equivalent treatment effect, phase II dose of nedaplatin combined with oral S-1 was but with less renal and gastrointestinal toxicity compared identified as 80 mg/m2. with cisplatin, and so more convenient administration could be achieved even on an out-patient basis. NDP was also About two-thirds of squamous cell carcinoma of the head reported to be efficacious and feasible combined with the and neck (SCCHN) present with locally advanced disease. pre-administration of 5FU (10). Therefore, improving the outcome of radiotherapy and Combination chemotherapy using S-1 and NDP, both surgery still remains an important issue. Concurrent highly active agents for SCCHN, is expected to have a chemoradiotherapy showed a significant survival advantage promising outcome with sufficient compliance even in the compared with radiotherapy for patients with locally out-patient setting. To the best of our best knowledge, this advanced SCCHN (1). Thus, chemotherapy is believed to be is the first phase I trial of S-1 and NDP in SCCHN. an important modality in the clinical practice for treating patients with locally advanced SCCHN. As for active agents, Materials and Methods 5-Fluorouracil (5FU) and cisplatin (CDDP) are most commonly used (2), but this treatment usually needs Eligibility. Patients with histologically confirmed head and neck cancer, excluding thyroid cancer, were enrolled in this trial. Written hospitalization because of the continuous infusion of these informed consent was obtained from each patient before agents and adequate support for gastrointestinal and renal enrollment. All patients were diagnosed as having recurrence with a toxicity. To improve compliance with treatment and reduce measurable region after their initial treatment. Previous treatments, including chemotherapy, radiotherapy and surgery, were allowed if the treatment had finished at least one month prior to registration for the present study. The specific eligibility criteria were: patients Correspondence to: Takeshi Kodaira, Department of Therapeutic were required to be within 20 to 75 years of age; to have an Eastern Radiation Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden Cooperative Oncology Group (ECOG) performance status of 0 to Chikusa-ku, 464-8681 Nagoya, Aichi, Japan. Tel: +81-52-762-6111, 1; to have adequate hematological, hepatic and renal function Fax: +81-52-752-8390, e-mail: [email protected] (WBCs >3,500/Ìl, neutrophil count >2,000/Ìl, platelet count >100,000/Ìl and hemoglobin level >9 g/dL; AST and ALT

0250-7005/2006 $2.00+.40 2265 ANTICANCER RESEARCH 26: 2265-2268 (2006) clearance >60 ml/min, respectively); and to have a life expectancy Table I. Patient characteristics. of at least three months. The patients also had to be able to comply with the oral administration of S-1. Patients enrolled 9 Gender Treatment schedule and dose escalation. S-1 was administered at male 7 fixed doses based on the body surface area of the patient. The female 2 following doses were administered orally: body surface area (BSA) Age 38-74 (median 60) less than 1.25 m2, 80 mg/day; BSA 1.25-1.5 m2, 100 mg/day; BSA Performance status (ECOG) 1.5 m2 or more, 120 mg/day. S-1 was administered orally twice a 19 Previous treatment day after breakfast and dinner, for 14 consecutive days, followed chemoradiotherapy 5 by a 2-week rest. NDP was administered intravenously over 1 h on chemoradiation and surgery 2 day 8. The starting dose of NDP was 80 mg/m2 (level 1). Additional Primary tumor location 2 2 increases by 10 mg/m up to 100 mg/m were permitted to find the nasopharynx 4 maximum tolerated dose (MTD). The schedule was repeated every hypopharynx 2 4 weeks until the occurrence of disease progression, unacceptable tongue 1 toxicity or the patient’s refusal. Treatment with antiemetics, maxillary sinus 1 antibiotics, sedatives, steroid, hematopoietic growth factors and hard palate 1 gastric protectors was permitted. An additional course was allowed Histopathology if WBCs >3,000/Ìl, platelet count >100,000/Ìl, serum creatinine squamous cell carcinoma 7 <1.2 times normal values, with febrile status and resolution of non- adenoid cystic carcinoma 2 hematological toxicity to be baseline or less than grade 1. Target region At least three patients were treated at each dose level. The primary region 4 dose-limiting toxicities (DLTs) were defined as grade 4 of the lung metastasis 2 National Cancer Institute common toxicity criteria (NCI-CTC) ver. mediastinal lymph nodes 2 3 for hematological toxicities, febrile neutropenia of grade 3, grade skin 1 3 of non-hematological toxicities excluding nausea and vomiting, grade 2 of serum creatinine and an over 2-week delay in the administration of the second cycle of chemotherapy. When the DLT appeared, three patients were added at the same dose level. The end-points to close the study were DLT in hematological or males and two females), with a median age of 60 years, were non-hematological toxicity if observed in two out of three or three out of six patients at the same dose levels. The previous dose level enrolled. Seven patients had been treated with to that at which the MTD appeared was considered to be the chemoradiotherapy before this protocol, while two patients recommended dose (RD). had received surgery followed by salvage treatment by chemoradiotherapy for recurrent disease. Table I gives Evaluation and follow-up. Baseline evaluation included a complete details of the patients and their treatment characteristics. medical history, physical examination, complete blood cell count, serum chemistry, cervical CT scan and chest X-ray. Blood chemistry and subjective/objective symptoms of toxicity were DLT. Table II shows the hematological toxicities observed monitored on a 2-weekly basis during treatment. The clinical at each dose level. At level 1 (NDP 80 mg/m2), one out of response was evaluated for each course of chemotherapy. three patients experienced a DLT of grade 4 neutropenia, Complete response (CR) was defined as the disappearance of all so an additional three patients were included at this dose clinically evident tumors and no new disease; a partial response level. At this dose level, one out of six patients experienced (PR) was defined as a greater than 50% reduction of the sum of DLT, then advanced to the next dose level. At dose level 2 the products of perpendicular tumor measurements and no new 2 disease; stable disease (SD) was defined as less than a partial (NDP 90 mg/m ), two out of three patients experienced response and less than a 25% increase in all dimensions of DLTs. One patient experienced grade 4 neutropenia and measurable disease; and progressive disease (PD) was defined as a grade 4 thrombocytopenia. One patient experienced more greater than 25% increase in all dimensions of measurable disease than a 2-week delay in the second chemotherapy. or new sites of disease. The survival time was calculated from the Table III shows the non-hematological toxicities observed initial date of the treatment to death from any cause or the last at each dose level. No patient experienced DLTs in this follow-up. Overall survival was assessed using the Kaplan-Meier category. In addition, at dose levels 1 and 2, no patient method starting from the date of treatment initiation. experienced grade 3 or above non-hematological toxicity. Results From these findings, it was concluded that dose level 2 (NDP 90 mg/m2) was the MTD. Characteristics of patients. Ten patients received this protocol from 2004 June to January 2005. However, one patient was Response and status. One out of nine patients achieved CR excluded from the analysis because of an insufficient interval after the second cycle of chemotherapy, and two, four and two since the previous chemotherapy. Thus nine patients (seven patients achieved PR, SD and PD, respectively. The response

2266 Kodaira et al: Phase-I study on Head and Neck Cancer

Table II. Hematological toxicity. Table III. Non-hematological toxicity.

Grade Grade Level Level 1 (80 mg/m2) Level 2 (90 mg/m2) 3-4(%) 1234 Grade 1 2 3 4 1 2 3 4

Level 1 (80 mg/m2) Fatigue 3 2 0 0 3 0 0 0 Anemia 3 1 2 0 33.3% Anorexia 3 2 0 0 1 0 0 0 Leukopenia 1 2 3 0 50.0% Nausea/vomiting 4 2 0 0 1 0 0 0 Neutropenia 1 1 2 1 50.0% Stomatitis 2 1 0 0 2 0 0 0 Thrombocytopenia 3 0 2 0 33.3% Diarrhea 0 1 0 0 0 0 0 0 Level 2 (90 mg/m2) Bilirubin 2 2 0 0 0 0 0 0 Anemia 1 0 2 0 66.7% Liver 3 2 0 0 1 0 0 0 Leukopenia 0 1 2 0 66.7% Renal 2 0 0 0 1 0 0 0 Neutropenia 0 0 2 1 100.0% Alopecia 3 0 0 0 1 0 0 0 Thrombocytopenia 0 2 0 1 33.3% Skin 1 1 0 0 0 1 0 0

rate to this treatment was 33.3% (95%CI=7.5-70.1%). One 1.9 times higher than that of the PVI of 5FU (11). Thus oral patient achieved CR. This patient was diagnosed with local S-1 80 mg/m2 was estimated to be equally effective as the PVI recurrence of nasopharyngeal cancer (level 1), and received a of 5FU 475 mg/m2. In addition S-1 appeared to have several total of five courses of this regimen on an out-patient basis. advantages, such as convenient oral form, high response rate, The patient had previously received intravenous chemo- mild toxicity and good compliance with therapy. therapy with combined CDDP and 5FU. A total of 20 cycles Therefore, in Japan, S-1 is intensively used for gastric were given to all patients. All patients could receive a cancer (11), colorectal cancer (12), non-small cell lung minimum of two cycles of chemotherapy (range 2-5). Six cancer (13), breast cancer (14) and SCCHN (7). In a courses of chemotherapy required hospitalization. However, Japanese phase II study for SCCHN, S-1 showed a response the reason for hospitalization for some patients undergoing rate of 28.8% with acceptable toxicities (7). The three courses was that they lived too far from the hospital to combination of S-1 and platinum was tested for patients make out-patient treatment feasible. with advanced gastric cancer (15, 16). According to two At the last follow-up, with a median of 11.7 months (range recently reported phase II studies, S-1 was administered 4.8-14.8 months), three patients were alive without disease orally at a dose of 80 mg/m2 per day for 2 weeks, followed progression, four patients were alive with disease progression, by a 2-week rest. A CDDP dose of 70-80 mg/m2 was and two patients had died of disease progression. administered intravenously on day 8 of each course. The dose of S-1 and the timing of the administration of platinum Discussion were quite similar to those applied in this study. The phase II studies reported that this treatment regimen was active, S-1 is a novel oral agent, which is based on the biochemical convenient and well tolerated. Therefore, we were modulation of tegafur by gimeracil and oteracil potassium encouraged to adapt our regimen for patients with SCCHN. (6). Gimeracil strongly inhibits dihydropyrimidine Fujii et al. reported a phase I/II study of S-1 and CDDP for dehydrogenase, and inhibits 5FU degradation more patients with head and neck cancer (17). They planned a effectively than uracil. Co-administration of gimeracil and dose of S-1 40 mg/m2 per day for 2 weeks and a CDDP dose tegafur markedly increases the antitumor activity of tegafur. of 60-70 mg/m2 was administered intravenously on day 8 of Oteracil potassium inhibits the phosphorylation of 5FU to each course. With an RD of 70 mg/m2, the confirmed 5-fluorouridine-5’-monophosphatate. As oteracil is response rate for disease was reported to be 44.1%. This distributed in the gastrointestinal tract after oral included recurrent disease. Thus, combination therapies administration, it is possible that it decreases 5-FU-induced with S-1 are thought to be effective and meaningful for the gastrointestinal tract toxicity. Continuous infusion of 5FU is treatment of SCCHN. thought to be effective, but requires hospitalization. S-1 is NDP was used instead of cisplatin in this study, because believed to be equally effective compared to protracted of its less toxic nature and convenience for use on an out- intravenous infusion (PVI) of 5FU. Yamada et al. reported patient basis. NDP is a platinum complex developed in the pharmacokinetics of oral S-1 80 mg/m2 compared with Japan (Shionogi Pharmaceutical Co., Ltd., Osaka, Japan). the 5-day PVI of 5FU 250 mg/m2, and the AUC of S-1 was It is believed to be an active agent for SCCHN. Inuyama et

2267 ANTICANCER RESEARCH 26: 2265-2268 (2006) al. reported a Japanese phase II study of NDP, with a 6 Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, response rate of 43.9% and mild non-hematological Yonekura K and Fukushima M: Development of a novel form of toxicities (9). In addition, we have reported the possibility an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two of dose-escalation of NDP when used in combination with biochemical modulators. Anticancer Drugs 7: 548-557, 1996. 5FU before the administration of NDP (10). We expected 7 Inuyama Y, Kida A, Tsukuda M, Kohno N, Satake B and S-1 a similar advantage if NDP was administered on day 8. To Cooperative Study Group (Head and Neck Cancer Working the best of our knowledge, this is the first phase I study of Group): Late phase II study of S-1 in patients with advanced the combination chemotherapy of S-1 and NDP. head and neck cancer. Gan To Kagaku Ryoho 28: 1381-1390, Combined with a fixed dose of oral S-1 of 80 mg/m2 per 2001. day for 2 weeks, 1-hour infusion of NDP appears feasible 8 Tsukuda M, Kida A, Fujii M, Kono N, Yoshihara T, Hasegawa Y and Sugita M: Randomized scheduling feasibility study of and tolerable at a dose of 80 mg/m2 for advanced SCCHN. S-1 for adjuvant chemotherapy in advanced head and neck Only three out of 20 cycles required hospitalization to cancer. Br J Cancer 93: 884-889, 2005. support adverse events. We believe this combination 9 Inuyama Y, Miyake H, Horiuchi M, Hayasaki K, Komiyama S chemotherapy could be administered safely on an out- and Ota K: An early phase II clinical study of cis-diammine patient basis. Considering the fact that all the enrolled glycolato platinum, 254-S, for head and neck cancers. Gan To patients had recurrent disease after receiving chemo- Kagaku Ryoho 19: 863-869, 1992. radiotherapy including 5FU and CDDP, we experienced a 10 Fuwa N, Kodaira T, Kamata M, Matsumoto A, Furutani K, Tachibana H and Ito Y: Phase I study of combination response rate of 33.3% in this phase I study. These data are chemotherapy with 5-fluorouracil (5-FU) and nedaplatin encouraging in that this combination regimen is a (NDP): adverse effects and recommended dose of NDP potentially active method, and a phase II study is warranted administered after 5-FU. Am J Clin Oncol 25: 565-569, 2002. to further evaluate its feasibility. We believe that the 11 Sakata Y, Ohtsu A, Horikoshi N, Sugimachi K, Mitachi Y and combination therapy of S-1 and NDP is sufficiently active Taguchi T: Late phase II study of novel oral fluoropyrimidine and well tolerated. This protocol appears promising for anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat neoadjuvant chemotherapy on an out-patient basis or as a potassium) in advanced gastric cancer patients. Eur J Cancer 34: 1715-1720, 1998. second-line chemotherapy for patients with recurrence. In 12 Ohtsu A, Baba H, Sakata Y, Mitachi Y, Horikoshi N, the future, the combination of this modality and Sugimachi K and Taguchi T: Phase II study of S-1, a novel oral radiotherapy should be tested, because these agents are fluorophyrimidine derivative, in patients with metastatic believed to enhance the radiation effect. colorectal carcinoma. S-1 Cooperative Colorectal Carcinoma Study Group. Br J Cancer 83: 141-145, 2000. References 13 Ichinose Y, Yoshimori K, Sakai H, NAkai Y, Sugiura T, Kawahara M and Niitani H: S-1 plus cisplatin combination 1 Pignon JP, Bourhis J, Domenge C and Designe L: Chemotherapy chemotherapy in patients with advanced non-small cell lung added to locoregional treatment for head and neck squamous-cell cancer: a multi-institutional phase II trial. Clin Cancer Res 10: carcinoma: three meta-analyses of updated individual data. 7860-7864, 2004. MACH-NC Collaborative Group. Meta-analysis of Chemotherapy 14 Sato N, Sato Y, Saeki T and Sano M: The cumulative dose of on Head and Neck Cancer. Lancet 355: 949-955, 2000. previous treatment does not relate to efficacy of S-1 in patients 2 Martin M, Hazan A, Vergnes L, Peytral C, Mazeron JJ, with taxane resistant breast cancer. San Antonio Breast Cancer Senechaut JP, Lelievre G and Peynegre R: Randomized study Symposium #1078, 2004. of 5 fluorouracil and cisplatin as neoadjuvant therapy in head 15 Iwase H, Shimada M, Tsuzuki T, Horiuchi Y, Kumada S, Haruta and neck cancer: a preliminary report. Int J Radiat Oncol Biol J, Yamaguchi T, Sugihara M, Ina K, Kusugami K and Goto S: Phys 19: 973-975, 1990. A phase II multicentric trial of S-1 combined with 24-h infusion 3 Rich TA, Shepard RC and Mosley ST: Four decades of of cisplatin in patients with advanced gastric cancer. Anticancer continuing innovation with fluorouracil: current and future Res 25: 1297-1301, 2005. approaches to fluorouracil chemoradiation therapy. J Clin 16 Sato Y, Kondo H, Honda K, Takahari D, Sumiyoshi T, Tsuji Y, Oncol 22: 2214-2232, 2004. Yoshizaki N and Niitsu Y: A phase I/II study of S-1 plus 4 Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, cisplatin in patients with advanced gastric cancer: 2-week S-1 Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M and administration regimen. Int J Clin Oncol 10: 40-44, 2005. Japan Lung Cancer Research Group on Postsurgical Adjuvant 17 Fujii M, Endo S, Tomita K, Nishijima W, Tsukuda M, Chemotherapy: A randomized trial of adjuvant chemotherapy Hasegawa Y, Ishitoya J, Yamane H, Fujii H, Honma A and with uracil-tegafur for adenocarcinoma of the lung. N Engl J Tomita T: A phase I/II study of S-1 plus cisplatin (CDDP) in Med 350: 1713-1721, 2004. patients with head and neck cancer (HNC). Proc Am Soc Clin 5 Noguchi S, Koyama H, Uchino J, Abe R, Miura S, Sugimachi Oncol 24: 513, 2005. (Abstr.5552). K, Akazawa K and Abe O: Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both in women with node- negative breast cancer: a pooled analysis of six randomized Received February 20, 2006 controlled trials. J Clin Oncol 23: 2172-2184, 2005. Accepted March 20, 2006

2268