ANTICANCER RESEARCH 29: 5137-5142 (2009) Docetaxel, Ifosfamide and Cisplatin (DIP) in Squamous Cell Carcinoma of the Head and Neck POL M. SPECENIER1, JAN VAN DEN BRANDE1, DIRK SCHRIJVERS1,2, MANON T. HUIZING1, SEVILAY ALTINTAS1, JOKE DYCK1, DANIELLE VAN DEN WEYNGAERT3, CARL VAN LAER4 and JAN B. VERMORKEN1 Departments of 1Medical Oncology, 3Radiotherapy and 4Otolaryngology, Antwerp University Hospital, Edegem; 2Department of Medical Oncology, ZNA Middelheim, Antwerp, Belgium Abstract. Background: Docetaxel, ifosfamide and cisplatin response, 19 partial responses, 1 stable disease); the complete have all shown activity in squamous cell carcinoma of the head response rate increased to 42% after 4 × DIP. No dose or and neck (SCCHN). The optimal combination of the three drugs sequence effect was evident. The minimum follow-up of the is, however, unknown. Considering the favorable results of surviving patients was 51 months, with median relapse-free taxane-containing triplets as induction chemotherapy in locally survival of 13.8 months and median overall survival of 18.8 advanced (LA) SCCHN, DIP (docetaxel, ifosfamide, cisplatin) months. Only four patients relapsed at distant sites. Conclusion: was studied in this setting as part of a phase I dose- and DIP is highly active in previously untreated LA SCCHN, sequence-exploring study. Patients and Methods: D (60 or 75 however, toxicity of DIP in this population is substantial. mg/m2) was given by 60-min infusion on day 1, I (1000 mg/m2/day), with mesna until 12 hours after I, by 24-h infusion For over two decades, cisplatin has been the backbone of days 1-5, and P (50 or 75 mg/m2) by 24-h infusion on days 1 or chemotherapeutic regimens which are used for the treatment 5. The cycles were repeated every 21 days. Toxicities according of patients with squamous cell carcinoma of the head and to the National Cancer Institute Common Toxicity Criteria neck (SCCHN) (1, 2). This is true for the treatment of both version 2 (NCI-CTC2) were evaluated weekly and response was patients with recurrent and/or metastatic disease and patients evaluated every 2 cycles according to the World Health with locoregionally advanced (LA) disease. Ifosfamide and Organization (WHO) criteria. Thereafter, radiotherapy (RT, docetaxel used as single agents have also shown promising cumulative dose 70 Gy) or chemoradiation (CRT), both with activity in patients with head and neck cancer (3-13). conventional fractionation, were planned. Results: Twenty-two Docetaxel, ifosfamide and cisplatin have different patients (18 male, 4 female; age 41-66 years, performance mechanisms of action and different safety profiles (14-16). status 0-1, 2 T4N0, 3 T3N2, 11 T4N2, 3 T unknown N3, 1 T1N3 The optimal sequence and dose of these agents in and 2 T4N3) received a median of 4 DIP cycles (range 1-5). combination have never been determined, but were studied Grade 4 neutropenia occurred in 18 patients, grade 3 and 4 by us in a dose- and sequence-exploring phase I study (17). thrombocytopenia in 5 and 1 patients, respectively, and grade In that study a substantial number of patients with 3 anemia in 5 patients. Gastrointestinal and mucosal toxicities locoregionally advanced head and neck cancer were were generally mild/moderate. Vascular complications included. The efficacy and toxicity outcomes of these (probably not DIP-related) precluded local treatment in two patients is the subject of the present report. patients. Moreover, one patient died on day 13 of the first DIP (neutropenic sepsis and myocardial infarction). The remaining Patients and Methods patients received RT (n=2) or CRT (n=17; 16 of these with Study design. A subset of patients with LA-SCCHN who were gemcitabine). The response to 2 × DIP was 95% (1 complete included in a non-randomized single-center dose- and sequence- exploring phase I study which tested the combination of docetaxel, ifosfamide and cisplatin (DIP) in patients with solid tumors are herein analyzed. The phase I study was conducted between May Correspondence to: Pol Specenier, Antwerp University Hospital, 2000 and October 2004 (17). Department of Medical Oncology, Wilrijkstraat 10, 2650 Edegem, Belgium. Tel: +32 038214014, Fax: +32 038214102, e-mail: Eligibility criteria. The patients were ≥18 years of age, with a [email protected] performance status of ≤2 according to World Health Organization (WHO) criteria (18) and a life expectancy of at least 12 weeks. Key Words: Docetaxel, ifosfamide, cisplatin, head and neck cancer. Adequate bone marrow, renal and liver functions were required. 0250-7005/2009 $2.00+.40 5137 ANTICANCER RESEARCH 29: 5137-5142 (2009) Table I. Patient characteristics. Table II. T and N stage. Characteristic N N0 N1 N2 N3 All Patients 22 Tx 3 3 Median age, years (range) 58 (41-66) T1 1 1 Gender male/female 18/4 T2 WHO performance status T3 3 3 0 5 T4 2 11 2 15 1 17 Tumor site All 2 14 6 22 Oropharynx 10 Hypopharynx 6 Larynx 2 Paranasal sinus 1 Unknown 3 patients were to be treated with methylene blue 50 mg intravenously N: Number of patients. every 4 hours until 72 hours after the end of the ifosfamide infusion and methylene blue was to be administered prophylacticly during the subsequent cycles at a dose of 50 mg, 4 times a day, starting from 4 hours before the start until 72 hours after the end of the ifosfamide infusion (20). Patients with known central nervous system involvement, congestive heart failure, angina pectoris, uncontrolled hypertension and Efficacy and safety evaluation. The patients were evaluated for arrhythmia requiring medication, hematological malignancies, response according to the WHO criteria (18) and the toxicities were history of significant neurological or psychiatric disorders, an active evaluated according to the NCI-CTC2 (19). infection, systemic peripheral neuropathy >2 according to National Cancer Institute Common Toxicity Criteria version 2 (NCI-CTC2) Statistics. The data were summarized using number of patients and (19) and those with prior radiotherapy to the skeleton on >30% of percentages. Time to locoregional relapse, time to distant metastasis, the bone marrow were excluded. relapse-free survival and overall survival were calculated using the In accordance with the Declaration of Helsinki, International Kaplan-Meier method (Statistical Package for the Social Sciences Conference on Harmonisation (ICH) / WHO Good Clinical Practice (SPSS) version 15; SPSS Inc., Chicago, IL, USA). (GCP) standards, and applicable local laws, all patients provided signed informed consent. The Ethics Committee of the Antwerp University Hospital approved the protocol. Results Study objectives. The objective of this report was to summarize the Patient population. The patients with locoregionally clinical outcome in terms of efficacy and toxicity of the subset of advanced SCCHN represented the largest subset of patients the 22 patients with LA-SCCHN who participated in the earlier included in the phase I study (22 patients out of a total of mentioned phase I study which had as the primary objective to 85). Two of these 22 patients had received prior determine the maximum tolerated dose (MTD) of docetaxel and chemotherapy±radiotherapy for esophageal cancer and non cisplatin in combination with a fixed dose of ifosfamide. Hodgkin lymphoma, respectively. The patient characteristics Treatment. The 22 LA-SCCHN patients included in the phase I are summarized in Tables I and II. study received docetaxel at a dose of 60 mg/m2 or 75 mg/m2 over 60 minutes on day 1 followed by a bolus of mesna 500 mg/m2 and Treatment and toxicity. Details of the received dose and by ifosfamide 1,000 mg/m2/day along with mesna 1,000 mg/m2/day schedule are summarized in Table III. The great majority of as a 24-h infusion on days 1 to 5 and cisplatin 50 mg/m2 or patients received DIP with 75 mg/m2 docetaxel combined 2 75 mg/m over 24 hours on day 5 (schedule A) or 1 (schedule B). with 50 mg/m2 cisplatin (n=8), or 60 mg/m2 docetaxel with Mesna was continued until 12 hours after the end of ifosfamide. 75 mg/m2 cisplatin (n=12). The median number of DIP cycles Additional mesna was administered either intravenously or orally in cases of hematuria. All the patients received methylprednisolone was 4 (range 1-5). The subsequent locoregional treatment 32 mg orally, 12 and 3 hours before the docetaxel administration after DIP was concurrent chemoradiation (n=17; 16 in and twice daily thereafter for two days (total number of 5 combination with gemcitabine at a dose of 100 mg/m2 weekly administrations). An additional dose of methylprednisolone 125 mg and 1 in combination with cisplatin at a dose of 100 mg/m2 was given intravenously on day 1 in order to prevent acute vomiting. day 1, 22 and 43 during radiotherapy) or radiotherapy alone Ondansetron 8 mg was administered intravenously on days 1 to 5. (n=2). Three patients did not receive any form of local Twelve patients received oral ciprofloxacin prophylactically on days treatment due to early toxic death (n=1) or early 5 to 15 of each cycle. The cycles were repeated every 21 days. Granulocyte colony simulating factors were not allowed. complications precluding adequate locoregional therapy (n=2) Erythropoietin or darbapoietin was administered at the physician’s (see below). The toxicities that were observed with the DIP discretion. In cases of ifosfamide-induced encephalopathy, the regimens are shown in Table IV. Gastrointestinal toxicity was 5138 Specenier et al: Docetaxel, Ifosfamide and Cisplatin Induction Chemotherapy in Head and Neck Cancer Table III. Dose and timing of docetaxel and cisplatin (N). Table IV. Hematological and nonhematological toxicity in 22 patients*. Cisplatin Type of toxicity grade 1 grade 2 grade 3 grade 4 grade 5 Dose Timing Hematological Leucopenia 1 9 12 Dose 50 mg /m2 75 mg/m2 Day 1 Day 5 Neutropenia 1 3 18 Thrombocytopenia 7 2 5 1 Docetaxel Anemia 5 125 60 mg/m2 2 12 4 10 Febrile neutropenia 7 1 75 mg/m2 8 2 6 Nonhematological Alopecia 2 19 Total 10 12 6 16 Nausea 4 2 Vomiting 5 1 N: Number of patients.