ANTICANCER RESEARCH 29: 5137-5142 (2009)

Docetaxel, Ifosfamide and (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: , 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 -containing triplets as induction 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 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 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 ). 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.

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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 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 , 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 , 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. Anorexia 9 4 1 Fatigue 11 7 Mucositis 2 Diarrhea 4 mild and not in excess of grade 2 except in one patient (anorexia grade 4). No mucositis was observed during DIP *NCI-CTC version 2. chemotherapy except in two patients (grade 1). The early complications that precluded further locoregional treatment in two patients included vascular Figure 2. The median relapse-free survival of all the patients problems i.e. multiple cerebral infarctions in one patient, was 13.8 months and the median overall survival was 18.8 compromising his general condition and mental status, and months. Eight patients relapsed locally, four at distant sites. lower limb ischemia in the second patient. Hematological toxicity was substantial, with grade 4 neutropenia occurring Discussion in 18 patients (82%), grade 3 thrombocytopenia in 5 patients (23%), grade 4 thrombocytopenia in 1 patient (5%) and The phase I study, from which the present subset was taken, grade 3 anemia in 5 patients (23%). Febrile neutropenia concluded that when use was made of prophylactic occurred in 8 patients (36%), 4 of whom had received antibiotics, the MTD was reached at 75 mg/m2 of docetaxel prophylactic ciprofloxacin. One patient died during the DIP in combination with 5 days of ifosfamide at 1,000 treatment (5%); this patient died on day 13 of cycle 1 due to mg/m2/day and 75 mg/m2 of cisplatin (17). All the patients neutropenic sepsis and myocardial infarction. Out of the 19 in the subset described in this report received doses of DIP patients who continued with locoregional therapy after below this MTD. induction with DIP one died after 18 Gy of radiotherapy and The response rate was high, with 95% of the evaluable 2 × weekly gemcitabine (100 mg/m2) due to septic shock. patients responding after two cycles of DIP. Hematological toxicity was substantial, with grade 4 neutropenia occurring Response and outcome. The number of DIP cycles was left in 91% of the patients. In contrast, gastrointestinal toxicity to the physician’s discretion and was based on the observed was mild and not in excess of grade 2 except in one patient response and toxicity. All the patients received at least 2 (anorexia grade 4). No mucositis was observed during DIP cycles, except the patient that died during the first DIP cycle. chemotherapy except in two patients (grade 1). Twenty-one patients were evaluable for response after 2 Prophylactic use of antibiotics seems advisable with this cycles of DIP. At that time 95% of the evaluable patients regimen and the incidence of febrile neutropenia (36%) responded (5% complete and 90% partial responses). Twelve exceeded the commonly recommended 20% threshold for patients were evaluable for response after 4 cycles of DIP; at prophylactic use of granulocyte colony stimulating factors that time there were 42% complete and 50% partial (21-23). Table V summarizes the literature on ifosfamide- responses. One patient with stable disease after four cycles based chemotherapy regimens in patients with locoregionally received a fifth cycle of DIP, before receiving definitive advanced SCCHN. Response rates were high in most of the irradiation. Elective radical neck dissection after completion studies, although hematological toxicity was a major of the chemoradiation was performed in 6 patients with initial drawback in the majority of the studies. N2 or N3 disease. Five out of the six resection specimens Sanchez Parra et al. (26) added ifosfamide to the classical were free of disease. The minimum follow-up of the surviving cisplatin and 5-. Nineteen patients with stage III patients was 51 months (median 53 months). The time to or stage IV nonmetastatic SCCHN received 100 mg/m2 of local failure and time to distant metastasis are shown in cisplatin on day 1, 5-fluorouracil 1,000 mg/m2/day as a 24-h Figure 1. The relapse-free and overall survival are shown in infusion on day 1 through 5 and ifosfamide 1,000 mg/m2/day

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Table V. Ifosfamide-based combination chemotherapy regimens in locoregionally advanced SCCHN.

Author (ref) N Ifosfamide Other agent(s) Interval Neutropenia FNa Toxic RR CR DCR OS dose (days) gr 3/gr 4 deaths (months)

Mantovani et al. (24) 28 1.5 or 2.2 Cisplatin 20 28 13%/13%b 11% 50% 0 75% g/m2/d d1-5 mg/m2/d d1-5

Pai et al. (25) 207 1.5 g/m2/d Cisplatin 15 28 0% 0% 67% 16% d1-5 mg/m2/d d1-5

Pai et al. (26) 312 2.2 g/m2/d Cisplatin 15 28 0% 0% 80% 24% d1-5 mg/m2/d d1-5

Sanchez et al. (26) 19 0.8-1 g/m2/d 5-FU 1,000 Cisplatin 21 42%/21%c 16% 50% 17% 83% 10 d2-4 mg/m2/d d1-5 100 mg/m2 d1

Recchia et al. (27) 24 1.2 g/m2/d Docetaxel Cisplatin 20 28 20%/34% 20% 0% 83% 25% 96% 22 d1-4 40-70 mg/m2 d1 mg/m2/d d1-4

Shin et al. (28) 54 1 g/m2/d 21-28 9% 2% 81% 31% 87% 82%§ d1-3 175 mg/m2 d1 AUC 6 d1

Hancock et al. (29) 18 1 g/m2/d Paclitaxel Cisplatin 21 94% 44% 94% d1-3 175 mg/m2 d1 60 mg/m2 d1

This series 22 1 g/m2/ d Docetaxel 60 or Cisplatin 50 or 21 14%/82% 36% 5% 95% 23%§§ 100% 18.8 d1-5 75 mg/m2 d1 75 mg/m2 d 1 or 5

N: Number of patients, FN: febrile neutropenia, RR: overall response rate, CR: complete response rate, DCR: disease control rate, OS: overall survival, ref: reference; a: no prophylactic myeloid growth factors were used, b: hematologic toxicty only occurred in high dose arm, c: also 16% grade 5; §: 2-year survival rate, §§: 5% after 2 cycles, 42% after 4 cycles, AUC: area under the concentration-time curve, gr: grade, 5-FU: 5-fluorouracil.

Figure 1. Time to local failure and time to distant metastasis. Figure 2. Relapse-free and overall survival.

5140 Specenier et al: Docetaxel, Ifosfamide and Cisplatin Induction Chemotherapy in Head and Neck Cancer as a 1-hour infusion on day 2, 3 and 4. Mesna 200 mg/m2 was Now that novel targeted agents are rapidly becoming given as a bolus prior to and 4 and 8 hours after each available, DIP will probably never be compared to TPF, ifosfamide administration. The cycles were repeated every 3 which has replaced PF as the standard induction regimen in weeks for a maximum of three cycles. The overall response those cases where induction chemotherapy is considered rate was 50% with 16.6% complete responses. The study was appropriate. Indeed, priority will most likely be given to the closed early because of the severe hematological toxicity. integration of these targeted therapies into the current Particularly high response rates were reported when a treatment strategies. combination of ifosfamide, a taxane and a platinum compound In conclusion, the combination of docetaxel, ifofamide was used in patients with locoregionally advanced squamous and cisplatin is very active in locoregionally advanced cell carcinoma (27-29). Recchia et al. (27) performed a dose squamous cell head and neck cancer, but the toxicity (mainly finding study of docetaxel in combination with ifosfamide hematological) is substantial. 1,200 mg/m2/d and cisplatin 20 mg/m2/d, both administered on days 1-4. Docetaxel was administered on day 1 at doses References escalating from 40 mg/m2 up to the dose limiting toxicity 1 Specenier PM and Vermorken JB: Current concepts for the which occurred at 70 mg/m2. The cycles were repeated every management of head and neck cancer: chemotherapy. Oral Oncol four weeks. Twenty-four patients received a median of four 45: 409-415, 2009. cycles (range 2-6). Febrile neutropenia occurred in 20% of the 2 Specenier PM and Vermorken JB: Recurrent head and neck patients. The overall response rate after induction cancer: current treatment and future prospects. Expert Rev chemotherapy was 83% with a complete response rate of 25%. Anticancer Ther 8: 375-391, 2008. Shin et al. (28) treated 54 patients with the TIC regimen 3 Verweij J, Alexieva-Figusch J, de Boer MF, Reichgelt B and which consisted of paclitaxel 175 mg/m2 by 3-h infusion on day Stoter G: Ifosfamide in advanced head and neck cancer. A phase II study of the Rotterdam Cooperative Head and Neck Cancer 1, ifosfamide 1000 mg/m2 as a 2-h infusion on days 1-3 with 2 2 Study Group. Eur J Cancer Clin Oncol 24: 795-796, 1988. i.v. mesna (200 mg/m before and 400 mg/m after ifosfamide) 4 Cervellino JC, Araujo CE, Pirisi C, Francia A and Cerruti R: and carboplatin using the Calvert formula for an area under the Ifosfamide and mesna for the treatment of advanced squamous plasma concentration-versus-time curve of 6 mg/ml min on day cell head and neck cancer. A GETLAC study. Oncology 48: 89- 1, repeated every 3 weeks. As in the present study and in the 92, 1991. study by Recchia et al., prophylactic hematopioetic growth 5 Buesa JM, Fernandez R, Esteban E, Estrada E, Baron FJ, Palacio factors and antibiotics were not given. Five patients (9%) I et al: Phase II trial of ifosfamide in recurrent and metastatic head and neck cancer. Ann Oncol 2: 151-152, 1991. developed neutropenic fever. The overall response rate after four 6 Martin M, Diaz-Rubio E, Gonzalez Larriba JL, Casado A, Sastre cycles was 81%, with 31% complete responses. J, Lopez-Vega et al: Ifosfamide in advanced epidermoid head and Hancock et al. (29) reported on a selected subset of 18 neck cancer. Cancer Chemother Pharmacol 31: 340-342, 1993. patients with base of tongue cancer treated with up to 3 7 Huber MH, Lippman SM, Benner SE, Shirinian M, Dimery IW, cycles of paclitaxel 175 mg/m2 and cisplatin 60 mg/m2, both Dunnington JS and Hong WK: A phase II study of ifosfamide in administered on day 1 followed by ifosfamide 1,000 mg/m2 recurrent squamous cell carcinoma of the head and neck. Am J on days 1-3. The overall and complete reponse rates were Clin Oncol 19: 379-382, 1996. 8 Sandler A, Saxman S, Bandealy M, Heilman D, Monaco F, 95% and 44%, respectively. McClean J and Arquette M: Ifosfamide in the treatment of Since the completion of the present study several large advanced or recurrent squamous cell carcinoma of the head and randomized studies have been published (30-34), indicating neck: a phase II Hoosier Oncology Group trial. Am J Clin Oncol that a taxane, particularly docetaxel (31-34), added to cisplatin 21: 195-197, 1998. and 5-fluorouracil (TPF) yields superior response rates and an 9 Dreyfuss AI, Clark JR, Norris CM, Rossi RM, Lucarini JW, Busse improved survival with less toxicity (32) and a better quality PM et al: Docetaxel: an active drug for squamous cell carcinoma of life (34) than the classical cisplatin-5-fluorouracil (PF) of the head and neck. J Clin Oncol 14: 1672-1678, 1996. 10 Catimel G, Verweij J, Mattijssen V, Hanauske A, Piccart M, regimen, when used as induction chemotherapy in patients with Wanders J et al: Docetaxel (Taxotere): an active drug for the locoregionally advanced head and neck cancer. Recently treatment of patients with advanced squamous cell carcinoma of reported preliminary data on the sequential approach (induction the head and neck. EORTC Early Clinical Trials Group. Ann chemotherapy followed by chemoradiation) were promising Oncol 5: 533-553, 1994. and the results of the randomized trials, comparing induction 11 Inuyama Y, Kataura A, Togawa K, Saijo S, Satake B, Takeoda S chemotherapy followed by concurrent chemoradiation with the et al: Late phase II clinical study of RP56976 (docetaxel) in current standard concurrent chemoradiation alone, are eagerly patients with advanced/recurrent head and neck cancer. Gan To Kagaku Ryoho 26: 107-116, 1999. awaited (35, 36). However, pending the publication of the final 12 Couteau C, Chouaki N, Leyvraz S, Oulid-Aissa D, Lebecq A, results of these trials, induction chemotherapy should still not Domenge C et al: A phase II study of docetaxel in patients with be considered standard treatment, which still remains cisplatin- metastatic squamous cell carcinoma of the head and neck. Br J based chemoradiation. Cancer 81: 457-462, 1999.

5141 ANTICANCER RESEARCH 29: 5137-5142 (2009)

13 Hitt R, Amador ML, Quintela-Fandino M, Jimeno A, del Val O, 27 Recchia F, Saggio G, Cesta A, Amiconi G, di Blasio A, Candeloro Hernando S and Cortes-Funes H: Weekly docetaxel in patients G et al: Dose-finding study of docetaxel added to ifosfamide and with recurrent and/or metastatic squamous cell carcinoma of the cisplatin followed by concomitant and radiotherapy head and neck. 106: 106-111, 2006. in the treatment of locally advanced squamous cell carcinoma of 14 O’Dwyer PJ, Johnson SW and Hamilton TC: Cisplatin and its the head and neck. Anticancer Res 26: 2317-2324, 2006. analogues. In: Cancer Principles and Practice of Oncology, 5th 28 Shin DM, Glisson BS, Khuri FR, Lippman SM, Ginsberg L, Diaz Edition. DeVita VT, Hellman S and Rosenberg SA (eds.). E Jr et al: Phase II study of induction chemotherapy with Philadelphia, Lippincott-Raven Publishers, pp. 418-432, 1997. paclitaxel, ifosfamide, and carboplatin (TIC) for patients with 15 Teicher BA: Antitumor alkylating agents. Cisplatin and its locally advanced squamous cell carcinoma of the head and neck. analogues. In: Cancer Principles and Practice of Oncology, 5th Cancer 95: 322-330, 2002. Edition. DeVita VT, Hellman S and Rosenberg SA (eds.). 29 Hancock SB, Krempl GA, Canfield V, Bogardus C, Kojouri K, Philadelphia, Lippincott-Raven Publishers, pp. 405-418, 1997. Kaneaster SK and Medina JE: Treatment of base of tongue cancer 16 Rowinski EK and Donehouwer RC: Antimicrotubule agents. In: with paclitaxel, ifosfamide, and cisplatinum induction Cancer Principles and Practice of Oncology, 5th Edition. DeVita chemotherapy followed by chemoradiotherapy. Laryngoscope VT, Hellman S and Rosenberg SA (eds). Philadelphia, 118: 1357-1361, 2008. Lippincott-Raven Publishers, pp. 418-432, 1997. 30 Hitt R, Lopez-Pousa A, Martinez-Trufero J, Escrig V, Carles J, 17 Specenier P, Rasschaert M, Van den Brande J, Dyck J, Schrijvers Rizo A et al: Phase III study comparing cisplatin plus fluorouracil D, Huizing MT and Vermorken JB: Docetaxel, ifosfamide and to paclitaxel, cisplatin, and fluorouracil induction chemotherapy cisplatin (DIP) in solid tumor treatment: A phase I study. followed by chemoradiotherapy in locally advanced head and Submitted. neck cancer. J Clin Oncol 23: 8636-8645, 2005. 18 Miller AB, Hoogstraten B, Staquet M and Winkler A: Reporting 31 Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist results of cancer treatment. Cancer 47: 207-214, 1981. E, Gorbounova V et al: Cisplatin and fluorouracil alone or with 19 Arbuck SG, Ivy SP, Setser A et al: The Revised Common docetaxel in head and neck cancer. N Engl J Med 357: 1705- Toxicity Criteria: Version 2.0. CTEP Website. http:// 1715, 2007. ctep.info.nih.gov, 1999. 32 Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, 20 Pelgrims J, De Vos F, Van den Brande J, Schrijvers D, Prové A Degardin M et al: Cisplatin, fluorouracil, and docetaxel in and Vermorken JB: Methylene blue in the treatment and unresectable head and neck cancer. N Engl J Med 357: 1695- prevention of ifosfamide-induced encephalopathy: report of 12 1704, 2007. cases and a review of the literature. Br J Cancer 82: 291-294, 33 Pointreau Y, Garaud P, Chapet S, Sire C, Tuchais C, Tortochaux 2000. J et al: Randomized trial of induction chemotherapy with 21 Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, cisplatin and 5-fluorouracil with or without docetaxel for larynx Balducci L et al: 2006 Update of recommendations for the use preservation. J Natl Cancer Inst 101: 498-506, 2009. of white blood cell growth factors: an evidence-based clinical 34 Bernier J, Coens C, Remenar E, Van Herpen C, Germa Lluch J, practice guideline. J Clin Oncol 24: 3187-3205, 2006. Stewart S et al: Impact on quality of life (QoL) of the addition of 22 Greil R, Psenak O and Roila F; ESMO Guidelines Working docetaxel (T) to neoadjuvant cisplatin plus 5-fluorouracil Group: Hematopoietic growth factors: ESMO recommendations treatment in patients with locally advanced unresectable squamous for the applications. Ann Oncol 19(Suppl 2): ii116-118, 2008. cell carcinoma of the head and neck (SCCHN): EORTC study 23 Aapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, 24971. J Clin Oncol 24(18S): 5522 (Abstract), 2006. Ellis M et al: EORTC guidelines for the use of granulocyte- 35 Hitt R, Grau J, Lopez-Pousa JA, Berrocal A, Garcia Giron C, colony stimulating factor to reduce the incidence of Irigoyen A et al: Final results of a randomized phase III trial chemotherapy-induced febrile neutropenia in adult patients with comparing induction chemotherapy with cisplatin/5-FU or and solid tumours. Eur J Cancer 42: 2433-2453, docetaxel/cisplatin/5-FU follow by chemoradiotherapy (CRT) 2006. versus CRT alone as first-line treatment of unresectable locally 24 Mantovani G, Ghiani M, Lai P, Maccio A, Dessi D, Succu G et advanced head and neck cancer (LAHNC). J Clin Oncol 27(15s): al: Clinical evaluation of two dosages and schedules of 6009 (Abstract), 2009. ifosfamide in combination with cisplatin in neoadjuvant 36 Paccagnella A, Buffoli A, Koussis H, Gava A, Franceschi T, chemotherapy of patients with advanced (stage III-IV) head and Gardani G et al: Concomitant chemoradiotherapy (CT/RT) vs. neck squamous cell carcinoma: a phase II randomized study. neoadjuvant chemotherapy with docetaxel/cispaltin/5-fluorouracil Oncol Rep 5: 1499-1505, 1998. (TPF) followed by CT/RT in locally advanced head and neck 25 Pai VR, Mazumdar AT, Deshmukh CD, Bakshi AV, Parikh DM, cancer. Final results of a phase II randomized study. J Clin Oncol Parikh PM et al: Neoadjuvant chemotherapy with ifosfamide and 26(20S): 6000 (Abstract), 2008. cisplatin combination in advanced head and neck cancer: a retrospective analysis of 519 patients: a single institution experience. Med Oncol 20: 1-5, 2003. 26 Sanchez Parra M, Churruca C, Paredes A, Lacasta A, Lopez de Argumedo G, Alvarez I et al: Phase II of cisplatin, 5- Received May 24, 2009 fluorouracil, and ifosfamide as treatment for advanced locoregional Revised October 21, 2009 head and neck carcinoma. Am J Clin Oncol 22: 6-7, 1999. Accepted October 23, 2009

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