Background: Cisplatin (CDDP) is among the most active single agents against squamous cell carcinoma of the head and neck (SCCHN), and it is still the reference drug in the induction chemotherapy setting, when used in combination with infusional 5-fluorouracil (5-FU). Raltitrexed has been shown to be devoid of clinical activity against SCCHN when used alone; however, both preclinical and early clinical data regarding the combination raltitrexed-CDDP hold promise. Thymidylate synthase is the target enzyme of both raltitrexed and 5-FU; however, the two drugs have distinct sites of action on the enzyme and the combination of the two agents may be synergistic. We have previously shown that the combination of raltitrexed, levofolinic acid (LFA) and 5-FU has clinical activity against SCCHN; in a subsequent phase I study, cisplatin was added, and the combination of CDDP plus raltitrexed on day 1, followed by LFA and 5-FU on day 2, was judged feasible and active, since a 67% response rate was shown across all dose levels, with a 100% response rate at the recommended dose for phase II. Methods: Patients with inoperable locally advanced or metastatic SCCHN, not pretreated with chemo- or radiotherapy were randomized to receive either CDDP 60 mg/m2 and raltitrexed 2.5 mg/m2 on day 1 and LFA 250 mg/m2 and 5-FU 900 mg/m2 on day 2 (arm A) or CDDP 65 mg/m2 and methotrexate 500 mg/m2 on day 1, and LFA 250 mg/m2 and 5-FU 800 mg/m2 on day 2 (arm B). Both treatments were repeated every 2 weeks. Evaluation for tumor response was performed after four cycles. According to Simon two-stage design, with a target complete response (CR) rate (p1) of 35%, at least 7 CR among the first 31 treated patients and 16 CR among the final sample size of 52 patients were required. Results: An interim analysis was performed when 36 patients were evaluable in each arm. In arm A, 10 CR (28%) and 19 partial responses (PR) (53%) were observed, for an overall response rate of 81%. In arm B, 3 CR (8%) and 12 PR (34%) were observed, for an overall response rate of 42%. The difference in both CR and overall response rate between the two arms was statistically significant (p = 0.03 and <0.001, respectively). Therefore, the accrual was stopped in arm B and continued only in arm A. Overall, 13 CR (21%) and 34 PR (56%) were observed among the 61 patients who were accrued in arm A, for an overall response rate of 77% (95% confidence interval 64–87%). Neutropenia was the main side effect in both arms (grade 3–4 in 45 and 23 patients in arm A and B, respectively). Extrahematologic toxicity was mild in both arms; however, 2 patients in arm B died due to toxicity (grade 4 mucositis in one case, grade 4 renal toxicity in the other). Conclusions: Although response data for our experimental treatment look encouraging, the hypothesis of a 35% activity, expressed as capability to induce a CR, cannot be accepted. The results obtained in this study are not substantially different from those of other trials of CDDP-5-FU-based regimens, and our combination is unlikely to represent a major breakthrough when used in this setting.

Keywords:
Cisplatin, Fluorouracil, Head and neck cancer, Levofolinic acid, Raltitrexed
1.
Merlano M, Corvò R, Margarino G, Benasso M, Rosso R, Sertoli MR, et al: Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial. Cancer 1991;67:915–921.
2.
Merlano M, Vitale V, Rosso R, Benasso M, Corvò R, Cavallari M, et al: Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 1992;327:1115–1121.
3.
Merlano M, Benasso M, Corvò R, Rosso R, Vitale V, Blengio F, Numico G, Margarino G, Bonelli L, Santi L: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 1996;88:583–589.
4.
Paccagnella A, Orlando A, Marchiori C, Zorat PL, Cavaniglia G, Sileni VC, Jirillo A, Tomio L, Fila G, Fede A, Eudrizzi L, Bari M, Sampognaro E, Belli M, Gava A, Pappagallo GL, Fiorentino MV: Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: A study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 1994;86:265–272.
5.
Toohill RJ, Anderson T, Byhardt RW, et al: Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. A preliminary report. Arch Otolaryngol Head Neck Surg 1987;113:758–761.
6.
Martin M, Hazan A, Vergnes L, Peytral C, Mazeron JJ, Senechaut JP, Lelievre G, Peynegre R: Randomized study of 5-fluorouracil and cisplatin as neoadjuvant therapy in head and neck cancer: A preliminary report. Int J Radiat Oncol Biol Phys 1990;19:973–975.
7.
Dimery IW, Hong WK: Overview of combined modality therapies for head and neck cancer. J Natl Cancer Inst 1993;85:95–111.
8.
Scanlon KJ, Newman EM, Lu Y, Priest DG: Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci USA 1986;83:8923–8926.
9.
Jacobs C, Lyman G, Velez-Garcia E, Shridhar KS, Knight W, Hochster H, Goodnough LT, Mortimer JE, Einhorn LH, Schacter L, et al: A phase III randomized study comparing cisplatin and 5-fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 1992;10:257–263.
10.
Clarke SJ, Zalcberg J, Olver I, Mitchell PLR, Rischin D, Dalley D, Green M, Davidson YE: Open label, multi-centre phase II study of raltitrexed (‘Tomudex’) in patients with inoperable squamous-cell carcinoma of head and neck. Ann Oncol 2000;11:239–241.
11.
Kelland LR, Kimbell R, Hardcastle A, Aherne GW, Jackman AL: Relationship between resistance to cisplatin and antifolates in sensitive and resistant cell lines. Eur J Cancer 1995;31:981–986.
12.
ten Bokkel Huinink D, Tesselaar MET, Baatenburg de Jong RJ, Verschuur HP, Keizer H: A phase I study of a fixed dose of cisplatin with increasing doses of raltitrexed (Tomudex) in the treatment of patients with locally advanced or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2001;12:357–363.
13.
Caponigro F, Avallone A, McLeod HL, Cartenì G, De Vita F, Casaretti R, Morsman J, Blackie R, Budillon A, De Lucia L, Gravina A, Catalano G, Comella P, Comella G: Phase I and pharmacokinetic study of Tomudex combined with 5-fluorouracil plus levofolinic acid in advanced head and neck cancer and colorectal cancer. Clin Cancer Res 1999;5:3948–3955.
14.
Caponigro F, Comella P, Rivellini F, Avallone A, Budillon A, Di Genaro E, Mozzillo N, Ionna F, De Rosa V, Manzione L, Comella G: Cisplatin, raltitrexed, levofolinic acid and 5-fluorouracil in locally advanced or metastatic squamous cell carcinoma of the head and neck: A phase I–II trial of the Southern Italy Cooperative Oncology Group (SICOG). Ann Oncol 2000;11:575–580.
15.
Caponigro F, Comella P, Marcolin P, Russo Spena F, Biglietto M, Cartenì G, De Lucia L, Avallone A, Gravina A, Comella G: A phase II trial of cisplatin, methotrexate, levofolinic acid, and 5-fluorouracil in the treatment of patients with locally advanced, metastatic squamous cell carcinoma of the head and neck. Cancer 1999;85:952–959.
16.
Simon R, Wittes RE, Ellenberg SS: Randomized phase II clinical trials. Cancer Treat Rep 1985;69:1375–1381.
17.
Clark JR, Busse PM, Norris CM, Andersen JW, Dreyfuss AI, Rossi RM, Poulin MD, Colevas AD, Tishler RB, Costello R, Lucarini JW, Lucarini D, Thornhill L, Lockey M, Peters E, Posner MR: Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: Long-term results. J Clin Oncol 1997;15:3100–3110.
18.
Colevas AD, Busse PM, Norris CM, Fried M, Tishler RB, Poulin M, Fabian RL, Fitzgerald TJ, Dreyfuss A, Peters ES, Adak S, Costello R, Barton JJ, Posner MR: Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: A phase I/II trial. J Clin Oncol 1998;16:1331–1339.
19.
Longo GS, Izzo J, Chang YM, Tong WP, Zielinski Z, Garlick R, Chan TC, Bertino JR: Pretreatment of colon carcinoma cells with Tomudex enhances 5-fluorouracil cytotoxicity. Clin Cancer Res 1998;4:469–473.
20.
Schwartz GK, Bertino J, Kemeny N, Saltz L, Kelsen DK, Haubisch A, Tong B, Piazza A, Endres S, Dimery I: Phase I trial of sequential raltitrexed (Tomudex) followed by 5-FU in patients with advanced colorectal cancer (abstract 977). Proc Am Soc Clin Oncol 2000;19:252a.
21.
Mayer S, Vanhoefer U, Hilger R, Heinrichs D, Muller C, Garcia Vargas J, Seeber S, Harstrick A: Extended phase I study of raltitrexed and infusional 5-FU in patients with metastatic colorectal cancer (abstract 1169). Proc Am Soc Clin Oncol 2000;19:299a.
22.
Farrugia DC, Aherne GW, Brunton L, Clarke SJ, Jackman AL: Leucovorin rescue from raltitrexed (Tomudex)-induced antiproliferative effects: In vitro cell line and in vivo mouse studies. Clin Cancer Res 2000;6:3646–3656.
23.
Caponigro F, Avallone A, Budillon A, Comella P, Comella G: Raltitrexed/5-fluorouracil-based combination chemotherapy regimens in anticancer therapy. Anticancer Drugs 2001;12:489–497.
24.
Caponigro F, Comella P, Daponte A, Gravina A, Cartenì G, Biglietto M, Casaretti R, Frasci G, Ionna F, Mozzillo N, Comella G: A phase I study of cisplatin, methotrexate, levofolinic acid and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck. Oncol Rep 1997;4:1207–1211.
25.
Schneider M, Demard F, Chauvel P: Induction chemotherapy with cisplatinum and continuous infusion 5-FU for the treatment of head and neck cancer. Six-year experience at the Nice Cancer Center; in Banzet P, Holland JF, Khayat D (eds): Neoadjuvant Chemotherapy: Third International Congress. Paris, Springer, 1991, pp 18–23.
26.
Schneider M, Etienne MC, Milano G, Thyss A, Otto J, Dassonville O, Mobayerr H, Sandes L, Guillot T, Demard F: Phase II trial of cisplatin, fluorouracil and pure folinic acid for locally advanced head and neck cancer: A pharmacokinetic and clinical survey. J Clin Oncol 1995;13:1656–1662.
27.
Pignon JP, Bourhis J, Domenge C, Designè L: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. Lanced 2000;355:949–955.
28.
Teicher BA, Ara G, Chen YN, Recht A, Coleman CN: Interaction of Tomudex with radiation in vitro and in vivo. Int J Oncol 1998;13:437–442.
© 2002 S. Karger AG, Basel
2002
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