Cisplatin head cancers

Higher response rates are seen when 5-FU is used in combination with other agents, such as cyclophosphamide and methotrexate (breast cancer), cisplatin (head and neck cancer), and with oxaliplatin or irinotecan in colon cancer. The combination of 5-FU and oxaliplatin or irinotecan has become the standard first-line treatment for patients with metastatic colorectal cancer. The use of 5-FU in combination regimens has improved survival in the adjuvant treatment for breast cancer, and with oxaliplatin and leucovorin, for colorectal cancer. 5-FU also... 

The antitumor activity of titanocene dichloride 21 was first recognized in 1979 (150), and since then the activity of several other metallocenes (V, Nb, Mo, Fe, Ge, and Sn) has been reported (151). Most interest has centered on titanocene dichloride and on vanadocene dichloride 22, which are active against a diverse range of human carcinomas, including gastrointestinal and breast carcinomas, but not against head and neck cancers. There appears to be a lack of crossresistance between titanocene dichloride and cisplatin. 

This is an unusual drug in that it contains a metal atom, platinum (Pt) in this case. Cisplatin reacts with DNA to cross-link bases, disrupting normal DNA structure and function. This agent has found broad use in cancer chemotherapy, including efficacy in tumors of the testis, ovary, bladder, head and neck, thyroid, cervix, and endometrium. It is also active against neuroblastoma and osteogenic sarcoma. 

Platinum is a relatively rare earth metal usually found with related metals osmium and iridium. While it has a number of industrial applications, its common consumer application is in catalytic converters. This application has actually increased platinum concentrations in roadside dust. The ability of platinum and its derivatives to kill cells or inhibit cell division was discovered in 1965. Platinum-based drugs, such as cisplatin, are used to treat ovarian and testicular cancer, and cancers of the head and neck, as well as others. Unfortunately, the toxic side effects of these agents often limit their usefulness. 

Gonzalez-Larriba J, Garcia Carbonero I, Sastre Valera J, Perez Segura P, Diaz-Rubino E. Neoadjuvant therapy with cisplatin/fluorouracil vs cisplatin/UFT in locally advanced squamous cell head and neck cancer. Oncology (Huntingtj 1997 11(9 Suppl 10) 90-97. 

Early clinical studies clearly demonstrated that cisplatin could be administered safely and concurrently with radiation therapy (73-75). Early clinical trials that demonstrated the promise of the combination of cisplatin and radiation therapy included the treatment of brain tumors (76,77), head and neck tumors (78), malignant melanoma (79), and bladder cancer (80). Early clinical trial integrating carboplatin administration with radiation therapy was carried out in patients with locally advanced nonsmall cell lung cancer (NSCLC) (81). A hypothesis put forth by Coughlin and colleagues (81) was that the best clinical outcomes would be achieved with the combination of cisplatin and radiation therapy in tumors that were responsive to cisplatin. 

The initial combination modality clinical studies with cisplatin and fractionated radiation therapy was carried out in head and neck cancer with weekly cisplatin (120-160 mg/m2) and conventional single daily fraction radiation (95). In a follow-up intergroup study, patients were randomized to radiation therapy alone or to radiation therapy plus 20 mg/ m2/wk cisplatin (96). Both studies showed no major increase in normal tissue toxicity in the radiation field and showed an increase in response rate. There was no increase in complete response rate or in survival. Bachaud et al.(97) carried out a randomized study comparing radiation therapy alone with concurrent cisplatin (50 mg/m2) and radiation therapy in postoperative patients. This trial produced a significant reduction in local recurrence and improved disease-free survival with 59% of the patients receiving the full planned dose of cisplatin. 

Wheeler et al. (100,101) took another tack and treated patients with unresectable head and neck cancer with cisplatin (40 mg/m2) daily for 5 d per course for three cycles along... 

Marcial VA, Paj ak TF, Mohuiddin M, et al. ConComitant cisplatin chemotherapy and radiotherapy in advanced mucosal squamous cell carcinoma of the head and neck. Cancer 1990 66 1861-1868. 

Wheeler R, Salter M, Stephens S, et al. Simultaneous high dose cisplatin and radiation therapy for unresectable squamous cancer of the head and neck a phase FI I study. MonogrNatl Cancer Inst 1988 6 339-341. 

Taylor SG, Murthy AK, Caldarelli DD, et al. Combined simultaneous cisplatin/5-FU infusion chemotherapy and split course radiation in head and neck cancer. J Clin Oncol 1989 7 846-856. 

Robbins KT, Kumar P, Regine WF, et al. Efficacy of targeted supradose cisplatin and concomitant radiation therapy for advanced head and neck cancer the Memphis experience. Int J Radiat Oncol Biol... 

In phase II studies with topotecan alone, there is cytotoxic activity in lung cancer with intermittent dose schedules (33), as well as in lung cancer patients with topoisomerase II refractory disease (34). In advanced head and neck cancer topotecan is well-tolerated and has single-agent activity similar to that of cisplatin, 5-fluorouracil, and methotrexate... 

A preliminary report on a randomized trial on 83 stage III or IV locally advanced squamous cell head and neck cancer (SCHNC) patients demonstrated improved 2-yr disease-free survival (65% vs 41%, p = 0.01) and increased rate of local control (85% vs 59%, p < 0.05) in the concomitant chemoradiation group (cisplatin 50 mg/m2 weekly) in comparison to radiation therapy alone (25). It should be noted that the DFS was improved overall in the concomitant arm despite 18% patients receiving only two-thirds of their scheduled dose of cisplatin as a result of nausea and vomiting. Mature results from this study have not been published to date. 

Adelstein DJ, Adams GL, Li Y. A phase III comparison of standard radiation therapy (RT) versus RT plus concurrent cisplatin (DDP) versus split-course RT plus concurrent DDP and 5-fluorouracil (5FU) in patients with unresectable squamous cell head and neck cancer (SCHNC), ProcAnnu Meet Am Soc Clin Oncol 2000 19 A 1624. 

Taylor SG, Murthy AK, Griem KL, et al. Concomitant cisplatin/5-FU infusion and radiotherapy in advanced head and neck cancer 8-year analysis of results. HeadNeck 1997 19 684—691. 

Posner MR, Glisson B, FrenetteG, etal. Multicenter phase I-II trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy for patients with locally advanced squamous cell cancer of the head and neck. J Clin Oncol 2001 19 1096-1104. 

Kish JA, Weaver A, Jacobs J, et al. Cisplatin and 5-fluorouracil infusion in patients with recurrent and disseminated epidermoid cancer of the head and neck. Cancer 1984 53 1819-1824. 

Schrijvers D, Johnson J, Jiminez U, et al. Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alfa-2b in patients with recurrent or metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group. J Clin Oncol 1998 16 1054-1059. 

Murphy B, Li Y, Celia D, et al. Phase III study comparing cisplatin (C) and 5-Fluorouracil (F) versus cisplatin and paclitaxel (T) in metastatic/recurrent head and neck cancer (MHNC). ProcAnnu Meet Am Soc Clin Oncol 2001 20 A894. 

Rishchin D, Peters L, Hicks R, et al. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol 2001 19 535-542. 

Khuri FR, Nemunaitis J, Ganly I, et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 2000 6 879-885. 

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