Fluorouracil Cisplatin

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. 

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. 

The first trial to address this question was a GOG trial (13) comparing concurrent hydroxyurea plus radiation therapy vs concurrent cisplatin and fluorouracil plus radiation therapy in patients with locally advanced disease who had negative para-aortic nodes at lymphadenectomy. An early analysis of this trial, which was completed in 1990, failed to yield definitive results. Publication of the study findings was delayed until more complete follow-up could be obtained. Ultimately, the study demonstrated a modest but significant advantage for the cisplatin-fluorouracil combination. 

North American prospective trials of radiation sensitizers for cervical cancer have focused on the use of cisplatin, fluorouracil, and hydroxyurea. However, a number of other drugs also hold promise as effective radiation sensitizers for cervical cancer, including mitomycin C, epirubicin, paclitaxel, and carboplatin. 

In 910 patients toxicity was life-threatening in 0.55% (41). A combination of cisplatin, fluorouracil, and eto-poside given for advanced non-small cell cancer of the lung caused only the expected amount of hematological toxicity, but was associated with a higher than expected incidence of cardiac, pulmonary, and cerebrovascular toxicity, including two myocardial infarctions, two cases of congestive heart failure, one pulmonary embolus, and one cerebrovascular accident in a study of 35 patients (42). 

The 5-fluorouracil (5-FU) and NONOate conjugates (Fig. 1.7) were prepared and their cytotoxicity was tested [90]. The median effect doses of the conjugates for DU145 and HeLa cancer cell lines were 2-4-fold lower than that of 5-FU. In another study by Wink et al, the cytotoxicity of cisplatin was enhanced about 60-fold after NONOate pretreatment for 30 min [91]. The enhancement of cytotoxicity of 5-FU/NONOate conjugates and cisplatin-NONOate combination has shown that there is a synergistic effect between anticancer drugs and NO. Another study by Jia et al. demonstrated that the cytotoxicity of Taxol was enhanced by S-nitrosocaptopril (Fig. 1.7) [92]. This effect is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded. 

THC is effective in several chemotherapy regimens, including methotrexate and the doxorubicin/cyclophosphamide/fluorouracil combination. Cisplatin treatment, however, is more resistant. Side effects of THC are generally well tolerated, and use may be limited in the elderly or with higher doses. Nabilone is a synthetic cannabinoid that is more effective than prochlorperazine in chemotherapy-induced emesis, including cisplatin. Its side effects are similar to THC. Levonantradol is another synthetic cannabinoid with antiemetic effects, and may be administered orally or intramuscularly. The side effect of dysphoria may limit its use. 

RT = radiation, EF = extended fields, C = cisplatin, 5FU = 5 fluorouracil, TAH = extrafascial hysterectomy, HU = hydroxyurea. 

Mahjoubi M, Sadek H, Francois E, et al. Epidermoid anal canal carcinoma (EACC) activity of cisplatin and continuous 5 -fluorouracil in metastatic and/or local recurrent disease. Proc Annu Meet Am Soc Clin Oncol 1990 9 114. 

Martenson JA, Lipitz S, Wagner H, et al. Phase II trial of radiation therapy, 5-fluorouracil and cisplatin in patients with anal cancer. Int J Radiat Oncol Biol Phys 1995 32(suppl 1) 158. 

The earliest combination chemotherapy and radiation trials in nonsmall-cell lung cancer included cisplatin and 5-fluorouracil and concurrent radiation therapy and found survival results comparable to those for sequential chemotherapy and radiation or to daily cisplatin and radiation therapy without surgery (119,121). Phase II studies of stage Ilia and Illb nonsmall-cell lung cancer patients treated with the combination of cisplatin with etoposide and 5 -fluorouracil and either single daily radiation fractionation or twice daily radiation fractionation prior to surgery produced similar clinical results (119,121). Complete surgical resection was accomplished in 70% of the patients, the median survival was 22 mo and the 2-yr survival rate was 45%. 

Weiden PL, Piantodosi S. Preoperative chemotherapy cisplatin and fluorouracil and radiation therapy in stage III non-small cell lung cancer A phase II study of the Lung Cancer Study Group. JNatl Cancer Oust 1991 83 266-272. 

Kaufman DS, Winter KA, Shipley WU, et al. The initial results in muscle-invading bladder cancer of RTOG 95-06 phase Ell trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil fohowed by selective bladder preservation or cystectomy depending on the initial response. The Oncologist 2000 5 471 —476. 

Wright et al. from the Massachusetts General Hospital reported interesting results from their intensive trial of preoperative paclitaxel, cisplatin, and 5-fluorouracil with hyperfractionated radiation (total tumor dose of 58.5 Gy and 45 Gy to the mediastinum)... 

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... 

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, Vannetzel JM, et al. Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 1994 12 385-395. 

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. 

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. 

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. 

C = Cisplatin, B = bleomycin, V = vindesine, F = 5-fluorouracil, S = surgery, See = squamous cell carcinoma, A = adenocarcinoma. 

Blanke CD, Chiappori A, Epstein B, et al. A Phase II Trial of Neoadjuvant Paclitaxel (T) and Cisplatin (P) with Radiotherapy, Followed by Surgery (S) and Postoperativve T with 5-Fluorouracil (F) and Leucovorin (L) in Patients (pts) with Locally Advanced Esophageal Cancer (LAEC). ProcAnnu Meet Am Soc Clin Oncol 1997 16 A1006. 

Studies of Cisplatin-Containing Chemotherapy in Combination with Radiation Therapy Studies of Fluorouracil in Combination with Radiation Therapy... 

F = fluorouracil, HU = hydroxyurea, LAG = lymphangiogram, PAN = paraaortic node, LND = lymph node dissection, NED = no evidence of disease, P = cisplatin. 

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