Cisplatin/fluorouracil/radiation

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%. 

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. 

B = bleomycin, C = chlorambucil, CT = chemotherapy, DFS = disease-free survival, Ep = epirubicin, F = fluorouracil, I = ifosfamide, M = mitomycin C, Mtx = methotrexate, O = vincristine, OS = overall survival, P = cisplatin, RT = radiation therapy, V = vinblastine. 

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. 

So far, the available evidence probably supports the use of either the GOG weekly cisplatin regimen or the RTOG schedule of cisplatin and fluorouracil. As yet, no data support the use of weekly cisplatin at doses below the 40 mg/m2/wk given in the GOG studies. The only randomized trial to investigate a lower dose of weekly cisplatin was an early study reported by Wong et al. (32) They were unable to demonstrate a benefit when 25 mg/m2/wk of cisplatin plus radiation therapy was compared to radiation therapy alone. It must be noted, though, that the study was compromised by the small number of patients (fewer than 30 in each arm). 

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

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. 

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)... 

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. 

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

Other potential radiation sensitizers for cervical cancer are being explored in phase I and II trials. Paclitaxel has been combined with cisplatin in several small phase I studies. Pignata et al. (29) found that 50 mg/m2 per week of paclitaxel could be combined with weekly cisplatin (30 mg/m2) and radiation therapy with acceptable toxicity, although 10 of 18 patients in their study had grade 3-4 hematologic toxicity. Chen etal. (30) also were able to give weekly paclitaxel at a dose of 50 mg/m2 (in this case combined with 50 mg/m2 of cisplatin every three weeks) with tolerable toxicity and minimal delay in planned radiation therapy. In both studies, the dose-limiting side effect appeared to be diarrhea. It should be noted that the total dose of cisplatin delivered in these trials was lower than that used in the most successful prospective trials of cisplatin or cisplatin and fluorouracil (Table 3). 

Trials of cisplatin-based chemoradiation have not yet demonstrated any dramatic increase in the incidence of major late complications with the addition of concurrent cisplatin. However, most of these trials did not have sufficiently mature follow-up at the time of publication to permit full evaluation of the comparative risks. Thomas et al. (35) reported a significantly higher rate of serious late bowel complications in patients who received mitomycin with or without fluorouracil than in patients who received fluorouracil alone (p = 0.004). However, Roberts etal. (27) have not yet reported an increased rate of late complications with chemotherapy in their Venezuelan study of radiation alone vs radiation plus mitomycin C and fluorouracil. Long-term follow-up of the randomized trials will be needed to improve our understanding of the influence of concurrent chemotherapy on late complications. 

FU = fluorouracil, CDDP = cisplatin, Mito = mitomycin-C, RT = radiation therapy. 

Berek JS, Heaps JM, Fu YS, et al. Concurrent cisplatin and 5-fluorouracil chemotherapy and radiation therapy for advanced-stage squamous carcinoma of the vulva. Gynecol Oncol 1991 42 197-201. 

Cunningham MJ, Goyer RP, Gibbons SK, et al. Primary radiation, cisplatin, and 5-fluorouracil for advanced squamous carcinoma of the vulva. Gynecol Oncol 1997 66 258-261. 

Squalamine has been tested in mammary, ovary, and lung cancer xenograft mouse models [20,23-26]. Results sho ved that squalamine alone had a modest effect on tumor growth delay and in some cases it resulted in decreased number of lung metastases. However, in most studies, squalamine treatment was more efficacious when combined with previously established anticancer agents such as cyclophosphamide, cisplatin, carboplatin, paclitaxel, 5-fluorouracil, or genestein, or with radiation therapy. 

External beam radiation used as sole therapy or in combination with 5-fluorouracil (5 FU) can be used to relieve dysphagia in over two-thirds of patients with SCC. Symptoms recur, however, due to recurrent cancer or fibrotic strictures. The most effective chemotherapeutic regimen in advanced esophageal cancer is epirubicin, cisplatin, and continuous infusion of 5 FU. Two-thirds of cases respond with improvement of dysphagia. ... 

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