Cisplatin/radiation therapy

Plasma digoxin levels may decrease when the drug is administered with bleomycin. When bleomycin is used witii cisplatin, there is an increased risk of bleomycin toxicity Pulmonary toxicity may occur when bleomycin is administered with other antineoplastic drugs. Plicamycin, mitomycin, mitoxantrone, and dactino-mycin have an additive bone marrow depressant effect when administered with other antineoplastic drugs. In addition, mitomycin, mitoxantrone, and dactinomycin decrease antibody response to live virus vaccines. Dactinomycin potentiates or reactivates skin or gastrointestinal reactions of radiation therapy There is an increased risk of bleeding when plicamycin is administered witii aspirin, warfarin, heparin, and the NSAIDs. 

Optimal management of locally advanced NSCLC (stages IIB, IIIA, and IIIB) is controversial. Cisplatin-based doublet combinations are recommended for adjuvant and neoadjuvant (preoperative) chemotherapy, with or without concurrent radiation therapy. 

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 greatest research effort on radiation sensitizers has focused on organic compounds however, platinum complexes conform to the hypotheses for radiation sensitizers since they are electron affinic and react preferentially with the hydrated electron in aqueous solution. Early studies of cisplatin in combination with radiation therapy suggested a synergistic effect in antitumor activity (50,51). Much of the initial data were obtained using cells in tissue culture (52), these data indicated that the potential of cisplatin to inhibit repair of radiation-induced damage to DNA could be an important contributor to the enhanced tumor cell killing seen in vivo by the combination of these two modes of treatment. 

Cisplatin was first characterized as a radiation sensitizer using hypoxic Bacillus megaterium spores (53). Radiation sensitization by cisplatin was confirmed in vegetative Escherichia coli with a maximum sensitizer enhancement ratio of 1.77 in anoxic bacteria at a cisplatin concentration of 50 uM (54). Zimbrick et al. (55) extended these studies to other platinum complexes. The earliest studies in mammalian cells used hypoxic V-79 Chinese hamster cells and showed a small radiation sensitization with 8 iM of cisplatin (56). Nias and Szumiel (57) first reported that pretreatment of Chinese hamster ovary (CHO) cells with a platinum complex could sensitize well-oxygenated cells to radiation. Wodinsky etal. (58) showed that cisplatin potentiated the effect of whole-body radiation therapy in mice inoculated intraperitoneally with P388 leukemia compared with either modality alone. Therapeutic potentiation was found in MTG-B subcutaneous tumors and intracerebral RBT when the animals were treated with cisplatin and radiation (59). 

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. 

The Southwest Oncology Group (SWOG) conducted a phase II trial with continuous thoracic radiation to a total dose of 61 Gy and simultaneous daily cisplatin (5 mg/m2) and found acceptable toxicity (130). Another trial utilized a split-course of thoracic radiation therapy to a total dose of 50 Gy and simultaneous daily continuous infusion cisplatin (5 mg/m2) and found a 35 % 2-yr survival rate with relatively mild toxicity (131). Weekly doses of carboplatin were administered with continuous thoracic irradiation to a total dose of 60 Gy in a phase II trial that resulted in a 45% response rate (132). 

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%. 

Reimer RR, Gahbauer R, Bukowski RM, et al. Simultaneous treatment with cisplatin and radiation therapy for advanced solid tumors a pilot study. Cancer Treat Rep 1981 65 219-222. 

Herr HW, Yagoda A, Batata M, Sogani PC, Whitmore WF. Planned preoperative cisplatin and radiation therapy for locally advanced bladder Cancer. Cancer 1983 52 2205-2208. 

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. 

Wheeler RH, Spencer S. Cisplatin plus radiation therapy. J Infusional Chemo 1995 5 61-66. 

Jeremie B, Shibamoto Y, Stanisavljevic B, Milojevic L, Milicic B, Nikolie N. Radiation therapy alone or with concurrent low-dose either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck a prospective randomized trial. Radiotherap Oncol 1997 43 29-37. 

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... 

Sharma VM, Wilson WR. Radiosensitization of advanced squamous cell carcinoma of the head and neck with cisplatin during concomitant radiation therapy. Eur Arch Otorhinolaryngol 1999 256 462 165. 

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. 

GOG-9804 Phase I/II Study of Extended Field Radiation Therapy With Concurrent Paclitaxel and Cisplatin Chemotherapy in Patients With Previously Untreated Carcinoma of the Cervix Metastatic to the Para-aortic Lymph Nodes. Study Protocol, http //www.cancer.gov/search/clinical trials... 

S af ar AM, Altamiro PS, Recht A, et al. Phase I trial of gemcitabine, cisplatin and external beam radiation therapy for pancreatic cancer. Proc Am Soc Clin Oncol 1999 18 227a. 

Landry JC, Harris W Yang GY, et al. Neoadjuvant treatment with GEM, cisplatin, 5-FU and accelerated hyperfractionated radiation therapy in advanced GI malignancy. Radiology 2000 217 147. 

Early interest concerning the role of cisplatin as a radiosensitizer led to several randomized clinical trials. A National Cancer Institute (NCI) sponsored intergroup trial of 371 unresectable patients comparing conventional radiation therapy to the use of weekly low dose cisplatin (20 mg/m2) as an adjunct to the same regimen of conventional radiotherapy found no statistical difference in complete response (34% for the concurrent modality vs 30% in the radiation therapy alone arm) or overall survival (24). The final results of this study were never published. 

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. 

Taylor and colleagues have published an 8-yr analysis of Rush Medical College s experience with stage in or IV patients that have received concomitant cisplatin (60 mg/m2, d 1), continuous infusion 5-FU (800 mg/m2, d 1-5), and single fraction radiation therapy (2 Gy) on d 1-5 (57). The cycle was repeated every other week for atotal of seven cycles. The sample size was small with 78 patients. Six weeks after initial therapy, 63% had no clinical evidence of disease, 37% had a partial response (PR). Overall, 31% of patients had recurred or progressed 24% died from nontumor-related causes. The 5-yr PFS was 60% in this small cohort of patients with an overall survival reported to be 43%. 

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