Cisplatin radiosensitization

The oral platinum compound 11 is capable of radiosensitizing a platinum-sensitive tumor line, as is cisplatin 1 (241). 

Fig. 1. Radiosensitization of hypoxic V79 cells by 5 pM cisplatin compared to 1 mM misonidazole. The enhancement ratio for the cisplatin (5 iiM) in this experiment was 1.15. Adapted from Stratford et al. (153).

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. 

The lack of data reinforces the need to conduct randomized trials in the area of carcinoma of the bladder, and given the radiosensitizing action of the taxanes, they are worthy of consideration in these protocols. The RTOG phase I/II trial looking at concurrent cisplatin, paclitaxel, and hyperfractionated radiation with selective bladder preservation and adjuvant chemotherapy is ongoing and it may serve as the basis for future randomized trials in the area (98). 

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. 

Irinotecan is an active chemotherapeutic agent that has been used in esophageal cancer and is also a potent radiosensitizer. In vitro studies have shown activity in esophageal cancer cell lines. A Phase I study has demonstrated its safety and tolerability with cisplatin. Phase I/II studies are currently underway determining the maximum tolerated weekly dose of irinotecan combined with concurrent radiation for locally advanced esophageal cancer (MSKCC 99081). 

Because SCLC has the propensity to disseminate early on in the disease, surgery is not usually indicated. SCLC is radiosensitive, and radiotherapy is used in combination with chemotherapy in patients with limited disease. Prophylactic cranial irradiation is used in select patients to reduce the risk of CNS metastases. Combination chemotherapy will prolong the survival of most patients with SCLC. Patients with limited disease are more likely to have a complete response to chemotherapy and longer survival than those who have extensive disease at the time of diagnosis. The most widely used chemotherapy regimens for SCLC include cisplatin or carboplatin plus etoposide. Despite very high response rates to chemotherapy, most patients with SCLC eventually have disease progression and die from this disease. 

Radiation-induced thymine release from DNA is also inhibited by cisplatin [78]. The possibility exists that platination of DNA (presumably via the purine bases at biologically relevant concentrations) may affect the inherent radiosensitivity of the bases, which for aerated solutions, follows the order Thy > Cyt > Ade > Gua. An analysis of this type of damage should take into consideration profiles of base release and decomposition with and without platination, as well as the effects the conformational and electronic changes in platinated DNA will have on the radiation interaction. In this respect the studies on radiosensitivity of Ag and Hg DNA complexes [85], as well as the effects on the radiation chemistry of simple bases of Cu(II) [86] and Fe(III) [87], are relevant. 

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