Platinum Compounds and Radiation

Abstract

Combining concurrent radiation with platinum compounds has been the subject of both preclinical and clinical cancer research for over two decades. The property of platinum to enhance the effect of radiation on a variety Of tumors has been successfully translated to the treatment of head and neck, non-small cell lung (NSCLC), and cervical cancer. Several molecular pathways accounting for the mechanisms of radiation potentiation and sensitization have been described. Platinums create DNA adducts causing cross links which eventually lead to double strand DNA breaks. Such damage to the DNA triggers the cellular mismatch repair (MMR) apparatus, leading to cell cycle arrest and apoptosis. This pathway can be harnessed to enhance radiotherapy by targeting the subset of hypoxic tumor cells, resistant to the traditional effects of radiation. Noticeably, in tumors with either a genetic defect or a gene tendered nonfunctional due to promoter hyper-methylation in the MMR pathway, resistance to both chemotherapies and ionizing radiation Occurs. Concurrent administration of both modalities though, has shown to overcome this form of resistance. The mechanism underlying the combined effects includes platinum interference with repair mechanisms of sub lethal radiation damage to DNA and radiation potentiation of the effects of platinum by enhancing uptake and binding to DNA. Experience from the clinic suggests that many variables govern the success of the combination. Specifically, the kind of platinum compound chosen and its dosing and scheduling during radiotherapy varies among tumor sites. The more manageable toxicity profile of carboplatin makes it a particularly attractive candidate for combined modality treatments. In a phase III CALBG and ECOG study, 283 patients with unrescetable stage III NSCLC received radiosensitization with carboplatin. Complete Response (CR) rate was 18% in the chemo-radiation arm vs. 10% in the radiation-only arm, without significant difference detected in the 4-year survival rates (13% vs. 10%). Conversely, in cervical cancer the combination of carboplatin and radiotherapy resulted in a survival improvement compared to other chemoradiation regimes. A better insight of the genomics and biology of cancer will soon provide clinicians with the necessary rationale to devise multimodality protocols that target individual tumor pathways of resistance. Combinations of platinum agents with ionizing radiation could then be selectively offered to carriers of cancers with genetic and phenotypic characteristics that make them more likely to be vulnerable to this approach.