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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 potentia-tion 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 rendered 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 unresectable 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 pheno-typic characteristics that make them more likely to be vulnerable to this approach. [ABSTRACT FROM AUTHOR]

The peripheral neuropathies induced by antineoplastic drugs are an important side effect of cancer treatment having a relevant impact on the field of research at the present time. Platinum compounds are the most widely used anti-cancer drugs and their neurotoxicity on the peripheral nervous system seems to be defined, using both in vitro and in vivo experimental models, by specific molecular pathways that involve programmed cell death. The goal of research is the understanding of the neurotoxic mechanisms of platinum compounds in order to develop neuroprotective agents that can ameliorate the quality of life of cancer patients. [ABSTRACT FROM AUTHOR]

Randomized clinical studies and meta-analyses of the literature have confirmed the improved survival of platinum-based chemotherapy doublets, that are considered standard therapy in patients with advanced non–small cell lung cancer (NSCLC) with a good performance status. The use of platinum compounds have also demonstrated a slight survival advantage over nonplatinum-based chemotherapy. Cisplatin remains the platinum agent of choice in the management of patients with NSCLC in both the advanced and adjuvant setting based on the results from recent meta-analyses. However, carboplatin may be offered to patients in advanced stages of the disease due to its more favorable toxicity profile. To date, four targeted agents (bevacizumab, cetuximab, erlotinib and gefitinib) have been studied in combination with platinum-based chemotherapy in the treatment of advanced NSCLC. Only bevacizumab has been shown to significantly prolong survival when added to carboplatin/paclitaxel as demonstrated in a large phase III study. However, issues of toxicity limit this treatment regimen to selected patients. The combination of bevacizumab with cisplatin and gemcitabine appears promising but is still awaiting the final results of the unpublished survival data. Preliminary studies indicate that molecular tumor markers may be able to identify tumors that are more likely to respond to chemotherapy. Excision repair cross-complementation group 1 (ERCC1) and Ribonucleotide Reductase M1 (RRM1) are two such genes critical to DNA synthesis and DNA damage repair pathways that have been studied. The results from the first prospective phase III randomized trial suggest that customizing chemotherapy based on ERCC1 expression in patients with advanced NSCLC is a feasible approach. In the future, selection of patients based on pharmacogenetics may help identify patients who will optimally benefit from specific therapies. [ABSTRACT FROM AUTHOR]