Radiation and third-generation chemotherapy.

All of the third-generation chemotherapeutic agents reviewed in this article are independently active against NSCLC, although the agents differ significantly in their cellular and molecular mechanisms of cytotoxicity. All have also been shown to potentiate radiation effects, and thus are promising in exerting further cytotoxicity when used in combination chemoradiation therapy for locally advanced NSCLC. Although the toxicity to normal tissue varies among these agents when used alone, phase I/II clinical results consistently demonstrated higher risk and severity of esophagitis and pneumonitis when these agents were administered concurrently with thoracic radiation. These results were consistent with the radiosensitization properties of all these agents. Nonetheless, most chemoradiation combinations have been made feasible through careful phase I studies that establish safe doses of these agents given concurrently with radiation. Indeed, phase I outcomes consistently have demonstrated the need for dose reduction compared with doses applied in the stage IV, metastatic disease setting (see Tables 1 and 2). There have been many different dose schedules in phase I/II studies for stage III NSCLC, and most have yielded improved response rates with these agents. For all these agents discussed, multiagent chemoradiation increased toxicity when compared with single agent chemoradiation, particularly in the risk of neutropenia, and the tumor response rates were no better than single-agent chemoradiation. Most studies have not reached an adequate interval for survival endpoint to assess the impact on survival using multiagent chemoradiation. A few earlier studies using paclitaxel chemoradiation, in fact, showed that the significant improvement in tumor response rate resulted in only a small gain in survival outcome. Despite much preclinical research conducted with these agents, the optimal sequence and dose of drug and the optimal schedule for combining the two modalities remain unknown. Optimal sequencing of the chemoradiation regimens may improve distant disease control and primary tumor control, as was seen in studies that administered both full-dose induction chemotherapy and concurrent chemoradiation at reduced drug dose and in studies that administered consolidative, full-dose chemotherapy after chemoradiation. Strategically altering the treatment schedule may also enhance the radiosensitizing effects while keeping toxicity low, such as was seen in the pulsed low-dose paclitaxel chemoradiation reported by Chen et al . This pulsed low-dose schedule resulted in superior tumor response (100%) and durable primary tumor control while keeping the toxicity low. Other methods to minimize normal tissue injury and to deliver higher radiation doses, such as conformal three-dimensional radiotherapy that excludes nontarget tissues from the radiation field, are under investigation. Marks and colleagues were able to deliver radiation to 80 Gy using accelerated hyperfractionation radiation after induction chemotherapy. Intensity-modulated radiotherapy is expected to revolutionize the targeting of tumor and exclusion of normal tissues from the high-dose radiation volume in the future. Integrating biologic response modifiers, radioprotectors, and molecular targeting strategies also are being investigated. It remains unclear which agent among the third-generation drugs performs better for combination chemoradiation. The CALGB 9431 study reported by Vokes et al provided some preliminary information, in that it was a randomized phase II study of a three-arm comparison of cisplatin-containing, two-drug combination chemoradiation with one of the third-generation agents. Although direct statistical comparison between the treatment arms was not valid for a phase II setting, such an analysis did indeed reveal similar overall response rates for these three arms. Chemoradiation using third-generation chemotherapeutic agents has improved local tumor response rates, with enhanced radiation toxicity such as esophagitis and pneumonitis. The challenge of targeting distant disease control for locally advanced NSCLC continues.