Treatment of the Unresectable Non Small Cell Lung Carcinoma

Overview

In recent years, treatment of the locally advanced unresectable Non Small Cell Lung Cancer (NSCLC) has evolved from the radiotherapy alone to sequential therapy settings with induction chemotherapy followed by radiotherapy. During recent years, concomitant chemoradiotherapy has become the standard treatment for these patients. The addition of chemotherapy during the course of radiotherapy provides better locoregional control of the disease by killing the radioresistant cells, inhibition of the reparation processes in the sublethally damaged cells and accumulation of the cells in the G₂/M phase, when the cells are sensitive to radiation. It also reduces the spread of the micrometastases. Administration of cisplatin-based regimens appears to be the most effective. Acute pneumonias can be effectively suppressed by amifostine administration. Locally advanced inoperable NSCLC can be cured by chemoradiotherapy in more than 10% of patients. Fractionation radiotherapy does not yield prolonged survival. Currently the other clinical studies investigating the effects of hyperfractionation, 3D conformal radiotherapy and IMRT (intense modified radiotherapy) are being conducted. Also the role of various radiosensitizing agents is currently under clinical evaluation. The results of a study, comparing various doublet combinations of taxanes and gemcitabine with cisplatin or carboplatin demonstrate, that as for the efficacy, the standard doublet regimens reached a certain plateau and that they prolong the survival in comparison with the standard regimens used before 1990. The only statistically significant difference in the efficacy among the individual treatment arms is the significantly longer time to the progressive disease in the arm treated by gemcitabine and cisplatin. Studies with triplet regimens show that the addition of the third cytotoxic agent might increase the overall response rate with the increase of toxicity and only a very small survival benefit. The replacement of the platinum derivate by some of the new cytotoxic agents does not appear to yield lower efficacy and also shows a more favorable toxicity profile; it is, however, significantly more expensive. Overall differences among the cytostatic combinations based on cisplatin in comparison with combinations based on carboplatin are not very distinct. Nevertheless, the combination of cisplatin with third generation cytotoxic agents is recommendable as it is more effective for patients with advanced NSCLC without renal impairment and with adequate bone marrow reserve. A high percentage of patients with NSCLC are older that 70 and this percentage will increase further. Earlier, chemotherapy was not used for these patients with the explanation that elderly people are usually polymorbid and the function of their organs which metabolize the cytostatics is reduced. However, a survival benefit in elderly patients treated by cytotoxic monotherapy was proven in comparison with the best supportive care. Other studies, however, found significant differences neither in toxicity nor in survival in comparison with younger patients, when using the same treatment regimens. Platinum doublets, based namely on carboplatin, are useful for patients older than 70, who are in good clinical condition. In the second-line therapy of NSCLC pemetrexed demonstrates identical efficacy as docetaxel, which is considered as a standard monotherapy in the second-line treatment of NSCLC. Moreover, pemetrexed is associated with less toxicity. These data show that in future, pemetrexed may become the standard treatment for second-line therapy of NSCLC. In patients with stage IIIB/IV of NSCLC, the addition of biological treatment to standard doublet cytostatic combination does not bring any survival benefit. In future, more detailed attention should be paid to selection of the patients for this treatment modality. When comparing survival time by meta-analysis, significantly longer survival time of the patients treated with gemcitabine combination was found in comparison with other treatment. Similarly, the progression-free survival is significantly longer in the patients treated with gemcitabine containing regimen. This data has proven good clinical efficacy of gemcitabine in the first-line therapy of advanced NSCLC. 

Key words:
advanced non-small cell lung cancer, NSCLC, chemotherapy, chemo-radiotherapy, phase III trials, meta-analysis.