Predictive factors in radiotherapy for non-small cell lung cancer: Present status

Purpose: To evaluate the predictive factors for radiation response in non-small cell lung cancer (NSCLC) and the role of such factors in guiding high dose radiation therapy. Methods: The first International Workshop on Prognostic and Predictive Factors in Lung Cancer was organized by the Hellenic Cooperative Oncology Group and held in Athens, Greece under the auspices of the International Association for the Study of Lung Cancer. Presentations at this meeting provided the outline of this report, which has also been supplemented with available data from the current literature. Results: The predictive factors for both the natural history and the therapy outcome of NSCLC are grouped as follows: (1) tumor related factors (anatomic factors); the extent of tumor (tumor stage) is one of most important prognostic factors affecting the therapy outcome. Tumor size (T stage), anatomical structures involved (T4 vs. T3 lesion), and the presence of regional lymph node metastasis have a significant impact on both prognosis and response to appropriate therapy; (2) host-related factors (clinical factors) that are important in therapy response include performance status, weight loss of more than 10% of body weight in the previous 6 months, and associated co-morbidities, i.e. pulmonary and cardiac diseases; (3) technical factors of radiation therapy which play a decisive role in successful outcome. The target volume should be defined accurately using modern imaging studies. The radiation dose fractionation schedule, in terms of the dose intensity and total dose, should be high enough to provide local tumor control in the majority of patients. Three-dimensional (3-D) conformal planning is an essential tool in dose escalation studies to determine the maximum tolerated dose of radiation; (4) biological/radiobiological/metabolic factors. Biologic markers resulting from genetic lesions in lung cancer are grouped as follows: (a) oncogene amplification and overexpression (aberrant gene expression) and mutated tumor suppressor genes - ras gene, myc gene, HER-2/neu and survivin gene, p53 and mutated β-tubulin gene; (b) tumor biologic/radiobiologic factors - tumor cell proliferation kinetics, hypoxia, intrinsic cellular radiosensitivity, gamma factor, and DNA content; (c) enzymes and hormones: neuron-specific enolase, serum lactate dehydrogenase, and enhanced glucose metabolic rate supported by increased glucose transporter protein. The surviving fraction of tumor cells at 2.0 Gy of radiation (SF2) as a measure of intrinsic tumor cell radiosensitivity, potential doubling time (TPot) as a measure of the rate of tumor cell proliferation and gamma factor representing the slope of the survival curve at 50% survival rate are being investigated as potential predictors for therapy response. Enhanced glucose utilization, a hallmark of malignant transformation, is being studied as a potential monitor for therapy response by using PET-FDG. Conclusion: Current data indicate that there is a dose-response relationship between radiation dose and local tumor control, and also between local tumor control and survival in stage III NSCLC. Therapeutic factors, i.e. total radiation dose, fractionation schedule and dose intensity, and use of 3-D conformal radiation to secure the optimum therapeutic ratio are important for improved local tumor control and survival. Future research should be directed towards radiation dose escalation using 3-D conformal therapy to determine the maximum tolerated dose (MTD) of radiation in chemo-radiotherapy, and the use of this MTD for improved local tumor control and survival. Radiobiological, molecular, and metabolic markers may have potential for monitoring tumor response and optimizing radiation therapy