Recent progress in optimizing radiotherapy in chemo-radiotherapy for stage III non-small cell lung cancer

Abstract

It is logical to tailor radiation dose schedule according to the therapeutic goals, i.e., curative versus pal-liative to achieve the best possible outcome for a given clinical condition. Not all patients with stage III served optimally by administering the same dose of radiation or chemo-radiotherapy regimen. The aim of this study is to update the recent progress in the clinical research in escalation of radiation dose/dose intensity and radiotherapeutic/predictive factors of radiation response which may be useful in guiding high dose radiation therapy in chemo-radiation (CT+RT) for beter outcome.The current literatures (1985–2001) on clinical research in escalation of radiation dose/dose intensity were reviewed for radiotherapeutic factors, which are important in tumor response and therapy outcome. Also reviewed were translational research in genetic/radiobiological/metabolic markers for the identification of useful biomarkers in predicting therapy response to radiation therapy or CT+RT. Reports on combined therapy for stage III NSCLC were also reviewed for the toxicity, tumor response and survival outcome.Factors important for predicting therapy outcome in NSCLC are grouped as follows: 1. Radiotherapeutic factors. The major factors of radiation therapy that play the decisive role for successful outcome include the accurately defined target volume, the dose intensity and total dose of radiation which is high enough to provide local tumor control for the majority of patients, and proper treatment planning, preferably three-dimensional (3-D) conformal radiation therapy planning with which the maximum and optimum dose of radiation can be determined within the limit of normal tissue tolerance. 2. Tumor related factors (anatomic factors). The extent of tumor (tumor stage) is one of the most important prognostic factors affecting the therapy outcome. Tumor size (T stage), anatomical structures involved (T4 versus T3 lesion), and the presence or absence of regional lymph node metastasis have a significant impact on both prognosis and response to appropriate therapy. 3. Host-related factors (clinical factors) that are important in therapy response include performance status, weight loss more than 10% of body weight in the previous 6 months, and associated co-morbidities, i.e., pulmonary and cardiac diseases. 4. Radiobiological/metabolic/genetic factors. Biologic markers resulting from genetic lesions in lung cancer are grouped as follows: a) Radiobiological factors—tumor cell proliferation kinetics (Tpot), hypoxia, intrinsic cellular radiosensitivity, gamma factor, DNA content; b) metabolic/enzymatic factors: increased glucose utilization measured with positron emission tomography-fluorodeoxyglucose (PET-FDG) may be a useful marker for therapy response to radiation therapy and chemotherapy, and also for the definition of biological tumor volume as opposed to anatomic tumor volume by computed tomographic scan, and c) genetic factors: allelic imbalance, methylation, gene overexpression, and polymorphisms. 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. Therafore, the radiotherapeutic factors, i.e., total radiation dose, fractionation schedule and dose intensity, the 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 a setting of chemo-radiotherapy, and the use of this MTD for improved local tumor control and survival. Radiobiological, molecular, and metabolic markers may offer a potential for monitoring tumor response and optimizing radiation therapy accordingly.