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2009 Sherif El Sharouni

Treatment of stage III non-small cell lung cancer and limited-disease small-cell lung cancer

This thesis concerns the treatment of stage III non-small cell lung cancer (NSCLC) and limited disease small-cell lung cancer (SCLC). We described a systematic review on the clinical results of radiotherapy, combined or not with chemotherapy, for inoperable NSCLC stage III with the aim to define the best sequence of radiotherapy and chemotherapy. We concluded that concurrent chemoradiotherapy demonstrated increased efficacy over sequential chemo-radiotherapy and should be the treatment of choice. The 5-year survival has increased from about 7% for radiotherapy alone to 10% for sequential and to about 15% for concurrent chemoradiotherapy. However, the concurrent chemo-radiotherapy schedules were associated with higher toxicity as compared to sequential therapy with the same drug doses. We investigated the influence of the waiting time for radiotherapy, i.e. the interval between end of induction chemotherapy and start radiotherapy, on the rate of tumour growth for patients with NSCLC stage III. We demonstrated that in the waiting time rapid tumour progression occurs as result of accelerated tumour cell proliferation. The mean waiting time was 80.3 days; in this period the median tumour volume increased with a factor of about 6. As a consequence, the gain obtained with induction chemotherapy with regards to volume reduction was lost in the waiting time for radiotherapy. Stage III NSCLC is correlated with tumour volumes in excess of 100 cm3. The tumour control probability analysis revealed that for tumours of that size local cure is almost impossible with the doses usually applied in radiotherapy. Due to the accelerated cell proliferation observed, we recommend that radiotherapy should start as soon as possible, preferably within two to three weeks after the last chemotherapy cycle. We investigated whether gemcitabine (dFdC) may cause radiosensitization. The radiosensitizing effect of dFdC might be less in normal healthy tissue and more restricted to undifferentiated tumour cells, making it a tumour-selective radiosensitizer. We tested whether dFdC acted as radiosensitizer in undifferentiated and well-differentiated rat tumours and on rat foot skin. We used undifferentiated L44 lung tumours in BN rats and MLL prostate tumours in Copenhagen rats, and well-differentiated L42 lung tumours in WAG/Rij rats. Radiosensitization was observed in the undifferentiated tumours but not in the well-differentiated tumour or the skin. Our data support further trials to evaluate the usefulness of dFdC as radiosensitizer in undifferentiated tumours. We described the results of a phase II national multicentre study with weekly docetaxel/cisplatin and concurrent thoracic radiotherapy followed, whenever possible, by surgery in patients with stage III non-small cell lung cancer. The 3-years overall survival was 38% and this is an encouraging result. We analysed the treatment results of our patients’ population with limited-disease small-cell lung cancer. They were treated with chemotherapy only and chemotherapy combined with radiotherapy. The treatment schemes with curative intention were sequential and concurrent chemoradiotherapy, both combined with prophylactic cranial irradiation. Our results indicate that the concurrently applied chemoradiotherapy resulted in longer median survival time and higher overall survival than sequential chemoradiotherapy, chemotherapy with palliative radiotherapy or chemotherapy only.