Stereotactic body radiotherapy in non-small cell lung cancer

Abstract

Patients with stage I non small cell lung cancer (NSCLC) are potentially curable. Eradication of the primary tumour is a prerequisite for cure with surgery as standard treatment. A large part of NSCLC patients, in parallel to their cancer, also suffer from other smoke related diseases like chronic obstructive pulmonary disease (COPD) and cardio vascular diseases (CVD). In about 15 % of the patients with stage I NSCLC these coexisting diseases confer inoperability. With conventionally fractionated radiotherapy (CFRT) local tumour control is obtained in less than 50% of stage I NSCLC patients. This is related to limitations in permissive dose mainly due to risk of unacceptable toxicity in surrounding normal lung parenchyma. With stereotactic body radiotherapy (SBRT) doses high enough to sterilize the tumour, without excessive toxicity in normal tissue, can be delivered. The aim of this doctoral thesis and the underlying papers has mainly been to collect clinical evidence for a role of SBRT in the treatment of NSCLC.

In the thesis, outcome and toxicity were analyzed in a retrospective and a prospective study on stage I NSCLC in altogether 195 patients treated with SBRT. COPD or CVD was the main reason for inoperability among the patients. The total radiation doses given had a median peripheral biologic effective dose (BED10) of 113 Gy and a central dose of 211Gy. Median follow up was 3 years. Local tumour control rate was 88% in the retrospective (ret.) and 92% in the prospective (pro.) study. Only 5% (pro.) and 7% (ret.) of the patients experienced regional failure. During follow up, distant metastases were recorded in 16% (pro.) and 25% (ret.) of the patients. Overall survival at 3-years was 52% (ret.) and 60% (pro.) but lung cancer specific survival was 66% (ret.) and 88% (pro.), a difference that likely is explained by death due to co-morbidity.

To further develop SBRT a better understanding of the risk of toxicity is needed. This is especially important in patients with COPD who already have an impaired lung capacity. On the whole, toxicity after SBRT was mild and in 59% (ret.) and 21% (pro.) of the patients no side-effects were recorded. Objective lung function measured as forced expiratory volume in 1 second (FEV1%) did not decrease more than what is expected in a non-irradiated patient cohort, during the follow-up period. Clinically important toxicity was seen in 10% (ret.) and 30% (pro.) where dyspnoea and thoracic pain were most common. No significant difference was seen between COPD and CVD patients. Notable is that COPD patients with the poorest lung function tolerated SBRT to the same extent as other patients.

In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of clinical radiation pneumonitis (RP2+) has been shown which is contradictory to the situation with conventionally fractionated radiotherapy (CFRT). Dose-volume-histogram (DVH) and toxicity data from the prospective study was used for normal tissue complication probability (NTCP) modelling. DVH data was corrected to 2 Gy/fraction using the universal survival curve (USC) model as well as the LQ model with á/â of 3 Gy and 20 Gy. In SBRT of lung tumours NTCP modelling with USC used for fractionation correction, resulted in a more serial architecture of functional subunits in the lung than what is seen after CFRT.

In conclusion, SBRT for early stage lung cancer provides local control rates similar to what is obtained with surgery. SBRT is also well tolerated with only limited side-effects even in patients with markedly decreased pulmonary function. The calculated risk of pneumonitis, using the models in this study, depended relatively more on the volume with the highest doses than what is seen after CFRT. Overall survival is favourable compared to other nonsurgical treatments and lung cancer specific survival is excellent and with these results it is reasonable to conclude that SBRT should be offered to medically inoperable patients with stage I NSCLC.