Stereotactic Body Radiation Therapy for Stage IIA to IIIA Inoperable Non-small Cell Lung Cancer – A Phase I Dose Escalation Trial

Introduction Larger tumors are underrepresented in most prospective trials on stereotactic body radiation therapy (SBRT) for inoperable non-small cell lung cancer (NSCLC). We performed this phase I trial to specifically study the maximum tolerated dose (MTD) of SBRT for NSCLC >3cm. Methods A 3+3 dose escalation design (cohort A) with an expansion cohort at the MTD (cohort B) was used. Patients with inoperable NSCLC >3cm (T2-4) were eligible. Select ipsilateral hilar and single station mediastinal nodes were permitted. The initial SBRT dose was 40 Gy in 5 fractions, with planned escalation to 50 and 60 Gy in 5 fractions. Adjuvant chemotherapy was mandatory for cohort A and optional for cohort B, but no patients in cohort B received chemotherapy. The primary endpoint was SBRT-related acute G4+ or persistent G3 toxicities (CTCAE v4.03). Secondary endpoints included local failure (LF), distant-metastases, disease progression and overall survival (OS). Results Median age was 80 years; tumor size was >3cm ≤5cm in 20 (59%) and >5cm in 14 (41%) patients. In cohort A (n=9), 3 patients treated to 50 Gy experienced G3 radiation pneumonitis (RP), thus defining the MTD. In the larger dose expansion cohort B (n=25), no RT-related G4+ toxicities and no G3 RP occurred; only 2 patients experienced G2 RP. The 2-year cumulative incidence of LF was 20.2%, distant failure was 34.7%, and disease progression was 54.4%. Two-year OS was 53%. A biologically effective dose <100 Gy was associated with higher LF (p=0.006); advanced stage and higher neutrophil/lymphocyte ratio (NLR) were associated with greater disease progression (both p=0.004). Conclusions 50 Gy in 5 fraSabsctions is the MTD for SBRT to tumors >3cm. A higher BED is associated with less local failures even in larger tumors. Cohort B appears to have had less toxicity, possibly due to the omission of chemotherapy. Trial Registration Clinicaltrials.gov: xxx