The APRIL Trial Evaluating Upfront Stereotactic Body Radiotherapy in Stage III Advanced Non-small Cell Lung Cancer

The standard of care for unresectable stage III NSCLC lung cancer is combination chemoradiotherapy and best results are achieved when radiation is given along with concurrent chemotherapy. Concurrent chemoradiotherapy (CRT) is associated an overall survival rate at 5 years between 15%-32%.

Local relapse in stage III NSCLC can vary from 20% to 50%. Conventional radiation therapy results in high local failure rates that theoretically could act as a nidus for metastasis. For NSCLC, there is a proposed dose effect on local control and survival with doses of at least 70 Gy and tumors with volumes >100 cc require higher doses for better local control. However, in a prospective randomized controlled trial setting, CRT dose escalation with conventional radiotherapy was associated with inferior local control, PFS, OS and higher toxicity.

Stereotactic body radiotherapy (SBRT) delivers high dose conformal radiation through multiple radiation beams with steep dose gradients in 3-8 fractions and has shown limited toxicity despite delivering a high dose BED10>100 in early NSCLC. Local control in early-stage NSCLC with SBRT is around 85-90% . One landmark paper demonstrated significant survival benefits for stage I lung cancer with SBRT doses of biological equivalent (BED)10 in excess of 100 Gy. SBRT with BED10>100 Gy has convincingly achieved excellent treatment out comes in early-stage NSCLC. Similar local control may be achieved SBRT in stage III NSCLC provided safe dose of BED10>100 Gy is delivered. This holds true when tumor diameter is ≤ 6 cms.

SBRT has been combined with conventional CRT in stage III NSCLC with intent to decrease local failure. A recently conducted systematic review of SBRT in inoperable stage III NSCLC has published SBRT outcomes .In this systematic review, 6 studies considered SBRT administration in stage III NSCLC, 1 employed SBRT in monotherapy and 5 employed SBRT as dose escalation after conventional chemoradiotherapy. Median dose of conventional radiotherapy was 50.4 Gy in 28 fractions and median dose of SBRT boost was 22.25 Gy in 2 to 7 fractions. SBRT was used to treat primary tumor and involved lymph nodes in 3 out of 5 studies. The systematic review concluded that dose-escalation with 2 fraction SBRT (20-24 Gy) was feasible and was associated with local control rate of 78% at 1 year with 3.7% grade 5 and 14.2% grade 3toxicity.

There is data emerging on use of SBRT as monotherapy in stage III NSCLC. Ultra-central tumors in a study were treated with SBRT to primary and lymph nodes to a dose of 35 Gy in 5 fractions. Despite large tumors (median tumor diameter was 6.8 cm [range: 2.1-12.4 cms] and ultra-central location median local control was 17 months for stage III patients. Grade 3 or higher toxicity was observed in 9.8% of patients. Another phase II trials examined the feasibility of SBRT is locally advanced NSCLC. The prescribed doses were 30 Gy/5daily fractions at the reference isodose (60-70%) to the tumor, and 25 Gy/5 daily fractions to the clinically involved lymph nodes. Median follow-up was 87 months (range: 6-87), local PFS was 19.8 months (95% CI 9.7 - not reached), OS was 23 months. Late toxicity was represented by 24% dyspnea G3.

Hilar/mediastinal SBRT is a safe technique for isolated nodal disease . A retrospective study that treated 40 patients of NSCLC with SBRT for primary/oligorecurrent hilar/mediastinal lymph nodes. The median dose of SBRT was 48 Gy in 4 fractions. The aortico-pulmonary window was the target in 40%, hilum in 25%, lower paratracheal in 20%, subcarinal in 10%, and prevascular in 5%. Acute grade 3+ morbidity was seen in 3 patients (hemoptysis, pericardial/pleural effusion, heart failure) and late grade 3+ morbidity (hemoptysis) in 1 patient. A systematic review of SBRT on mediastinal \& hilar lymph nodes that included 196 patients has been recently conducted. Non-small cell lung cancer (NSCLC) was the most common primary (65%) tumor subjected to mediastinal \& hilar node SBRT. The reported dose and fractionation ranged from 21 Gy to 60 Gy in 3-11 fractions, with median BED ranged from 46-106 Gy. SBRT was associated with excellent local control (LC) rates of 69%-97% \& 1 year OS of 69%-75%. Pooled grade 3-5 toxicity rate according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 was 6% (n=11). Pooled SABR-related mortality (grade 5 toxicity) rate was 2% (n=4). Three SABR-related deaths from esophageal fistulae (2 to trachea, 1 to mediastinum) were reported, with all 3 having prior RT to the subcarinal nodes Given the safety \& excellent efficacy of SBRT for small tumors (≤ 6cms) as well as hilar \& mediastinal lymph nodes, the present phase study is designed evaluate SBRT in stage III NSCLC.