The aim of the study is to test the feasibility & loco-regional control rate by combining high precision SBRT with chemotherapy in stage III NSCLC in tumor/lymph nodes if tumors/lymph node size with ≤ 6cms in size.

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 [1]. Concurrent chemoradiotherapy (CRT) is associated an overall survival rate at 5 years between 15%-32% [1,2].

Local relapse in stage III NSCLC can vary from 20% to 50% [1-3]. Conventional radiation therapy results in high local failure rates that theoretically could act as a nidus for metastasis [1,3]. 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 [3]. However, in a prospective randomised controlled trial setting, CRT dose escalation with conventional radiotherapy was associated with inferior local control, PFS, OS and higher toxicity [2].

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% [5, 6]. Ohnishi et al. in their landmark paper demonstrated significant survival benefits for stage I lung cancer with SBRT doses of biological equivalent (BED)10 in excess of 100 Gy[5]. SBRT with BED10>100 Gy has convincingly achieved excellent treatment out comes in early-stage NSCLC [7]. 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 [8].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 [8]. 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 [8].

There is data emerging on use of SBRT as monotherapy in stage III NSCLC [9, 10]. Yang et al treated ultra-central tumors 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 [9]. Another phase II trials examined the feasibility of SBRT is locally advanced NSCLC[10]. 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 [11-13]. 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[11].A systematic review of SBRT on mediastinal & hilar lymph nodes that included 196 patients has been recently conducted [13]. 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 [13].

Given the safety & excellent efficacy of SBRT for small tumors (≤ 6cms) as well as hilar & medistinal lymph nodes, the present phase study is designed evaluate SBRT in stage III NSCLC.

References

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14. Brunt AD, Haviland JS, Wheatley DA, et al. Hypofractionated breast radiotherapy for 1 week versus3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial. The Lancet 2020;395 (10237):1613-26.

Inclusion Criteria:

1. Aged 18 or above and less than 75 years.
2. Histologically proven non-small cell lung cancer.
3. Stage T1-4, N1-3, M0 with maximum tumor size less than 6 cms and ≤ 3 stations of largest lymph node size less than 4 cms.
4. ECOG status 0-1.
5. Available to attend long term follow- up.
6. Written informed consent for treatment.

Exclusion Criteria:

1. Metastatic disease.
2. Tumor size > 6cm.
3. Involved Lymph node size greater than 4 cms & more than 3 station of lymph nodes involved.
4. Patients with superior vena cava obstruction.
5. Tumor invading/encasing the proximal bronchial tree/, esophagus, pericardium.
6. Previous radiotherapy to thorax.
7. Small cell histology.
8. Age< 18 or > 75 years.
9. Patients on anticoagulant therapy & ultra-central cavitary tumors.
10. Poor performance status ECOG 2-3.
11. Immunocompromised states.
12. Viral Markers negative.
13. Pregnant women