Description

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

1. Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:2181-2190,
2. Bradley JD, Hu C, Komaki RR, et al. Long-term results of NRG oncology RTOG 0617: standard- versus high-dose chemoradiotherapy with or without cetuximab for unresectable Stage III non-small-cell lung cancer. J Clin Oncol. 2020; 38:706-714.
3. McGarry RC. Integrating stereotactic body radiation therapy in stage II/III non-small cell lung cancer: is local control important? Expert Rev Anticancer Ther2014; 14:1419-27.
4. Willner J, Baier K, Caragiani E, et al. Dose, volume and tumor control predictions in primary radiotherapy of non-small cell lung cancer. Int J Rad Oncol Biol Phys 2002;52: 382-9.
5. Onishi H, Araki T, Shirato H, Nagata Y, et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multi-institutional study. Cancer 2004; 101: 1623-31.
6. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010; 303: 1070-6.
7. Zhang J, Yang F, Li B, et al. Which is the optimal biologically effective dose of stereotactic body radiotherapy for Stage I non-small-cell lung cancer? A meta-analysis. Int J Radiat Oncol Biol Phys 2011; 81: e305-16.
8. Alcibar OL, Nadal E, Palomar IR, et al. Systematic review of stereotactic body radiotherapy in stage III non-small cell lung cancer. Transl Lung Cancer Res 2021;10(1):529-538.
9. Cong Y, Sun B, Wang J, et al. Outcomes and toxicity of stereotactic body radiation therapy for advanced stage ultra-central non-small cell lung cancer. Thoracic Cancer 2019;10:1567-1575.
10. Parisi E, GenestretiG ,Sarnelli A, et al. Accelerated hypofractionated radiotherapy plus chemotherapy for inoperable locally advanced non-small-cell lung cancer: final results of a prospective phase-II trial with a long-term follow-up. Radiation Oncology 2019 14:112.
11. Horne ZD, Richman AH, Dohopolski MJ, Clump DA, Burton SA, Heron DE. Stereotactic body radiation therapy for isolated hilar and mediastinal non-small cell lung cancers. Lung Cancer. 2018;115:1-4.
12. Meng MB, Wang HH, Zaorsky NG, et al., Clinical evaluation of stereotactic radiation therapy for recurrent or second primary mediastinal lymph node metastases originating from non-small cell lung cancer, Oncotarget 6 (17) (2015)15690-15703
13. Tjong MC, Malik NH, Hanbo Chen H, et al. Stereotactic ablative radiotherapy for malignant mediastinal and hilar lymphadenopathy: a systematic review. J Thorac Dis 2020;12(5):2280-2287
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.