A Phase II Trial Evaluating Upfront Stereotactic Body Radiotherapy in Stage III Advanced Non-small Cell Lung Cancer (APRIL)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Non Small Cell Lung Cancer
• Intervention / Treatment: Radiation: SBRT in stage III NSCLC

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Aman Sharma, MD; Phone Number: +91117018529339; Email: amans757@gmail.com

Study Locations

• India
  • Haryana
    • Jhajjar, Haryana, India, 124105
      • Recruiting
      • Nci, Aiims-Jhajjar
      • Contact: Aman Sharma, MD; Email: amans757@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SBRT in stage III NSCLC; The study will evaluate efficacy & toxicity of SBRT in stage III NSCLC	Radiation: SBRT in stage III NSCLC; SBRT to primary tumor and lymph nodes in stage III NSCLC when gross disease is < 6 cms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Loco-regional control rate	Loco regional control rate assessment till 2 years	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival	Longitudinal assessment every 2 months for initial six months and every 3 months till next 2 years	2 years
Overall survival	Longitudinal assessment every 2 months for initial six months and every 3 months till next 2 years	2 years
CTCAE V5 Toxicity	CTCAE Grades Grade refers to the severity of the adverse event. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL*. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL**. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. Assessed at base line, post SBRT, post Chemotherapy, first follow up, at 6 months and then 6 monthly	2 years
EORTC QLQ C30 Quality of life	The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. High score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems. Assessed at base line, post SBRT, post Chemotherapy, first follow up, at 6 months and then 6 monthly	2 years
EORTC LC-13 Quality of life	The lung cancer module incorporates one multi-item scale to assess dyspnoea, and a series of single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and haemoptysis. It has scoring system from 1 to 4, higher score represents higher symptom burden. Assessed at base line, post SBRT, post Chemotherapy, first follow up, at 6 months and then 6 monthly	2 years

Collaborators and Investigators

• Sponsor: All India Institute of Medical Sciences

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2023
• Primary Completion (Actual): January 30, 2025
• Study Completion (Estimated): January 30, 2027

Study Registration Dates

• First Submitted: December 5, 2022
• First Submitted That Met QC Criteria: April 30, 2026
• First Posted (Actual): May 4, 2026

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Investigative Techniques; Therapeutics; Surgical Procedures, Operative; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; Radiosurgery
• Other Study ID Numbers: The APRIL Trial

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No