[Skip to Navigation]
Sign In
Visual Abstract. RCT: Accelerated Hypofractionated Image-Guided vs Conventional Radiotherapy for Stage II/III NSCLC Patients
RCT: Accelerated Hypofractionated Image-Guided vs Conventional Radiotherapy for Stage II/III NSCLC Patients
Figure 1.  CONSORT Diagram of Trial Patients
CONSORT Diagram of Trial Patients

CFRT indicates conventionally fractionated radiotherapy; IGRT, image-guided radiotherapy.

Figure 2.  Study Outcomes
Study Outcomes

A, Median overall survival was 8.2 (95% CI, 5.4-12.4) months in the hypofractionated image-guided radiotherapy (IGRT) group vs 10.6 (95% CI, 8.4-15.3) months in the conventionally fractionated radiotherapy (CFRT) group (P = .17). B, Median progression-free survival was 6.4 (95% CI, 4.1-7.8) months in the hypofractionated IGRT group vs 7.3 (95% CI, 5.0-10.6) months in the CFRT group (P = .77). C, Neither group reached median time to local relapse (P = .34). D, Median time to distant metastasis was not reached in the hypofractionated IGRT group vs 18.0 (95% CI, 7.4-36.0) months in the CFRT group (P = .16).

Table 1.  Patient Characteristics and Outcomes
Patient Characteristics and Outcomes
Table 2.  Multivariate and Univariate Analysis of Overall Survival
Multivariate and Univariate Analysis of Overall Survival
Table 3.  Adverse Events
Adverse Events
1.
Siegel  RL, Miller  KD, Jemal  A.  Cancer statistics, 2020.   CA Cancer J Clin. 2020;70(1):7-30. doi:10.3322/caac.21590 PubMedGoogle ScholarCrossref
2.
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(13):2181-2190. doi:10.1200/JCO.2009.26.2543 PubMedGoogle ScholarCrossref
3.
Schaake-Koning  C, van den Bogaert  W, Dalesio  O,  et al.  Effects of concomitant cisplatin and radiotherapy on inoperable non–small-cell lung cancer.   N Engl J Med. 1992;326(8):524-530. doi:10.1056/NEJM199202203260805 PubMedGoogle ScholarCrossref
4.
Komaki  R, Scott  C, Ettinger  D,  et al.  Randomized study of chemotherapy/radiation therapy combinations for favorable patients with locally advanced inoperable nonsmall cell lung cancer: Radiation Therapy Oncology Group (RTOG) 92-04.   Int J Radiat Oncol Biol Phys. 1997;38(1):149-155. doi:10.1016/S0360-3016(97)00251-4 PubMedGoogle ScholarCrossref
5.
Komaki  R, Seiferheld  W, Ettinger  D, Lee  JS, Movsas  B, Sause  W.  Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non–small-cell lung cancer: long-term follow-up of RTOG 92-04.   Int J Radiat Oncol Biol Phys. 2002;53(3):548-557. doi:10.1016/S0360-3016(02)02793-1 PubMedGoogle ScholarCrossref
6.
Furuse  K, Fukuoka  M, Kawahara  M,  et al.  Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non–small-cell lung cancer.   J Clin Oncol. 1999;17(9):2692-2699. doi:10.1200/JCO.1999.17.9.2692 PubMedGoogle ScholarCrossref
7.
Antonia  SJ, Villegas  A, Daniel  D,  et al; PACIFIC Investigators.  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer.   N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937 PubMedGoogle ScholarCrossref
8.
Antonia  SJ.  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. Reply.   N Engl J Med. 2019;380(10):990. doi:10.1056/NEJMc1900407PubMedGoogle Scholar
9.
Bradley  JD, Paulus  R, Komaki  R,  et al.  Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non–small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.   Lancet Oncol. 2015;16(2):187-199. doi:10.1016/S1470-2045(14)71207-0 PubMedGoogle ScholarCrossref
10.
Curran  WJ  Jr, Paulus  R, Langer  CJ,  et al.  Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410.   J Natl Cancer Inst. 2011;103(19):1452-1460. doi:10.1093/jnci/djr325PubMedGoogle ScholarCrossref
11.
Clamon  G, Herndon  J, Cooper  R, Chang  AY, Rosenman  J, Green  MR.  Radiosensitization with carboplatin for patients with unresectable stage III non–small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group.   J Clin Oncol. 1999;17(1):4-11. doi:10.1200/JCO.1999.17.1.4 PubMedGoogle ScholarCrossref
12.
Dillman  RO, Seagren  SL, Propert  KJ,  et al.  A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non–small-cell lung cancer.   N Engl J Med. 1990;323(14):940-945. doi:10.1056/NEJM199010043231403 PubMedGoogle ScholarCrossref
13.
Cheung  P, Faria  S, Ahmed  S,  et al.  Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non–small cell lung cancer: NCIC CTG BR.25.   J Natl Cancer Inst. 2014;106(8):dju164. doi:10.1093/jnci/dju164 PubMedGoogle Scholar
14.
Bradley  JD, Scott  CB, Paris  KJ,  et al.  A phase III comparison of radiation therapy with or without recombinant beta-interferon for poor-risk patients with locally advanced non–small-cell lung cancer (RTOG 93-04).   Int J Radiat Oncol Biol Phys. 2002;52(5):1173-1179. doi:10.1016/S0360-3016(01)02797-3 PubMedGoogle ScholarCrossref
15.
Amini  A, Lin  SH, Wei  C, Allen  P, Cox  JD, Komaki  R.  Accelerated hypofractionated radiation therapy compared to conventionally fractionated radiation therapy for the treatment of inoperable non–small cell lung cancer.   Radiat Oncol. 2012;7:33. doi:10.1186/1748-717X-7-33 PubMedGoogle ScholarCrossref
16.
Nguyen  LN, Komaki  R, Allen  P, Schea  RA, Milas  L.  Effectiveness of accelerated radiotherapy for patients with inoperable non–small cell lung cancer (NSCLC) and borderline prognostic factors without distant metastasis: a retrospective review.   Int J Radiat Oncol Biol Phys. 1999;44(5):1053-1056. doi:10.1016/S0360-3016(99)00130-3 PubMedGoogle ScholarCrossref
17.
Gomez  DR, Gillin  M, Liao  Z,  et al.  Phase 1 study of dose escalation in hypofractionated proton beam therapy for non–small cell lung cancer.   Int J Radiat Oncol Biol Phys. 2013;86(4):665-670. doi:10.1016/j.ijrobp.2013.03.035 PubMedGoogle ScholarCrossref
18.
Westover  KD, Loo  BW  Jr, Gerber  DE,  et al.  Precision hypofractionated radiation therapy in poor performing patients with non–small cell lung cancer: phase 1 dose escalation trial.   Int J Radiat Oncol Biol Phys. 2015;93(1):72-81. doi:10.1016/j.ijrobp.2015.05.004 PubMedGoogle ScholarCrossref
19.
Owen  JR, Ashton  A, Bliss  JM,  et al.  Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial.   Lancet Oncol. 2006;7(6):467-471. doi:10.1016/S1470-2045(06)70699-4 PubMedGoogle ScholarCrossref
20.
Koay  EJ, Hanania  AN, Hall  WA,  et al.  Dose-escalated radiation therapy for pancreatic cancer: a simultaneous integrated boost approach.   Pract Radiat Oncol. 2020;10(6):e495-e507. doi:10.1016/j.prro.2020.01.012 PubMedGoogle ScholarCrossref
21.
Tao  R, Krishnan  S, Bhosale  PR,  et al.  Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis.   J Clin Oncol. 2016;34(3):219-226. doi:10.1200/JCO.2015.61.3778 PubMedGoogle ScholarCrossref
22.
Bentzen  SM, Agrawal  RK, Aird  EG,  et al; START Trialists’ Group.  The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.   Lancet. 2008;371(9618):1098-1107. doi:10.1016/S0140-6736(08)60348-7 PubMedGoogle Scholar
23.
Haviland  JS, Owen  JR, Dewar  JA,  et al; START Trialists’ Group.  The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.   Lancet Oncol. 2013;14(11):1086-1094. doi:10.1016/S1470-2045(13)70386-3 PubMedGoogle ScholarCrossref
24.
Zelen  M.  The randomization and stratification of patients to clinical trials.   J Chronic Dis. 1974;27(7-8):365-375. doi:10.1016/0021-9681(74)90015-0 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Original Investigation
    August 12, 2021

    Accelerated Hypofractionated Image-Guided vs Conventional Radiotherapy for Patients With Stage II/III Non–Small Cell Lung Cancer and Poor Performance Status: A Randomized Clinical Trial

    Author Affiliations
    • 1Department of Radiation Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas
    • 2Department of Medical Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas
    • 3Department of Biostatistics, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas
    • 4Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas
    • 5Department of Radiation Oncology, Baylor Scott & White Memorial Hospital, Temple, Texas
    • 6Department of Radiation Oncology, Austin Cancer Center, Austin, Texas
    • 7Department of Radiation Oncology, Texas Oncology Tyler, Tyler
    • 8Department of Radiation Oncology, Texas Oncology Sherman, Sherman
    • 9Department of Radiation Oncology, Texas Center for Proton Therapy, Irving
    • 10Department of Radiation Oncology, Levine Cancer Institute, Atrium Heath, Charlotte, North Carolina
    • 11Department of Radiation Oncology, Banner MD Anderson Cancer Center, Gilbert, Arizona
    JAMA Oncol. 2021;7(10):1497-1505. doi:10.1001/jamaoncol.2021.3186
    Key Points

    Question  For patients with stage II/III non–small cell lung cancer (NSCLC) who cannot receive concurrent chemoradiotherapy owing to comorbidities and/or performance status, can hypofractionated image-guided radiotherapy (IGRT) alone be superior to conventionally fractionated radiotherapy (CFRT) with respect to overall survival?

    Findings  In this randomized phase 3 clinical trial of 96 patients with NSCLC, hypofractionated IGRT failed to demonstrate an improvement in overall survival compared with CFRT.

    Meaning  Additional trials will need to be powered for assessing equivalence between hypofractionated IGRT and CFRT for patients with stage II/III NSCLC who cannot receive concurrent therapies.

    Abstract

    Importance  A significant subset of patients with stage II/III non–small cell lung cancer (NSCLC) cannot receive standard concurrent chemoradiotherapy owing to the risk of toxic effects outweighing potential benefits. Without concurrent chemotherapy, however, the efficacy of conventional radiotherapy is reduced.

    Objective  To determine whether hypofractionated image-guided radiotherapy (IGRT) would improve overall survival in patients with stage II/III NSCLC who could not receive concurrent chemoradiotherapy and therefore were traditionally relegated to receiving only conventionally fractionated radiotherapy (CFRT).

    Design, Setting, and Participants  This nonblinded, phase 3 randomized clinical study enrolled 103 patients and analyzed 96 patients with stage II/III NSCLC and Zubrod performance status of at least 2, with greater than 10% weight loss in the previous 6 months, and/or who were ineligible for concurrent chemoradiotherapy after oncology consultation. Enrollment occurred at multiple US institutions. Patients were enrolled from November 13, 2012, to August 28, 2018, with a median follow-up of 8.7 (3.6-19.9) months. Data were analyzed from September 14, 2018, to April 11, 2021.

    Interventions  Eligible patients were randomized to hypofractionated IGRT (60 Gy in 15 fractions) vs CFRT (60 Gy in 30 fractions).

    Main Outcomes and Measures  The primary end point was 1-year overall survival.

    Results  A total of 103 patients (96 of whom were analyzed [63 men (65.6%); mean (SD) age, 71.0 (10.2) years (range, 50-90 years)]) were randomized to hypofractionated IGRT (n = 50) or CFRT (n = 46) when a planned interim analysis suggested futility in reaching the primary end point, and the study was closed to further accrual. There was no statistically significant difference between the treatment groups for 1-year overall survival (37.7% [95% CI, 24.2%-51.0%] for hypofractionated IGRT vs 44.6% [95% CI, 29.9%-58.3%] for CFRT; P = .29). There were also no significant differences in median overall survival, progression-free survival, time to local failure, time to distant metastasis, and toxic effects of grade 3 or greater between the 2 treatment groups.

    Conclusions and Relevance  This phase 3 randomized clinical trial found that hypofractionated IGRT (60 Gy in 15 fractions) was not superior to CFRT (60 Gy in 30 fractions) for patients with stage II/III NSCLC ineligible for concurrent chemoradiotherapy. Further studies are needed to verify equivalence between these radiotherapy regimens. Regardless, for well-selected patients with NSCLC (ie, peripheral primary tumors and limited mediastinal/hilar adenopathy), the convenience of hypofractionated radiotherapy regimens may offer an appropriate treatment option.

    Trial Registration  ClinicalTrials.gov Identifier: NCT01459497

    Introduction

    Lung cancer is the leading cause of cancer-related mortality in the US, with an estimated 228 820 new cases and 135 720 deaths each year.1 For inoperable locally advanced non–small cell lung cancer (NSCLC), concurrent chemotherapy and conventionally fractionated radiotherapy (CFRT; chemoradiotherapy) followed by immunotherapy is the most effective curative option.2-9 However, the improvements in local control and survival achievable by adding concurrent chemotherapy to radiotherapy come at the expense of increased toxic effects.10-13 Therefore, certain patients with NSCLC cannot receive concurrent chemoradiotherapy owing to either medical comorbidities or cancer-associated decline, with treatment-related toxic effects outweighing potential benefits.

    The efficacy of CFRT without concurrent chemotherapy is, therefore, limited.14 Accelerated radiotherapy has subsequently emerged as an alternative treatment for these patients to improve efficacy while reducing overall treatment times. Retrospective data have supported use of hypofractionation to accelerate with regimens of 3 Gy per fraction to treat patients with NSCLC and poor performance status who are not candidates for concurrent chemotherapy.15,16 With advances in image-guided radiotherapy (IGRT), treatment accuracy has improved further over the past 2 decades, eliminating the need for large target margins that have traditionally been used to compensate for errors in localization. As a result, the amount of healthy tissue exposed to radiation can be reduced, allowing radiation oncologists to increase the total prescribed dose or total dose potency. Phase 1 trials with protons17 and photons with use of IGRT18 have since demonstrated the tolerability of dose escalation to 60 Gy in 15 fractions (4 Gy per fraction).

    Based on these results, we hypothesized in this phase 3 randomized clinical trial that hypofractionated IGRT (60 Gy in 15 fractions delivered over 3 weeks) without concurrent chemotherapy would be more effective than CFRT (60 Gy in 30 fractions delivered over 6 weeks) in patients with locally advanced NSCLC and poor performance status. With the premise that higher biologically equivalent doses with hypofractionated radiotherapy would improve local control,19-21 we further hypothesized that this improvement in local control would also translate to a delay in metastatic disease dissemination and benefit in overall survival with hypofractionation,20-23 informing our statistical approach to design a superiority study. To our knowledge, this study represents the largest prospective experience comparing hypofractionated IGRT vs CFRT for locally advanced NSCLC.

    Methods
    Patients

    In this phase 3 randomized clinical study, we recruited adults with histologically proven stage II/III or recurrent NSCLC from 9 cancer centers across Texas. Patients had a Zubrod performance status of 2 or greater (0 indicates asymptomatic; 5, death), had greater than 10% weight loss in the previous 6 months, and/or were ineligible for concurrent chemoradiotherapy after consultation with radiation and medical oncologists. Patients were ineligible if they had a total gross tumor volume greater than 500 mL, had undergone prior regional radiotherapy, received chemotherapy within 1 week of study registration, or were pregnant or lactating. Staging workup included computed tomography of the chest and upper abdomen, magnetic resonance imaging of the brain, pulmonary function tests, and complete blood cell count with differential. Positron emission tomography was recommended but not mandated. Patients in either group were allowed sequential consolidative chemotherapy after radiotherapy at the discretion of the enrolling physicians. The trial protocol is found in Supplement 1 and was approved by the institutional review board of each study site. All patients provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

    Randomization

    We randomly assigned (1:1) eligible patients to 1 of 2 nonmasked treatment groups: experimental hypofractionated IGRT (60 Gy in 15 fractions) vs CFRT (60 Gy in 30 fractions). Patients were allocated by the primary enrolling site using a randomized permuted block24 and stratified by Zubrod performance status (2 vs >2) and stage (II vs III).

    Radiotherapy

    All patients underwent computed tomographic simulation, target delineation, and treatment planning as described previously18 (additional methods are described in the eMethods in Supplement 2; constraints are described in eTable 1 in Supplement 2). All deidentified plans were reviewed for quality assurance by a co–principal investigator (L.C.), and the first enrolled case at each institution was reviewed by another investigator (R.T.). Daily IGRT was performed with cone beam computed tomography, planar kilovoltage radiographs, or fluoroscopy.

    Outcomes

    The primary objective of this study was to compare overall survival at 1 year among patients treated with experimental hypofractionated IGRT vs CFRT. Secondary objectives included median overall survival, progression-free survival, local control, and toxic effects. Toxic effects were scored according to Common Terminology Criteria for Adverse Events (version 4), assigned causation by the treating site investigators, and verified by the data safety and monitoring committee of the Simmons Comprehensive Cancer Center, Dallas, Texas.

    Statistical Analysis

    Data were analyzed from September 14, 2018, to April 11, 2021. We hypothesized that the patients randomly assigned to the control and experimental groups have a 1-year survival rate of 45% (hazard rate [λc] of 0.80) and 60% (hazard rate [λe] of 0.51), respectively, resulting in a hazard ratio (HR) of λe/λc = 0.64. With the assumption that patients would be accrued for 2 years with a 1-year follow-up, we calculated a total sample size of 226 patients (113 in the control group and 113 in the experimental group) was needed to achieve the desired 80% statistical power and 2-sided statistical significance level of P < .05 using a 2-sample log-rank test. Guarding against ineligibility or lack-of-data rate to 5%, the final targeted accrual for this study was 238 patients (119 per group). Sample size was estimated using the sample size software East, version 5 (Cytel). Further statistical methods may be found in the eMethods in Supplement 2.

    Results

    From November 13, 2012, to August 28, 2018, we screened 126 patients; 20 were excluded owing to improper stage, incomplete staging, or recruitment to other studies; 3 patients refused consent; and 103 patients were randomized. After approximately 50% of patients had enrolled in the study, a planned interim analysis suggested futility in reaching the primary end point with conditional power of 20.6%, leading to study closure for further accrual. Median follow-up was 8.7 (3.6-19.9) months. Figure 1 shows the trial CONSORT diagram. After exclusions, 103 patients were randomized, 96 of whom (63 men [65.6%] and 33 women [34.4%]; mean [SD] age, 71.0 [10.2] years [range, 50-90 years]) were available for analysis (50 patients for the hypofractionated IGRT group and 46 patients for the CFRT group).

    Table 1 shows patient characteristics. There were similar percentages of patients with squamous (27 of 50 [54.0%] vs 29 of 46 [63.0%]) and nonsquamous (23 of 50 [46.0%] vs 17 of 46 [37.0%]) histologic findings in both groups of the cohort (P = .41). There were significantly more patients with N1 disease in the hypofractionated IGRT group (12 of 50 [24.0%]) compared with the CFRT group (3 of 46 [6.5%]; P = .02) and fewer patients with N3 disease in the hypofractionated IGRT group (4 of 50 [8.0%]) compared with the CFRT group (11 of 46 [23.9%]; P = .02). Most patients completed their planned radiotherapy (44 of 50 [88.0%] for IGRT vs 41 of 46 [89.1%] for CFRT; P > .99). A similar percentage of patients in each cohort received systemic therapy before enrollment (4 of 50 [8.0%] for IGRT vs 3 of 46 [6.5%] for CFRT; P > .99) or between completion of radiotherapy and last follow-up (13 of 50 [26.0%] for IGRT vs 17 of 46 [37.0%] for CFRT; P = .28).

    There was no statistically significant difference between the treatment groups for 1-year overall survival, the study’s primary end point (37.7% [95% CI, 24.2%-51.0%] for hypofractionated IGRT vs 44.6% [95% CI, 29.9%-58.3%] for CFRT; P = .29), median overall survival (8.2 [95% CI, 5.4-12.4] months for hypofractionated IGRT vs 10.6 [95% CI, 8.4-15.3] months for CFRT; P = .17) (Figure 2A), or progression-free survival (6.4 [95% CI ,4.1-7.8] months for hypofractionated IGRT vs 7.3 [95% CI, 5.0-10.6] months for CFRT; P = .77) (Figure 2B). Of the 5 patients in the hypofractionated IGRT group who died during treatment, 4 died after receiving fewer than 4 fractions, and 1 died of a traumatic fall in the context of altered mental status after 8 fractions.

    In an exploratory analysis of the 77 patients treated at the main site for this study (38 patients for the hypofractionated IGRT group and 39 patients for the CFRT group), permitting evaluation of follow-up imaging, time to local relapse (neither group reached median; at 24 months, probability of local relapse-free survival was 85.8% [66.2%-94.5%] in the hypofractionated IGRT group and 66.1% [40.0%-83.0%] in the CFRT group; P = .34) (Figure 2C) and time to distant metastasis (median not reached for hypofractionated IGRT vs 18.0 [95% CI, 7.4-36.0] months for CFRT; P = .16) (Figure 2D) were similar. Of note, there were significantly more patients who ultimately developed distant metastatic disease in the CFRT group (Table 1) (10 of 38 [26.3%] for hypofractionated IGRT vs 20 of 39 [51.3%] for CFRT; P = .04), which may reflect the increased proportion of patients with N3 disease in the CFRT group. Eleven of 38 patients (28.9%) in the hypofractionated IGRT group vs 19 of 39 (48.7%) in the CFRT group died of NSCLC (P = .10).

    We then performed univariate and multivariate Cox proportional hazards regression analyses of factors associated with overall survival outcomes (Table 2). Treatment group was not significantly associated with overall survival on univariate analysis (HR, 0.73 [95% CI, 0.47-1.14]; P = .16), consistent with our Kaplan-Meier analysis (P = .17) (Figure 2A). Only administration of subsequent systemic therapy after completion of radiotherapy and esophageal maximum point (maximum dose received by any 0.035 mL of the esophagus) biologically effective dose were significantly associated with survival on univariate analysis. On multivariate analysis, subsequent systemic therapy was associated with better survival (HR, 0.51 [95% CI, 0.29-0.87]; P = .01), and the biologically effective maximum dose to any 0.035 mL of the esophagus was associated with worsened survival (HR, 1.01 [95% CI, 1.00-1.02]; P = .03). Within the hypofractionated IGRT group, age was the only significant factor associated with overall survival (HR, 1.05 [95% CI, 1.02-1.09]; P = .003) (eTable 2 in Supplement 2).

    Despite the effect of esophageal dose on survival, we noted no difference in higher-grade (3-5) toxic effects attributable to radiation between the 2 treatment groups (18 patients in the hypofractionated IGRT group and 19 in the CFRT group) (Table 3). By contrast, there were 47 grade 2 toxic effects observed in 26 of 50 patients (52.0%) in the hypofractionated IGRT group vs 17 grade 2 toxic effects observed in 11 of 46 patients (23.9%) in the CFRT group (P = .006). The most common grade 2 toxic effect was esophagitis (observed in 11 of 50 patients [22.0%] in the hypofractionated IGRT group vs 4 of 46 [8.7%] in the CFRT group; P = .09) (Table 3). Grade 2 respiratory toxic effects were observed in 20 of 50 patients (40.0%) in the hypofractionated IGRT group vs 7 of 46 (15.2%) in the CFRT group (P = .41); the most common grade 2 respiratory toxic effect was dyspnea, observed in 7 of 50 patients (14.0%) in the hypofractionated IGRT group vs 1 of 46 (2.2%) in the CFRT group (P = .06).

    Discussion

    Accelerated radiotherapy is an emerging alternative treatment for patients with solid tumors who are poor candidates for standard chemoradiotherapy owing to performance status and comorbidities. To our knowledge, this is the first phase 3 trial comparing hypofractionated vs conventional radiotherapy for stage II/III NSCLC in this patient population. Despite the fact that the study reached futility, our data provide thoracic oncologists a window on the role of 2 different fractionation schemas on a patient population with poor performance status, absent concurrent therapies. In addition, our study shows that randomization to varying fractionation schedules is feasible and high accrual is possible.

    Our results show that hypofractionated IGRT did not improve overall survival compared with CFRT. In a subgroup analysis of patients from the primary enrolling site, there was a trend toward improvement with hypofractionated IGRT in times to local recurrence and distant metastasis, resulting in a trend of fewer patients dying of NSCLC. However, there was overall an almost 3-fold increase in grade 2 toxic effects with hypofractionation. Although there were no differences in grades 3 to 5 toxic effects, the increase in grade 2 toxic effects may have been critical in this patient population with poor performance status, highlighting the importance of selecting patients who would tolerate fewer toxic effects such as esophagitis and dyspnea owing to factors such as age, tumor location, or comorbidities. As a future direction, patient-reported outcomes will help to guide clinical decision-making.

    Limitations

    Our study has several limitations. First, it was closed to accrual before the enrollment goal was attained due to futility in reaching the primary end point; consequently, the lower than anticipated number of participants limited our multivariate analysis. Second, more than half of the patients were from a single site (University of Texas Southwestern). However, the fact that the primary enrolling institution has substantial experience with hypofractionated IGRT suggests that the significant grade 2 adverse events observed with hypofractionation could be a fundamental finding when treating patients who have stage III NSCLC and poor performance status. Finally, the outcomes may have differed in an immunotherapy setting.

    Conclusions

    The findings of this phase 3 randomized clinical trial suggest that younger patients ineligible for concurrent chemoradiotherapy owing to performance status could potentially benefit from this hypofractionated approach (eTable 2 in Supplement 2); favorable outcomes have been observed in a phase 2 trial of patients with node-negative disease receiving 60 Gy of radiotherapy in 15 fractions.13 Our study meanwhile poses the question of whether these toxic effects may not be appreciated in patients with good or borderline performance status. If so, hypofractionation in combination with immunotherapy may be tolerated. Indeed, this regimen is being tested in an early-phase trial through the NRG (LU-004) and SWOG (formerly the Southwest Oncology Group) (S1933).

    Because our trial was designed to assess the superiority of hypofractionated IGRT and was not powered to show equivalence, hypofractionated IGRT to these dose levels should be considered with caution. Further investigations on the addition of concurrent immunotherapy to either hypofractionation or CFRT are ongoing at our institution and at the NRG and will continue to clarify the most effective treatment regimens for patients who cannot tolerate concurrent chemoradiotherapy.

    Back to top
    Article Information

    Accepted for Publication: May 24, 2021.

    Published Online: August 12, 2021. doi:10.1001/jamaoncol.2021.3186

    Corresponding Author: Robert Timmerman, MD, Simmons Comprehensive Cancer Center, Department of Radiation Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235 (robert.timmerman@utsouthwestern.edu).

    Author Contributions: Drs Iyengar and Zhang-Velten contributed equally to this work as co–first authors. Drs Iyengar and Zhang-Velten had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Iyengar, Court, Lin, Patel, Saunders, Lee, Heinzerling, Choy, Timmerman.

    Acquisition, analysis, or interpretation of data: Iyengar, Zhang-Velten, Court, Westover, Yan, Xiong, Patel, Rivera, Chang, Saunders, Shivnani, Hughes, Gerber, Dowell, Gao, Li, Ahn, Timmerman.

    Drafting of the manuscript: Iyengar, Zhang-Velten, Court, Xiong, Gerber, Choy, Timmerman.

    Critical revision of the manuscript for important intellectual content: Iyengar, Zhang-Velten, Westover, Yan, Lin, Patel, Rivera, Chang, Saunders, Shivnani, Lee, Hughes, Gerber, Dowell, Gao, Heinzerling, Li, Ahn, Timmerman.

    Statistical analysis: Iyengar, Zhang-Velten, Yan, Xiong, Gao, Ahn.

    Obtained funding: Choy, Timmerman.

    Administrative, technical, or material support: Iyengar, Court, Westover, Yan, Lin, Xiong, Chang, Saunders, Lee, Gerber, Heinzerling, Li, Choy, Timmerman.

    Supervision: Iyengar, Westover, Patel, Lee, Dowell, Timmerman.

    Other (study design): Patel.

    Other (study patient enrollment): Patel, Li.

    Conflict of Interest Disclosures: Dr Iyengar reported serving on the advisory board of AstraZeneca plc outside the submitted work. Dr Westover reported receiving personal fees from Vibliome Therapeutics, LLC, for participation in the scientific advisory board and grants from Revolution Medicines, Inc, outside the submitted work. Dr Chang reported receiving grants from Bristol Myers Squibb and personal fees from Varian Medical Systems, Legion Healthcare Partners, and AstraZeneca plc outside the submitted work. Dr Dowell reported receiving personal fees from AstraZeneca plc, Genentech, Inc, and Boehringer Ingelheim 1-time advisory board outside the submitted work. Dr Heinzerling reported receiving grants from AstraZeneca plc and Vision RT outside the submitted work. Dr Timmerman reported receiving grants from Varian Medical Systems, Elekta, and Accuray Incorporated to his institution as a principal investigator outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was supported by a grant from the Cancer Prevention and Research Institute of Texas (principal investigator, Dr Timmerman).

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Meeting Presentation: This work was presented in part at the 58th Annual Meeting of ASTRO (American Society for Radiation Oncology); September 26, 2016; Boston, Massachusetts.

    Data Sharing Statement: See Supplement 3.

    Additional Contributions: Alexander Louie, MD, PhD, and Hanbo Chen, MD, both from the Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada, reviewed the manuscript.

    References
    1.
    Siegel  RL, Miller  KD, Jemal  A.  Cancer statistics, 2020.   CA Cancer J Clin. 2020;70(1):7-30. doi:10.3322/caac.21590 PubMedGoogle ScholarCrossref
    2.
    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(13):2181-2190. doi:10.1200/JCO.2009.26.2543 PubMedGoogle ScholarCrossref
    3.
    Schaake-Koning  C, van den Bogaert  W, Dalesio  O,  et al.  Effects of concomitant cisplatin and radiotherapy on inoperable non–small-cell lung cancer.   N Engl J Med. 1992;326(8):524-530. doi:10.1056/NEJM199202203260805 PubMedGoogle ScholarCrossref
    4.
    Komaki  R, Scott  C, Ettinger  D,  et al.  Randomized study of chemotherapy/radiation therapy combinations for favorable patients with locally advanced inoperable nonsmall cell lung cancer: Radiation Therapy Oncology Group (RTOG) 92-04.   Int J Radiat Oncol Biol Phys. 1997;38(1):149-155. doi:10.1016/S0360-3016(97)00251-4 PubMedGoogle ScholarCrossref
    5.
    Komaki  R, Seiferheld  W, Ettinger  D, Lee  JS, Movsas  B, Sause  W.  Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non–small-cell lung cancer: long-term follow-up of RTOG 92-04.   Int J Radiat Oncol Biol Phys. 2002;53(3):548-557. doi:10.1016/S0360-3016(02)02793-1 PubMedGoogle ScholarCrossref
    6.
    Furuse  K, Fukuoka  M, Kawahara  M,  et al.  Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non–small-cell lung cancer.   J Clin Oncol. 1999;17(9):2692-2699. doi:10.1200/JCO.1999.17.9.2692 PubMedGoogle ScholarCrossref
    7.
    Antonia  SJ, Villegas  A, Daniel  D,  et al; PACIFIC Investigators.  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer.   N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937 PubMedGoogle ScholarCrossref
    8.
    Antonia  SJ.  Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. Reply.   N Engl J Med. 2019;380(10):990. doi:10.1056/NEJMc1900407PubMedGoogle Scholar
    9.
    Bradley  JD, Paulus  R, Komaki  R,  et al.  Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non–small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.   Lancet Oncol. 2015;16(2):187-199. doi:10.1016/S1470-2045(14)71207-0 PubMedGoogle ScholarCrossref
    10.
    Curran  WJ  Jr, Paulus  R, Langer  CJ,  et al.  Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410.   J Natl Cancer Inst. 2011;103(19):1452-1460. doi:10.1093/jnci/djr325PubMedGoogle ScholarCrossref
    11.
    Clamon  G, Herndon  J, Cooper  R, Chang  AY, Rosenman  J, Green  MR.  Radiosensitization with carboplatin for patients with unresectable stage III non–small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group.   J Clin Oncol. 1999;17(1):4-11. doi:10.1200/JCO.1999.17.1.4 PubMedGoogle ScholarCrossref
    12.
    Dillman  RO, Seagren  SL, Propert  KJ,  et al.  A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non–small-cell lung cancer.   N Engl J Med. 1990;323(14):940-945. doi:10.1056/NEJM199010043231403 PubMedGoogle ScholarCrossref
    13.
    Cheung  P, Faria  S, Ahmed  S,  et al.  Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non–small cell lung cancer: NCIC CTG BR.25.   J Natl Cancer Inst. 2014;106(8):dju164. doi:10.1093/jnci/dju164 PubMedGoogle Scholar
    14.
    Bradley  JD, Scott  CB, Paris  KJ,  et al.  A phase III comparison of radiation therapy with or without recombinant beta-interferon for poor-risk patients with locally advanced non–small-cell lung cancer (RTOG 93-04).   Int J Radiat Oncol Biol Phys. 2002;52(5):1173-1179. doi:10.1016/S0360-3016(01)02797-3 PubMedGoogle ScholarCrossref
    15.
    Amini  A, Lin  SH, Wei  C, Allen  P, Cox  JD, Komaki  R.  Accelerated hypofractionated radiation therapy compared to conventionally fractionated radiation therapy for the treatment of inoperable non–small cell lung cancer.   Radiat Oncol. 2012;7:33. doi:10.1186/1748-717X-7-33 PubMedGoogle ScholarCrossref
    16.
    Nguyen  LN, Komaki  R, Allen  P, Schea  RA, Milas  L.  Effectiveness of accelerated radiotherapy for patients with inoperable non–small cell lung cancer (NSCLC) and borderline prognostic factors without distant metastasis: a retrospective review.   Int J Radiat Oncol Biol Phys. 1999;44(5):1053-1056. doi:10.1016/S0360-3016(99)00130-3 PubMedGoogle ScholarCrossref
    17.
    Gomez  DR, Gillin  M, Liao  Z,  et al.  Phase 1 study of dose escalation in hypofractionated proton beam therapy for non–small cell lung cancer.   Int J Radiat Oncol Biol Phys. 2013;86(4):665-670. doi:10.1016/j.ijrobp.2013.03.035 PubMedGoogle ScholarCrossref
    18.
    Westover  KD, Loo  BW  Jr, Gerber  DE,  et al.  Precision hypofractionated radiation therapy in poor performing patients with non–small cell lung cancer: phase 1 dose escalation trial.   Int J Radiat Oncol Biol Phys. 2015;93(1):72-81. doi:10.1016/j.ijrobp.2015.05.004 PubMedGoogle ScholarCrossref
    19.
    Owen  JR, Ashton  A, Bliss  JM,  et al.  Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial.   Lancet Oncol. 2006;7(6):467-471. doi:10.1016/S1470-2045(06)70699-4 PubMedGoogle ScholarCrossref
    20.
    Koay  EJ, Hanania  AN, Hall  WA,  et al.  Dose-escalated radiation therapy for pancreatic cancer: a simultaneous integrated boost approach.   Pract Radiat Oncol. 2020;10(6):e495-e507. doi:10.1016/j.prro.2020.01.012 PubMedGoogle ScholarCrossref
    21.
    Tao  R, Krishnan  S, Bhosale  PR,  et al.  Ablative radiotherapy doses lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis.   J Clin Oncol. 2016;34(3):219-226. doi:10.1200/JCO.2015.61.3778 PubMedGoogle ScholarCrossref
    22.
    Bentzen  SM, Agrawal  RK, Aird  EG,  et al; START Trialists’ Group.  The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial.   Lancet. 2008;371(9618):1098-1107. doi:10.1016/S0140-6736(08)60348-7 PubMedGoogle Scholar
    23.
    Haviland  JS, Owen  JR, Dewar  JA,  et al; START Trialists’ Group.  The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials.   Lancet Oncol. 2013;14(11):1086-1094. doi:10.1016/S1470-2045(13)70386-3 PubMedGoogle ScholarCrossref
    24.
    Zelen  M.  The randomization and stratification of patients to clinical trials.   J Chronic Dis. 1974;27(7-8):365-375. doi:10.1016/0021-9681(74)90015-0 PubMedGoogle ScholarCrossref
    ×