Accelerated Hypofractionated Radiotherapy for Locally Advanced NSCLC: A Systematic Review From the International Association for the Study of Lung Cancer Advanced Radiation Technology Subcommittee

Abstract

Introduction:

Accelerated hypofractionated radiotherapy has gained increasing interest for locally advanced NSCLC, as it can potentially increase radiobiologically effective dose and reduce health care resource utilization. Nevertheless, there is sparse prospective evidence supporting routine use of accelerated hypofractionation with or without concurrent chemotherapy. For this reason, the International Association for the Study of Lung Cancer Advanced Radiation Technology Subcommittee conducted a systematic review of prospective studies of accelerated hypofractionation for locally advanced NSCLC.

Methods:

A systematic search was conducted on Ovid MEDLINE, Ovid EMBASE, Wiley Cochrane Library, and ClinicalTrials.gov for English publications from 2010 to 2024 for prospective clinical trials and registries investigating accelerated hypofractionated radiotherapy defined as more than 2 Gy delivered in 10 to 25 fractions for non-metastatic locally advanced (stage III) NSCLC.

Results:

There were 33 prospective studies identified that met the criteria for inclusion. Of 14 prospective studies evaluating definitive accelerated hypofractionation (without concurrent chemotherapy), there were six prospective registries, seven phase 1 to 2 trials, and one phase 3 randomized clinical trial, with a median dose of 60 Gy delivered in a median of 16 fractions, median progression-free survival of 6.4 to 25 months, median survival of 6 to 34 months, and 0% to 8% severe grade ≥3 esophagitis. There were 19 studies evaluating accelerated hypofractionated chemoradiation with platinum doublet-based chemotherapy as the most common concurrent regimen. Of these accelerated hypofractionated chemoradiation studies, there were 18 phase 1 to 2 trials and one prospective registry with a median radiation dose of 61.6 Gy delivered in a median of 23 fractions, median progression-free survival of 10 to 25 months, median survival of 13 to 38 months, grade ≥3 esophagitis of 0% to 23.5%, and grade ≥3 pneumonitis of 0% to 11.8%.

Conclusions:

Despite the increasing use of accelerated hypofractionation for locally advanced NSCLC, the supporting randomized evidence remains sparse. Only one randomized clinical trial comparing 60 Gy in 15 fractions with 60 Gy in 30 fractions without concurrent chemotherapy did not reveal the superiority of accelerated hypofractionation. Therefore, the use of accelerated hypofractionated radiotherapy should be approached with caution, using advanced radiation techniques, especially with concurrent chemotherapy or targeted agents. Accelerated hypofractionated radiotherapy should be carefully considered alongside other multidisciplinary options and be further investigated through prospective clinical trials.

Introduction

Concurrent conventionally fractionated chemoradiation followed by consolidative programmed death-ligand 1 (PD-L1) immunotherapy is an established standard for locally advanced unresectable NSCLC. Nevertheless, there has been great interest in developing accelerated fractionated regimens for locally advanced NSCLC because of advances in radiation technique that have the potential to deliver equivalent or greater doses in fewer treatments. The most important rationale is that accelerated hypofractionation delivers a higher radiobiologically effective (RBE) dose because locoregional recurrence after standard fractionation (defined as approximately 60 Gy delivered at 1.8–2 Gy per fraction) remains a major pattern of failure.¹ This is particularly important for patients who are medically ineligible for concurrent chemotherapy for whom there are few long-term survivors with conventionally fractionated radiotherapy alone.^2,3 In addition to radiobiologic rationale, there are important health care delivery considerations as accelerated hypofractionation offers a more convenient and cost-effective approach for locally advanced NSCLC. Moreover, accelerated hypofractionation was a strategy to reduce health care resource utilization and improve social distancing at the height of the coronavirus disease-2019 pandemic.⁴

Although accelerated hypofractionation has been increasingly adopted for stage III, locally advanced NSCLC,⁵ prospective evidence supporting this approach as equivalent to conventionally fractionated radiotherapy remains sparse, especially when delivered with concurrent chemotherapy. To address the increasing use of accelerated hypofractionated radiotherapy, the International Association for the Study of Lung Cancer (IASLC) Advanced Radiation Technology and IASLC Board of Directors determined that a systematic review was warranted to identify the strength of evidence and guide practice. Herein, the IASLC Advanced Radiation Technology subcommittee has conducted a systematic review of prospective studies using accelerated hypofractionated radiotherapy for locally advanced NSCLC with or without concurrent chemotherapy.

Materials and Methods

A systematic search of Ovid MEDLINE, Ovid EMBASE, Wiley Cochrane Library, and ClinicalTrials.gov for publications and protocols in English from 2010 to 2024 was performed to identify prospective trials or registries using accelerated hypofractionated radiotherapy for nonmetastatic locally advanced unresectable NSCLC (Supplementary Appendix). Accelerated hypofractionated radiotherapy was defined as more than 2 Gy per fraction delivered in 10 to 25 fractions. The following search terms were included: “non-small-cell lung cancer,” “radiation dose hypofractionation,” “mini-beam,” “reduced fractionation,” “accelerated fractionation,” “accelerated radiotherapy,” “stage II,” “stage III,” “locally advanced NSCLC,” “unresectable,” and “non-metastatic,” using both subject headings and keywords, and the terms were combined using AND OR Boolean operators. Animal studies, in vitro studies, conference abstracts, review articles, conference abstracts, case reports, case series, and retrospective studies were excluded. Search results were then manually redacted to exclude studies that were not relevant including standard fractionation (>25 fractions), extreme hypofractionation or stereotactic body radiation therapy (<10 fractions), accelerated hyperfractionated radiotherapy, palliative radiotherapy regimens, nonprospective studies, non-NSCLC, and stage IV or oligometastatic disease (Fig. 1). Studies were evaluated for key outcomes including local control (LC), progression-free survival (PFS), survival, and severe toxicity defined as grade greater than or equal to 3. Linear quadratic modeling was used as previously reported to calculate biologically equivalent doses for tumor control,⁶ using an α:β ratio of 10 for lung cancer (Tables 1 and 2).^7–40

Figure 1.

PRISMA diagram. PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses.

Table 1.

Accelerated Hypofractionated Radiotherapy Alone as Definitive Treatment for Unresectable Locally Advanced NSCLC

RF	Authors (y)	Study Design	Radiation Fractionation (Technique)	N	Primary End Point	LC	PFS	OS	Key Toxicity Outcomes
7	Ohri et al.7 (2023)	Phase 2	48-55 Gy in 20 (photon) BED = 59.5-70.1 Gy	25	1-y PFS	Not reported	1 y: 76% Median: 26 mo	1 y: 92% 2 y: 76%	Grade ≥ 3 esophagitis: 4% Grade ≥ 3 pneumonitis: 4%
8	Iyengar et al.8 (2021)	Randomized phase 3	60 Gy in 15 vs. 60 Gy in 30 (IMRT) BED = 84 Gy	103	1-y survival	2 y: 85.8% vs. 66.1% (p = 0.34)	Median: 6.4 vs. 7.3 mo (p = 0.77)	Median: 8.2 vs. 10.6 mo (p = 0.17)	Any grade 2 52% vs. 23.9% (p = 0.006)
9	Aye et al.9 (2021)	Prospective registry	45 Gy in 15 (3D-CRT) BED = 58.5 Gy	65	N/A	6-wk: 100%	Not reported	Not reported	Grade 2 dysphagia: 4.62% No ≥ Grade 3
10	Zygogianni et al.10 (2020)	Prospective randomized	30 Gy in 13 vs. 17 Gy in 2 + 6 Gy (3D-CRT) BED = 36.9 Gy vs. 31.5 Gy + 9.6 Gy	29	PFS	Not reported	Median: 4.78 vs. 7.07 mo (p = 0.023)	Median: 7.43 vs. 8.67 mo (p = 0.231)	Mean RTOG grade 1.6 vs. 1.1 (p = 0.046)
11	Li et al.11 (2020)	Prospective registry	60 Gy in 15-20 (Tomotherapy) BED = 78-84 Gy	43	OS and PFS	3 y: 95.3%	Median: 25 mo	Median: 34.23 mo	N = 1 Grade 3 hematologic
12	Saitoh et al.12 (2018)	Phase 1	64 Gy in 16 (carbon ion) BED = 89.6 Gy	6	Toxicity	2 y: 100%	2 y: 50%	2 y: 33%	No ≥ Grade 3
13	Cagney et al.13 (2018)	Phase 2	60-72 Gy in 20-24 (3D-CRT) BED 60 Gy = 75-78 Gy BED 72 Gy = 90.4-94.5Gy	60	Toxicity	1 y: 63% 3 y: 43%	3 mo: 61%	Median: 13.6 mo	Acute grade 3 esophageal: 9% Late grade 3 esophageal: 7% Late grade 3 pulmonary: 8% Late grade 5 esophageal: 8%
14	Takahashi et al.14 (2015)	Phase 1-2	68 → 76 Gy in 16 dose escalation (carbon ion) BED = 96.9 Gy → 112.1 Gy	62	Phase 1: toxicity Phase 2: local control	2 y: 93.1%	Not reported	Median: 24.1 mo	N = 1 Grade 3 pneumonitis N = 1 Grade 3 tracheoesophageal fistula
15	Zhang et al.15 (2015)	Prospective registry	45 Gy in 15 to PTV 60Gy in 15 to CTV 75 Gy in 15 to GTV (IMRT) BED PTV = 58.5 Gy BED CTV = 84 Gy BED GTV = 112.5	28	N/A	1 y: 92% 2 y: 83% 3 y: 74%	3 y: 64%	3 y: 61%	No ≥ Grade 3
16	Westover et al.16 (2015)	Phase 1	50 → 60 Gy in 15 dose escalation (IMRT) BED = 66.7 Gy → 84 Gy	55	Toxicity	Not reported	Not reported	Median: 6 mo	N = 2 Grade ≥ 3 esophageal N = 2 Grade ≥ 3 dyspnea
17	Agolli et al.17 (2015)	Prospective registry	60 Gy in 20 3D-CRT BED = 78 Gy	60	N/A	2 y: 53%	Median: 12 mo	Median: 13 mo	N =3 Grade ≥ 3 esophagitis N = 4 Grade ≥ 3 pneumonitis
18	Gomez et al.18 (2013)	Phase 1	45 → 60 Gy in 15 dose escalation (Proton) BED = 58.5 Gy → 84 Gy	25	Toxicity	Not reported	Not reported	Not reported	N = 1 Grade ≥ 3 esophageal N = 1 Grade ≥3 pneumonitis
19	Cannon et al.19 (2013)	Phase 1	57 → 85.5 Gy in 25 dose escalation IMRT BED = 70 → 114.7 Gy	79	Toxicity	3-y estimate: ~60%	Not reported	Median: 16 mo	Maximum tolerated dose: 63.25 Gy N = 6 Any Grade ≥ 4 toxicities
20	Zhu et al.20 (2011)	Phase 2	50 Gy in 20 + 3 Gy (3D-CRT) BED = 62.5 Gy + 3.9 Gy = 66.4 Gy	34	Toxicity	1 y: 69.6% 3 y: 60.9%	Median: 10 mo	Median: 19 mo	N = 2 Grade ≥ 3 esophageal N = 1 Grade ≥3 pneumonitis

3D-CRT, three dimensional-conformal radiotherapy; BED, biologically equivalent dose; CTV, clinical target volume; GTV, gross tumor volume; IMRT, intensity modulated radiotherapy; LC, local control; N/A, not applicable; OS, overall survival; PFS, progression-free survival; PTV, planning target volume; RF, reference number; RTOG, Radiation Therapy Oncology Group.

Table 2.

Accelerated Hypofractionated Radiotherapy With Concurrent Chemotherapy as Definitive Treatment for Unresectable Locally Advanced NSCLC

RF	Authors (y)	Study Design (Concurrent CT)	Radiation Fractionation (Technique)	N	Primary End Point	LC	PFS	OS	Key Toxicity Outcomes
21	Wu et al.21 (2024)	Phase 1 (carboplatin and paclitaxel)	40 Gy in 10 (IMRT) → 25-35 Gy in 5 (SBRT) BED = 56 Gy → 37.5-59.5 Gy	28	Maximum tolerated dose	2 y: 85.7%	2-y: 22%	2 y: 52.5%	Treatment mortality: 7% Acute grade ≥ 3: 11% Late grade ≥ 3: 7%
22	Cooke et al.22 (2023)	Phase 2 randomized PET adapted vs. whole tumor (platinum doublet)	PET-adapted IMRT 72 → 129.6 Gy in 24 BED = 93.6 → 199.5 Gy	107	Freedom from local failure	1 y: 97%	1 y: 46% vs. 43%	Median: 18 mo	Grade ≥ 3 esophageal: 11% Grade ≥ 3 pneumonitis: 4%
23	Hoppe et al.23 (2022)	Phase 1-2 (platinum doublet)	60 Gy in 24 → 15 dose escalation (proton) BED = 75 → 84 Gy	28	Toxicity and Survival	Not reported	Median: 18 mo	Median: 34 mo	Grade ≥ 3 pulmonary: 14%
24	Contreras et al.24 (2022)	Phase 1 (carboplatin, paclitaxel)	52.5 → 60 Gy in 15 dose escalation (technique not reported) BED = 70.9 → 84 Gy	23	Toxicity	2-y: 84%	Not reported	2-y OS: 48%	N = 1 Grade ≥ 3 late pulmonary N = 1 Grade ≥ 3 late pneumonitis N = 1 Grade ≥ 3 vocal cord paralysis
25	Qiu et al.25 (2021)	Phase 2 (docetaxel, nedaplatin)	51 Gy in 17 Split course 15-18 Gy in 5-6 (IMRT) BED = 66.3 Gy + 19.5-23.4 Gy	89	PFS	Not reported	Median: 11 mo	Median: 27 mo	Grade ≥ 3 esophagitis: 16.9% Grade ≥ 3 pneumonitis: 7.9% Treatment-related mortality: 3.3%
26	Katsuta et al.26 (2021)	Phase 2 (multiple regimens)	60 Gy in 24 to 70 Gy in 28 at physician discretion (3D-CRT) BED = 75-87.5 Gy	36	PFS and safety	5 y: 61.9%	Median: 10.7 mo	5 y: 54.1%	Acute grade ≥ 3 esophagitis: 2.8% Grade ≥ pneumonitis: 8.3% Late grade ≥ 3 esophagitis: 2.8%
27	de Haan et al.27 (2021)	Phase 1 (olapirib with or without cisplatin)	66 Gy in 24 (IMRT) BED = 84.2 Gy	28	Toxicity	2 y: 84%	Median: 12 mo	Median: 28 mo	Any grade ≥ 4: 22%
28	van Diessen et al.28 (2020)	Randomized phase 2 (cisplatin with or without cetuximab)	66 Gy in 24 (IMRT) BED = 84.2 Gy	47	Prognostic value of post-treatment PET scan	2 y: 65.7%	Not reported	5 y: 34.8%	Not reported
29	Hoppe et al.29 (2020)	Phase 1 (platinum doublet)	60 Gy in 24 → 15 (proton) BED = 75 → 84 Gy	18	Toxicity	Not reported	Not reported	Not reported	N = 1 Grade ≥ 4 pneumonitis
30	Glinski et al.30 (2020)	Phase I-II (cisplatin, vinorelbine)	58.8 Gy in 21 (3D-CRT or IMRT) BED = 75.3 Gy	92	Toxicity/OS	Not reported	Median: 25 mo	Median: 38 mo	Acute Grade ≥ 3 esophagitis: 14% N = 5 Grade ≥ 3 pulmonary N = 7 Grade 5 any cause
31	Parisi et al.31 (2019)	Phase II (cisplatin, docetaxel)	25 Gy in 5 (IMRT) BED = 38.5 Gy	23	Objective response	Not reported	Median: 19.8 mo	Median: 23 mo	N = 1 Grade ≥ 3 cardiac N = 1 Grade ≥ 3 dyspnea
32	Urbanic et al.32 (2018)	Phase 1 (carboplatin, paclitaxel)	60 Gy in 27 → 20 (3D-CRT or IMRT) BED = 73.3 → 78 Gy	22	Toxicity	Not reported	Median: 12 mo	Median: 19 mo	Maximum tolerated dose: 60 Gy in 24 N = 3 Grade 5 any cause
33	Kim et al.33 (2017)	Phase 1 (cisplatin, etoposide)	48 Gy in 20 followed by boost 16.8 → 22.7 Gy in 7 dose escalation (IMRT) BED = 59.5 Gy → 28-30 Gy	12	Toxicity	1 y: 80.8%	Not reported	1 y: 58%	No Grade ≥ 3
34	Walraven Ivd et al.34 (2016)	Randomized phase 2 (with or without cetuximab)	66 Gy in 24 (3D-CRT or IMRT) BED = 84.2 Gy	102	OS	Not reported	Not reported	Median: 31.5 mo	Not reported
35	Roy et al.35 (2016)	Randomized phase 2 (with or without cisplatin)	60 Gy in 30 vs. 48 Gy in 20 (3D-CRT) BED = 59.5 Gy	36	Overall response	Not reported	Median: 5.4 vs. 17 mo (p = 0.053)	Median: 12.3 vs. 23.7 mo (p = 0.007)	Similar severe toxicity profile between arms
36	Ren et al.36 (2016)	Phase 2 (platinum doublet)	69 Gy in 23 (3D-CRT) BED = 89.7 Gy	12	Toxicity	1 y: 59.3%	Mean: 12.3 mo	Mean: 14.3 mo	N = 5 Grade ≥ 3 esophagitis
37	Zhu et al.37 (2014)	Phase 2 (cisplatin, vinorelbine)	50 Gy in 20 → 68 Gy in 26 dose escalation (3D-CRT) BED = 62.5 → 85.7 Gy	34	OS	Not reported	2 y: 29.8%	Median: 19 mo	Grade ≥ 3 pneumonitis: 11.8% Grade ≥ 3 esophagitis: 23.5%
38	Liu et al.38 (2013)	Prospective registry (carboplatin, vinorelbine)	60-75 Gy in 15-25 (3D-CRT) BED 60 Gy = 74.4-84 Gy BED 75 Gy = 97.5-112.5 Gy	26	Safety	Not reported	Median: 10 mo	Median: 13 mo	Grade ≥ 3 esophagitis: 15.4% Grade ≥ 3 pneumonitis: 7.7%
39	Lin et al.39 (2013)	Phase 1 (carboplatin, vinorelbine)	66 Gy in 22 → 72 Gy in 24 dose escalation (3D-CRT) BED = 85.8 → 93.6 Gy	13	Safety	Not reported	Median: 12 mo	Not reported	Maximum tolerated dose: 72 Gy N = 2 Grade ≥ 3 esophagitis N = 1 Grade ≥ 3 pneumonitis

3D-CRT, three dimensional-conformal radiotherapy; BED, biologically equivalent dose; CT, computed tomography; IMRT, intensity modulated radiotherapy; LC, local control; OS, overall survival; PET, positron emission tomography; PFS, progression-free survival; RF, reference number; SBRT, stereotactic body radiation therapy.

Results

Literature Search Results

The search identified 197 articles, of which 164 were manually excluded for not meeting the inclusion criteria (Fig. 1), which resulted in 33 prospective studies. Most studies were phase 1 to 2 trials (N = 25), or prospective registries (N = 7), and there was one phase 3 randomized controlled trial (RCT). The studies were classified by use of accelerated hypofractionated radiotherapy without concurrent chemotherapy (Table 1^7–20) or accelerated hypofractionated concurrent chemoradiation (Table 2^21–39). Radiation modalities in these studies included carbon ion therapy (n = 2), protons (n = 3), and photons (n = 28). Primary end points varied across studies, including overall survival, PFS, and determination of dose-limiting toxicity.

Accelerated Hypofractionated Radiotherapy

There were 14 prospective studies evaluating definitive accelerated hypofractionated radiotherapy for locally advanced NSCLC without concurrent chemotherapy, including six prospective registries and eight prospective clinical trials. Among these, one phase 3 RCT directly compared conventionally fractionated radiotherapy to a dose of 60 Gy in 30 fractions with accelerated hypofractionated radiotherapy to a dose of 60 Gy in 15 fractions.⁸ Among these studies, the median dose was 60 Gy, median number of fractions was 16, and median fraction size was 3.3 Gy. In addition, radiation technique was unspecified photons (n = 1), three dimensional-conformal radiotherapy (n = 5), intensity modulated radiotherapy (n = 5), carbon ion therapy (n = 2), and proton therapy (n = 1). Furthermore, LC was 43% to 100%, median PFS was 6.4 to 25 months (median = 10 mo), and median survival was 6 to 34 months (median = 14.8 mo). The most notable severe toxicity was grade ≥3 esophagitis, which occurred at a rate of 0% to 8% with sporadic cases of ≥3 pneumonitis reported.

Accelerated Hypofractionated Concurrent Chemoradiation

There were 19 prospective studies that used accelerated hypofractionated concurrent chemoradiation including 18 phase 1 to 2 trials and one prospective registry (Table 2^21–39). Median radiation dose was 61.5 Gy delivered in a median of 23 fractions, and median –fraction size was 2.8 Gy. The most used concurrent regimens were platinum doublets in 13 studies, single-agent cisplatin in one, poly-adenosine diphosphate-ribose-polymerase inhibition with olapirib in one, and the EGFR-directed antibody cetuximab in one. Consolidative PD-L1 immunotherapy was administered to three patients in a study by Hoppe et al.²³ Furthermore, among the studies reporting, LC at various time points was 59.35% to 85.7%, median PFS was 10 to 25 months (median = 12 mo), and median survival was 13 to 38 months (median = 23.7 mo). The severe toxicity profile included grade ≥3 esophagitis that occurred at rates of 0% to 23.5% and grade ≥3 pneumonitis that occurred at rates of 0% to 11.8%.

Discussion

With improvements in thoracic radiotherapy technique, there has been interest in accelerated hypofractionation to improve LC and convenience to patients with unresectable locally advanced NSCLC, especially for patients who are ineligible for concurrent chemotherapy. This interest was further augmented during the coronavirus disease 2019 pandemic to promote social distancing and reduce strain on health care system resources.⁴ Nevertheless, prospective evidence supporting routine use of accelerated hypofractionated radiotherapy for locally advanced NSCLC remains sparse. In this systematic review of modern accelerated hypofractionation for locally advanced NSCLC, we identified 33 prospective studies composed mostly of phase 1 to 2 trials with two RCTs.^8,35 Despite a paucity of evidence supporting accelerated hypofractionated radiotherapy from RCTs, this approach has been increasingly adopted worldwide. For context, it is noteworthy that in other disease sites, such as breast cancer,^41–43 prostate cancer,^44,45 and even glioblastoma multiforme,^46,47 mature results from RCTs often with non-inferiority end points were necessary before accelerated hypofractionation was routinely adopted. For this reason, we urge continued caution when using accelerated hypofractionated radiotherapy for locally advanced NSCLC and encourage continued exploration through prospective clinical trials to refine indications and planning constraints.

Accelerated Hypofractionated Radiotherapy

For frail patients who are not candidates for concurrent chemotherapy, definitive accelerated hypofractionated radiotherapy has emerged as an alternative to standard fractionation. As conventionally fractionated radiotherapy is unlikely to provide LC or cure for locally advanced NSCLC, accelerated hypofractionation provides a strategy to increase the RBE dose akin to concurrent chemotherapy. Among these prospective studies, the one phase 3 RCT comparing 60 Gy in 15 fractions with 60 Gy in 30 fractions was terminated early due to futility, ultimately revealing significantly worse grade ≥2 toxicity without oncologic benefit.⁸ Among the 14 prospective studies we identified in this population, it is notable that the median survival among them was 13.6 months. As these prospective trials were largely conducted before the advent of PD-L1 immunotherapy, we must emphasize that PD-L1 immunotherapy alone for metastatic NSCLC would be expected to have similar survival.^48,49 Thus, the use of accelerated hypofractionation for locally advanced NSCLC should be weighed against other multidisciplinary options, such as programmed cell death protein-1 or PD-L1 immunotherapy, which will yield similar outcomes and provide durable responses in a subset of patients. Findings from ongoing trials, such as the durvalumab after radiotherapy (DUART) trial⁵⁰ and NRG Oncology-LU004, are likely to provide further insight on combining PD-L1 immunotherapy with accelerated hypofractionated radiation. It is also notable that accelerated hypofractionation (60 Gy in 15 fractions) was recently removed from the NRG Oncology-LU004 amendment due to toxicity concerns after publication of the randomized trial by Iyengar et al.⁸

Given the frail nature of patients who are ineligible for concurrent chemotherapy, it is also important to carefully consider side effects and the quality of life of accelerated hypofractionation for locally advanced NSCLC. A prospective, single-center, phase 1 trial conducted by Cannon et al.¹⁹ revealed a maximum tolerated dose of 63.25 Gy with 2.53 Gy per fraction, with six cases of grade 4 to 5 pneumonitis with late occurrence beyond a year of follow-up. Westover et al.¹⁶ in another phase 1 trial revealed that escalation to 60 Gy in 15 fractions was associated with severe dyspnea and cases of fatal esophageal injury. Another phase 2 study revealed a clear relationship between severe esophageal toxicity and the length of the circumferential esophagus receiving 97% of the prescribed dose with a 4% rate of fatal toxicity if length exceeded 1 cm.¹³ As such, we recommend using advanced radiation technologies such as intensity modulated radiotherapy or particle therapy to avoid circumferential esophageal irradiation and constraining the maximum dose to the esophagus at less than 55 Gy in 15 to 20 fractions to mitigate risk of severe esophageal injury. Efforts should also be made to minimize the volume of the lung receiving 20 Gy (lung V20 Gy) and the volume of the heart receiving 20 to 60 Gy (heart V20–V60 Gy), based on emerging long-term evidence from NRG Oncology-RTOG 0617.⁵¹ Lastly, these toxicities should be balanced with the side effects of other multidisciplinary options such as PD-L1 immunotherapy for this frail population in multidisciplinary collaboration.

Accelerated Hypofractionated Chemoradiation

Although the benefit of concurrent chemotherapy with the standard fractionated radiation for locally advanced NSCLC has been found in numerous RCTs and corroborated by a landmark meta-analysis,² prospective evidence supporting accelerated hypofractionated chemoradiation is limited to registries and phase 1 to 2 trials (Table 2^21–39). Of these prospective studies, the median survival of 26 months was similar to what would be expected of standard chemoradiation in the pre–PD-L1 immunotherapy era.^52,53 As accelerated hypofractionation escalates RBE dose, caution is urged when using concurrent chemotherapy, particularly in patients with large and centrally located tumors that will expose the heart and esophagus to high radiation dose. For example, in the phase 1–2 study by Glinski et al.³⁰ using 58.8 Gy in 21 fractions with concurrent cisplatin and vinorelbine,³⁰ there were several treatment-related deaths from fatal hemoptysis and severe esophageal injury, along with at least five additional deaths within 1 year after treatment which were deemed probably treatment related without further attribution. In the CALGB 31102 phase 1 trial by Urbanic et al.,³² it is notable that with a total dose of 60 Gy, the safest degree of hypofractionation achievable was 60 Gy in 24 fractions (2.5 Gy per fraction). Perhaps, a randomized trial using the 60 Gy in 24-fraction regimen identified in CALGB 31102 is warranted using dosimetric insight gained from this trial. The observed benefits of integrating chemotherapy with hypofractionated radiation must therefore be pursued with caution, particularly in the absence of phase 3 RCTs validating this approach. In addition, given recent results of the PACIFIC-2 trial reported in abstract form revealing no discernable benefit for combining concurrent durvalumab with chemoradiation for locally advanced NSCLC, it may be necessary to revisit our radiobiologic understanding of concurrent programmed cell death protein 1 or PD-L1 immunotherapy with hypofractionated radiation.

Particle Therapy

Particle therapy has the potential to improve the therapeutic ratio by reducing normal tissue exposure through the Bragg peak and increasing RBE dose with heavy particles such as carbon,⁵⁴ and there have been a number of prospective studies exploring accelerated hypofractionated radiotherapy with particle therapy for locally advanced NSCLC. The findings of a phase 1 to 2 trial of hypofractionated proton therapy with concurrent chemotherapy to a dose of 60 Gy in 15 to 24 fractions had an encouraging median survival of 34 months with a 14% rate of grade greater than or equal to 3 pulmonary toxicity.²³ There has also been interest in carbon ion therapy for locally advanced NSCLC. Studies by Saitoh et al.¹² and Takahashi et al.¹⁴ have highlighted the effectiveness of hypofractionated carbon ion radiotherapy with LC rates exceeding 90% at 2 years without severe toxicity. In the PD-L1 immune therapy era, particle therapy may take on increasing importance to reduce radiation-induced lymphopenia and immunosuppression. The findings of these prospective pilot trials of particle therapy for accelerated hypofractionation for locally advanced NSCLC are promising, and further exploration in larger confirmatory trials is warranted.

Limitations

One of the primary limitations of our review is the inherent heterogeneity among the included studies regarding patient populations, treatment regimens, and outcome measures, which may limit the generalizability of our findings. Given the rapid evolution of radiation technologies and techniques, some of the included studies may not fully represent the current state of practice, thereby affecting the applicability of our results. Our analysis was also constrained by the reliance on aggregate data from published studies, limiting our ability to perform statistical analyses that account for individual patient characteristics and treatment variables. In addition, differences in the reporting of toxicity outcomes further complicate the synthesis of safety data. Finally, our review did not include a quality assessment of the included studies, which means that the strength of evidence supporting our conclusions may be influenced by the methodological quality of the individual studies.

Summary

Prospective evidence supporting accelerated hypofractionated radiotherapy with or without concurrent chemotherapy or targeted agents remains sparse despite the increasing utilization of this approach. Caution and further clinical research are needed to obtain supporting evidence from RCTs before adopting this strategy routinely for locally advanced NSCLC. Patients with large and centrally located tumors, in particular, are at increased risk of toxicity with accelerated hypofractionation, and advanced radiation technologies with strict dose constraints are recommended to maximize conformity. Promising results of proton and carbon ion therapy warrant cautious optimism, but high cost and limited availability will limit widespread adoption for the foreseeable future. Given the paucity of strong evidence supporting accelerated hypofractionation, clinicians should consider patient-specific factors and weigh other multidisciplinary options, such as PD-L1 immune therapy. It is essential to support continued prospective clinical trials to further evaluate the efficacy and safety of accelerated hypofractionation for locally advanced NSCLC.