This nonrandomized controlled trial aims to determine the maximum tolerated dose and use of hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy boost for patients with locally advanced, unresectable non–small cell lung cancer (NSCLC).
Key Points
Question
What is the maximum tolerated dose of hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy boost for patients with locally advanced, unresectable non–small cell lung cancer (NSCLC)?
Findings
In this early-phase, dose-escalation nonrandomized controlled trial of 28 patients with NSCLC, the maximum tolerated dose was not exceeded. Patients advanced to the high-dose cohort (75 Gy in 15 fractions), though this was met with 2 events of grade 5 toxic effects; patients in the intermediate-dose cohort (70 Gy in 15 fractions) achieved 2-year local control of 85.7% without any grade 3 or higher toxic effects.
Meaning
Hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy boost to 70 Gy in 15 fractions holds promise as an effective and well-tolerated regimen for further exploration and integration with immunotherapy in patients with locally advanced, unresectable NSCLC.
Abstract
Importance
Intrathoracic progression remains the predominant pattern of failure in patients treated with concurrent chemoradiation followed by a consolidation immune checkpoint inhibitor for locally advanced, unresectable non–small cell lung cancer (NSCLC).
Objective
To determine the maximum tolerated dose (MTD) and use of hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy (SABR) boost.
Design, Setting, and Participants
This was an early-phase, single-institution, radiation dose-escalation nonrandomized controlled trial with concurrent chemotherapy among patients with clinical stage II (inoperable/patient refusal of surgery) or III NSCLC (American Joint Committee on Cancer Staging Manual, seventh edition). Patients were enrolled and treated from May 2011 to May 2018, with a median patient follow-up of 18.2 months. Patients advanced to a higher SABR boost dose if dose-limiting toxic effects (any grade 3 or higher pulmonary, gastrointestinal, or cardiac toxic effects, or any nonhematologic grade 4 or higher toxic effects) occurred in fewer than 33% of the boost cohort within 90 days of follow-up. The current analyses were conducted from January to September 2023.
Intervention
All patients first received 4 Gy × 10 fractions followed by an adaptive SABR boost to residual metabolically active disease, consisting of an additional 25 Gy (low, 5 Gy × 5 fractions), 30 Gy (intermediate, 6 Gy × 5 fractions), or 35 Gy (high, 7 Gy × 5 fractions) with concurrent weekly carboplatin/paclitaxel.
Main Outcome and Measure
The primary outcome was to determine the MTD.
Results
Data from 28 patients (median [range] age, 70 [51-88] years; 16 [57%] male; 24 [86%] with stage III disease) enrolled across the low- (n = 10), intermediate- (n = 9), and high- (n = 9) dose cohorts were evaluated. The protocol-specified MTD was not exceeded. The incidences of nonhematologic acute and late (>90 days) grade 3 or higher toxic effects were 11% and 7%, respectively. No grade 3 toxic effects were observed in the intermediate-dose boost cohort. Two deaths occurred in the high-dose cohort. Two-year local control was 74.1%, 85.7%, and 100.0% for the low-, intermediate-, and high-dose cohorts, respectively. Two-year overall survival was 30.0%, 76.2%, and 55.6% for the low-, intermediate-, and high-dose cohorts, respectively.
Conclusions and Relevance
This early-phase, dose-escalation nonrandomized controlled trial showed that concurrent chemoradiation with an adaptive SABR boost to 70 Gy in 15 fractions with concurrent chemotherapy is a safe and effective regimen for patients with locally advanced, unresectable NSCLC.
Trial Registration
ClinicalTrials.gov Identifier: NCT01345851
Introduction
In the pre-PACIFIC era,1 unresectable, locally advanced non–small cell lung cancer (NSCLC) was characterized by a poor prognosis. Five-year overall survival (OS) rates for patients treated with definitive concurrent chemoradiation (cCRT) ranged from 15% to 20%.2,3 Efforts to improve locoregional control with dose-escalated conventional fractionation were explored by multiple prospective studies and ultimately met with poor results, establishing a total dose to 60 Gy as standard of care.4,5 Rationale for inferior long-term progression-free survival (PFS) and OS observed in the dose-escalation arm of RTOG 0617 was likely multifactorial and evidenced by higher rates of grade 5 treatment-related toxic effects, chemotherapy incompletion, cardiopulmonary toxic effects, and target undercoverage to meet organ-at-risk (OAR) constraints.6
To address the aforementioned challenges seen with conventionally fractionated dose escalation, there is growing interest in dose escalation with respect to biologic effective dose (BED). First, as evidenced by the excellent long-term local control (LC) observed with stereotactic ablative radiotherapy (SABR) in the treatment of early-stage NSCLC,7 a more hypofractionated approach by increasing the dose per fraction beyond 2 Gy may improve locoregional control in locally advanced disease. Attempting to deliver doses greater than 1.8 to 2 Gy per fraction in locally advanced NSCLC began in the early 2000s, but subsequent phase 1 and 2 trials8,9,10,11,12,13,14 yielded inconsistent results and significant toxic effects. Second, using 18F-fludeoxyglucose–positron emission tomography (FDG-PET)-based adaptive radiotherapy (RT) midradiation course may identify and target residual metabolically active tumor, enable shrinking target volumes, and facilitate a tailored stereotactic boost for durable disease control.
In this single-institution, early-phase radiation dose-escalation nonrandomized controlled trial, our hypothesis focused on harnessing the technical benefits of SABR, thoughtful margin design, and biological adaptation to reduce toxic effects, improve outcomes, and shorten the overall duration of treatment in locally advanced NSCLC. We therefore sought to determine the maximum tolerated dose (MTD) in the use of definitive hypofractionated cCRT with an adaptive SABR boost (HyCRT-SABR).
Methods
Patient Eligibility
Institutional review board approval was obtained from the University of California, Los Angeles and Data and Safety Monitoring Board monitoring put in place. At the University of California, Los Angeles, any patient 18 years or older with a Karnofsky Performance Scale score of 70 or higher and considering RT for histologically confirmed clinical stage II NSCLC with documented medical inoperability/patient refusal of surgery or clinical stage III NSCLC, per the American Joint Committee on Cancer Staging Manual, seventh edition, were eligible for this trial.15 Exclusion criteria included previous thoracic RT, active infection requiring antibiotics, and use of concurrent gemcitabine-based chemotherapy during RT. Written informed consent was obtained from all study participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.
Study Design and Treatment Protocol
This study was designed as a single-cohort, open-label, RT dose-escalation trial with concurrent chemotherapy. All patients first received a base dose of 4 Gy × 10 fractions followed by an adaptive SABR boost to residual, metabolically active disease (based on an interim FDG-PET/computed tomography [CT]) without treatment break. The SABR boost consisted of an additional 25 Gy (low, 5 Gy × 5 fractions), 30 Gy (intermediate, 6 Gy × 5 fractions), or 35 Gy (high, 7 Gy × 5 fractions) in accordance with the patient’s assigned dose-escalation boost cohort (Figure 1). Between 7 and 15 patients were enrolled into each boost cohort, depending on the sequence and incidence of treatment-related dose-limiting toxic effects (DLTEs) during cCRT and the risk-assessment period (90 days of follow-up). Within each boost cohort, if none of the first 7 patients, 2 or fewer of the first 9 patients, or 3 or fewer of the first 12 patients experienced a DLTE during the risk-assessment waiting period, then the SABR boost would proceed to the next dose level. The study was designed to close if any of the following events occurred: (1) an MTD was reached or (2) the highest protocol dose level was treated and tolerated. See Supplement 1 for the full trial protocol.
Figure 1. Trial Flow Diagram.
4DCT indicates 4-dimensional computed tomography; FDG-PET/CT, 18F-fludeoxyglucose–positron emission tomography/computed tomography; NSCLC, non–small cell lung cancer; RT, radiotherapy.
RT and Systemic Therapy Specifications
Patients were immobilized using a custom vacuum bag or equivalent immobilization device for simulation and treatment planning with FDG-PET/CT and 4-dimensional CT with intravenous contrast (if eligible). An FDG-PET–based gross target volume and initial internal target volume (iITV) were contoured, then expanded 5 mm to form the initial planning target volume (PTV1). This was prescribed to 4 Gy × 10 fractions for all enrolled patients. Smaller PTV1 margins (<5 mm) were allowed at the treating physician’s discretion depending on individual anatomy and target proximity to OARs. Elective nodal irradiation of uninvolved mediastinal nodal stations was not permitted.
After the eighth or ninth fraction, a restaging FDG-PET/CT and 4-dimensional CT simulation (omission of FDG-PET/CT permissible at the treating physician’s discretion) was obtained to plan the adaptive 5-fraction SABR boost. On the resimulation scan, an ITV of the residual metabolically active disease was contoured and designated as the boost ITV (bITV), which directly formed the PTV2, without additional margin expansion. Participants received a total prescribed dose of 65, 70, or 75 Gy in 15 fractions, depending on which phase of the dose-escalation protocol the patient was enrolled in.
For planning purposes, the initial ITV without additional margin was used to plan the theoretical boost, representing a “worst-case” boost plan, assuming no metabolic treatment response after 40 Gy. The cumulative dosimetry from the first 10 fractions plus the worst-case 5-fraction boost served as the basis to evaluate whether a plan optimally met dosimetric constraints and planning parameters. Goal dose coverage was at least 95% of the PTV1 and PTV2 to receive 100% of the dose. OAR dose constraints used to assess the cumulative dosimetry included a spinal cord dose maximum (Dmax) of less than 40 Gy, esophagus mean dose less than 34 Gy, heart/pericardium mean dose less than 38 Gy, normal lung V20Gy less than 40%, mean lung dose less than 20 Gy, brachial plexus V65Gy less than 5 cc, tracheal/bronchial tree V75Gy less than 10 cc, and skin V75Gy less than 5 cc.
Chemotherapy
Carboplatin and paclitaxel doublet chemotherapy was administered once weekly at a maximal dose of the area under the curve of 2 and 45 mg/m2, respectively. Patients who received additional standard platinum-based doublet chemotherapy were required to observe a 2-week treatment holiday following cCRT. The choice of consolidation chemotherapy was at the discretion of the treating medical oncologist.
Objectives and Toxic Effect Evaluation
The primary objective was to determine the MTD (defined as the highest total dose in which <33% of patients experienced a DLTE within the 90-day risk-assessment period). This was achieved by either reaching the MTD or a total dose of 75 Gy (high-dose cohort), whichever came first, by escalating the dose per fraction of the SABR boost. DLTE was defined by (1) treatment-related grade 3 or higher pulmonary, upper gastrointestinal, or cardiac toxic effect, or (2) any nonhematologic treatment-related grade 4 or higher toxic effect. Toxic effects were graded by the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4, and all reported DLTEs were verified by the principal investigator (P.L.) and the Data and Safety Monitoring Board.
Secondary objectives included evaluation of LC, PFS (per Response Evaluation Criteria in Solid Tumors, version 1.1), lung cancer disease-specific survival (DSS), and OS. Additionally, serum inflammatory biomarkers were collected at 3 time points (before, during, and after cCRT) to correlate with incidence of treatment-related pneumonitis and esophagitis for future biomarker studies.
Follow-Up
Follow-up occurred weekly during cCRT. The first posttreatment visit took place 4 to 6 weeks after completion of cCRT, with a restaging FDG-PET/CT at 3 months. Subsequent FDG-PET/CT scans were obtained once a year with interval CT chest, abdomen, and pelvis scans every 3 months for the first 2 years. In the third year, follow-up visits and imaging were based on the treating physician’s preference in compliance with standard of care.16
Statistical Analysis
Continuous data were summarized using the median and range unless otherwise specified. Time to event was measured from trial enrollment. Kaplan-Meier estimates were used to calculate LC, PFS, OS, and DSS, and compared using the log-rank test. One-way analysis of variance was used to assess differences in iITV, PTV1, and bITV among the different boost cohorts. Patients without a known date or cause of death were censored at date of last follow-up and excluded in the DSS analysis, respectively. A sensitivity analysis was completed to evaluate the overall robustness of these findings, as well as the potential confounding effect of treatment volumes on outcomes. The bITV volumes were divided into 2 groups using the median bITV and divided into 4 groups by isolating the upper quartile. The association of these bITV groupings on the primary and secondary outcomes were then assessed. Statistical significance of toxic effects was assessed using the χ2 test in all cases. R, version 4.1.0 (R Foundation for Statistical Computing), was used for all analyses, and a 1-sided P < .05 was considered statistically significant. One patient withdrew from the study prior to treatment and was excluded from all analyses.
Results
Patient Characteristics
Twenty-eight patients were enrolled and treated between May 2011 and May 2018, with the first 10 patients assigned to the low-dose cohort, the subsequent 9 patients assigned to the intermediate-dose cohort, and the final 9 patients assigned to the high-dose cohort. More than half of study participants were male (n = 16 [57%]), with a median (range) age of 70 (51-88) years and KPS score of 80 (70-100). The majority of patients (n = 24 [86%]) were diagnosed with unresectable stage III disease. The median (range) iITV was 74.9 (7.5-591.4) cc, with a corresponding PTV1 of 177.3 (29.6-850.3) cc and bITV of 56.3 (3.6-576.6) cc. No statistically significant differences in iITV, PTV1, or bITV were identified between boost-dose cohorts. Most initial and adaptive boost plans included central and ultracentral targets. The median (IQR) percentage of remaining FDG-active tumor (bITV/iITV) after interim FDG-PET/CT for all patients was 83.3% (60.5%-94.8%). Six patients (21%) received consolidation carboplatin/paclitaxel, and a single patient (the final participant enrolled) received durvalumab, while no other patients received consolidation immunotherapy. All patients completed cCRT according to protocol with an interim restaging FDG-PET/CT, and apart from 1 patient in the low-dose cohort, all patients received concurrent chemotherapy. Table 1 summarizes the detailed patient characteristics. Median (range) follow-up was 18.2 (1.8-99.7) months for the entire cohort.
Table 1. Patient Characteristics for All Study Participants.
| Characteristic | No. (%) | |||
|---|---|---|---|---|
| Total (N = 28) | Low-dose cohort (n = 10) | Intermediate-dose cohort (n = 9) | High-dose cohort (n = 9) | |
| Age, median (range), y | 70 (51-88) | 72 (51-84) | 71 (60-88) | 69 (60-84) |
| Sex | ||||
| Female | 12 (43) | 6 (60) | 3 (33) | 3 (33) |
| Male | 16 (57) | 4 (40) | 6 (67) | 6 (67) |
| KPS score, median (range) | 80 (70-100) | 80 (70-100) | 80 (80-100) | 80 (80-100) |
| Histology | ||||
| Squamous cell carcinoma | 10 (36) | 6 (60) | 2 (22) | 2 (22) |
| Adenocarcinoma | 18 (64) | 4 (40) | 7 (78) | 7 (78) |
| Oncogenic mutation status (EGFR or ALK) | ||||
| Yes | 4 (14) | 1 (4) | 1 (4) | 2 (7) |
| No | 17 (61) | 3 (11) | 7 (25) | 7 (25) |
| Unknown | 7 (25) | 6 (21) | 1 (4) | 0 |
| T stagea | ||||
| 1 | 8 (29) | 1 (4) | 4 (14) | 3 (11) |
| 2 | 10 (36) | 3 (11) | 3 (11) | 4 (14) |
| 3 | 6 (21) | 4 (14) | 1 (4) | 1 (4) |
| 4 | 4 (14) | 2 (7) | 1 (4) | 1 (4) |
| N stagea | ||||
| 0 | 3 (11) | 1 (4) | 2 (7) | 0 |
| 1 | 3 (11) | 1 (4) | 1 (4) | 1 (4) |
| 2 | 15 (54) | 4 (14) | 4 (14) | 7 (25) |
| 3 | 7 (25) | 4 (14) | 2 (7) | 1 (4) |
| Group stagea | ||||
| IIA | 3 (11) | 1 (10) | 2 (22) | 0 |
| IIB | 1 (4) | 1 (10) | 0 | 0 |
| IIIA | 14 (50) | 2 (20) | 5 (56) | 7 (78) |
| IIIB | 10 (36) | 6 (60) | 2 (22) | 2 (22) |
| Median initial ITV, cc | 74.9 | 131.2 | 56.3 | 71.8 |
| Median boost ITV, cc | 56.3 | 76.4 | 45.3 | 64.4 |
| Follow-up, median (range), mo | 18.2 (1.8-99.7) | 14.3 (4.9-55.4) | 41.7 (1.8-99.7) | 24.2 (2.1-77.3) |
| Total dose, Gy | NA | 65 | 70 | 75 |
| No. of fractions | NA | 15 | 15 | 15 |
| Consolidation treatment | ||||
| Carboplatin/paclitaxel | 6 (21) | 2 (20) | 3 (33) | 1 (11) |
| Durvalumab | 1 (4) | 0 | 0 | 1 (11) |
Abbreviations: ITV, internal target volume; KPS, Karnofsky Performance Scale; NA, not applicable.
Per the American Joint Committee on Cancer Staging Manual, seventh edition.
Toxic Effects
The cumulative incidences of nonhematologic acute and late grade 3 or higher toxic effects were 11% and 7%, respectively (Figure 2). In the low-dose cohort, 1 event of acute grade 3 bronchial stenosis (Dmax, 69.0 Gy; V62Gy of 3.9 cc; V75Gy of 0 cc) with right lower-lobe collapse and 1 event of late grade 3 esophageal stenosis with ulceration (Dmax, 70.7 Gy; V48Gy of 1.1 cc; mean dose of 25.0 Gy) were observed. There were no grade 4 or 5 toxic effects in the low-dose cohort. Notably, there were no grade 3 or higher toxic effects (acute or late) observed in the intermediate-dose cohort. The brunt of grade 3 or higher toxic effects was borne by the high-dose cohort (eTable 1 in Supplement 2). On plan evaluation for the 2 events of grade 5 pulmonary toxic effects, the mean lung dose was 16.1 Gy and 17.4 Gy, along with V20Gy values of 32.6% and 33.7%, respectively. The cumulative treatment-related mortality was 7% (n = 2), with both deaths occurring in the high-dose cohort. Selected dosimetric parameters for patients who did not develop any form of grade 3 or higher toxic effects included a median (IQR) mean lung dose of 9.4 (7.8-14.1) Gy, lung V20Gy of 12.7% (10.8%-19.0%), bronchial tree Dmax of 71.5 (66.1-75.1) Gy, esophagus Dmax of 57.7 (37.9-64.4) Gy, and a mean esophagus dose of 12.6 (8.1-21.2) Gy.
Figure 2. Toxic Effects Stratified by Boost Cohort.
Int indicates intermediate.
Although there were no statistically significant differences in toxic effects identified among the 3 cohorts, the high-dose cohort accounted for the majority of grade 3 or higher toxic effects (eTable 1 in Supplement 2). Most patients (n = 25 [89%]) experienced some form of acute grade 1 or 2 toxic effect. Late grade 1 or 2 toxic effects were observed in 17 patients (63%) (eFigure 1 and eTable 2 in Supplement 2). The study did not reach the MTD, and all 3 dose-escalation cohorts were completed with limited DLTEs. Following a sensitivity analysis, there were no statistically significant differences in either acute or late toxic effects when the bITV was categorized by the median (56.3 cc) or quartile separated to isolate the upper quartile (≥106.7 cc) (eFigure 2 and eTable 3 in Supplement 2).
Secondary Outcomes
The median OS for all patients was 25.9 months, with 1- and 2-year pooled OS rates of 78.6% and 52.5%, respectively, and a 2-year DSS of 61.9% (eFigure 3 in Supplement 2). One- and 2-year pooled LC rates were 90.8% and 85.7%, respectively. Three patients developed local progression (2 in the low-dose cohort and 1 in the intermediate-dose cohort). The median PFS for all patients was 9.8 months, with 1- and 2-year pooled PFS rates of 35.1% and 22.0%, respectively. Two-year OS rates were 30.0%, 76.2%, and 55.6% for the low-, intermediate-, and high-dose cohorts, respectively (Table 2). There was a trend toward a statistical difference in OS among boost cohorts, with intermediate- and high-dose cohorts having a longer overall survival (Figure 3A). Two-year LC rates were 74.1%, 85.7%, and 100.0% for the low-, intermediate-, and high-dose cohorts, respectively; however, there was not a statistically significant difference in LC among the boost cohorts (Figure 3B). The majority of patients (n = 16 [57%]) progressed distantly. Two-year PFS rates were 0.0%, 37.5%, and 25.4%, in the low-, intermediate-, and high-dose cohorts, respectively; there was also not a statistically significant difference among the boost cohorts (Figure 3C). Sensitivity analysis examining the affect of bITV volumes on patient outcomes revealed similar LC and OS between the cohorts but improved PFS in patients with a smaller bITV (eTable 3 in Supplement 2).
Table 2. Summary of Kaplan-Meier Curve Outcomes.
| Outcome | % | |||
|---|---|---|---|---|
| All patients | Low-dose cohort | Intermediate-dose cohort | High-dose cohort | |
| Local control | ||||
| 1 y | 90.8 | 74.1 | 100.0 | 100.0 |
| 2 y | 85.7 | 74.1 | 85.7 | 100.0 |
| Progression-free survival | ||||
| Median, mo | 9.8 | 9.8 | 11.2 | 10.5 |
| 1 y | 35.1 | 15.0 | 50.0 | 38.1 |
| 2 y | 22.0 | 0.0 | 37.5 | 25.4 |
| Overall survival | ||||
| Median, mo | 25.9 | 15.3 | 42.5 | Not reached |
| 1 y | 78.6 | 70.0 | 88.9 | 77.8 |
| 2 y | 52.5 | 30.0 | 76.2 | 55.6 |
Figure 3. Kaplan-Meier Curves Stratified by Boost Cohort.
Int indicates intermediate; RT, radiotherapy.
Discussion
To our knowledge, this early-phase dose-escalation HyCRT-SABR trial investigated one of most intensive, definitive cCRT regimens evaluating hypofractionation and chemotherapy for unresectable, locally advanced NSCLC. This study advanced to the highest dose-escalation cohort (75 Gy in 15 fractions with an adaptive stereotactic boost of 7 Gy × 5 fractions); however, it was met with 2 treatment-related grade 5 events. At a median follow-up of 3.5 years for the intermediate-dose cohort, patients treated with 70 Gy in 15 fractions exhibited the most promising therapeutic ratio, indicated by a favorable toxic effects profile and a trend toward improved LC. Nevertheless, these results should be approached with caution due to the limited sample size. The present findings suggest that increasing the BED through hypofractionation may enhance LC, but this approach is limited by grade 5 toxic effects beyond a certain BED, which was 70 Gy in 15 fractions in this study.
While conventional RT to a total dose of 60 Gy with concurrent platinum-based doublet chemotherapy has been the standard of care for locally advanced NSCLC for many decades,16 persistent patterns of locoregional failure and suboptimal outcomes drove the investigation of alternative treatments. The landmark PACIFIC trial demonstrated meaningful improvements in PFS and OS with the addition of consolidation durvalumab after definitive CRT.17 Although paradigm changing, almost half of patients who received durvalumab experienced progression at 2 years largely from intrathoracic failures.18 This failure pattern underscores the ongoing need to improve locoregional control in the present time despite recent paradigm shifts, including further investigation of concurrent immune checkpoint inhibitors (ICIs) with cCRT19,20 and altered fractionation schema with systemic therapy. Hypofractionation has been adopted as a strategy to improve local control across many disease sites.21,22,23 In addition to patient convenience and cost-effectiveness, achieving BED escalation while truncating total treatment time may reduce tumor repopulation risk and acute radiation effects.24,25,26
This study exceeded previous dose-escalation attempts (eTable 4 in Supplement 2) and used an innovative metabolic-based adaptive SABR boost (eFigure 4 in Supplement 2) to mitigate toxic effects. Similar techniques have shown promise in previous investigations.12,27,28,29,30,31,32 We believe that these findings are notable for several reasons. This study’s pooled and individual 2-year LC rates surpass historical standards set by RTOG 0617, suggesting the potential for enhancing LC with higher BED, a consideration that remains pertinent in the era of consolidation ICIs. Furthermore, the 4 Gy or higher per fraction fractionation scheme, administered concurrently with platinum-based chemotherapy, supports an acceptable safety profile for combined treatment to central/ultracentral targets. Lastly, though we did not exceed the protocol-specified DLTE limit and advanced to the high-dose cohort, 2 treatment-related grade 5 events occurred, despite advanced image guidance and planning techniques, an adaptive SABR boost, and adherence to dosimetric criteria. These findings underscore the importance of caution against dose escalation beyond the BED equivalent of 70 Gy in 15 fractions in future hypofractionation trials.
Limitations
Limitations include the nonrandomized design, limited sample size, and need for longer follow-up time to assess late toxic effects, especially in the high-dose cohort, given later trial enrollment and higher late toxic effect risk based on radiobiological principles. Additionally, due to this trial’s nonrandomized design, there were fewer patients in the intermediate-dose cohort with stage III disease and lower iITV/bITV volumes, which may have favorably influenced dosimetry and toxic effect outcomes; however, a statistically significant difference in bITV volumes across cohorts was not detected. Lastly, since the study completed accrual shortly after the publication of PACIFIC,1 only the final patient received consolidation durvalumab. This could have limitations in assessing toxic effect outcomes, as it may not consider the dynamics of hypofractionated cCRT with consolidation ICIs. Although just a single account, it is noteworthy that the patient who received durvalumab experienced only acute grade 2 esophagitis and did not develop any late treatment-related toxic effects. Nevertheless, we assert that the fundamental concept of leveraging hypofractionation to enhance LC addresses a pressing and ongoing need to reduce intrathoracic failures.
Conclusions
In this nonrandomized controlled trial, patients in the intermediate-dose cohort, treated with 70 Gy in 15 fractions with an adaptive SABR boost and concurrent platinum-based chemotherapy, achieved excellent LC without severe acute or late grade 3 or higher toxic effects at a median follow-up of 3.5 years. The results of HyCRT-SABR are notable because (1) biologically guided RT may now be enabled with devices that combine a linear accelerator with FDG-PET/CT guidance, (2) they support active phase 2 efforts to study definitive hypofractionated RT alone followed by consolidation ICIs (SWOG S1933, DUART, NRG-LU004),33,34,35 and (3) they encourage exploration of higher dose escalation with concurrent sensitizing chemotherapy in future prospective trials.
Trial Protocol
eTable 1. Events of Grade ≥ 3 Toxicity, Stratified by Boost Cohort
eTable 2. Events of Grade ≤ 2 Toxicity, Stratified by Boost Cohort
eTable 3. Sensitivity Analysis of Boost ITV (bITV) Split by the Median (56.3 cc) or Upper Quartile (≥106.7 cc) into Low and High Groups
eTable 4. Selected Prior Studies Evaluating Definitive Hypofractionation for Locally Advanced Non-Small Cell Lung Cancer
eFigure 1. Highest Acute (A) and Late (B) Toxicity Grade per Patient Stratified by Boost Cohort
eFigure 2. Comparison of Acute and Late Toxicity (Highest Grade per Patient) when Boost ITV is Split by the Median (56.3 cc) (A) or Upper Quartile (large bITV ≥106.7 cc) (B)
eFigure 3. Local Control (A), Progression-Free Survival (B), and Overall Survival (C) for All Patients (n=28)
eFigure 4. Clinical IIIA (T1bN2M0) adenocarcinoma of the LUL with PETCT at time of simulation scan (A) and original base plan to receive 40 Gy in 10 fractions (B) with marked radiographic response upon mid-treatment PETCT (SUV decrease from 8.9 to 3.3 in aortopulmonary window lymph nodes) (C) facilitating reduction of treatment volumes to receive an adaptive SABR boost (30 Gy in 5 fractions) to the FDG-PET/CT avid disease alone (D)
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eTable 1. Events of Grade ≥ 3 Toxicity, Stratified by Boost Cohort
eTable 2. Events of Grade ≤ 2 Toxicity, Stratified by Boost Cohort
eTable 3. Sensitivity Analysis of Boost ITV (bITV) Split by the Median (56.3 cc) or Upper Quartile (≥106.7 cc) into Low and High Groups
eTable 4. Selected Prior Studies Evaluating Definitive Hypofractionation for Locally Advanced Non-Small Cell Lung Cancer
eFigure 1. Highest Acute (A) and Late (B) Toxicity Grade per Patient Stratified by Boost Cohort
eFigure 2. Comparison of Acute and Late Toxicity (Highest Grade per Patient) when Boost ITV is Split by the Median (56.3 cc) (A) or Upper Quartile (large bITV ≥106.7 cc) (B)
eFigure 3. Local Control (A), Progression-Free Survival (B), and Overall Survival (C) for All Patients (n=28)
eFigure 4. Clinical IIIA (T1bN2M0) adenocarcinoma of the LUL with PETCT at time of simulation scan (A) and original base plan to receive 40 Gy in 10 fractions (B) with marked radiographic response upon mid-treatment PETCT (SUV decrease from 8.9 to 3.3 in aortopulmonary window lymph nodes) (C) facilitating reduction of treatment volumes to receive an adaptive SABR boost (30 Gy in 5 fractions) to the FDG-PET/CT avid disease alone (D)
Data Sharing Statement