Abstract
Background:
The utility of adaptive radiotherapy (ART) for head and neck squamous cell carcinoma (HNSCC) remains poorly defined. Daily ART (DART) promises both anatomic adaptation and planning target volume (PTV) reduction. In this prospective trial using cone-beam computed tomography-based ART, patients with HNSCC undergoing definitive radiotherapy (RT) or chemoradiotherapy (CRT) were randomly assigned to DART with reduced PTV margins or no ART with standard margins (image-guided RT [IGRT]).
Methods:
Eligibility criteria included a diagnosis of oropharynx, larynx, or hypopharynx HNSCC receiving definitive radiotherapy. All individuals received involved nodal radiotherapy per previous institutional study. The PTV margins were 1 mm (2 mm craniocaudal) vs 5 mm in the DART and IGRT arms, respectively. The primary endpoint was patient-reported xerostomia at 1 year, assessed with the Xerostomia Questionnaire (XQ).
Results:
Fifty patients were enrolled (26 IGRT, 24 DART) between March 2022 and June 2023. The cohort consisted of 38 oropharynx and 12 larynx/hypopharynx patients. The mean ipsilateral parotid gland, ipsilateral and contralateral submandibular gland doses were significantly lower with DART. There was significantly less acute dermatitis in the DART arm (Grade 0/1/2 0%/69%/31% vs 17%/75%/8% DART, P = .01) but no significant difference in any patient-reported outcome at 1 year. The adjusted difference in XQ score at 1 year was 10.0 (95% CI = −4.7 to 24.7, P = .58).
Conclusion:
Online DART for HNSCC is oncologically sound and improved acute toxicity profiles, but it did not reduce patient-reported xerostomia, the primary endpoint. Additional evidence is needed to understand the potential benefits and limitations of this paradigm, including its cost-effectiveness.
Trial registration:
clinicaltrials.gov identifier, NCT04883281
Introduction
The development of intensity-modulated radiation therapy (IMRT) revolutionized radiation oncology, because it allowed the delivery of highly conformal radiotherapy (RT) to fully irradiate the target while sparing normal tissues, termed organs-at-risk (OAR).1 Head and neck radiotherapy particularly benefited from the use of IMRT, which has been shown in randomized trials to reduce xerostomia.2,3 However, modern radiotherapy still delivers the same treatment over the whole course while the anatomy is constantly changing. There is also an unavoidable need to account for inter- and intra-fractional motion with a margin around the target, necessitating the irradiation of normal tissue.
Adaptive radiotherapy (ART) refers to a paradigm in which the radiotherapy plan changes over the course of treatment according to the patient’s updated anatomy.4 Although retrospective studies of head and neck ART have suggested improvements in dosimetric outcomes to the salivary glands, a prospective randomized trial of weekly ART for patients with oropharyngeal squamous cell carcinoma was negative for any meaningful improvement.5 Over the past several years, newer commercial ART systems have been developed with which online ART can be performed on cone-beam computed tomography (CBCT), such as with the Varian Ethos system. This linear accelerator allows for daily online ART (DART) based on that fraction’s CBCT.6 In addition to the hypothetical benefit of updating the radiation plan according to that day’s anatomy, DART also allows for minimization of the daily treatment margin to generate the planning target volume (PTV), to which the dose is targeted. Because a new plan is generated daily, only intra-fractional motion needs to be considered.
The dosimetric benefit of reducing the PTV margin from the standard 5 mm to 1 mm has been shown in prior studies,7,8 and the marked improvement in salivary gland dose suggests that patient-reported xerostomia may be improved with DART. In DARTBOARD (Daily Adaptive Radiotherapy to Better OAR Doses), a prospective phase II randomized trial of patients with head and neck squamous cell carcinoma (HNSCC) treated with RT or chemoradiotherapy (CRT), we compared the toxicity and patient-reported quality-of-life outcomes using standard PTV margins vs a near marginless PTV with DART on the Ethos system.
Methods
This prospective randomized phase II study was approved by the University of Texas Southwestern (UTSW) Institutional Review Board; all procedures were in accordance with the Helsinki Declaration, and the trial is registered on clinicaltrials.gov (NCT04883281).9 Patients were enrolled from March 2022 through June 2023 at UTSW. The study was funded by Varian Medical Systems.
Eligibility and treatment paradigm
Patients with newly diagnosed HNSCC of the oropharynx, larynx, or hypopharynx who were candidates for primary radiotherapy treatment were eligible for enrollment. All stages of cancer were included, except glottic larynx T1–2N0 disease. Patients were required to have a neck CT or MRI and 18F FDG PET-CT (positron emission tomography-CT). Patients were treated with RT or CRT as a function of stage (see Supplementary Methods).
In order to deliver a highly compact dose distribution and fully test the viability of DART with very narrow margins, all patients were treated with the involved nodal radiotherapy (INRT) scheme previously studied on our INRT-AIR trial.10 Neither arm received elective nodal irradiation (ENI).
Random assignment
After each patient was enrolled on the study, he/she was randomized to either standard, nonadaptive IMRT with daily image-guided radiotherapy (IGRT) or DART (Figure 1). Neither patients nor physicians were blinded to the treatment. Patients were stratified by oropharynx vs nonoropharynx site, with sequence generated in REDCap. The CONSORT diagram is shown in Figure 1.
Figure 1.
CONSORT diagram. Abbreviations: IGRT = image-guided radiotherapy (5 mm margins); DART = daily adaptive radiotherapy (1 mm margins); PRO = patient-reported outcomes.
Treatment
Treatment planning specifics are detailed in the Supplementary Methods. Patients on the IGRT arm were treated with IMRT and daily CBCT alignment on a Varian Halcyon machine. Adaptation on this arm was only allowed if felt to be clinically urgent (eg, dramatic weight or anatomic change for which standard replanning would be expected). Patients on the DART arm were treated on the Ethos system with daily adaptation. The PTV margins were 5 mm on the IGRT arm and 1 mm (2 mm superior/inferior) on the DART arm. A sample patient treated on the DART arm is shown in Figure S1, with an emulated IGRT plan. The patient’s radiation oncologist typically adapted his own cases, but there was cross-coverage if necessary. The Supplementary Methods detail the adaptive fraction process and dosimetric comparisons. Concomitant/supportive care was delivered in accordance with institutional protocol.
Assessment scheme
Patients underwent restaging PET-CT 11 to 14 weeks from the completion of treatment and surveillance neck CT 6 and 12 months after therapy. Patients completed 4 patient-reported outcome (PRO) questionnaires at baseline and in follow-up: EORTC (European Organization for the Treatment of Cancer) QLQ-30 and HN35, MDADI (MD Anderson Dysphagia Inventory), and the Xerostomia Questionnaire (XQ).
Statistical methods
The primary endpoint of the study was patient-reported xerostomia at 1 year after treatment, assessed with the XQ instrument, in which a lower score is better. A prospective randomized trial of acupuncture with routine XQ measurements after IMRT for head and neck cancer found that at 1 year, the mean XQ score was 42.2 (standard deviation, SD, 17.6).11 Our hypothesis was that DART will reduce the XQ score from 40 to 25, and a sample size of 46 patients is required with a power of 80% and an alpha of 0.05. Assuming 10% dropout, we aimed to enroll 50 patients.
Secondary endpoints of the study included PRO assessment, acute and late swallowing toxicity and dermatitis, as well as overall survival (OS), progression-free survival (PFS), and the cumulative incidences of local, regional, and distant recurrence. Survival analyses were performed using the Kaplan-Meier method and the stratified log-rank test, and cumulative incidence risks were calculated with death as a competing risk. All survival times were measured from the start of radiotherapy, and patients were censored at the end of known follow-up for all endpoints.
Differences in patient-reported outcome between the arms at each time point were analyzed with a linear regression, accounting for stratification by disease site. Treatment arm, oropharynx site, and an interaction term were included in the regression. In order to account for repeated measures among the same individuals, we performed a linear mixed-effect regression model including arm, time, and an interaction term between arm and time and arm and disease site. Although the interaction term between arm and disease site was consistently nonsignificant, these PRO comparisons were repeated for the oropharynx subset based on the a priori assumption that the physiology and treatment response may be different in oropharyngeal cancer patients. The primary analysis of the XQ results was performed in all patients alive who completed the survey, and PRO results were analyzed for both the entire responding cohort as well as patients who were disease-free at the time of completion. Toxicity differences were evaluated using the Mantel-Haenszel test, stratified by disease site. All analyses were made by intent-to-treat. Statistical analyses were performed with SAS 9.4 (Cary, NC, USA).
Results
Patient characteristics
The patient characteristics are described in Table 1. The median age of the cohort was 61.2 years, and the vast majority of individuals were male and Caucasian. In total, 34 patients (68%) presented with p16+ oropharyngeal cancer, with 23 patients (46% of total population) reporting a minimal to nil smoking history. Overall, more than half of patients had T3-4 disease, and 33 individuals had multiple ipsilateral or bilateral malignant lymphadenopathy. All but 4 patients received CRT, most (68% of cohort) with cisplatin. There were numerically more patients with bilateral lymphadenopathy (3 vs 0) and treatment with radiotherapy alone (3 vs 1) in the DART arm. Two patients on the IGRT arm developed substantial weight loss during treatment necessitating adaptation, which was considered a standard-of-care intervention for the department.
Table 1.
Patient and disease characteristics.
| Total n = 50 |
IGRT n = 26 |
DART n = 24 |
|
|---|---|---|---|
| Age (mean, SD) | 61.2 (9.8) | 61.5 (10.9) | 60.8 (8.7) |
| Sex | |||
| Male | 43 (85%) | 21 (81%) | 22 (92%) |
| Female | 7 (14%) | 5 (19%) | 2 (8%) |
| Ethnicity | |||
| Caucasian | 40 (80%) | 19 (73%) | 21 (88%) |
| African American | 4 (8%) | 3 (12%) | 1 (4%) |
| Hispanic | 6 (12%) | 4 (15%) | 2 (8%) |
| Site | |||
| p16+ oropharynx | 34 (68%) | 18 (69%) | 16 (67%) |
| p16− oropharynx | 4 (8%) | 2 (8%) | 2 (8%) |
| Larynx/hypopharynx | 12 (24%) | 6 (23%) | 6 (25%) |
| Smoking history (p16+) | |||
| <10 pack-years | 23 (68%) | 12 (67%) | 11 (69%) |
| >10 pack-years | 11 (32%) | 6 (33%) | 5 (31%) |
| Tumor stage (AJCC 7) | |||
| T1-T2 | 23 (46%) | 12 (46%) | 11 (46%) |
| T3-T4 | 27 (54%) | 14 (54%) | 13 (55%) |
| Nodal stage (AJCC 7) | |||
| N0 | 12 (24%) | 5 (19%) | 7 (29%) |
| N1–2a | 5 (10%) | 4 (16%) | 1 (3%) |
| N2b | 30 (60%) | 17 (65%) | 13 (54%) |
| N2c | 3 (6%) | 0 | 3 (13%) |
| Treatment | |||
| RT alone | 4 (8%) | 1 (4%) | 3 (13%) |
| Cisplatin | 34 (68%) | 17 (65%) | 17 (71%) |
| Carboplatin/paclitaxel | 12 (24%) | 8 (31%) | 4 (16%) |
Abbreviation: SD = standard deviation.
Treatment characteristics
A dosimetric comparison of critical OARs between the two arms is shown in Table 2, with the DART arm metrics reported from the initial plan. Salivary gland dosimetry was statistically superior in the DART arm, with lower doses to the ipsilateral parotid, contralateral submandibular gland, and ipsilateral submandibular gland. Although the dysphagia OARs (DARS) were numerically lower in the DART arm, only the superior/middle constrictor doses were statistically improved in the DART oropharyngeal patients. Patients on the DART arm had significantly smaller volumes of skin receiving both high and lower doses; for example, the volume of skin receiving 30 Gy or more was approximately halved in the DART arm vs the IGRT patients. The volume of mucosa around and including the CTV also received significantly less high-dose irradiation in the baseline DART plans, with nearly half as much volume treated to 70 Gy or more. Additional dosimetric analyses are described in Table S1.
Table 2.
Dosimetric parameters for key organs-at-risk. Numbers are mean doses with standard deviation unless otherwise indicated. The constrictors were defined identically to the DARS study.19
| Organ-at-risk | IGRT n = 26 |
DART n = 24 |
P |
|---|---|---|---|
| Entire cohort | |||
| Contralateral parotid | 11.8 (9.8) | 8.9 (5.4) | .195 |
| Ipsilateral parotid | 16.0 (7.5) | 11.5 (5.2) | .019 |
| Contralateral SMG | 36.5 (14.7) | 28.2 (13.2) | .043 |
| Ipsilateral SMG | 56.3 (12.5) | 42.2 (16.1) | .011 |
| Superior/middle constrictors | 39.8 (10.0) | 34.9 (8.9) | .074 |
| Cervical esophagus | 5.2 (4.9) | 6.3 (7.2) | .550 |
| Skin V70 Gy (cc) | 0.89 (1.4) | 0.52 (2.1) | .004 |
| Skin V56 Gy (cc) | 10.1 (8.9) | 3.8 (7.7) | .002 |
| Skin V30 Gy (cc) | 80.8 (35.1) | 47.8 (30.8) | .004 |
| Primary PTV70 V103% | 10.7 (11.3) | 4.4 (5.0) | .038 |
| V70 Gy around primary (cc) | 70.3 (45.4) | 37.6 (36.9) | .017 |
| V63 Gy around primary (cc) | 124 (66.7) | 90.7 (64.7) | .12 |
| V56 Gy around primary (cc) | 132 (70.5) | 105 (70.3) | .35 |
| Oropharynx | |||
| Oral cavity | 29.5 (10.2) | 24.7 (9.1) | .139 |
| Primary PTV70 V103% | 13.2 (12.0) | 4.9 (5.6) | .02 |
| V70 Gy around primary (cc) | 78.7 (47.5) | 44.7 (39.6) | .03 |
| V63 Gy around primary (cc) | 133.3 (70.0) | 102.5 (71.5) | .24 |
| Larynx | 29.6 (14.8) | 27.2 (18.5) | .663 |
| Inferior constrictor | 11.1 (13.5) | 9.3 (4.3) | .618 |
| Superior/middle constrictors | 42.4 (9.1) | 36.3 (8.2) | .036 |
| Cervical esophagus | 4.2 (3.6) | 5.3 (7.5) | .577 |
Abbreviation: SMG = submandibular gland.
Among the patients on the DART arm, the average in-room time was 39.4 minutes (SD 6.0). The mean total treatment time, starting from the first CBCT to the last beam, was 33 minutes (SD 5.3). The mean physician contouring time was 12.6 minutes (SD 3.4), and the mean total physician time at the console (including time required for plan calculation and all approvals) was 22 minutes (SD 4.4).
Acute and late toxicity
Acute toxicity outcomes are shown in Table 3. There was significantly less acute dermatitis in the DART cohort than in the IGRT patients, and this difference was also significant among the oropharynx patients. There was a nonsignificant trend for less severe mucositis among oropharynx patients. There were no other significant differences in acute toxicity. Only 7 (14%) patients required gastrostomy tubes (5 in IGRT arm, 2 in DART arm), and this difference was not statistically significant. Late toxicity outcomes are also shown in Table 3. There were no differences in late xerostomia, late dysphagia, or soft-tissue necrosis, the latter of which is described in the Supplementary Results.
Table 3.
Acute and late toxicity outcomes. All toxicities are defined by CTCAE version 5. The P value reflects the difference between the distribution of toxicities, stratified by arm.
| Toxicity | IGRT | DART | P | ||||||
|---|---|---|---|---|---|---|---|---|---|
| None | G1 | G2 | G3 | None | G1 | G2 | G3 | ||
| Acute | |||||||||
| Dermatitis | 0 | 18 (69%) | 8 (31%) | 0 | 4 (17%) | 18 (75%) | 2 (8%) | 0 | .01 |
| Mucositis | 0 | 2 (8%) | 16 (62%) | 8 (31%) | 0 | 6 (25%) | 15 (63%) | 3 (12%) | .13 |
| Dysphagia | 0 | 5 (19%) | 16 (62%) | 5 (19%) | 2 (8%) | 4 (17%) | 16 (67%) | 2 (8%) | .20 |
| Late | |||||||||
| Xerostomia | 10 (43%) | 13 (57%) | 0 | 0 | 13 (54%) | 11 (46%) | 0 | 0 | .48 |
| Soft-tissue necrosis | 18 (78%) | 0 | 3 (13%) | 1 (4%) | 21 (87%) | 0 | 3 (13%) | 0 | .53 |
| Dysphagia | 13 (57%) | 7 (30%) | 0 | 3 (13%) | 17 (71%) | 5 (21%) | 1 (4%) | 1 (4%) | .39 |
Patient-reported outcomes
Baseline and subsequent patient-reported outcomes are displayed in Table 4. In the entire cohort, there were unanticipated baseline numerical differences favoring the DART arm in xerostomia (XQ, 28 vs 16.3, P = .91), HN35 dry mouth (34.6 vs 15.9, P = .48), and HN35 sticky saliva (28.2 vs 13.0, P = .046). These baseline differences were either statistically significant or nearly significant in the oropharyngeal patients in xerostomia (XQ, 30.6 vs 14.7, P = .062), HN35 dry mouth (40.0 vs 11.8, P = .0035), and HN35 sticky saliva (28.3 vs 11.8, P = .048).
Table 4.
Patient-reported outcomes at baseline, 3, 6, and 12 months for the entire cohort and oropharynx patients. The P value reflects the interaction term between arm and time. A star (*) indicates that the difference between a 3-, 6-, or 12-month score and baseline is significantly smaller (ie, P < .05) in that arm vs the other.
| Instrument | Arm | Baseline (n = 49) |
3 months (n = 47) |
6 months (n = 47) |
12 months (n = 49) |
P |
|---|---|---|---|---|---|---|
| Entire cohort | ||||||
| QLQ30 Global | IGRT | 74 (21) | 72.7 (25.3) | 79.5 (14.9) | 82 (20.5) | .12 |
| DART | 73.9 (23.4) | 76.2 (16.7) | 77.9 (18.2) | 72.6 (21.3) | ||
| HN35 Dry mouth | IGRT | 34.6 (31.9) | 52.6 (28.6) | 54.2 (37.8) | 41.7 (29.7) | .98 |
| DART | 15.9 (22.2) | 46 (26.8) | 37.9 (21.3) | 31.9 (23) | ||
| HN35 Sticky saliva | IGRT | 28.2 (30.8) | 46.2* (35.4) | 40.3 (41.7) | 26.7* (31.9) | .46 |
| DART | 13 (16.6) | 46 (32.4) | 33.3 (25.2) | 30.4 (30) | ||
| HN35 Senses | IGRT | 12.8 (24.6) | 24.4 (27.6) | 22.2 (25.9) | 10.4 (17.6) | .42 |
| DART | 10.1 (23.4) | 30.2 (24.5) | 19.7 (25) | 20.8 (27.9) | ||
| HN35 Pain | IGRT | 33 (26.3) | 20.5 (22.5) | 19.8 (22.2) | 8.7 (13.9) | .13 |
| DART | 25 (22.2) | 23 (23) | 16.7 (16.9) | 15.6 (25.6) | ||
| HN35 Speech | IGRT | 24.4 (22.4) | 21.4 (25.3) | 20.8 (29) | 16.4 (25.7) | .77 |
| DART | 22.7 (27.7) | 15.9 (16.3) | 20.2* (29.6) | 17.6 (27.6) | ||
| Composite MDADI | IGRT | 75.9 (18.8) | 77.4 (17.6) | 77 (19.1) | 79.4 (17.9) | .88 |
| DART | 78.8 (17.4) | 80.9 (15.1) | 82.6 (14.2) | 81.6 (20) | ||
| XQ | IGRT | 28 (26) | 38.6 (28.9) | 32.2 (26.4) | 32.8 (26.7) | .98 |
| DART | 16.3 (23.1) | 33.3 (25.3) | 30.2 (20.7) | 22.8 (24.4) | ||
| Oropharynx | ||||||
| QLQ30 Global | IGRT | 73.8 (21.7) | 76.7 (22.3) | 81.6 (14.8) | 87.7 (14.8) | .13 |
| DART | 72.1 (26.3) | 75.5 (16.3) | 78.4 (18.4) | 74.1 (22.7) | ||
| HN35 Dry mouth | IGRT | 40 (33.5) | 56.7* (30.8) | 59.6 (39.4) | 44.4 (25.6) | .99 |
| DART | 11.8 (20.2) | 45.1 (23.4) | 41.2 (22.1) | 29.6 (22.5) | ||
| HN35 Sticky saliva | IGRT | 28.3 (31.1) | 50 (35) | 45.6 (43) | 28.1 (29.9) | .89 |
| DART | 11.8 (16.4) | 39.2 (29.4) | 33 (23.6) | 21.6 (20.2) | ||
| HN35 Senses | IGRT | 14.2 (27.7) | 28.3 (29.2) | 23.7 (28) | 11.1 (17.2) | .34 |
| DART | 11.8 (26.2) | 27.5 (22.8) | 23.5 (26.4) | 21.3 (29) | ||
| HN35 Pain | IGRT | 37.5 (25.4) | 22.9* (21.3) | 21.5 (21.8) | 8.3 (10) | .23 |
| DART | 26.5 (24.3) | 26.5 (24) | 13.7 (13.2) | 13 (24.1) | ||
| HN35 Speech | IGRT | 22.2 (22.8) | 21.7 (25.9) | 17.5 (27.8) | 14.6 (21) | .98 |
| DART | 17.6 (23.3) | 11.8 (10) | 7.8 (9.4) | 9.9 (17) | ||
| Composite MDADI | IGRT | 75.1 (19.4) | 77.1 (18) | 78.7 (17.1) | 81.4 (16.2) | .81 |
| DART | 76.8 (19.3) | 81.1 (15.6) | 85.0 (12.7) | 84.2 (17.4) | ||
| XQ | IGRT | 30.6 (26.5) | 40.6 (26.8) | 36.3 (25.9) | 35 (23.1) | .79 |
| DART | 14.7 (24.2) | 31.7 (25.4) | 30.0 (22) | 19.1 (21.9) |
Abbreviations: MDADI = MD Anderson dysphagia inventory; EORTC = European Organization for Research and Treatment of Cancer. For the XQ and EORTC symptom scales, a lower score is better. For the QLQ30 global score and MDADI, a higher score is better.
At 1 year, the mean XQ scores for the IGRT vs DART patients were 32.8 and 22.8, respectively. The adjusted difference was not statistically significant (10.0, 95% CI = −4.7 to 24.7, P = .58), nor were the mean differences between 1 year and baseline significantly different between the arms (IGRT: 5.6, 95% CI = −5.6 to 16.8; DART: 6.6, 95% CI = −3.4 to 16.5, P = .67). The interaction term on the multivariable regression was also not significant (P = .98), indicating no difference in XQ over time between the arms.
Among oropharyngeal patients, the XQ scores for the IGRT vs DART patients were 35.0 vs 19.1 at 1 year, which was statistically significant (mean difference 15.9, 95% CI = 0.9 to 31.0, P = .039). However, the difference between 1 year and baseline XQ scores (IGRT: 5.3, 95% CI = −9.2 to 19.8; DART 4.4, 95% CI = −6.6 to 15.5, P = .92) was not significant, and the interaction term on the multivariable linear regression was also not significant (P = .79).
There were no significant differences at 1 year between the other PRO measures and treatment arm, including HN35 dry mouth (P = .71) and HN35 sticky saliva (P = .06), nor were there any significant differences in outcome when measured over the course of the year. However, as indicated in the table, there were a few statistically significant differences between the arms, typically favoring the IGRT arm, when comparing the difference between PRO measurement at baseline and subsequent discrete time points.
These results were all recapitulated when strictly evaluating patients who had not recurred before outcome measurement (Table S2).
Disease outcomes
The median follow-up for surviving patients from the start of radiotherapy was 29.2 months (IQR 25.9–33 months, minimum 17.4 months). The overall survival probabilities at 24 months for the IGRT and DART arms were 96% (95% CI = 76% to 99%) and 96% (95% CI = 74% to 99%), respectively. The progression-free survival probabilities at 24 months for the IGRT and DART arms were 81% (95% CI = 60% to 92%) and 88% (95% CI = 66% to 96%), respectively (P = .49). The cumulative incidences of locoregional recurrence at 24 months for IGRT and DART were 15% (95% CI = 5% to 32%) and 8% (95% CI = 1% to 24%), respectively. The cumulative incidences of distant recurrence at 24 months for IGRT and DART were 8% (95% CI = 1% to 22%) and 8% (95% CI = 1% to 24%), respectively. Seven patients developed a recurrence event, none of which were marginal recurrences (see Supplementary Results).
Discussion
This trial is the first prospective clinical study of daily adaptive radiotherapy in head and neck cancer, requiring more than 800 individual fractions in which the attending radiation oncologist and physicist were at the console. Nevertheless, after adjustment for baseline scores, this novel treatment regimen did not improve patient-reported xerostomia or other patient-reported outcomes at 1 year. In fact, these results were quite favorable in both arms. That said, we have shown that this novel therapy, with reduced treatment margins, is associated with significantly improved acute toxicity, without an increased risk of tumor recurrence.
The longstanding rationale for implementing ART in head and neck cancer has been that anatomic changes over the course of treatment lead to the delivery of higher-than-planned normal tissue doses, especially in the salivary glands, and an updated plan can remediate this adverse dosimetry. However, the one prospective randomized trial of weekly offline ART in locally advanced oropharynx cancer was negative for any improvement in xerostomia.5 An alternative use of ART is to adapt every day in order to implement much tighter planning margins,7 because the only positional uncertainty is intra-fractional motion. Indeed, salivary gland dosimetry was clearly superior in the DART patients, even though the IGRT dosimetry of INRT in the study was itself generally favorable in comparison to conventional IMRT treatments.
Nevertheless, our results suggest that DART was not associated with meaningful change in patient-reported outcomes after treatment, including xerostomia. One possible explanation for this result is that the parotid gland doses with the INRT treatment paradigm are so low that even statistically significant improvements are insufficient to make a clinical impact in these domains. At this lower dose range, the relationship between dose and toxicity may relate more to underlying host or genetic factors than any modifiable parameter.12 We have also found that the adaptations performed by Ethos can preserve the baseline salivary dosimetry but do not further improve on their dose.13 On the other hand, the improvement in acute dermatitis and near statistical improvement in mucositis in oropharynx cancer patients highlight the clinically meaningful benefit of overall treatment volume reduction.
There are now 2 randomized trials of adaptive radiotherapy in HNSCC that have shown no difference in long-term patient-reported outcomes. Whereas ARTIX14 preserved standard treatment margins and adapted weekly with a delay between the resimulation and updated treatment, DARTBOARD delivered daily adaptive treatment with very narrow margins, with a similar converging of outcomes over time. To fully leverage adaptive technologies to improve long-term treatment-related side effects, a more novel scheme may be needed to aggressively reduce the volume receiving the highest doses of treatment. Such concepts may use PET-CT or MRI to meaningfully reduce these high-dose target volumes and are the subject of ongoing work.15–17
It is not possible to discern whether the improved acute toxicity was due to the reduced margins or the dosimetric benefit of daily replanning, which led to a more homogeneous dose distribution. However, the baseline dosimetric differences in irradiated skin and mucosal volume with different margins are clearly more pronounced than the benefit from adaptation, suggesting that margin reduction—feasible only because of daily adaptation—is the critical difference, although the volumes of mucosal heterogeneities were mitigated by daily replanning. It is important to distinguish between the relative weight of these two advantages of the experimental arm to consider the next step in this evolving field, as the tight margin control requires a different level of daily supervision than delivering more conventional volumes.
Although the acute toxicity improvement with DART may be clinically relevant, the current implementation of the technology requires extensive and likely prohibitive resources for routine practice. Our department was able to conduct this study with 3 head and neck radiation oncologists and 2 adaptive machines. However, the average treatment took longer than 30 minutes, and the attending physician was at the machine console for more than 20 minutes for each fraction. Future planning systems will more deeply integrate AI-based contouring into the daily workflow, to the point that physician supervision may be markedly limited or even eliminated, increasing efficiency.18 Nevertheless, acute dermatitis and mucositis ultimately heal, and thus the cost-effectiveness of this technology should be weighed in assessing its benefits.
This study has several limitations that must be considered in its interpretation. First, the overall sample size was small, such that a few outliers may affect the results. There were differences between the arms, such as baseline XQ score, that would have been mitigated with larger sample sizes. Given the resources needed for DART, we were limited with the total numbers of patients we could enroll on this study. In addition, it is difficult to know how the INRT scheme influenced the result, which is a notable limitation to the interpretation of the results. On one hand, the lack of marginal failures even without ENI shows that daily adaptation with tight margins is oncologically sound. These treatment volumes were probably the smallest ever reported in the literature. On the other hand, it is difficult to translate these results to radiotherapy with larger elective neck fields, where there is higher baseline toxicity. More investigation is needed to understand the effects of DART in patients receiving more standard elective nodal volumes. Finally, patients were not blinded to their assignment, which may have meaningfully influenced their perception of the various quality-of-life domains. Although blinding is clearly preferable, given the fundamental differences in the overall treatment process, we believe that patients would have easily determined their assignment.
In conclusion, DART did not improve patient-reported xerostomia, which was the primary endpoint of the study. However, to our knowledge, it is the first radiotherapy technology to significantly reduce acute dermatitis, and the borderline significant improvement in oropharyngeal mucositis with DART is also encouraging, results that suggest clinical utility to margin reduction and daily replanning. More research and innovation are needed not only to confirm these results, but also to operationalize the delivery of DART and to develop a workflow that is viable in most clinics.
Supplementary Material
Supplementary material is available at JNCI: Journal of the National Cancer Institute online.
Acknowledgments
Role of the funder: The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Prior presentation: ASTRO 2023 National Meeting.
Funding
Varian Medical Systems. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Footnotes
Conflicts of interest
Dr Lin has received research funding (separate from this study) and honoraria from Varian Medical Systems. The remainder of the authors report no conflicts of interest.
Data availability
Deidentified data may be available by request of the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Deidentified data may be available by request of the corresponding author.