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. Author manuscript; available in PMC: 2026 Jan 26.
Published in final edited form as: Clin Cancer Res. 2026 Feb 17;32(4):684–693. doi: 10.1158/1078-0432.CCR-25-2820

FDG-PET-based Selective De-escalation of Chemoradiation in Human Papillomavirus-related Oropharyngeal Squamous Cell Carcinoma: a Multi-center Phase II Trial

Michelle Mierzwa 1,#, Benjamin Rosen 1,#, Krithika Suresh 2, Arjun Dinesh 3, Samuel Regan 1, Colin Brummel 3, Kakit Wong 4, Keith Casper 3, Mark Prince 3, Kelly Malloy 3, Andrew Shuman 3, Steven Chinn 3, Yue Cao 1, Madhava Aryal 1, Molly Heft-Neal 3, Chaz Stucken 3, Marisa Buchakjian 3, David Forner 3, Pratyusha Yalamanchi 3, Paul Swiecicki 5, Theodore S Lawrence 1, Rawan Akhdar 3, Muneesh Tewari 5, Chandan Bhambhani 5, Heather Walline 3, J Chad Brenner 3, Jennifer Shah 1,*, Francis Worden 5,*
PMCID: PMC12832149  NIHMSID: NIHMS2131748  PMID: 41385605

Abstract

Purpose:

We conducted a phase II multicenter clinical trial to test the hypothesis that FDG-PET based chemoradiation (CRT) dose de-escalation would provide non-inferior loco-regional control compared to historical controls among patients with early-stage p16+ oropharyngeal cancer. We also hypothesized that HPVctDNA changes during treatment predict loco-regional recurrence (LRR).

Patients and Methods:

Patients with Stage I/II p16+ oropharyngeal squamous cell carcinoma were planned to receive radiation 70Gy in 35 fractions with concurrent weekly carboplatin and paclitaxel. All patients underwent FDG-PET at baseline and at RT fraction 10. Patients with ≥50% decrease from baseline to mid-treatment metabolic tumor volume (MTV)2.5 had treatment deescalated to 54Gy in 27 fractions. The primary endpoint was LRR. Plasma HPVctDNA was evaluated weekly and in surveillance.

Results:

Of 84 evaluable patients, 43% met de-escalation criteria. With a median follow-up of 37.8 months, 24-month LRR for the entire cohort was 7.8% (90% CI: 2.6% – 12.6%), which was less than the 25% rate specified for assessing non-inferiority, thereby meeting the primary endpoint. At 1 month post RT, the mean of multiple quality of life measures between the two groups were improved in the 54Gy cohort, exceeding the minimal clinically important difference (MCID) threshold. During CRT, week 1 percentage increase in ctDNA relative to baseline was significantly associated with worse LRC (HR=1.052 per 10 percentage points increase in ctDNA, 95% CI: 1.007–1.099; p=0.023) and LRPFS (HR=1.038, 95% CI: 1.002–1.076; p=0.035).

Conclusion:

FDG-PET-based RT dose personalization resulted in promising LRR outcomes in early stage oropharynx cancer with improved short- term PROs. Furthermore, HPVctDNA changes early in treatment may predict LRC.

Keywords: oropharynx cancer, radiation, de-escalation, HPV, FDG-PET

Statement of Translational Relevance

The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing. While patients with early-stage disease have high cure rates, definitive treatment with chemoradiation can be associated with significant toxicity. Real-time biomarkers such as FDG-PET imaging markers early in treatment and/or HPV circulating tumor DNA (ctDNA) have been shown to increase prediction of progression free survival and are promising to identify which patients may be eligible for treatment de-escalation. In a prospective clinical trial of patients with AJCC8 stage I/II p16+ OPSCC, we selectively de-escalated RT dose in patients based on their midtreatment FDG-PET response. We also collected HPV ctDNA at baseline, weekly during radiation and in surveillance. The results showed FDG-PET-based RT dose personalization resulted in promising LRR outcomes in early stage oropharynx cancer with improved short- term PROs. Furthermore, we saw that HPVctDNA changes early in treatment may predict LRC.

Introduction

Primary chemoradiation (CRT) or surgery with adjuvant therapy are effective treatment options for early-stage human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). The incidence of HPV-related OPSCC is increasing (1), and the prevalence of survivors continues to rise, as does the incidence of short- and long-term treatment toxicities. There is significant interest in de-escalating therapy to minimize treatment-related toxicity, maximize long-term quality of life, and maintain excellent disease control. Several de-escalation strategies have been explored (2–6), though an optimal approach has yet to be established.

Despite the overall good prognosis of early-stage HPV-related OPSCC, approximately 5–15% of patients will recur after receiving current standard of care therapy (2,7). Thus, de-intensification is not suitable for all patients. Large multi-institutional trials attempting to uniformly de-escalate either systemic therapy or radiation therapy have resulted in worse survival outcomes without improving toxicity, showcasing the risk of de-intensification in an unselected population (4, 8–10). Selective de-escalation is needed to avoid compromising oncologic outcomes. Furthermore, there is no robustly validated predictive biomarker for response to primary radiation. 18F-fluorodeoxyglucose positron-emission tomography with computed tomography (FDG-PET/CT) performed at 12 weeks post-chemoradiation is indicative of excellent treatment response and has become a standard of care (11,12). Furthermore, quantitative metrics from baseline and mid-radiation treatment FDG-PET/CT are associated with survival outcomes in head and neck cancer patients (13–17). PET-based imaging metrics are widely available, promising biomarkers to detect early response to definitive chemoradiotherapy. HPV circulating tumor DNA (ctDNA) represents another candidate biomarker for treatment response to CRT. Preliminary studies suggest changes at week 2 or 4 during CRT or early post treatment are predictive of response (18–20).

We conducted a prospective, non-randomized, multi-institutional phase II trial using pre- and mid-treatment FDG-PET metrics to select early-stage HPV-related OPSCC patients for reduced dose definitive chemoradiation. We hypothesized this approach could safely de-escalate treatment in early responders to minimize toxicity, while maintaining oncologic outcomes within the entire cohort. We furthermore hypothesized that changes in HPV ctDNA kinetics during treatment may predict outcome.

Methods

Participants

The study protocol was approved by the Institutional Review Board at the University of Michigan and the Ann Arbor Veterans Affairs Hospital, CONSORT guidelines were followed and the study was registered at clinicaltrials.gov (NCT03416153) prior to enrollment. The trial was conducted in accordance with the Declaration of Helsinki, the Belmont Report, and U.S. Common Rule. All patients provided written informed consent.

Eligibility criteria included 18 years or older, ECOG score 0–1, with previously-untreated AJCC 8th edition Stage I or II (cT1–T3,N0 – N2) oropharyngeal squamous cell carcinoma that was p16 positive by immunohistochemistry. Consent was obtained from all patients, and all patients underwent FDG-PET/CT for staging within 4 weeks of trial registration, with primary and/or nodal disease with a maximum SUV of at least 4.0 or greater. Patients were required to have adequate hematologic and renal function. Key exclusion criteria included prior surgical excision, prior head and neck radiotherapy, or malignancy within three years. Patients with unknown primary or matted nodes (21,22) were ineligible. Those with poorly controlled diabetes (fasting blood glucose >200 mg/dL), despite two attempts to improve control (i.e., fasting duration, medication adjustment), were excluded. Eligibility was not restricted based on tobacco smoking status.

Treatment and Study Design

Enrolled patients underwent CT and DCEMRI simulation and were planned for standard CRT: 70 Gy in 35 fractions to gross disease and 56 Gy to at-risk lymph node regions. The initial protocol permitted concurrent weekly cetuximab but was amended to eliminate its use in response to the publication of RTOG 1016. Chemotherapy was administered concurrently with weekly carboplatin (AUC = 1) and paclitaxel (30 mg/m2) for seven weeks. A mid-treatment FDG-PET/CT was obtained between fractions 8 and 12. The FDG-PET imaging metrics used were the metabolic tumor volume (MTV) ≥50% of the maximum SUV (MTV50%) and the MTV at or above an SUV of 2.5 (MTV2.5), calculated for all gross disease (i.e., combined primary and nodal volumes). Using the pre- and mid-treatment PET imaging, criteria for de-escalation were: 1) pre-treatment MTV50% ≤22 cc and 2) ≥50% decrease from baseline in mid-treatment MTV2.5. These criteria were chosen based on previous institutional cohort analysis (including unpublished data) and literature where failures occurred below these thresholds (17,19, 20). Patients who met both criteria, as determined by independent review by both a nuclear medicine physician and a radiation oncologist, completed de-escalated therapy at fraction 27 (total 54 Gy to gross disease, 43.2 Gy to at-risk nodal regions) and six cycles of weekly carboplatin/paclitaxel. After treatment, patients proceeded with standard of care surveillance, including FDG-PET/CT 12 weeks post-therapy and clinical evaluations every 3 months. Blood draws for HPVctDNA were collected in Paxgene cell free DNA tubes and banked for post hoc analyses from the following timepoints: pre-treatment, weekly during CRT, and every 3 months post treatment. MyHPVscore HPV ctDNA assay methods are described in the Data Supplement.

QOL/Toxicity Measures

Detailed descriptions of prospective toxicity measures were previously published (24). Briefly, physician graded toxicity was recorded weekly during treatment and at each follow-up using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (25). Videofluoroscopic swallow studies (VFSS) were performed at baseline, 3 months post-treatment, and 12 months post-treatment, and a penetration-aspiration score (PAS) was calculated. Patient reported outcomes (PROs) were measured prospectively with a number of instruments, including the University of Washington Quality of Life RTOG modification (UWQOL-RTOG) (26), the Xerostomia Questionnaire (XQ) (27), the Functional Assessment of Cancer Therapy – Head and Neck (FACT-HN) (28), and the National Cancer Institute’s patient-reported outcomes version of CTCAE (NCI-PRO-CTCAE; 18 items selected) (29). All PRO instruments were collected at baseline, then 1-, 3-, 6-, 12-, and 24-months post-treatment.

Study Objectives and Analysis

The primary study endpoint was non-inferiority of 24-month locoregional recurrence (LRR) in the overall cohort compared to a historical institutional cohort. Based on our prior retrospective analysis of previously treated HPV-related OPSCC (30), we saw a historic LRR of 12% and sought to demonstrate that the true LRR with our approach was less than 25%. The null hypothesis tested in this non-inferiority analysis was H0: LRR > 25% and the alternative hypothesis is HA: LRR < 25%. We initially calculated that a sample size of 68 patients would provide 80% power at a significance level of 0.10. However, presented outcomes improved over the course of this trial (10) and thus the enrollment target was increased to 84 evaluable patients to improve statistical power.

Secondary endpoints included patterns of failure, survival, toxicity and determination of the fraction of patients with detectable HPV ctDNA during week 4 of RT/correlation of 4 week HPV ctDNA with PFS. Secondary survival endpoints were assessed using an intention-to-treat analysis. Details of survival endpoint definitions for PFS, LRPFS, LRC, DMFS and OS are available in the Data Supplement. Exploratory endpoints included summarization of ctDNA kinetics at baseline, weeks 1, 2, 6–7 and correlations with oncologic outcomes. The 2-year time-to-event outcomes were estimated using Kaplan-Meier (KM) methodology. A complementary log-log transformation of the survival function was used to calculate the upper 90% confidence limit for the primary study endpoint of 2-year LRR. Linear mixed effects models with a random effect for patients were fit to longitudinal patient-reported outcomes data. Differences in the change in PRO scores between the treatment groups were estimated. A minimal clinically important difference (MCID) threshold was evaluated as greater than 0.5 standard deviations of the change in score (31). Cox models were used to assess associations between ctDNA kinetics and PFS, LRPFS, and DFMS. Based on previously published ctDNA kinetics and timepoints of interest (18, 19, 21), we assessed continuous log-transformed ctDNA values at weeks 1 and 2, continuous percentage change in ctDNA values from baseline at weeks 1 and 2 with truncation at 500% to reduce the impact of outliers, early increase at weeks 1 and 2 of CRT (defined as a binary indicator of any increase from baseline), and clearance of ctDNA at week 4 and end of CRT (defined as >95% decrease from baseline). All analyses were performed using R version 4.4.2.

Results

Clinical Characteristics

A total of 99 patients were assessed for eligibility, of whom 89 were enrolled, and 84 who completed a mid-treatment FDG-PET were included in the final analysis (Figure 1). Thirty-six patients (43%) met de-escalation criteria, while 48 did not and completed standard CRT. One patient met PET criteria for de-escalation to 54Gy but chose to continue therapy to 70Gy (included in the as-treated population). Patient characteristics are described in Table 1. The cohorts did not differ in clinical or tumor characteristics, except baseline weight, which was lower in the de-escalated cohort (median 186 vs. 208 lbs, p=0.01). Neither gross tumor volume (GTV), smoking status, nor smoking duration were associated with meeting de-escalation criteria. The majority (96.4%) received concurrent carboplatin/paclitaxel, while three patients received cetuximab prior to a protocol amendment.

Figure 1:

Figure 1:

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CONSORT Diagram

Table 1:

Patient Characteristics

Treatment Cohort
All Patients,
N = 841 		Standard CRT,
N = 481 		De-escalated CRT,
N = 361 		p-value2
Age (years) 60 (53, 68) 60 (54, 69) 60 (52, 67) 0.7
Sex 0.5
 Male 76 (90%) 42 (88%) 34 (94%)
 Female 8 (9.5%) 6 (13%) 2 (5.6%)
Baseline Weight (lbs) 197 (177, 229) 208 (185, 237) 186 (168, 213) 0.01
Smoking Status 0.4
 Never 40 (48%) 23 (48%) 17 (47%)
 Former 41 (49%) 22 (46%) 19 (53%)
 Current 3 (3.6%) 3 (6.3%) 0 (0%)
Smoking Duration 0.7
 ≤10 years 58 (69%) 34 (71%) 24 (67%)
 >10 years 26 (31%) 14 (29%) 12 (33%)
Smoking Pack Years 1 (0, 15) 1 (0, 15) 1 (0, 20) 0.8
AJCC 8th ed. Stage 0.3
 I 63 (75%) 34 (71%) 29 (81%)
 II 21 (25%) 14 (29%) 7 (19%)
T Stage 0.2
 1 39 (46%) 22 (46%) 17 (47%)
 2 34 (40%) 17 (35%) 17 (47%)
 3 11 (13%) 9 (19%) 2 (5.6%)
N Stage 0.7
 0 2 (2.4%) 2 (4.2%) 0 (0%)
 1 70 (83%) 39 (81%) 31 (86%)
 2 12 (14%) 7 (15%) 5 (14%)
Tumor Subsite 0.5
 Base of Tongue 41 (49%) 22 (46%) 19 (53%)
 Tonsil 40 (48%) 25 (52%) 15 (42%)
 Other 3 (3.6%) 1 (2.1%) 2 (5.6%)
GTV, Total (cc), IQR 30 (21, 42) 29 (22, 46) 32 (21, 40) 0.7
GTV, Primary (cc), IQR 12 (7, 18) 12 (7, 19) 12 (7, 17) >0.9
RTOG0129 Risk Classification 0.8
 Low 54 (64%) 30 (63%) 24 (67%)
 Intermediate 30 (36%) 18 (38%) 12 (33%)
 High 0 (0%) 0 (0%) 0 (0%)
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Abbreviations: CRT = chemoradiation, lbs = pounds, AJCC = American Joint Committee on Cancer

1

n (%); median (interquartile range)

2

Wilcoxon rank sum test; Fisher’s exact test; Pearson’s chi-squared test

Oncologic Outcomes and Patterns of Failure

Median follow-up for the standard and de-escalated cohorts were 36.2 months and 39.6 months, respectively. There were 6 patients with loco-regional recurrence during follow-up (3 in standard CRT, 3 in de-escalated). The estimated 24-month LRR for the entire cohort was 7.8% (90% CI: 2.6% – 12.6%), which was below the pre-specified non-inferiority limit of 25%, thereby meeting the primary endpoint (Figure 2A).

Figure 2:

Figure 2:

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Cumulative Incidence and Kaplan-Meier survival curves for (A) locoregional recurrence, (B) distant metastasis free survival, (C) progression free survival, and (D) overall survival

There was no difference in LRR between standard and de-escalated cohorts (6.8% [0.3% – 12.8%], and 9.0% [0.4 – 16.8%]; p=0.719)(Figure 2A). The estimated 24-month PFS, DMFS, and OS were 86.4%, 92.6%, and 96.3%, respectively (Figure 2B–2D). Table 2 details the patterns of failure for all study patients. All detected failures occurred within the first two years of therapy, and the median time to recurrence was 12.4 months (range, 8.5 – 22.8 months). Four of five LRRs were surgically salvaged, without evidence of disease at most recent follow-up. One patient declined surgical salvage in favor of non-traditional therapy. All patients with LRR are alive. One cancer-related death occurred after distant-only failure in a patient who received 70 Gy. Stratification of our cohorts into low and intermediate RTOG 0129 risk groups showed a 2 year PFS with 95% CI as follows: low risk with 54Gy, 89.7 % (77.2, 1.00), low risk with 70Gy, 93.3% (84.8, 1.00), intermediate risk with 54Gy, 77.8% (60.8, 99.6), intermediate risk with 70Gy, 75.0% (54.1, 1.00).

Table 2:

Patterns of Failure and Initial Salvage Therapies

Treatment Cohort Stage1 Pack Years Site(s) of First Recurrence Time to First Recurrence (mo)2 Initial Salvage Therapy Follow-Up (mo)2 Evidence of Disease?3
De-escalated CRT II ≤10 Local 17.6 TORS 58.4 No
I ≤10 Distant 22.8 SBRT to Oligometastatic Lung Lesion 49.0 No
I >10 Local + Regional 11.3 Oropharyngectomy + Neck Dissection 32.8 No
I ≤10 Regional + Distant 12.4 Carboplatin/Paclitaxel + Pembrolizumab 22.0 On Therapy
Standard CRT I ≤10 Distant 9.0 SBRT to Oligometastatic Bone Lesion 69.3 No
I ≤10 Regional 15.7 Pembrolizumab Alone 30.8 On Therapy
I 0 Distant 8.90 Yttriium-90 Segmentectomy 15.2 Cause-specific Death
I ≤10 Regional 8.5 Neck Dissection 26.1 No
I >10 Local + Regional 17.1 Tonsillectomy, Neck Dissection, Re-CRT 18.9 On Therapy
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1

AJCC 8th Edition

2

Measured from date of enrollment

3

At time of data collection

Abbreviations: CRT = chemoradiation, mo = month, TORS = trans-oral robotic surgery, SBRT = stereotactic body radiotherapy, AJCC = American Joint Committee on Cancer

Toxicity and Objective Swallowing Measures

Toxicity endpoints were analyzed in the as-treated populations for each cohort. Treatment compliance was high, with 92% of patients receiving all planned chemotherapy. All de-escalated patients completed their scheduled radiation, while four standard CRT patients experienced an unplanned radiation break ≥2 days. Patients receiving de-escalated CRT had significantly lower doses to every organ-at-risk (OAR) compared to their initial standard-dose plan, while initial doses to OARs were not lower than those of the standard CRT cohort (Supplemental Table 1). Physician-assessed toxicity assessed by CTCAE was worse in the standard CRT cohort, particularly at the 1-month post-treatment timepoint, with significantly higher frequencies of grade 2–3 mucositis and radiation dermatitis (Supplemental Table 2). However, by 12-months post-treatment, grade ≥2 toxicity was very rare, regardless of cohort. One likely treatment related death occurred 13 days post-treatment in a patient receiving standard CRT. The patient, with a known prior history of non-ischemic cardiomyopathy, suffered a cardiac arrest in the setting of dehydration, diarrhea, and hypokalemia. One patient who received standard CRT experienced a persistent ulcer and grade 4 carotid artery injury after biopsy approximately six months after treatment; the patient remains alive at last follow-up but chronically feeding tube dependent. No CTCAE grade 4–5 toxicities were recorded in the de-escalated cohort.

De-escalated patients experienced significantly less weight loss from baseline compared to standard CRT patients (Table 3). This represented a median percent loss of 6% vs. 12.6% at 3 months, despite differences in baseline weights between the cohorts. Few (14%; n = 12) patients required placement of a nasogastric tube during CRT or within 1 month after treatment, which did not significantly differ between the cohorts with no feeding tubes beyond 3 months (Table 3). Change in Penetration Aspiration Scale (PAS) scores, measured by VFSS, at 3- and 12-months post-treatment did not differ between the cohorts (Table 3; Supplemental Figure 1).

Table 3:

Objective Weight and Swallowing Metrics

Treatment Cohort
All Patients,
N = 841 		Standard CRT,
N = 491 		De-escalated CRT,
N = 351 		p-value2
Weight Loss from Baseline (lbs)
 1 month post-CRT 17 (11, 26) 21 (15, 29) 13 (7, 19) <0.001
 3 months post-CRT 19 (11, 29) 23 (15, 35) 11 (7, 17) <0.001
Weight Loss from Baseline (%)
 1 month post-CRT 9.4 (5.8, 12.5) 10.6 (8.2, 13.5) 6.5 (4.4, 10.5) <0.001
 3 months post-CRT 9.7 (5.3, 14.9) 12.6 (7.5, 15.4) 6.0 (3.5, 9.7) <0.001
Feeding Tube Usage
 During RT to 1-month post-RT 12 (14%) 8 (16%) 4 (11%) 0.5
 At 1 month post-CRT visit 5 (6.0%) 2 (4.1%) 3 (8.6%) 0.6
 At 3 month post-CRT visit 0 (0%) 0 (0%) 0 (0%) ---
Penetration-Aspiration Scale (PAS)
 Baseline PAS 1.00 (1.00, 2.00) 1.00 (1.00, 2.00) 1.00 (1.00, 3.00) 0.8
 3 month PAS 2.00 (1.00, 3.00) 2.00 (1.00, 4.00) 2.00 (1.00, 3.00) 0.5
 12 month PAS 2.00 (1.00, 2.00) 2.00 (1.00, 2.00) 2.00 (1.00, 3.00) 0.7
 Change in PAS from Baseline, 3 mo 0.00 (0.00, 1.00) 0.00 (0.00, 2.00) 0.00 (−0.25, 1.00) 0.09
 Change in PAS from Baseline, 12 mo 0.00 (0.00, 1.00) 0.00 (0.00, 1.00) 0.00 (0.00, 0.00) 0.2
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1

Median (Interquartile Range); n (%)

2

Wilcoxon rank sum test; Wilcoxon rank sum exact test

Abbreviations: CRT = chemoradiation, lbs = pounds

Patient Reported Outcomes

Figure 3 presents estimated mean scores of PRO measures for each treatment cohort. At one-month post-treatment, the differences in UW-QOL and FACT-HN, UWQOL-Pain, FACT-HNCS, FACT-TOI, and XQ total measures between the 70Gy and 54Gy cohorts were statistically significant and exceeded the minimal clinically important difference threshold of 0.5 standard deviations. These differences between cohorts decreased as time from treatment increased, and were non-significant by 3 months post-CRT. Differences in estimated mean scores between treatment cohorts at different time points are shown in Supplemental Table 3 and analysis of standardized effect sizes across all PROM subscales is illustrated in Supplemental Figure 2.

Figure 3:

Figure 3:

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Estimated Mean Scores from Baseline in Patient-Reported Quality of Life Measures: (A) UW-QOL Total score, (B) UW-QOL Pain score, (C) FACT-HN, (D) FACT-HN Cancer Subscale, (E) FACT-HN Trial Outcome Index, (F) and Xerostomia Questionnaire Total Score.

HPV ctDNA Kinetics

There were 78 patients with ctDNA samples available, of which 68 patients had a detectable baseline ctDNA value and were included in analyses. An early increase in ctDNA from baseline was observed in 46% of patients by week 2, while >95% clearance at week 4 and last week of RT were observed in 71% and 92% of patients, respectively (Supplementary Figure 3 and Supplementary Table 4). Higher values of log-transformed HPV ctDNA in weeks 1 and 2 but not baseline were significantly associated with worse outcomes (Supplementary Table 5). The percent change in ctDNA at week 1 relative to baseline was associated with worse LRC (HR per 10 percentage point increase= 1.052, 95% CI: 1.007–1.099, p=0.023) and LRPFS (HR = 1.038, 95% CI: 1.002–1.076, p=0.035), with similar although not statistically significant association with PFS (HR=1.034, 95% CI: 0.999–1.070; p=0.057). No other evaluated midtreatment ctDNA metrics were associated with outcomes. In surveillance, all patients with recurrence and available blood samples for MyHPVScore had detectable ctDNA prior to clinical detection of recurrence (Supplementary Figure 4).

Discussion

We present a de-escalation strategy utilizing individual imaging response-adapted definitive chemoradiation based on FDG-PET for early-stage oropharynx cancer patients. Our data demonstrate excellent LRC for the entire cohort while de-escalating nearly half of such patients, producing lower toxicity and improved PROs in patients who were able to be de-escalated (2–5, 32, 33). A notable strength of an FDG-PET de-escalation strategy is the availability of FDG-PET, which is a widely used imaging study and is a component of standard work-up for oropharyngeal cancer.

On the current trial, we observed no regional recurrences in the elective nodal regions in either the 70 Gy or 54 Gy cohorts, which received 56 Gy and 43.2 Gy elective nodal irradiation, respectively. This contributes to the increasing literature indicating that 30–45 Gy EQD2 is adequate to achieve excellent regional control in anatomic sites being treated electively during definitive CRT in early-stage HPV-related oropharynx cancer (6,32,34).

Unique features of our strategy were the inclusion of patients with a smoking history and the use of concurrent weekly carboplatin and paclitaxel chemotherapy in place of cisplatin. We previously demonstrated excellent outcomes for patients with HPV-related oropharyngeal cancer treated concurrently with carboplatin and paclitaxel and radiation, with low toxicity overall and notably without oto or renal toxicity (35). Overall lower toxicity associated with carbotaxol may be taken into consideration as we move towards tradeoffs in oropharynx cancer treatment, weighing risks of loco-regional failure against risks of toxicity. With regard to smoking, we have previously found that imaging metrics were significant predictors for LRR, while smoking history was not (17). In the current trial, there was no association between smoking history and either likelihood of meeting de-escalation criteria or LRR, likely influenced by overall excellent outcomes.

Patients who were able to have de-escalated CRT had less toxicity, including less weight loss and infrequent need for feeding tubes with no feeding tubes beyond 3 months post-radiation. We report improved PROs at 1 month post radiation in patients receiving 54Gy, meeting MCID differences. These included the UWQOL, FACT-HN, and XQ total measures, and the UWQOL-Pain, FACT-HNCS, FACT-TOI subscales. These early differences seen are encouraging as they are correlated with lower RT dose to normal tissues, which has not been the case in other de-escalation trials (36,37). The convergence of PROs we saw ≥6 months post treatment is consistent with the literature and may reflect patient adaptation to a new normal reported in many cancer studies where patients report their quality of back to baseline within one year (38).

The ideal biomarker for personalization of RT dose in HPV-related oropharynx cancer should be widely available, reproducible, and measurable before or early enough in treatment to make a meaningful change to the treatment plan. Our trial suggests that FDG-based imaging markers may achieve these goals. We also saw that percentage increase in ctDNA at week 1 of treatment was associated with worse LRC and LRPFS. These results were statistically significant although they represent small relative increases in risk of failure in this low-risk population. These results, consistent with NRG HN 002 (21), suggest that early changes in ctDNA may provide complementary information in patient selection for treatment deintensification.

Limitations of our study, as with other trials in early-stage HPV-related oropharynx cancer, include the rarity of treatment failures, making it difficult to measure smaller differences in outcomes between standard and de-escalated cohorts. We also note the limitation of patient numbers in our single institution trial making wider confidence intervals in our outcomes, making it difficult to compare results with other trials. Our 2 year PFS is 86% (95% CI 79.2, 94.2) in the current trial. In the HN005 trial (39), patients treated with de-escalation to 60 Gy with cisplatin noted 2 year PFS of 88.6% (95% CI 82.4, 94.7) albeit in more favorable patients. In a mixed cohort trial similar to the current work, Chera et all reported a 2 Yr PFS of 86% (95% CI, 77.5% to 91.3%) using 60 Gy with cisplatin in an unselected population (33). Our findings suggest that outcomes with de-escalation in PET-selected patients were non inferior to those expected with standard CRT, while toxicity and patient reported outcomes were improved. However, as this is a single-arm non-inferiority study, it does not evaluate whether interim PET provides prognostic or predictive stratification beyond treating all patients with de-escalated therapy comparable to other de-escalation studies noted above that did not use interim PET.

We note that very high 2 yr PFS of 97% with 70Gy in 6 weeks and concurrent cisplatin on HN005 has been presented in abstract form (39), but our trial included a potentially higher risk population with N2 and radiographic extranodal extension patients but not “matted nodes”. Furthermore, TORS ineligibility has been associated with worse outcomes (40) and 8 of 9 failures in our trial were deemed TORS ineligible pretreatment due to bilateral base of tongue involvement, >3+ lymph nodes, radiographic extranodal extension or level II lymph nodes extending into the parapharyngeal space. Additional limitations of the FDG-PET approach to personalization of radiation therapy include the need for physics expertise for volumetric FDG analysis and mid-treatment imaging differentiation between peri-tumoral mucositis/inflammation and tumor response. Here we successfully spatially confined the pretreatment imaging volume of analysis using MRI.

Multiple trials are attempting to identify biomarkers in early stage oropharyngeal cancer including evaluating HPV ctDNA kinetics during RT (NCT05268614, NCT04900623), MRI ADC metrics (NCT03224000) and FDG-PET (NCT04667585). We used conservative FDG metrics for de-escalation. De-escalation of a larger percentage of patients might be possible if more aggressive mid-treatment metrics are used in future studies (Supplementary Figure 5). A future strategy may be selective decrease in RT dose to the primary tumor and individual lymph nodes based on their individual spatial FDG mid-treatment response. An exciting prospective study utilizing hypoxia-based 18F-fluoromisonidazole (F-MISO) PET was able to deescalate RT dose to 30Gy in 84% of patients and demonstrated high locoregional control with decreased toxicity (32). To date, no biomarker or imaging marker has been prospectively validated in multiple patient cohorts. Given the complexity of patient factors such as immune status, tumor factors such as relative primary and nodal tumor volume, treatment factors such as choice of systemic therapy and RT fraction size, we anticipate that multimodality biomarkers and imaging markers, including FDG-PET and HPVctDNA, may be required to understand early treatment response to chemoradiation in HPV-related OPSCC.

In summary, a de-escalation strategy utilizing individual imaging response-adapted definitive chemoradiation based on FDG-PET for early-stage oropharynx cancer patients is feasible and achieves outcomes non-inferior to the historical control rate.

Supplementary Material

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Funding Source:

This clinical trial is primarily funded by the Department of Radiation Oncology at the University of Michigan and the Rogel Cancer Center. The imaging costs were supported in part by National Institutes of Health/National Cancer Institute grant 1U01CA183848 (Y.C.).

Footnotes

Conference Presentation: This work was presented as a Podium Presentation at the ASCO-ASTRO Head and Neck Cancer Symposium in Phoenix, AZ February 2024.

Conflicts of Interest: J Chad Brenner, Paul Swiecicki, Muneesh Tewari report COI that are on file at ASCO. All other authors report no COI related to this work.

Data Availability Information

All data generated or analyzed during this study are included in this published article and its supplementary materials as well as through clinicaltrials.gov (NCT03416153). In order to protect patient privacy, the data is not publically available, but the University of Michigan will grant access to all study data upon reasonable request sent to the corresponding author at mmierzwa@med.umich.edu.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS2131748-supplement-1.docx (56KB, docx)
2
NIHMS2131748-supplement-2.docx (241.9KB, docx)
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NIHMS2131748-supplement-3.docx (128.6KB, docx)
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NIHMS2131748-supplement-4.docx (329.2KB, docx)
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NIHMS2131748-supplement-5.docx (41.6KB, docx)
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NIHMS2131748-supplement-6.docx (16.5KB, docx)
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NIHMS2131748-supplement-7.docx (19KB, docx)
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NIHMS2131748-supplement-8.docx (16.3KB, docx)
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NIHMS2131748-supplement-9.docx (16.4KB, docx)
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NIHMS2131748-supplement-10.docx (21.7KB, docx)
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NIHMS2131748-supplement-11.docx (14.4KB, docx)
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NIHMS2131748-supplement-12.docx (15.2KB, docx)

Data Availability Statement

All data generated or analyzed during this study are included in this published article and its supplementary materials as well as through clinicaltrials.gov (NCT03416153). In order to protect patient privacy, the data is not publically available, but the University of Michigan will grant access to all study data upon reasonable request sent to the corresponding author at mmierzwa@med.umich.edu.

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