Use of Fluoro-[18F]-Deoxy-2-D-Glucose Positron Emission Tomography/Computed Tomography to Predict Immunotherapy Treatment Response in Patients With Squamous Cell Oral Cavity Cancers

Abstract

Importance: Neoadjuvant immunotherapy is a novel approach with the potential to improve outcomes for patients with oral cavity squamous cell cancer (OCSCC). Adverse events of varying severity are reported with immunotherapy, and a biomarker to predict response would be clinically useful to avoid toxic effects in those unlikely to benefit.

Objective: To correlate changes on fluoro-[18F]-deoxy-2-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans with primary tumor pathologic response and immunologic biomarkers in patients with OCSCC receiving neoadjuvant immunotherapy.

Design, setting, and participants: This was a retrospective analysis of serial FDG-PET/CT scans obtained prospectively as part of a phase 2 open-label randomized clinical trial investigating neoadjuvant immunotherapy in patients with untreated OCSCC between 2016 and 2019. Included were a total of 29 patients from a single academic medical center with untreated OCSCC (≥T2, or clinically node positive) randomized 1:1 to receive neoadjuvant therapy with single agent nivolumab or combination nivolumab and ipilimumab followed by surgery and standard of care adjuvant therapy.

Interventions: The interventions in this study were FDG-PET/CT scans before (T0) and after (T1) preoperative immunotherapy.

Main outcomes and measures: Data collected from FDG-PET/CT scans included maximum standardized uptake value (SUVmax) of primary OCSCC and cervical lymph nodes (LNs) at T0 and T1 and new LN uptake and uptake consistent with radiologic immune-related adverse events (irAEs) at T1. Primary OCSCC pathologic response reported as percentages of viable vs nonviable tumor. The number of CD8+ cells/mm2 was determined in the primary tumor biopsy specimen and at surgery.

Results: There was no correlation between pathologic response and change in SUVmax in the primary OCSCC between T0 and T1. Out of 27 total participants, 13 had newly FDG-avid ipsilateral LNs at T1, most negative on pathology. A total of 9 had radiologic irAEs, most commonly sarcoid-like LN (7 of 27). No correlations were found between primary OCSCC SUVmax at T0 and CD8+ T-cell number in the primary tumor biopsy, and no correlations were found between primary OCSCC SUVmax at T1 and CD8+ T-cell number in the primary tumor at surgery.

Conclusions and relevance: There were no correlations between changes in FDG uptake after neoadjuvant immunotherapy and pathologic primary tumor response. Importantly, newly FDG-avid ipsilateral LNs following neoadjuvant immunotherapy were commonly observed but did not represent progressive disease or indicate pathologically disease positive nodes in most cases. These findings argue against altering surgical plans in this setting and suggest that the role of FDG-PET/CT may be limited as an early imaging biomarker for predicting pathologic response to preoperative immunotherapy for OCSCC.

Trial registration: ClinicalTrials.gov Identifier: NCT02919683.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lako is a current employee of Bristol Myers Squibb. Dr Rodig receives research support from Bristol Myers Squibb, Merck, Affimed, and KITE/Gilead, as well as personal fees from Immunitas Therapeutics. Dr Uppaluri reported grants from Bristol Myers Squibb during the conduct of the study and personal fees from Merck. Dr Jo reports immediate family member employment/equity at Merck. Dr Haddad reported personal fees from Bristol Myers Squibb, Merck, AstraZeneca, Pfizer, GlaxoSmithKline, Genentech, Celgene, Eisai, Nanobiotix, ISA, and Bayer, and grants from from GlaxoSmithKline, Merck, Bristol Myers Squibb, Pfizer, AstraZeneca, Genentech, and Kura. Dr Schoenfeld reported grants from Bristol Myers Squibb during the conduct of the study; grants from Merck, Regeneron, and Debiopharm, and personal fees from Genentech, Immunitas, Astellas, Stimit, Catenion, LEK, and ACI, as well as other from Doximity Equity outside the submitted work. Dr Jacene reported honoraria from Janssen Pharmaceuticals, Bayer Healthcare, and Blue Earth Diagnostics; research support paid to institution from Siemens Healthcare, GTx, and Blue Earth Diagnostics; personal fees from Advanced Accelerator Applications and Cambridge Publishing; and grants from the National Institutes of Health. No other disclosures were reported.

Figures

Figure 1.. Study Schema and Participants

Abbreviation: FDG-PET/CT, fluoro-[18F]-deoxy-2-D-glucose positron emission tomography/computed tomography.

Figure 2.. Primary OCSCC FDG-PET/CT Findings vs Pathologic Response

No correlations were found between pathologic response and baseline primary oral cavity squamous cell cancer (OCSCC) maximum standardized uptake value (SUVmax) (A) and primary OCSCC SUVmax after preoperative immunotherapy (B). No correlations were found for absolute (C) or percentage change (D), in primary tumor SUVmax between T0 and T1.

Figure 3.. Changes in Ipsilateral Nodal SUVmax and Association With Primary Tumor Response and Lymph Node Pathology

Changes of maximum standardized uptake value (SUVmax) of ipsilateral lymph nodes between T0 and T1 compared with pathologic response in the primary oral cavity squamous cell cancer (OCSCC) and pathology results from the neck dissection in participants with (A) vs without (B), without newly fluoro-[18F]-deoxy-2-D-glucose (FDG)-avid ipsilateral lymph nodes at T1. More and larger changes in lymph nodes between the scans were observed in participants with newly FDG-avid ipsilateral nodes compared with those without.

Figure 4.. Visualization of Radiologic irAEs vs SUVmax Changes in Primary OCSCC and Ipsilateral Cervical Lymph Nodes

A, Nο correlation was found between pathologic response in primary tumor and visualization of radiologic immune-related adverse effects (irAEs) on the T1 fluoro-[18F]-deoxy-2-D-glucose positron emission tomography/computed tomography (FDG-PET/CT). B, Change in maximum standardized uptake value (SUVmax) of the most FDG-avid metastatic cervical lymph nodes between T0 and T1 was not different between participants with (median 14%, range −11% to 75%) and without radiologic irAEs (median 20%, range −48% to 35%, ESwrs = −5% [90% CI, –20% to 45%] for with or without) after preoperative immunotherapy. C, Primary oral cavity squamous cell cancer (OCSCC) SUVmax increased more in participants with (median 34%, range −5 to 47%) vs without (median −1%, range −29 to 25%, ESwrs = 30% [90% CI, 6% to 67%] for with or without) radiologic irAEs on T1 FDG-PET/CTs.