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Purpose: The aim of this study was to investigate the utility of apparent diffusion coefficient (ADC) for prediction and early detection of treatment response in head and neck squamous cell carcinomas (HNSCC).Experimental Design: Diffusion-weighted magnetic resonance imaging studies were performed on 40 patients with newly diagnosed HNSCC before, during, and after the end of chemoradiation therapy. Analysis was done on data from 33 patients after exclusion of 7 patients that had incomplete data.Results: Pretreatment ADC value of complete responders (1.04 ± 0.19 × 10−3 mm2/s) was significantly lower (P < 0.05) than that from partial responders (1.35 ± 0.30 × 10−3 mm2/s). A significant increase in ADC was observed in complete responders within 1 week of treatment (P < 0.01), which remained high until the end of the treatment. The complete responders also showed significantly higher increase in ADC than the partial responders by the first week of chemoradiation (P < 0.01). When pretreatment ADC value was used for predicting treatment response, the area under the receiver operating characteristic curve was 0.80 with a sensitivity of 65% and a specificity of 86%. However, change in ADC within the first week of chemoradiation therapy resulted in an area under the receiver operating characteristic curve of 0.88 with 86% sensitivity and 83% specificity for prediction of treatment response.Conclusions: These results suggest that ADC can be used as a marker for prediction and early detection of response to concurrent chemoradiation therapy in HNSCC.

Supplementary Data from Diffusion-Weighted Magnetic Resonance Imaging for Predicting and Detecting Early Response to Chemoradiation Therapy of Squamous Cell Carcinomas of the Head and Neck

Supplemental figure and table legends

Purpose: We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC.Experimental Design: SMAD4 expression was assessed by IHC in 130 newly diagnosed and 43 patients with recurrent HNSCC. Correlative statistical analysis with clinicopathologic data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo.Results: Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of prosurvival and antiapoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in an HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo. We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss.Conclusions: Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors. Clin Cancer Res; 23(17); 5162–75. ©2017 AACR.

Supplemental Table 1. Criteria for Unresectable Disease Supplemental Table 2. Modified RECIST Criteria for Head and Neck Cancer. Supplemental Table 3. Summary of Serum Analyte Levels. Supplemental Figure 1. Study Schematic Supplemental Figure 2. Time to locoregional failure for all eligible and treated patients (a) and by tumor HPV status (b). Log rank test comparing time to failure for HPV+ versus HPV- p value provided. Supplemental Figure 3. Representative tissue cores with high or low expression levels of XPF or ERCC1 as assessed by AQUA. Tumors were stained for cytokeratin (CK) to create a tumor mask and with DAPI to define the nuclear compartment. Supplemental Figure 4. Representative tumor IHC molecular correlates ERCC1, XPF and MET.

Representative SMAD4 IHC, FaDu negative control, SCC25/SCC61 positive control.

Matrigel colony formation assay of FaDu-mock and FaDu-SMAD4 cells treated with PBS or Cetuximab in combination with JNKi (SP600125) or MEKi (U0126) at indicated concentrations for 7 days. (*p

(A) Western blot confirming the knockdown of SMAD4 levels by stable expression of short-hairpin RNA in SCC25 cell line. (SC: scrambled control shRNA, SMAD4KD: shRNA against SMAD4). (B) Matrigel colony formation assay was performed for SCC25 cell line (controls and SMAD4 knock-downs) treated with PBS, 100nM or 1000nM cetuximab. (C) Western blot showing MAPK and JNK activity in SMAD4-depleted or control SCC25 cells.

List of Supplemental Materials: Supplemental Table 1. Criteria for Unresectable Disease Supplemental Table 2. Modified RECIST Criteria for Head and Neck Cancer. Supplemental Table 3. Summary of Serum Analyte Levels. Supplemental Figure 1. Study Schematic Supplemental Figure 2. Time to locoregional failure for all eligible and treated patients (a) and by tumor HPV status (b). Log rank test comparing time to failure for HPV+ versus HPV- p value provided. Supplemental Figure 3. Representative tissue cores with high or low expression levels of XPF or ERCC1 as assessed by AQUA. Tumors were stained for cytokeratin (CK) to create a tumor mask and with DAPI to define the nuclear compartment. Supplemental Figure 4. Representative tumor IHC molecular correlates ERCC1, XPF and MET.

Western blot analysis of SCC61L-SC and SMAD4KD cells for phospho-SMAD2 and total SMAD2/3 expression levels. Actin was used as a loading control.

Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination.Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m2) followed by 250 mg/m2/week and cisplatin 75 mg/m2 q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival.Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%–61%]. Two-year overall survival (OS) was 66% (95% CI, 53%–77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV+ patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively).Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV+ tumors. Clin Cancer Res; 20(19); 5041–51. ©2014 AACR.

Supplemental Table 1. Summary of patient characteristics with newly diagnosed HNSCC. Supplemental Table 2. Summary of patient characteristics with recurrent and/or metastatic HNSCC. Supplemental Table 3. Injection of FaDu-SMAD4 cells results in lower take rate in mice compared to the control cell line and shows no signs of metastatic lesion.

The purpose of this paper is to summarize the literature and practical recommendations from experienced centers for close margins following transoral robotic surgery (TORS) for HPV-positive oropharyngeal carcinoma.

Background Radiation-induced skin dermatitis (RISD) is a common outcome experienced by adult patients with head and neck cancer (HNC) who have undergone radiation therapy. There is no standardized recommended agent for the prevention or management of RISD. Objectives The primary objective of this study was to retrospectively evaluate for effectiveness of a botanical topical agent, CamWell® Herb to Soothe® cream, on RISD. Methods 112 patients with HNC undergoing radiation therapy self-reported their RISD topical skin care agent during treatment as standard of care, CamWell used prophylactically, or CamWell use started after the first week of treatment. The primary endpoint was impact of RISD on the patient, as measured by mean Skindex-16 score throughout treatment. Measures were completed weekly. Findings The mean Skindex score was statistically significantly lower for the prophylactic group than for the standard-of-care group. CamWell may have played a role in managing RISD when compared to standard-of-care agents.

This study aimed to investigate the relationship between intensity-modulated radiation therapy (IMRT) dosimetry and swallowing kinematic and timing measures. Thirteen kinematic and timing measures of swallowing from videofluoroscopic analysis were used as outcome measures to reflect swallowing function. IMRT dosimetry was accessed for thirteen swallowing-related structures. A cohort of 44 nasopharyngeal carcinoma (NPC) survivors at least 3 years post-IMRT were recruited. The cohort had a mean age of 53.2 ± 11.9 years, 77.3% of whom were male. There was an average of 68.24 ± 14.15 months since end of IMRT; 41 (93.2%) had undergone concurrent chemotherapy. For displacement measures, female sex and higher doses to the cricopharyngeus, glottic larynx, and base of tongue were associated with reduced hyolaryngeal excursion and pharyngeal constriction, and more residue. For timing measures, higher dose to the genioglossus was associated with reduced processing time at all stages of the swallow. The inferior pharyngeal constrictor emerged with a distinctly different pattern of association with mean radiation dosage compared to other structures. Greater changes to swallowing kinematics and timing were observed for pudding thick consistency than thin liquid. Increasing radiation dosage to swallowing-related structures is associated with reduced swallowing kinematics. However, not all structures are affected the same way, therefore organ sparing during treatment planning for IMRT needs to consider function rather than focusing on select muscles. Dose-response relationships should be investigated with a comprehensive set of swallowing structures to capture the holistic process of swallowing.

PURPOSE: We investigate whether esophageal dose–length parameters (L(dose)) can robustly predict significant weight loss—≥5% weight loss during radiation therapy (RT) compared with the weight before RT—in patients with lung cancer treated with definitive intent. METHODS AND MATERIALS: Patients with lung cancer treated with conventionally fractionated RT between 2010 and 2018 were retro-spectively identified. L(Fdose) and L(Pdose), the length of full- and partial-circumferential esophagus receiving greater than a threshold dose in Gy, respectively, were created. Multivariate logistic regression examined the associations between individual L(dose) and weight loss after adjusting for clinical parameters and correcting for multiple comparisons. Ridge logistic regression examined the relative importance of L(dose) compared with dose–volume (V(dose)), mean dose (D(mean)), and clinical parameters in determining weight loss. Univariate logistic regression examined the unadjusted probability of weight loss for important L(dose) parameters. RESULTS: Among the 214 patients identified, median age was 66.9 years (range, 31.5–88.9 years), 50.5% (n = 108) were male, 68.2% (n = 146) had stage III lung cancer, median RT dose was 63 Gy (range, 60–66 Gy), and 88.3% (n = 189) received concurrent chemotherapy. Esophagus lengths receiving high full-circumferential (L(F50)-L(F60)) and high partial-circumferential doses (L(P60)) were associated with significant weight loss (P ≤.05). L(F65) and L(P65) reached near significance (P = .06 and .053, respectively). L(F65) > L(F60) > L(P65) were the most important dose parameters in determining weight loss compared with other L(dose), V(dose), and D(mean) parameters. CONCLUSIONS: Esophageal L(dose) parameters are an efficient way of interpreting complex dose parameters in relation to weight loss toxicity among patients with lung cancer receiving definitive RT.

PURPOSE Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus–associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC. METHODS E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index. RESULTS Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6]) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented. CONCLUSION Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC.

Objective To examine associations between quality, short-term and long-term treatment-related outcomes, and costs in elderly patients treated for oropharyngeal squamous cell cancer (OPSCC). Methods We retrospectively evaluated Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 666 patients diagnosed with OPSCC from 2004 to 2007 using multivariate regression and survival analysis. Quality indicators were derived from guidelines for recommended care and performance measures. Results Higher quality care was associated with lower risk of death in patients with dysphagia (hazard ratio [HR] = 0.44 [0.32-0.60]), weight loss (HR = 0.42 [0.28-0.62]), gastrostomy (HR = 0.47 [0.33-0.68]), airway obstruction (HR = 0.41 [0.27-0.62]), tracheostomy (HR = 0.17 [0.05-0.67]), and pneumonia (HR = 0.53 [0.33-0.85]). There were no significant differences in mean incremental costs associated with airway and swallowing impairment for patients receiving higher quality care. Conclusions Higher quality OPSCC care was associated with improved survival in elderly patients with airway and swallowing impairment. These data suggest that greater adherence to evidence-based guidelines has favorable implications for long-term outcomes.

Modern medicine, including the care of the cancer patient, has significantly advanced, with the evidence-based medicine paradigm serving to guide clinical care decisions. Yet we now also recognize the tremendous heterogeneity not only of disease states but of the patient and his or her environment as it influences treatment outcomes and toxicities. These reasons and many others have led to a reevaluation of the generalizability of randomized trials and growing interest in accounting for this heterogeneity under the rubric of precision medicine as it relates to personalizing clinical care predictions, decisions, and therapy for the disease state. For the cancer patient treated with radiation therapy, characterizing the spatial treatment heterogeneity has been a fundamental tenet of routine clinical care facilitated by established database and imaging platforms. Leveraging these platforms to further characterize and collate all clinically relevant sources of heterogeneity that affect the longitudinal health outcomes of the irradiated cancer patient provides an opportunity to generate a critical informatics infrastructure on which precision radiation therapy may be realized. In doing so, data science-driven insight discoveries, personalized clinical decisions, and the potential to accelerate translational efforts may be realized ideally within a network of institutions with locally developed yet coordinated informatics infrastructures. The path toward realizing these goals has many needs and challenges, which we summarize, with many still to be realized and understood. Early efforts by our group have identified the feasibility of this approach using routine clinical data sets and offer promise that this transformation can be successfully realized in radiation oncology.

PURPOSE/OBJECTIVE(S) Imaging quantified by radiomics has yielded reproducible predictions of both oncologic outcomes and treatment-related toxicity. Much of the correlation with oncologic outcomes has focused on image features from the primary tumor. However, both primary tumor and nodal features can impact outcomes, and it is known that differences in gene expression in primary tumors and nodal metastases provide distinct information regarding survival in head and neck squamous cell carcinomas (HNSCC). Nevertheless, current radiomic biomarkers often make no distinction between primary and nodal radiomic features. Therefore, we hypothesize that combining CT image features of primary tumors and nodal metastases in HNSCC will improve our ability to predict progression-free survival (PFS) compared to primary features alone. MATERIALS/METHODS Pre-treatment CT images were prospectively collected from 115 HNSCC patients undergoing RT at our institution from 2008-2018. PFS was determined at time of last follow-up prior to 2018. Clinical data were systemically captured from patient medical charts. 107 radiomic features were extracted for the primary tumor and the ipsilateral/contralateral nodal regions. Features were pre-selected by literature review for those possibly significant in predicting loco-regional control of HNSCC. Tumor volume, correlation of gray level co-occurrence matrix (Corr-GLCM), run length non-uniformity of gray level of gray level run length matrix (RLN-GLRLM), and coarseness of neighboring gray tone difference matrix (Coarse-NGTDM) for the primary contours; and tumor volume and Corr-GLCM of the nodal contours were included in the model. A regression analysis of pre-selected features was performed using ridge regularization in the training set (n = 93 primary; n = 48 primary & nodal), and a generalized linear model was built with repeated ten-fold cross validation of patients treated from 2008-2017. Model performance was evaluated in a test set (patients treated 2017-2018) using the area under the receiver operating characteristic curve (AUC). Models were built separately for patients with primary tumor only and primary + nodal radiomic features. RESULTS The AUC/sensitivity/specificity on the test set for the model with primary features (n = 22) was 0.91/1.00/0.75, and for the model with primary and nodal features (n = 18) was 0.75/0.60/0.92. The features with the highest coefficients in the combined model included primary Coarse-NGTDM (β = -0.21), primary Corr-GLCM (β = 0.0082), and nodal Corr-GLCM (β = -0.00041). CONCLUSION In a small cohort of HNSCC patients, combining nodal features with primary features did not improve the prediction performance compared to primary features alone. This work suggests that primary tumor radiomic features may influence PFS more than nodal features. Future work is required in a larger cohort to validate these findings.

Purpose: Pleomorphic adenoma is a benign salivary tumor that may recur multifocally. In case series, the benefit of radiation therapy (RT) for recurrent pleomorphic adenoma remains unclear. We hypothesized that the combination of surgery and adjuvant RT reduces risk of subsequent recurrence compared with surgery alone for recurrent pleomorphic adenoma. Methods and Materials: Patients who received diagnoses of recurrent pleomorphic adenoma between 1980 and 2016 were identified using an institutional pathology database. Medical records were retrospectively reviewed to determine clinical, operative, pathologic, and imaging characteristics. Kaplan-Meier methods were used to estimate local control after surgery, stratified by completeness of resection and receipt of adjuvant RT. The association of variables with risk of subsequent local recurrence was analyzed using Cox proportional hazards model, and variance estimates were calculated to account for multiple recurrences in the same patient. Toxicities were prospectively recorded in a departmental database. Results: A total of 49 patients presented with at least 1 recurrence, of which 28 were managed with surgery alone, and 21 were treated with surgery and RT. The median follow-up time after the initial recurrence was 48 months (range, 6-531 months). There were 35 subsequent recurrences; 34 after surgery alone and only 1 after surgery with RT. On multivariate analysis, adjuvant RT was associated with decreased risk of recurrence (hazard ratio, 0.09; 95% confidence interval, 0.02-0.41, P = .002), whereas increasing number of prior recurrences was associated with increased risk (hazard ratio, 1.23; 95% confidence interval, 1.13-1.35, P < .001). Common toxicities of RT included dermatitis, xerostomia, and mucositis. Conclusions: For patients with recurrent pleomorphic adenoma, the addition of adjuvant RT after surgery is associated with a significant decrease in risk of subsequent tumor recurrence.

Lymphopenia is associated with decreased survival outcomes in head and neck squamous cell carcinoma (HNSCC). This is a significant concern especially for frail individuals who are more vulnerable to immunological dysregulations. A robust analysis is needed to understand whether we should expend efforts to limit treatment-related hematological toxicities in HNSCC. First, we would like to understand the prognostic significance for baseline (BL) vs. treatment-related lymphopenia (TRL). We want to know if lymphopenia is merely a reflection of the patient’s frailty at baseline, or if this is iatrogenic and therefore can be a target for treatment modifications in a bid to improve survival. Here, we identified 222 newly diagnosed M0 HNSCC patients treated with radiation ± systemic therapy in 2015-2018 at our institution. Clinical frailty is defined by age ≥ 65 or KPS ≤ 70. Using Kaplan Meier estimates and Cox regression with dichotomous variables, we performed multivariate analysis for both overall survival (OS) and progression-free survival (PFS). Important predictors included frailty (p ≤ 0.002) and ≥ 2K/mm3 decrease in absolute lymphocyte counts (ALC) (p ≤ 0.006). BL did not significantly impact OS or PFS (p ≤ 0.37). For TRL, ALC decrease had greater prognostic significance compared with ALC nadirs (p ≤ 0.45). Next, we simplified our survival model to include only frailty and TRL. Overall, fit patients with modest ALC decline (< 2K/mm3) achieved excellent survival outcomes while frail patients with severe ALC decline (≥ 2K/mm3) had inferior outcomes (3-year OS 95% vs. 56%, p < 0.0001; 3-year PFS 84% vs. 42%, p = 0.002). On subgroup analyses, similar outcomes were also identified for HPV+ HNSCC (n = 172, 3-year OS 96% vs. 71%, p = 0.002; 3-year PFS 89% vs. 54% p = 0.03). Finally, we want to know if ALC decline is determined primarily by treatment intensity, or if frail patients are naturally predisposed to greater ALC decline during treatment. In our data, frail patients had more modest ALC decline when compared to fit patients (1.26 ± 0.57 vs. 1.54 ± 0.58 K/mm3 p = 0.0006). In our survival model, we did not observe any first-order interactions between frailty and ALC decline (p = 0.54). The extent of ALC decline was also higher for patients with concurrent administrations of cisplatin (as opposed to radiation alone, p < 0.0001). Thus, we postulate that the extent of ALC decline is determined primarily by treatment intensity. It is possible that frail patients with severe ALC decline have inferior survival outcomes because they cannot maintain immunological balance and respond poorly when there is significant TRL. This opens opportunities to re-evaluate if the risk of TRL is modifiable by limiting the number of concurrent cycles of chemotherapy administered, and by considering radiation dose de-intensification especially for HPV-associated HNSCC. Lastly, TRL becomes an important consideration when immunotherapeutics are grafted onto existing CRT treatment paradigms. Citation Format: Carmen Kut, Todd McNutt, Carole Fakhry, Theodore DeWeese, Harry Quon. Lymphocyte kinetics, frailty and survival outcomes in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1971.

6062 Background: Induction chemotherapy (IC) is being studied as a chemoradiation (CRT) de-intensification strategy in HPV-related head and neck cancer (HNC), but using imaging response for eligibility selection is distinctly limited by delayed correlation with biological response and difficulty in distinguishing active tumor from treatment effect. We report serial cell free HPV DNA (cfHPV DNA) dynamics as a quantitative measure of early treatment responsiveness for HPV-related HNC patients receiving IC followed by CRT. Methods: Patients with high-risk HPV-positive (by in situ hybridization), locally advanced HNC who received IC followed by definitive CRT were enrolled starting on Sept 26, 2021. Patients received 1-2 cycles of platinum/taxane IC prior to initiating standard-dose CRT. Peripheral blood cfHPV DNA levels were measured biweekly during IC and weekly during CRT with the SafeSEQ HPV test from Sysmex Inostics, an NGS-based, CLIA-certified assay designed to sensitively detect and quantify HPV16 and HPV18 DNA in plasma. Tumor volumes were assessed on the pre- and post-IC planning CT scans by the treating radiation oncologist. Results: To date, 72 plasma samples have been processed across 11 enrolled patients with median age 66 years (range: 35-79). The primary disease sites included 7 oropharynx (OPX), 1 sinonasal, 2 nasopharyngeal, and 1 larynx. All patients had at least cT3 disease or cN3 disease (AJCC 8), with 6 patients having cT4 disease. Five (45.5%) have a smoking history, each > 10 pack-years. We report cfHPV DNA and tumor volume measurements at key timepoints for the 8 patients who have completed IC below. Conclusions: Serial cfHPV DNA identifies a group of locally advanced HPV-related HNC patients who have complete/near-complete cfDNA clearance during IC. This may provide an earlier readout of individualized treatment responsiveness compared to radiologic assessment, and may therefore be a preferred metric for CRT de-intensification eligibility. Clearance velocity will be evaluated with our granular biweekly IC and weekly CRT cfHPV DNA dataset to help further elucidate tumor response kinetics with this paradigm. [Table: see text]