Purpose/Objective(s) We conducted a single arm prospective phase II trial evaluating the addition of priming, concurrent, and adjuvant nivolumab to definitive chemoradiation (CRT) in locoregionally advanced p16+ oropharynx squamous cell carcinoma (OPSCC). Exploratory endpoints included pre- and mid-treatment quantitative imaging metrics and circulating tumor DNA (ctDNA) kinetics, which we hypothesized would predict disease recurrence. Materials/Methods Eligible patients had p16+ OPSCC with ≥1 high-risk feature: cT4, cN3, matted lymph nodes/radiographic extracapsular extension, and/or retropharyngeal adenopathy. Patients were treated with RT to 70Gy with concurrent weekly carboplatin, paclitaxel, and nivolumab followed by adjuvant nivolumab. Physiologic MRI and FDG-PET were performed pre-treatment and between fractions 8-12. For both primary and nodal gross tumor volumes (GTV), the mean blood volume (BV), sub-volume with low BV (LBV), mean apparent diffusion coefficient (ADC), sub-volume of low ADC (LADC), and metabolic tumor volume (MTV50%) were calculated. Blood was collected pre-treatment and weekly during CRT and was analyzed with the MyHPVScore CLIA-certified ctDNA assay. Cox models were used to test imaging and HPV ctDNA metrics for prediction of LRPFS, DMFS and PFS, with p-values and c-indices to describe their predictive performance. Results Twenty-six patients were enrolled; most had cT4 disease (n = 17/26, 65%), with median GTVp = 36 cc (0-110) and median GTVtotal = 60 cc (35-165). Estimated 2-year progression-free survival (PFS) was 65% (90% CI = 53% - 84%) with 4, 3 and 1 patients having local only, distant only, and local+distant failures, respectively. Both pre- and mid-treatment mean BV and mean ADC were lower in the primary versus nodal tumors. Increasing values of primary tumor GTV, LBV, LADC, and MTV50% from pre- and mid-treatment imaging were significantly associated with inferior PFS and DMFS but not LRPFS (Table). Nodal imaging metrics were not predictive of outcome. Neither relative change in HPV ctDNA at weeks 1 or 2 nor week 4 or 7 clearance were significantly associated with PFS. Conclusion In a single institution prospective trial of concurrent and adjuvant immuno-chemoradiation in high-risk HPV+ OPSCC, we were able to validate prior findings that pre- and mid-treatment primary tumor sub-volumes on MRI and PET correlated with disease control. Albeit with small numbers, pre- or mid-treatment ctDNA kinetics were not predictive of outcome. Imaging metrics may guide future therapy escalation strategies in locally advanced OPSCC.

Purpose/Objective(s)Treatment de-escalation in HPV-related oropharyngeal squamous cell carcinoma (OPSCC) aims to minimize toxicity without compromising oncologic outcomes. We conducted a prospective phase II nonrandomized trial using FDG-PET imaging biomarkers to selectively de-escalate chemoradiotherapy (CRT). We hypothesized this would maintain locoregional control in all patients while decreasing toxicity in the de-escalated cohort.Materials/MethodsEligible patients had stage I-II p16+ or HPV+ OPSCC with baseline tumor FDG-PET-avidity. All were planned to receive 70 Gy to gross disease and 56 Gy to elective nodal regions in 35 fractions with concurrent weekly carboplatin/paclitaxel. Mid-treatment PET was performed at fraction 10. If metabolic tumor volume was reduced by ≥50%, CRT was completed at 54 Gy in 27 fractions. The primary objective was to demonstrate non-inferiority of 24-month locoregional recurrence (LRR) overall by comparing the upper 90% confidence interval (CI) to 25%. Secondary objectives were failure patterns, survival, ctDNA trends, mpMRI, and toxicity. Toxicity measures included patient-reported outcomes (UWQOL-RTOG, FACT-HN, XQ). Kaplan-Meier analyses were used for survival outcomes.ResultsEligible patients (n = 84) were enrolled from 2018 - 2023; 90% male, 75% stage I, and 48% never-smokers. De-escalation criteria were met in 42% (n = 35). The 54 Gy cohort had fewer patients with T3 tumors (3% vs 20%, p = 0.02) and lower median baseline weight (188 vs. 207 lbs, p = 0.015); no other differences in distribution of baseline factors nor initial RT plans were found. Median follow up at this analysis was 28.9 mo overall, 31.6 mo for 54 Gy and 25.9 mo for 70 Gy patients. LRR at 24 mo was 7% (90% CI: 2% - 12.1%) in the entire cohort, 5% (90% CI: 0% – 10.5%) with 70 Gy, and 10% (90% CI: 1% - 18.2%) with 54 Gy. There were 5 LRR and 3 distant recurrences overall. Of 4 patients with only LRR, 3 were salvaged surgically without systemic therapy and have no evidence of disease, and 1 (70 Gy cohort) declined surgery. There was 1 cancer-related death after a distant-only recurrence in the 70 Gy cohort. Median weight loss from baseline in the 54 Gy cohort was significantly less at 1 mo (6.5% vs. 10.6%, p <0.001) and 3 mo (6% vs. 12.6%, p <0.001) post-RT. Use of feeding tube during RT or ≤1 mo post-RT was numerically better in 54 Gy patients (11% vs. 16%, p = 0.5). The 70 Gy cohort had one grade 4 (G4) carotid artery injury and one likely treatment-related death. The 54 Gy cohort had no G4+ toxicities, with less decrement from baseline in median UWQOL-RTOG scores for pain subscale at 1 mo (5 vs 10, p = 0.01) and mucus subscale at 12 mo (0 vs. 5, p = 0.2) post-RT. Remaining PRO instrument analyses are ongoing and will be presented.ConclusionMid-treatment FDG-PET may be a reliable biomarker to selectively de-escalate radiation dose in early-stage HPV+ OPSCC to improve toxicity while preserving oncologic outcomes.

Purpose/Objective(s)To develop and CLIA validate a droplet digital PCR (ddPCR) assay capable of enhancing the detection of multiple high-risk types of human papillomavirus (hrHPV) circulating tumor DNA (ctDNA) in plasma from patients with HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC).Materials/MethodsWe advanced our previously developed HPV16 probes, and newly developed hrHPV probes designed to detect HPV-18, HPV-31, HPV-33, HPV-35 and HPV-39 (total 26 primers and 13 probes) as a new high-performance assay for validation in our CLIA certified laboratory using Clinical and Laboratory Standards Institute (CLSI) guidelines. Analytical control and plasma samples from HPV+ OPSCC patients were used to characterize and validate the performance as a lab developed test (LDT).ResultsThe assay demonstrated analytical accuracy and precision during in depth evaluation consistent with requirements for clinical use. For HPV16, the assay had a limit of the blank (LOB) of 0 copies/µL, a limit of detection (LOD) of 0.53 copies/µL, and a limit of quantification (LOQ) ranging from 1.29 - 4.36 copies/µL. For detection of other hrHPV types, the assay had a LOB of 0 copies/µL, a LOD of 0.77 copies/µL, and a LOQ ranging from 1.72 – 14.0 copies/µL. Regression of the observed copy number versus measured concentration of HPV DNA, and the observed versus expected copy number had excellent correlation in the linear range of the assays (R2 = 0.99 for each). For HPV16, the assay had a linear range from 0.53 to 9384 copies/µL. For other hrHPV types, the assay had a linear range from 0.77 to 6000 copies/µL. Above the linear range of each assay, the analyte was detected resulting in a positive test, but recovery was <90%. Testing of blanks following known positive samples did not find any substantial carry over. Testing of analytes over a 96-hour period showed appropriate stability of the analyte (both primary and processed) and assay over time. Cross-reactivity was assessed using each assay (alone and in combination) to evaluate contrived samples of HPV16, HPV18, HPV31, HPV33, HPV35, and HPV39 (individually and in combination) and found that there was no substantial cross-reactivity between the assays or HPV types, confirming the high specificity of the assay for HPV type.ConclusionThese results confirm this assay has both high analytical sensitivity and specificity for detection of multiple hrHPV types and is capable of detecting low levels of HPV ctDNA from clinical plasma samples.

BACKGROUND AND PURPOSE:Free flap reconstruction in patients with head and neck cancer carries a risk of postoperative complications, and radiologic predictive factors have been limited. The aim of this study was to assess the factors that predict free flap reconstruction failure using CT and MR perfusion.MATERIALS AND METHODS:& nbsp;This single-center prospective study included 24 patients (mean age, 62.7 [SD, 9.0]?years; 16 men) who had free flap reconstruction from January 2016 to May 2018. CT perfusion and dynamic contrast-enhanced MR imaging with conventional CT and MR imaging were performed between 2 and 4?days after the free flap surgery, and the wound assessments within 14?days after the surgery were conducted by the surgical team. The parameters of CT perfusion and dynamic contrast-enhanced MR imaging with conventional imaging findings and patient demographics were compared between the patients with successful free flap reconstruction and those with wound failure as appropriate. P < .05 was considered significant.RESULTS:& nbsp;There were 19 patients with successful free flap reconstruction and no wound complications (mean age, 63.9 [SD, 9.5]?years; 14 men), while 5 patients had wound failure (mean age, 58.0 [SD, 5.7]?years; 2 men). Blood flow, blood volume, MTT, and time maximum intensity projection (P?=?.007, .007, .015, and .004, respectively) in CT perfusion, and fractional plasma volume, volume transfer constant, peak enhancement, and time to maximum enhancement (P=.006, .039, .004, and .04, respectively) in dynamic contrast-enhanced MR imaging were significantly different between the 2 groups.CONCLUSIONS:& nbsp;CT perfusion and dynamic contrast-enhanced MR imaging are both promising imaging techniques to predict wound complications after head and neck free flap reconstruction.

Purpose/Objective(s) Optimal surveillance algorithms are not well defined in p16+ oropharynx cancer. Prior work suggests that recurrences are rarely detected during routine clinical follow up but we previously have shown a minimal clinically important difference (MCID) in PRO symptoms may be sensitive for detection of treatment failure. We instituted a prospective registry incorporating electronic PROs (ePRO) and blood ctDNA into surveillance. Primary objective was feasibility of electronic survey administration and compliance, with noncompliance defined as failure to complete 2 consecutive surveys. Materials/Methods Eligibility included stage I-III p16+ oropharynx cancer 3-38 months post definitive therapy and negative 3mo PET (HUM00183387). EORTC QLQ30/HN35 were collected by email monthly and blood HPV ctDNA was drawn every 3 months. Results Since 1/2021, 85 patients have been enrolled, of which 63 completed electronic consent while 24 patients were lost due to disinterest (3/24), technological challenges (3/24) and unable to be contacted by phone (18/24). Of the 63 consented patients, 41 (65%) were compliant (C) and 22 (35%) noncompliant (non-C) in answering monthly surveys, with a median follow up of 7.9 months and a median 7.5 surveys/participant. There was no difference in frequency of standard clinic-based follow up between C and non-C patients (p=0.97). Non-C patients were older (mean age 66.2 vs 60.5, p=0.007) and more likely to be enrolled in Medicare/Medicaid (54.5% vs 22%, p=0.009). There were no significant differences in baseline reported ePRO subscales at 1 month among C and non-C patients, suggesting that patient perception of QOL did not impact initial survey participation. Longitudinal ePRO analysis revealed that 29/53 patients with analyzable data reported a MCID change in at least 1/8 prespecified symptom categories, however there was no correlation between change in patients' perceived symptoms and continued survey compliance (p =0.9). 67 patients (79%) had ctDNA collected, with 151 post-treatment tests and a mean of 1.9 tests per patient. Five tests were detectable: 3 "indeterminate" values followed by undetectable tests, 1 detectable in a patient currently NED, and 1 detectable in a patient with recurrence. To date, there are 2 recurrences in this registry. Conclusion Patient participation in longitudinal ePROs was challenging in our cohort particularly among elderly patients, with only 65% compliance; however, about half of patients reported clinically meaningful MCID changes in at least 1/8 subcategories. This presents an opportunity for future studies to assess whether intervention upon reported MCID changes may impact compliance or post treatment QOL. ctDNA collection is feasible and may be incorporated into future surveillance algorithms given high patient compliance.

Purpose/Objective(s) Pre- and mid-treatment FDG-PET parameters are prognostic of treatment response in p16+ oropharynx cancer (OPC). Our prospective Phase 2 de-escalation study utilizes FDG-PET response criteria to select patients eligible for de-escalated radiotherapy and hypothesizes that early swallow function and quality of life will improve with lower dose radiation. Materials/Methods Eligibility criteria stipulated stage I-II (AJCC 8) p16+ OPC with FDG-avid disease. Patients with matted lymph nodes or history of head and neck surgery were excluded. All patients received concurrent weekly carboplatin/paclitaxel. FDG-PET was obtained at baseline and at fraction 10. Patients were de-escalated to 54 Gy in 27 fractions if both pretreatment metabolic tumor volume (MTV) 50% of SUVmax was ≤22cc and interval MTV above SUV 2.5 decreased ≥50% from baseline. Those not meeting FDG-PET response criteria received 70 Gy in 35 fractions. Planned interim analysis examined early toxicity and patient-reported outcomes (PROs: xerostomia questionnaire, UWash QoL, FACT-HN, PRO-CTCAE) after accrual of 48 of 75 evaluable patients. Change from baseline scores of PROs was assessed with a mixed-effects model regarding +/- 0.5 standard deviations as clinically significant, consistent with prior work. Results Overall population (n=48) characteristics were: median age 59.5 years, 85% male, 44% ever smoker with 20 pack-year median, 90% T1-2, and 81% N1 and similar between cohorts. Pre-treatment GTV size was not different (30.8 cc 54 Gy vs 33.1 cc 70 Gy cohort, p=0.54). Exactly 50% of patients (n=24) met the de-escalation cohort criteria with median decrease in interval MTV2.5 of 63% (IQR 56-82%) vs median decrease of 26% (IQR 4-40%) among the 70 Gy cohort. The dose to the larynx, constrictors, oral cavity, and salivary glands in the 54 Gy cohort was 70-78% of that received by the 70 Gy cohort (all comparisons p<0.01). De-escalated patients lost significantly less weight as percent of baseline (7.0% vs 11.5%, p<0.001) and fewer required feeding tube placement during treatment (1 vs 5, p=0.08). The 70 Gy cohort also had significantly worse videofluoroscopic swallowing function at 3 months compared to baseline with average increase in Penetration Aspiration Scale of 2 points (vs 0 points in the 54 Gy cohort, p=0.023). Across all 4 PRO surveys, while 54 Gy patients reported faring numerically better than the 70 Gy patients at 1 month post-treatment, this did not reach clinical or statistical significance. Conclusion Mid-treatment FDG-PET response adaptation allows for approximately half of stage I-II p16+ OPC patients to be de-escalated to 54 Gy. This results in an approximately 25% reduction in dose delivered to organs known to affect toxicity and quality of life with significantly better objective measures of toxicity and numerically improved PROs. Pre- and mid-treatment FDG-PET parameters are prognostic of treatment response in p16+ oropharynx cancer (OPC). Our prospective Phase 2 de-escalation study utilizes FDG-PET response criteria to select patients eligible for de-escalated radiotherapy and hypothesizes that early swallow function and quality of life will improve with lower dose radiation. Eligibility criteria stipulated stage I-II (AJCC 8) p16+ OPC with FDG-avid disease. Patients with matted lymph nodes or history of head and neck surgery were excluded. All patients received concurrent weekly carboplatin/paclitaxel. FDG-PET was obtained at baseline and at fraction 10. Patients were de-escalated to 54 Gy in 27 fractions if both pretreatment metabolic tumor volume (MTV) 50% of SUVmax was ≤22cc and interval MTV above SUV 2.5 decreased ≥50% from baseline. Those not meeting FDG-PET response criteria received 70 Gy in 35 fractions. Planned interim analysis examined early toxicity and patient-reported outcomes (PROs: xerostomia questionnaire, UWash QoL, FACT-HN, PRO-CTCAE) after accrual of 48 of 75 evaluable patients. Change from baseline scores of PROs was assessed with a mixed-effects model regarding +/- 0.5 standard deviations as clinically significant, consistent with prior work. Overall population (n=48) characteristics were: median age 59.5 years, 85% male, 44% ever smoker with 20 pack-year median, 90% T1-2, and 81% N1 and similar between cohorts. Pre-treatment GTV size was not different (30.8 cc 54 Gy vs 33.1 cc 70 Gy cohort, p=0.54). Exactly 50% of patients (n=24) met the de-escalation cohort criteria with median decrease in interval MTV2.5 of 63% (IQR 56-82%) vs median decrease of 26% (IQR 4-40%) among the 70 Gy cohort. The dose to the larynx, constrictors, oral cavity, and salivary glands in the 54 Gy cohort was 70-78% of that received by the 70 Gy cohort (all comparisons p<0.01). De-escalated patients lost significantly less weight as percent of baseline (7.0% vs 11.5%, p<0.001) and fewer required feeding tube placement during treatment (1 vs 5, p=0.08). The 70 Gy cohort also had significantly worse videofluoroscopic swallowing function at 3 months compared to baseline with average increase in Penetration Aspiration Scale of 2 points (vs 0 points in the 54 Gy cohort, p=0.023). Across all 4 PRO surveys, while 54 Gy patients reported faring numerically better than the 70 Gy patients at 1 month post-treatment, this did not reach clinical or statistical significance. Mid-treatment FDG-PET response adaptation allows for approximately half of stage I-II p16+ OPC patients to be de-escalated to 54 Gy. This results in an approximately 25% reduction in dose delivered to organs known to affect toxicity and quality of life with significantly better objective measures of toxicity and numerically improved PROs.

Purpose/Objective(s) Despite recent changes in treatment for unresectable recurrent or metastatic head and neck squamous cell carcinoma (R/M HNC) survival remains poor. Clinical trials fail to capture the diversity of patients and spectrum of disease presentation. This study examines clinically pertinent prognostic variables, efficacy of treatment regimens, and factors associated with response to first line treatment at a high-volume NCI cancer center. Materials/Methods A retrospective analysis of patients diagnosed with R/M HNC between 1998- 2018 was performed (n=477). Bivariate and multivariate Cox regression analysis identified independent predictors of survival. Covariates included HPV status, primary site, smoking, ECOG performance status, Charleson comorbidity index, organ dysfunction, BMI, neutrophil/lymphocyte ratio (NLR), tumor volume, platinum sensitivity, location of metastases, and disease-free interval (DFI, time from definitive therapy to R/M diagnosis). Variables with significant bivariate comparisons and no collinearity were included in multivariate analysis. Given retrospective nature of the database, time on treatment was used as a surrogate marker of treatment response. We examined clinical variables associated with time on treatment and patterns of metastasis using T tests and Chi square analyses. Results Median overall survival (OS) improved from 6.7 mo (95% CI 4.6-8.7) in 1998- 2007 to 11.8 mo (95% CI 10.0-13.6) in 2008- 2018 (p<0.01). Mean DFl was 11.7 mo (SD 22.2 mo). Patients who recurred within 6 mo of receiving platinum chemotherapy had worse OS compared to those sensitive to platinum agents (6.9 vs 11.1 mo, p<0.05). Predictors of worse OS included HPV negativity (HR 1.5, 95% CI 1.1-2.2), high NLR (HR 1.0, 95% CI 1.0-1.1), DFI ≤6 mo (HR 1.4, 95% CI 1.0-1.9), and poor performance status (ECOG ≥2, HR 1.8, 95% CI 1.0-3.0). Patients with oligometastatic disease amenable to local treatment had improved OS over those receiving systemic therapy (26.1 vs 12.1 mo, p<0.01). Immune checkpoint inhibitor (ICI) in combination with EGFR inhibition was associated with the longest time on treatment compared to other systemic therapies (265 vs 120 d, p<0.001). HPV+ patients were more likely to respond to ICI compared to HPV- (243 vs 119 d, p<0.05). Patients with locoregional recurrence and/or bone metastases were more likely to respond to ICIs compared to other systemic therapies (p=0.01). Platinum sensitive patients were more likely to respond to VEGF inhibition compared to platinum refractory (196 vs 76 d, p<0.05). Conclusion These data support the promising activity of novel agents in R/M HNC while highlighting the efficacy of ICIs and improved survival of patients over time. The patterns of distant metastasis and treatment failures in R/M HNC can help guide development of surveillance guidelines especially with the advent of non-invasive biomarkers. Despite recent changes in treatment for unresectable recurrent or metastatic head and neck squamous cell carcinoma (R/M HNC) survival remains poor. Clinical trials fail to capture the diversity of patients and spectrum of disease presentation. This study examines clinically pertinent prognostic variables, efficacy of treatment regimens, and factors associated with response to first line treatment at a high-volume NCI cancer center. A retrospective analysis of patients diagnosed with R/M HNC between 1998- 2018 was performed (n=477). Bivariate and multivariate Cox regression analysis identified independent predictors of survival. Covariates included HPV status, primary site, smoking, ECOG performance status, Charleson comorbidity index, organ dysfunction, BMI, neutrophil/lymphocyte ratio (NLR), tumor volume, platinum sensitivity, location of metastases, and disease-free interval (DFI, time from definitive therapy to R/M diagnosis). Variables with significant bivariate comparisons and no collinearity were included in multivariate analysis. Given retrospective nature of the database, time on treatment was used as a surrogate marker of treatment response. We examined clinical variables associated with time on treatment and patterns of metastasis using T tests and Chi square analyses. Median overall survival (OS) improved from 6.7 mo (95% CI 4.6-8.7) in 1998- 2007 to 11.8 mo (95% CI 10.0-13.6) in 2008- 2018 (p<0.01). Mean DFl was 11.7 mo (SD 22.2 mo). Patients who recurred within 6 mo of receiving platinum chemotherapy had worse OS compared to those sensitive to platinum agents (6.9 vs 11.1 mo, p<0.05). Predictors of worse OS included HPV negativity (HR 1.5, 95% CI 1.1-2.2), high NLR (HR 1.0, 95% CI 1.0-1.1), DFI ≤6 mo (HR 1.4, 95% CI 1.0-1.9), and poor performance status (ECOG ≥2, HR 1.8, 95% CI 1.0-3.0). Patients with oligometastatic disease amenable to local treatment had improved OS over those receiving systemic therapy (26.1 vs 12.1 mo, p<0.01). Immune checkpoint inhibitor (ICI) in combination with EGFR inhibition was associated with the longest time on treatment compared to other systemic therapies (265 vs 120 d, p<0.001). HPV+ patients were more likely to respond to ICI compared to HPV- (243 vs 119 d, p<0.05). Patients with locoregional recurrence and/or bone metastases were more likely to respond to ICIs compared to other systemic therapies (p=0.01). Platinum sensitive patients were more likely to respond to VEGF inhibition compared to platinum refractory (196 vs 76 d, p<0.05). These data support the promising activity of novel agents in R/M HNC while highlighting the efficacy of ICIs and improved survival of patients over time. The patterns of distant metastasis and treatment failures in R/M HNC can help guide development of surveillance guidelines especially with the advent of non-invasive biomarkers.

We were able to combine a comprehensive set of clinical, dosimetric and toxicity grading factors to identify an actionable clinical profile for anticipating ED. This forms the basis for next steps to develop and test interventions based on the model as reduction in unplanned acute care is a priority for clinical transformation in oncology. The scope of high-ranking inputs underscores the importance of constructing data ware house systems, that enable constructing multi-domain models. Significance of "distance of hospital" in our model and similar limitations for all ED studies underscores the need for integrated EHR across all hospital systems.

LRC improvement was numerically but not significantly improved with DCE-MRI directed boost for all randomized patients and p16+ oropharynx subgroup; DFS was not improved. Boost volume < 1cc was associated with good prognosis. Grade 3+ toxicities and 3 mo FT use were non-significantly higher in Arm B. Table 1. Outcomes according to treatment arm for randomized patients.

Despite increased smoking history and RT boost, CRT patients exhibited fewer acute toxicities compared to iCRT patients. iCRT patients reported severe taste changes, mucositis, and xerostomia early in treatment. As many trials are currently ongoing to establish the oncologic benefit of concurrent immunotherapy, attention must be paid to acute and late toxicities as well as their impact on QOL in order to define their therapeutic utility.

Purpose/Objective(s)Biomarkers of immunotherapy response are increasingly important in oropharyngeal cancer with the rapid expansion of treatment in the R/M population and many ongoing upfront trials. CPS score is the most commonly used method to quantify immune infiltration and predict response to immunotherapy, although limited by its static nature and sampling error. Previous studies show that pre-RT to mid-treatment changes in MRI-derived blood volume (BV) and apparent diffusion coefficient (ADC) as well as FDG-PET derived metabolic tumor volume (MTV) and total lesion glycolysis (TLG) serve as imaging markers for pattern failure of HNC treated by CRT. The goal of this study is to evaluate changes in image metrics during concurrent immunotherapy and CRT compared to those from CRT.Materials/MethodsMRI and FDG-PET scans were acquired pre- and mid-treatment (fx 10) from 75 patients with high risk p16+ OPSCC (AJCC stage 3 or “matted nodes”) who were treated with definitive concurrent CRT on 2 prospective institutional trials. The patients included: 1) the first 15 patients treated with definitive CRT 70Gy/concurrent carboplatin/taxol and concurrent nivolumab (iCRT) and 2) 60 patients treated with 70-80Gy/concurrent weekly cisplatin/carboplatin (CRT). Changes in quantitative image metrics from pre- to mid-treatment of primary tumors and individual lymph nodes were evaluated: gross tumor volume (GTV), MTV at 50% max SUV, TLG, mean SUV, mean BV and ADC between the two treatment groups using unpaired t test.ResultsClinical characteristics and baseline quantitative image metrics were similar between CRT and iCRT groups, except the iCRT group had a lower BV value of primary tumors and a greater MTV of nodal tumors than CRT group (P = 0.05). However, at mid-treatment, iCRT patients had: 1) significantly greater increases in mean BV and ADC of primary tumors than CRT patients (49% vs. 23% and 21% vs. 12%, P < 0.007 and 0.03, respectively); but 2) less decreases in MTV, TLG and mean SUV of primary tumors than CRT patients, for which 11% of the TLG decrease was significantly different from 43% decrease of CRT group (P < 0.05); and 3) 12% decrease in mean SUV of nodal tumors that was significantly less than 25% in CRT group (P < 0.0001). With a mean follow-up of 11 months in the iCRT group, there has been only 1 DM in a patient with persistent low BV in the primary tumor, consistent with our previous findings in CRT patients.ConclusionThis analysis suggests that high risk p16+ OPSCC patients treated with iCRT had larger increases in BV and ADC and a smaller decrease in TLG in primary tumors mid-treatment compared to CRT group. Increases in BV and ADC have been identified to be associated with improved tumor control by previous studies of CRT. The minimal reduction of FDG metrics of iCRT group may be due to inflammatory response to anti-PD1. These findings warrant further investigation as predictive biomarkers for iCRT response to treatment.

To our knowledge, this is the first investigation of dosimetric parameters associated with SL following H&N RT. Our findings suggest that higher volume of low-mid RT dose within the anterior neck is associated with developing SL. This may be related to circumferential neck dose and/or the role of superficial lymphatics within level VI after H&N RT. These findings warrant prospective validation in a larger cohort, but may be considered in the context of RT treatment planning to minimize SL after RT. (HUM00176639).

Bioselection with induction chemotherapy in larynx cancer is associated with excellent larynx preservation and disease-specific survival (DSS). The current approach to evaluating bioselection response consists of visual inspection of the primary tumor with operative direct laryngoscopy (DL) where ≥ 50% response to induction chemotherapy prompts continuation to definitive chemoradiation. Here, we retrospectively compare clinical and imaging response in bioselected patients.

In advanced larynx cancer, the use of induction chemotherapy (IC) to select patients for organ preservation offers outcomes comparable to upfront laryngectomy. Assessment of tumor response to IC is performed with direct laryngoscopy (DL), and barriers to this approach exist. In this study, we retrospectively investigate radiomic and clinical features as predictors of OS and laryngectomy free survival (LFS). Larynx cancer patients from a single institution with usable CT and PET scans were included. Clinical variables investigated were tumor subsite, T-stage, N-stage, neutrophil-lymphocyte ratio (NLR), and lymphocyte-monocyte ratio (LMR). CT-based variables were pre-IC GTV, GTV change between pre and post IC (ΔGTV), and 43 radiomic texture features. Cox proportional hazards was utilized for OS and LFS; logistic regression was used for IC response. Feature selection for each model was performed by identifying variables with a significant (p ≤ 0.05) Spearman rank. Model accuracy was assessed using the average concordance index from 100 iterations of stratified, 5-fold cross validation. Of 84 patents with CT, and clinical features, 5 features were found to have significant correlations with surgeon-assessed IC response: 3 texture-based radiomic features (coarseness, busyness, grey level nonuniformity (GLN)), ΔGTV, and N-stage. The latter 3 features contributed significantly to the final model (see table). For OS, only N-stage had significant correlation. For LFS, 8 features were found to have significant correlations, including 5 texture features (coarseness, busyness, strength, grey level variance (GLV), large zone emphasis (LZE)), NLR, LMR, and ΔGTV. Of these 8 features, 2 contributed significantly to the final model (see table). When including PET features for 54 patients, only LFS was found to correlate significantly with PET-based features. Of 12 features found to have significant correlation with LFS, 5 contributed significantly to the final model: PET contrast (hazard ratio (HR) = 1.70, p = 0.02), PET correlation (HR = 3790, p = 0.03), PET dissimilarity (HR = 1.20E-05, p = 0.048), ΔGTV (HR = 0.959, p = 0.001), and NLR (HR = 3.67, p = 0.04). The average concordance index for this model was 0.628 ± 0.149. In this study, we investigate the role of CT-based, PET-based, and clinical features as predictors for OS, LFS, and surgeon-assessed response to IC in a bioselection approach to larynx cancer. Initial results indicate that several features may have value as predictors for OS, LFS, and IC response. Due to limited data size, further studies with larger datasets are necessary to validate these results and further explore the potential of these variables.Tabled 1Abstract 2698; TableModelFeatureHazard/Odds ratiop-valueMean C-idxICGLN0.4750.0280.808 ± 0.099ΔGTV5.23< 0.001N-stage1.860.003OSN-stage1.8740.010.643 ± 0.102LFSΔGTV0.578< 0.001NLR2.740.0050.664 ± 0.101 Open table in a new tab

CSCC of the head and neck (CSCCHN) is a common malignancy due to chronic sun exposure. While most cases are localized and cured with surgery, the current standard of adjuvant radiation therapy to patients with regional metastases is suboptimal. Nodal involvement reduces the likelihood of cure with 70-80% 2-yr overall survival (OS) reported for N1 disease, and 25-50% with N2-3 disease. Cemiplimab was recently approved for recurrent/metastatic patients, but there remains a need to intensify adjuvant therapy in the definitive setting in order to maximize locoregional control (LRC). Given that CSCCHN highly expresses EGFR, we prospectively studied the addition of concurrent cetuximab (EGFR targeted antibody) to radiotherapy for locally advanced CSCCHN in the post-operative setting (NCT01979211). This is a single-institutional phase II trial of patients with pathologically proven CSCCHN with skeletal muscle, cartilage, or bone invasion, or lymph nodes (≥N1) after definitive resection. Prior invasive malignancy, except prior cSCC and cutaneous basal cell carcinomas, were excluded. Patients underwent adjuvant radiation to 60 Gy via daily 2 Gy fractions via megavoltage photon beam therapy, with or without electrons. Treating to 66 Gy was allowed for close margins or nodal extracapsular extension. Cetuximab was given as a loading dose of 400 mg/m2 one week prior to radiation, followed by 250 mg/m2 weekly concurrent with radiation. Primary endpoint of 2-year LRC, and secondary objectives of 2-year disease-free survival (DFS) and 2- and 5-year OS were assessed by Kaplan-Meier analysis. 24 patients age 47 – 88 (median 71 yrs) were treated with adjuvant chemoradiation from 2014-2017. 22 (91.7%) completed the full course of radiation and 21 (87.5%) received all cetuximab infusions. 6 patients had T3 or higher disease, 4 had N1 disease and 6 were staged as N2/3. Resected lesions ranged from 1.0 – 9.9cm in size (median 4cm), and most often involved the parotid gland (13 lesions, 54.2%) or cheek (5 lesions, 20.8%). At a median follow up of 42 months, 6 patients had progressed: 2 locally, 3 distantly, and 1 patient both locally and distantly. Median OS was not reached. Median DFS was 64 mo. 2-year OS was 75%, and 5-year OS was 67.5%. 2-year DFS was 70.8%, and 5-year DFS was 55.9%. LRC was 91.6% at 2 years and 85% at 5 years, and no node positive patients failed locoregionally. All grade 3 adverse events were related to skin toxicity (16.7%). There were no Grade 4/5 toxicities. In this prospective trial of adjuvant cetuximab and radiation for locally advanced CSCCHN, OS and DFS compare favorably to historical data. Cetuximab was well tolerated with a low rate of adverse effects. Cetuximab-based chemoradiation may be a reasonable approach in CSCCHN patients who are at high risk of disease recurrence or progression but requires investigation in a randomized study.

The excellent prognosis of p16+ oropharyngeal squamous cell carcinoma (OPSCC) invites efforts to reduce surveillance burden after treatment. Current surveillance guidelines suggest frequent clinical examination, demanding time, costs, and discomfort with nasopharyngoscopy. Recent publications demonstrated low rates of asymptomatic locoregional recurrence (LRR) detection in these frequent visits, but no alternatives exist. We sought to assess correlation of changes in patient reported quality of life (QOL) forms with LRR to evaluate feasibility of using such forms in an individualized surveillance approach.

Adjuvant RT in oral cavity squamous cell carcinoma (OCSCC) frequently requires bilateral level IB within the clinical target volume (CTV). However, submandibular gland (SMG) embryology and physiology suggest that its treatment may increase xerostomia without increasing cure. Histologic and embryologic data suggest that the SMG becomes encapsulated before lymphatic development and therefore differs from parotid in containing no intraglandular nodes/lymphatics. Except in cases of direct extension, the intraglandular recurrence risk should therefore be low. We have previously shown that the contralateral SMG (cSMG) could be safely spared in oropharynx cancer. In OCSCC, we have shown the cSMG can be spared dosimetrically to a mean dose ≤36 Gy with slight underdosing of the surrounding level 1B PTV where the PTV overlaps with the SMG. Here, we review our institutional outcomes with cSMG sparing in OCSCC. Using a prospective database, we identified patients with OCSCC who underwent definitive surgery/adjuvant RT. Surgery consisted of primary tumor resection +/- free flap reconstruction and uni- or bilateral neck dissection. Adjuvant RT was planned to 60-66Gy to PTVhigh including post-operative bed/dissected neck, 54Gy to PTVlow at risk undissected neck including level 1B using VMAT. Concurrent chemotherapy was given for + margin or ECE. Bilateral parotid glands and bilateral SMG were contoured if present and mean dose to glands calculated. We aimed for a mean SMG dose of ≤39 Gy and allowed slight underdosing of the surrounding IB PTV where there was overlap with the SMG. Patterns of failure were reviewed. Physician and PRO graded xerostomia were collected during and after RT. 147 patients who underwent adjuvant RT were identified overall with 9% local, 7% regional, and 14% distant recurrences. We excluded 68 patients with bilateral neck dissections/no SMGs and 37 patients who had unilateral neck RT. 42 remaining patients had SMG sparing bilateral neck RT with cSMG spared with SMG mean dose 34.2Gy. Mean age was 62, 60% oral tongue/FOM and 40% N+ other oral cavity sites, 3/42 (7%) with <2mm margin, 9/42 (22%) with PNI, and 14/42 (32%) with ECE. AJCC 8 staging included 27% pT1/30%T2/8% T3/35% T4, and 24% pN0/26% N1/21% N2a/17% N2b/12% N3b; mean D95% to PTV54_1B to was 42.5Gy, mean D95% to CTV_1B was 50Gy. Mean doses to ipsilateral/contralateral parotid were 30Gy/26Gy. With mean follow-up 19 mo and minimum follow-up 6 mo, we observed 8% local, 3% regional, and 6% distant recurrences. There were no patients with recurrences in ipsilateral or contralateral level IB. Ongoing study includes analysis of physician and patient reported xerostomia (XQ). Our experience in 42 OCSCC patients after undergoing bilateral neck RT with cSMG sparing shows no recurrence in level IB, suggesting safety of this approach. Xerostomia analysis is ongoing. Clinical trials evaluating cSMG sparing in OCSCC are warranted to assess impact of patterns of recurrence and quality of life.