Routman, David M.

ObjectiveTo describe and compare rates of metachronous and synchronous second primaries of the contralateral tonsil in patients with primary HPV(+) tonsillar squamous cell carcinoma (SCC).Study DesignRetrospective cohort study.Materials and MethodsThis is a single tertiary care center retrospective case series, from 2006 to 2019, of HPV(+) tonsillar SCC patients who underwent primary surgical resection with unilateral wide‐field tonsillectomy or bilateral tonsillectomy for diagnostic or therapeutic purposes. A metachronous second primary is one diagnosed >6 months after completion of surgical treatment. A synchronous second primary is one diagnosed during bilateral tonsillectomy for unilateral HPV(+) tonsillar SCC. Rates of second primary and patient characteristics were compared using chi‐square tests.ResultsAbout 303 patients underwent unilateral surgical resection +/− adjuvant therapy for HPV(+) tonsillar SCC. One (0.3%) developed a metachronous second primary in the contralateral tonsil 11.9 years following treatment. Fifty‐seven patients with HPV(+) tonsillar SCC underwent bilateral tonsillectomy, and 37/57 (65%) had no clinical signs for contralateral disease. Of these, only 1/37 (2.7%) was incidentally found to have a synchronous second primary. Twenty patients underwent bilateral tonsillectomy due to clinical concern for contralateral disease. Of these, 3/20 (15%) were found to have a synchronous HPV(+) SCC in the contralateral tonsil.ConclusionsThe prevalence of metachronous second primary after appropriate treatment of HPV(+) tonsillar SCC is very low (0.3%) and so is the chance of incidentally discovering a synchronous second primary during bilateral tonsillectomy (2.7%). We do not recommend bilateral tonsillectomy as a part of the routine algorithm in the surgical management of these patients.Level of Evidence3 Laryngoscope, 132:332–338, 2022

6049 Background: In the head and neck, human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) has a better prognosis and more tumor infiltrating lymphocytes (TILs) compared to its HPV(-) counterpart. Within HPV(+)OPSCC, the prognostic value of TILs in the primary tumor and in metastatic lymph nodes is not well understood. Methods: This is a matched case-control study at a tertiary care center of HPV(+)OPSCC patients who underwent primary surgery between 05/2007–12/2016. Cases developed locoregional recurrence or distant metastases during follow-up, while controls did not during a similar duration of follow-up. Pairs were matched on age, American Joint Committee on Cancer (AJCC) 8th edition pathologic stage, sex, year of surgery, degree of adjuvant treatment, comorbidities, and smoking status. One representative H&E slide of the primary tumor and lymph node (when nodal disease was present) from each patient was independently reviewed by two pathologists (JG, MR) blinded to outcome, for tumor TILs (tTILs) density (defined as % TILs), presence/absence of desmoplastic stroma, and when stroma was present, for stromal TILs (sTILs) density (defined as relative crowding of TILs). The Brandwein-Gensler pattern of invasion (POI) score was used to grade the primary tumor. Interrater agreement was assessed using Cohen’s kappa. Associations between TILs and time to disease progression were assessed using Cox proportional hazards regression models. Results: 41 case-control pairs (N=82) were included in the study: 38 (46%) were AJCC pStage I, 37 (45%) were pStage II, and 7 (9%) were pStage III; 22 (27%) underwent surgery alone, 15 (18%) underwent surgery with adjuvant radiotherapy, and 45 (55%) underwent surgery with adjuvant chemoradiation. Interrater agreement was fair for tTILs density in the primary tumor ( k=0.24) and lymph node ( k=0.23), moderate for desmoplastic stroma in the primary tumor ( k=0.58) and lymph node ( k=0.64), moderate for sTILs density in the primary tumor ( k=0.58) and lymph node ( k=0.48), and fair for the POI score ( k=0.17). tTILs density ≥10% (HR 0.35, 95% CI 0.14-0.90, p=0.028) and a moderate/dense sTILs density (HR 0.15, 95% CI 0.04-0.68, p=0.014) in the primary tumor were significantly associated with decreased risk of disease progression. An aggressive POI score of III or IV was significantly associated with increased risk of disease progression (HR 4.00, 95% CI 1.34-11.96, p=0.013). None of the study measures in the lymph node were significantly associated with disease progression. Conclusions: In HPV(+)OPSCC, a higher density of tumor and stromal TILs and nonaggressive POI in the primary tumor specimen may indicate a lower risk of disease progression. TILs may serve as a powerful prognostic marker for the adaptive immune response to this disease.

AbstractBackgroundParotid gland mucoepidermoid carcinoma (MEC) has published five‐year cancer‐specific survival (CSS) rates of 77%–97%, with variance related to grade.MethodsPatients receiving primary surgery for parotid gland MEC from 1995 to 2014 at a tertiary medical center underwent clinical review, histopathologic review, and cytogenetic analysis. Survival outcomes were evaluated.ResultsAmong 58 patients, T/N/M classification was as follows: T1 in 35 patients, T2 in 14, T4a in 9, N0 in 53, N1 in 2, N2b in 3. Histologic grade was low in 27, intermediate in 17, and high in 12 patients with 98% MAML2 positivity. All patients underwent parotidectomy, and seven patients received adjuvant radiation therapy. CSS was 100% at 5 years and 94.1% at 10 and 15 years. Two patients experienced locoregional recurrence.ConclusionsTreatment with adequate surgical resection and adjuvant radiation therapy for high‐grade or advanced‐stage tumors yields excellent survival, independent of clinical stage or pathologic grade.

ObjectiveDiagnostic delay in human papillomavirus–associated oropharynx squamous cell carcinoma (HPV(+)OPSCC) is common due to nonspecific symptoms. We aim to describe the disease burden and oncologic outcomes of patients with HPV(+)OPSCC diagnosed >12 months after symptom onset.Study DesignThis is a retrospective cohort study of HPV(+)OPSCC patients receiving intent‐to‐cure treatment (including surgery ± adjuvant therapy or primary chemoradiation).Setting2006‐2016, tertiary care center.MethodsTumor stage was compared between patients with and without delayed diagnosis using χ2 tests. Kaplan‐Meier survival analysis with univariate and multivariable Cox regressions were used to determine the effect of diagnostic delay on oncologic outcomes.ResultsIn total, 664 patients were included. Compared to patients diagnosed <12 months from symptom onset (n = 601), those diagnosed at >12 months (n = 63) were more likely to have T4 disease and higher overall American Joint Committee on Cancer (AJCC) clinical stage at presentation (P <. 01 for both). At 5 years, rates of overall survival, cancer‐specific survival, progression‐free survival, and distant metastases–free survival in the delayed diagnosis cohort were 80%, 90%, 80%, and 89%, respectively. A >12‐month delay in diagnosis did not significantly impact overall survival (adjusted hazard ratio [aHR], 1.16; 95% CI, 0.58‐2.31), cancer‐specific survival (aHR, 0.83; 95% CI, 0.29‐2.39), progression‐free survival (aHR, 1.15; 95% CI, 0.56‐2.37), or distant metastases–free survival (aHR, 1.00; 95% CI, 0.42‐2.40) after adjusting for age, sex, and clinical AJCC stage (P >. 05 for all).ConclusionsDelayed diagnosis of HPV(+)OPSCC is associated with greater burden of disease at presentation, but oncologic outcomes remain favorable across treatment modalities. When appropriate, intent‐to‐cure therapy should be pursued despite diagnostic delay.Level of EvidenceLevel III.

AbstractPurposeTo prospectively assess acute differences in patient‐reported outcomes in bowel and urinary domains between intensity‐modulated radiotherapy (IMRT) and proton beam therapy (PBT) for prostate cancer.Methods and MaterialsBowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC‐26 were collected in patients with T1‐T2 prostate cancer receiving IMRT or PBT at a tertiary cancer center (2015‐2018). Mean changes in domain scores were analyzed from pretreatment to the end of and 3 months post‐radiotherapy for each modality. A clinically meaningful change was defined as a score change >50% of the baseline standard deviation.ResultsA total of 157 patients receiving IMRT and 105 receiving PBT were included. There were no baseline differences in domain scores between cohorts. At the end of radiotherapy, there was significant and clinically meaningful worsening of BF and UO scores for patients receiving either modality. In the BF domain, the IMRT cohort experienced greater decrement (−13.0 vs −6.7, P < .01), and had a higher proportion of patients with clinically meaningful reduction (58.4% vs 39.5%, P = .01), compared to PBT. At 3 months post‐radiotherapy, the IMRT group had significant and clinically meaningful worsening of BF (−9.3, P < .001), whereas the change in BF score of the PBT cohort was no longer significant or clinically meaningful (−1.2, P = .25). There were no significant or clinically meaningful changes in UO or UI 3 months post‐radiotherapy.ConclusionsPBT had less acute decrement in BF than IMRT following radiotherapy. There was no difference between the two modalities in UO and UI.

AbstractBackgroundAggressive dose de‐escalated adjuvant radiation therapy (RT) in patients with human papillomavirus–associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC).MethodsPatients with HPV(+)OPSCC on a phase II clinical trial of primary surgery and neck dissection followed by dose de‐escalated RT (N = 79) were compared with a cohort of patients who received standard adjuvant therapy (N = 115). Local recurrence‐free, regional recurrence‐free, distant metastases‐free survival, and progression‐free survival (PFS) were assessed.ResultsOf 194 patients, 23 experienced progression at a median of 1.1 years following surgery (interquartile range [IQR] 0.7‐2.0; range 0.3‐5.4); 10 patients in the de‐escalated cohort and 13 patients in the standard cohort. The 3‐year PFS rate for the de‐escalated cohort was 87%, and in the standard cohort was 90% (hazard ratio [HR] 1.18, 95% confidence interval (CI) [0.50‐2.75]).ConclusionPatients with HPV(+)OPSCC who undergo surgical resection and neck dissection and meet criteria for adjuvant therapy can undergo aggressive dose de‐escalation of RT without increasing risk of progression locally, regionally or at distant sites.

We sought to determine the incidence and location of human papillomavirus (HPV)–associated anogenital disease in women with HPV‐positive oropharyngeal squamous cell carcinoma (OPSCC) via a retrospective cohort study with prospective contact to update history at Mayo Clinic in Rochester, Minnesota. Females undergoing treatment for nonmetastatic HPV‐positive OPSCC from 2011 to 2019 were identified. Clinical history and outcomes were abstracted from medical records. Patients without documented anogenital history were contacted, consented, and administered a survey, and external records were requested and reviewed. Seventeen of 46 patients (37.0%) had a history of anogenital HPV‐associated disease, and 16 of 17 (94.1%) required procedures to diagnose or treat HPV lesions. The cervix was the most common site (16/17, 94.1%). Procedures included colposcopy (n = 6), cervical excision (n = 3), cryotherapy (n = 4), and hysterectomy (n = 3). One case of fatal cervical carcinoma was noted, diagnosed 1 year following OPSCC. Three of 17 (17.6%) had HPV‐related vulvovaginal disease, and 1 of 17 had anal disease. Patients with a history of HPV‐positive OPSCC may be at elevated risk for HPV‐associated anogenital disease.

e17535 Background: Androgen Deprivation Therapy (ADT) is commonly used to treat prostate cancer (PC), but has been associated with cardiac morbidity and mortality. The exact mechanisms of this association are unclear. We sought to use an artificial intelligence (AI) enabled algorithm to identify ECG changes in PC patients who received ADT compared to PC patients who did not receive ADT. Methods: From 1,000,000 ECGs performed on 210,414 patients between 1993 and 2017 at our institution, a convolutional neural network was developed to detect predictive signatures for cardiac pathologies. During this process, the ability to predict “estimated sex” of the patient was developed, with output values ranging from 0 (female) to 1 (male). We applied this algorithm to 8,619 ECGs performed on 1,057 men age 75 or younger treated with radiation for high-risk or recurrent PC at our institution, and compared estimated sex after receiving ADT (n = 1,065) to ADT-naive ECGs (n = 7,554). We correlated ECG-identified estimated sex with serum testosterone levels using Spearman rank correlation. Results: Patients who had received ADT had a mean (SD) estimated sex value of 0.81 (0.26) compared to 0.92 (0.17) for those who did not (p < 0.001). Difference between estimated sex in post-ADT ECGs and ADT-naive ECGs remained significant across age groups (Table). Decreased serum total testosterone correlated with decreased estimated sex values in men receiving ADT (R = .57, p < 0.001). Conclusions: ADT for prostate cancer is associated with changes in AI-identified ECG parameters, including lower estimated male sex after receiving ADT. Lower ECG male sex estimate was associated with decreased serum testosterone. In this study, we provide preliminary proof of concept for a potential non-invasive means of monitoring treatment effect and physiologic change using ECGs. [Table: see text]

Abstract Oligometastasis represents an intermediate disease stage between localized and widely metastatic cancer. Efficient identification of patients with oligometastasis remains a barrier for accrual on clinical trials of oligometastasis-directed therapy. Here we review the prospect of circulating tumor DNA–based monitoring to promote sensitive, specific, and cost-efficient detection of cancer recurrence during posttreatment surveillance. Thus, an impetus for the development and implementation of clinical-grade circulating tumor DNA assays should be for the positive impact they will have on clinical investigations of oligometastasis-directed therapy.

305 Background: Toxicity due to radiotherapy (RT) may differ in patients (pts) with prostate cancer who receive intensity-modulated radiotherapy (IMRT) or proton beam therapy (PBT). Methods: Patient-reported bowel function (BF), urinary incontinence (UI), and urinary irritative/obstructive symptoms (UO) domains of the Expanded Prostate Index Composite Questionnaire (EPIC-26) were prospectively collected in pts with localized prostate cancer receiving either IMRT (n=157) or PBT (n=105) to the prostate +/- proximal seminal vesicles for clinical stage T1-T2 N0 prostate cancer at a single tertiary cancer center between 2015 and 2018. Changes in domain scores were analyzed from pretreatment to the end of RT and 3 months post-RT, assessing the acute effects of each modality. A clinically relevant change was defined as a score change that exceeded 50% of the standard deviation of a baseline value. Results: At baseline there was no difference in the scores of BF, UI, and UO domains between IMRT and PBT cohorts. At the end of RT, pts treated with either modality had a statistically significant and clinically relevant worsening of BF and UO compared to baseline. Pts treated with IMRT experienced a significantly greater decrement in BF compared to the PBT cohort (-13 vs -9, p<0.01), including significantly more IMRT pts having a clinically relevant deterioration in BF compared to PBT pts (58% vs 40%, p=0.01). Though there was a statistically significant deterioration in UI in the IMRT cohort (-4, p<0.001), this did not reach the predefined threshold for clinical relevance. Three months following RT, the IMRT group continued to have statistically significant and clinically relevant worsening of BF (-9, p<0.001), whereas the change in BF domain score of the PBT cohort was no longer statistically significant or clinically relevant compared to baseline (-1, p=0.25). There were no statistically significant or clinically relevant changes in UO or UI in either cohort at three months when compared to baseline. Conclusions: Pts who received IMRT or PBT reported unique patterns of toxicity, and pts treated with IMRT had worse decrement in BF immediately after and three months following RT, compared to those treated with PBT.