18FDG positron emission tomography mining for metabolic imaging biomarkers of radiation-induced xerostomia in patients with oropharyngeal cancer.

PURPOSE: Head and neck cancers radiotherapy (RT) is associated with inevitable injury to parotid glands and subsequent xerostomia. We investigated the utility of SUV derived from 18FDG-PET to develop metabolic imaging biomarkers (MIBs) of RT-related parotid injury. METHODS: Data for oropharyngeal cancer (OPC) patients treated with RT at our institution between 2005 and 2015 with available planning computed tomography (CT), dose grid, pre- & first post-RT 18FDG-PET-CT scans, and physician-reported xerostomia assessment at 3-6 months post-RT (Xero 3-6 ms) per CTCAE, was retrieved, following an IRB approval. A CT-CT deformable image co-registration followed by voxel-by-voxel resampling of pre & post-RT 18FDG activity and dose grid were performed. Ipsilateral (Ipsi) and contralateral (contra) parotid glands were sub-segmented based on the received dose in 5 Gy increments, i.e. 0-5 Gy, 5-10 Gy sub-volumes, etc. Median and dose-weighted SUV were extracted from whole parotid volumes and sub-volumes on pre- & post-RT PET scans, using in-house code that runs on MATLAB. Wilcoxon signed-rank and Kruskal-Wallis tests were used to test differences pre- and post-RT. RESULTS: 432 parotid glands, belonging to 108 OPC patients treated with RT, were sub-segmented & analyzed. Xero 3-6 ms was reported as: non-severe (78.7%) and severe (21.3%). SUV- median values were significantly reduced post-RT, irrespective of laterality (p = 0.02). A similar pattern was observed in parotid sub-volumes, especially ipsi parotid gland sub-volumes receiving doses 10-50 Gy (p < 0.05). Kruskal-Wallis test showed a significantly higher mean RT dose in the contra parotid in the patients with more severe Xero 3-6mo (p = 0.03). Multiple logistic regression showed a combined clinical-dosimetric-metabolic imaging model could predict the severity of Xero 3-6mo; AUC = 0.78 (95%CI: 0.66-0.85; p < 0.0001). CONCLUSION: We sought to quantify pre- and post-RT 18FDG-PET metrics of parotid glands in patients with OPC. Temporal dynamics of PET-derived metrics can potentially serve as MIBs of RT-related xerostomia in concert with clinical and dosimetric variables.

Risk and Clinical Risk Factors Associated With Late Lower Cranial Neuropathy in Long-term Oropharyngeal Squamous Cell Carcinoma Survivors.

Importance: Lower cranial neuropathy (LCNP) is a rare, but permanent, late effect of radiotherapy and other cancer therapies. Lower cranial neuropathy is associated with excess cancer-related symptoms and worse swallowing-related quality of life. Few studies have investigated risk and clinical factors associated with late LCNP among patients with long-term survival of oropharyngeal squamous cell carcinoma (OPSCC survivors). Objective: To estimate the cumulative incidence of and identify clinical factors associated with late LCNP among long-term OPSCC survivors. Design, Setting, and Participants: This single-institution cohort study included disease-free adult OPSCC survivors who completed curative treatment from January 1, 2000, to December 31, 2013. Exclusion criteria consisted of baseline LCNP, recurrent head and neck cancer, treatment at other institutions, death, and a second primary, persistent, or recurrent malignant neoplasm of the head and neck less than 3 months after treatment. Median survival of OPSCC among the 2021 eligible patients was 6.8 (range, 0.3-18.4) years. Data were analyzed from October 12, 2019, to November 13, 2020. Main Outcomes and Measures: Late LCNP events were defined by neuropathy of the glossopharyngeal, vagus, and/or hypoglossal cranial nerves at least 3 months after cancer therapy. Cumulative incidence of LCNP was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were fit. Results: Among the 2021 OPSCC survivors included in the analysis of this cohort study (1740 [86.1%] male; median age, 56 [range, 28-86] years), 88 (4.4%) were diagnosed with late LCNP, with median time to LCNP of 5.4 (range, 0.3-14.1) years after treatment. Cumulative incidence of LCNP was 0.024 (95% CI, 0.017-0.032) at 5 years, 0.061 (95% CI, 0.048-0.078) at 10 years, and 0.098 (95% CI, 0.075-0.128) at 15 years of follow-up. Multivariable Cox proportional hazards regression identified T4 vs T1 classification (hazard ratio [HR], 3.82; 95% CI, 1.85-7.86) and accelerated vs standard radiotherapy fractionation (HR, 2.15; 95% CI, 1.34-3.45) as independently associated with late LCNP status, after adjustment. Among the subgroup of 1986 patients with nonsurgical treatment, induction chemotherapy regimens including combined docetaxel, cisplatin, and fluorouracil (TPF) (HR, 2.51; 95% CI, 1.35-4.67) and TPF with cetuximab (HR, 5.80; 95% CI, 1.74-19.35) along with T classification and accelerated radiotherapy fractionation were associated with late LCNP status after adjustment. Conclusions and Relevance: This single-institution cohort study found that, although rare in the population overall, cumulative risk of late LCNP progressed to 10% during the survivors' lifetime. As expected, clinical factors associated with LCNP primarily reflected greater tumor burden and treatment intensity. Further efforts are necessary to investigate risk-reduction strategies as well as surveillance and management strategies for this disabling late effect of cancer treatment.

Self-Reported Trismus: prevalence, severity and impact on quality of life in oropharyngeal cancer survivorship: a cross-sectional survey report from a comprehensive cancer center.

OBJECTIVE: The purpose of this study was to estimate prevalence/severity of self-reported trismus, determine association with quality of life (QOL), and examine clinical risk factors in a large population of patients treated for oropharyngeal cancer. MATERIALS AND METHODS: A cross-sectional survivorship survey was conducted among patients who completed definitive treatment for oropharyngeal carcinoma, disease-free ≥ 1-year post-treatment (median survival, 7 years among 892 survivors). Associations between trismus and QOL were also analyzed using MDASI-HN, EQ-5D, and MDADI. Dietary and feeding tube status were also correlated to trismus status. RESULTS: Trismus was self-reported in 31%. Severity of trismus positively correlated (r = 0.29) with higher mean interference scores reflecting a moderate association with quality of life (p < 0.0001). There was a negative correlation for MDADI composite scores (r = - 0.33) indicating increased perceived dysphagia related to trismus severity (p < 0.0001). EQ-5D VAS scores were also negatively correlated with trismus severity (r = - 0.26, p < 0.0001). Larger T-stage (p ≤ 0.001), larger nodal stage (p = 0.03), tumor sub-site (p = 0.05), and concurrent chemoradiation (p = 0.01) associated with increased prevalence of trismus. Diet negatively correlated (r = - 0.27) with trismus severity (p = < 0.0001), and survivors with severe trismus were also more likely to be feeding tube-dependent. CONCLUSION: Severity of trismus appears to negatively impact quality of life and associate with various adverse functional outcomes in long-term oropharyngeal cancer survivorship. Trismus remains associated with advanced disease stages, tumor sub-site (tonsil), and addition of chemotherapy. Further investigation is merited for the dose-effect relationship to the muscles of mastication.

Subjective functional outcomes in oropharyngeal cancer treated with induction chemotherapy using the MD Anderson Symptom Inventory (MDASI).

OBJECTIVES: Evaluate the use of induction chemotherapy (IC) in oropharyngeal cancer (OPC) and its impact on subjective functional outcomes using a validated MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) survey tool. METHODS: A single institution retrospective review of OPC patients who received IC, including reasons given for using IC, regimens employed, responses, and patient-reported outcomes (PRO). The latter included pain, distress, dysphagia, xerostomia, and feeding tube placement and dependency. PRO's were assessed using the validated MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) conducted at baseline, during treatment, and at six-month follow up. RESULTS: One hundred and twenty-five patients were evaluable. They were more likely to have large primary and/or bulky or low neck nodal disease as a reason for IC. A taxane-containing regimen was most common. Primary tumor response was seen in 83.2% and the nodal response in 81.6%. Pain and xerostomia improved with IC, dysphagia was not adversely affected with IC. These symptoms all increased with consolidation chemoradiotherapy (CRT) but returned to baseline by 6 months post treatment. Feeding tube placement did not increase with IC but did with CRT, most patients were no longer feeding tube dependent at 6 months. CONCLUSION: This retrospective review of subjective functional outcomes, especially swallowing and feeding tube dependency, using the MDASI survey tool in 125 oropharyngeal cancer patients with large primary tumors and/or bulky adenopathy treated predominantly with platinum-taxane based induction chemotherapy showed that such outcomes were not adversely impacted. While not standard, such approach may be beneficial in such patients. LEVEL OF EVIDENCE: 2.

Factors associated with employment discontinuation among older and working age survivors of oropharyngeal cancer.

BACKGROUND: Oropharyngeal cancer survivors experience difficulty returning to work after treatment. To better understand specific barriers to returning to work, we investigated factors associated with discontinuing employment among older and working-age survivors. METHODS: The sample included 675 oropharyngeal cancer survivors (median: 6 years posttreatment) diagnosed from 2000 to 2013 and employed at diagnosis. Relative risk models were constructed to examine the independent associations of demographic and health factors, and symptom experiences per the MD Anderson Symptom Inventory - Head and Neck Module (MDASI-HN) with posttreatment employment, overall and by age (<60 years vs ≥60 years at survey). RESULTS: Symptom interference was not statistically significantly associated with posttreatment employment status among respondents ≥60 years. Among working-age respondents <60 years, symptom interference was strongly associated with posttreatment employment. CONCLUSIONS: Efforts to assess and lessen symptom burden in working-age survivors should be evaluated as approaches to support regaining core functions needed for continued employment.

Dysphagia After Primary Transoral Robotic Surgery With Neck Dissection vs Nonsurgical Therapy in Patients With Low- to Intermediate-Risk Oropharyngeal Cancer.

IMPORTANCE: A major goal of primary transoral robotic surgery (TORS) for oropharyngeal cancer is to optimize swallowing outcomes by personalized treatment based on pathologic staging. However, swallowing outcomes after TORS are uncertain, as are the outcomes compared with nonsurgical options. OBJECTIVES: To estimate rates of acute dysphagia and recovery after TORS and to compare swallowing outcomes by primary treatment modality (TORS or radiotherapy). DESIGN, SETTING, AND PARTICIPANTS: This case series study was a secondary analysis of prospective registry data from 257 patients enrolled from March 1, 2015, to February 28, 2018, at a single academic institution who, according to the AJCC Staging Manual, 7th edition TNM classification, had low- to intermediate-risk human papillomavirus-related oropharyngeal squamous cell carcinoma possibly resectable by TORS. EXPOSURE: Patients were stratified by primary treatment (75 underwent TORS and 182 received radiotherapy). MAIN OUTCOMES AND MEASURES: Modified barium swallow (MBS) studies graded per Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) and the MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN) questionnaires were administered at standard intervals. Prevalence and severity of dysphagia were estimated per DIGEST before and after TORS and 3 to 6 months after treatment. Moderate-severe dysphagia (DIGEST grade ≥2) was assessed using logistic regression and compared by primary treatment group. The MDASI swallowing symptom severity item scores during and after radiotherapy were compared using generalized estimating equations by treatment status at the start of radiotherapy, after induction, and after TORS. RESULTS: A total of 257 patients (mean [SD] age, 59.54 [9.07] years; 222 [86.4%] male) were included in the study. Dysphagia severity (per DIGEST) was significantly worse after TORS (r = -0.63; 95% CI, -0.78 to -0.44): 17 patients (22.7%; 95% CI, 13.8%-33.8%) had moderate-severe (DIGEST grade ≥2) acute post-TORS dysphagia significantly associated with primary tumor volume (odds ratio, 1.43; 95% CI, 1.11-1.84). DIGEST improved by 3 to 6 months but remained worse than that at baseline; at 3 to 6 months, the number of patients with DIGEST grade 2 or higher dysphagia was 5 (6.7%; 95% CI, 2.2%-14.9%) after primary TORS and 29 (15.9%; 95% CI, 10.9%-22.1%) after radiotherapy. At the start of radiotherapy, MDASI swallowing symptom severity item scores were significantly worse in the post-TORS group compared with postinduction (mean [SD] change, 2.6 [1.1]) and treatment-naive (mean [SD] change, 1.7 [0.3]) patients. This result inverted at radiotherapy end, and all groups converged at 3 to 6 months. CONCLUSIONS AND RELEVANCE: Subacute swallowing outcomes were similar regardless of primary treatment modality among patients with low- to intermediate-risk oropharyngeal squamous cell carcinoma.

Swallowing-related outcomes associated with late lower cranial neuropathy in long-term oropharyngeal cancer survivors: cross-sectional survey analysis.

BACKGROUND: The purpose of this study was to quantify the association of late lower cranial neuropathy (late LCNP) with swallowing-related quality of life (QOL) and functional status among long-term oropharyngeal cancer (OPC) survivors. METHODS: Eight hundred eighty-nine OPC survivors (median survival time: 7 years) who received primary treatment at a single institution between January 2000 and December 2013 completed a cross-sectional survey (56% response rate) that included the MD Anderson Dysphagia Inventory (MDADI) and self-report of functional status. Late LCNP events ≥3 months after cancer therapy were abstracted from medical records. Multivariate models regressed MDADI scores on late LCNP status adjusting for clinical covariates. RESULTS: Overall, 4.0% (n = 36) of respondents developed late LCNP with median time to onset of 5.25 years post-treatment. LCNP cases reported significantly worse mean composite MDADI (LCNP: 68.0 vs no LCNP: 80.2; P < .001). Late LCNP independently associated with worse mean composite MDADI (ß = -6.7, P = .02; 95% confidence interval [CI], -12.0 to -1.3) as well as all MDADI domains after multivariate adjustment. LCNP cases were more likely to have a feeding tube at time of survey (odds ratio [OR] = 20.5; 95% CI, 8.6-48.9), history of aspiration pneumonia (OR = 23.5; 95% CI, 9.6-57.6), and tracheostomy (OR = 26.9; 95% CI, 6.0-121.7). CONCLUSIONS: In this large survey study, OPC survivors with late LCNP reported significantly poorer swallowing-related QOL and had significantly higher likelihood of poor functional status. Further efforts are necessary to optimize swallowing outcomes to improve QOL in this subgroup of survivors.

Patient-reported outcomes of symptom burden in patients receiving surgical or nonsurgical treatment for low-intermediate risk oropharyngeal squamous cell carcinoma: A comparative analysis of a prospective registry.

PURPOSE: To explore treatment-related changes in symptom burden and quality of life (QOL) in oropharyngeal squamous cell cancer (OPSCC) patients treated surgically and non-surgically. PATIENTS AND METHODS: Eighty-six patients with human papillomavirus-associated OPSCC treated at the Head and Neck Center at The University of Texas MD Anderson Cancer Center were recruited to a prospective registry study between 2014 and 2016 and completed the core, head and neck-specific, and symptom interference sections of the MD Anderson symptom inventory (MDASI) multi-symptom questionnaire and the EQ-5D health status assessment as a measure of QOL at four time points. RESULTS: Longitudinal improvements from post-treatment nadir were observed across all groups. For patients treated with single modality, symptom interference, but not core and head and neck specific, MDASI scores were significantly better at 6 months in patients treated with surgery than radiation (P = 0.04). For patients treated with multiple modalities, scores for each of the three domains (i.e., core, head and neck -specific, and interference MDASI) were significantly better in the surgical group than the nonsurgical group at treatment completion (P = 0.0003, P = 0.0006 and P = 0.02) and 6 weeks (P = 0.001, P = 0.05 and P = 0.04), but not 6 months (P = 0.11, P = 0.16 and P = 0.040). No significant differences in EQ5D health status were observed between groups at any time point, reflecting similar overall QOL in all groups. CONCLUSION: Symptom burden and QOL improves after treatment in OPSCC survivors over time regardless of whether primary surgical or nonsurgical treatment is used, although acute symptom profiles may differ.

Single-item discrimination of quality-of-life-altering dysphagia among 714 long-term oropharyngeal cancer survivors: Comparison of patient-reported outcome measures of swallowing.

BACKGROUND: Two patient-reported outcomes (PROs) of swallowing and their correlation to quality of life (QOL) were compared in long-term survivors of oropharyngeal cancer (OPC). METHODS: Scores on the single dysphagia item from the 28-item, multisymptom MD Anderson Symptom Inventory-Head and Neck (MDASI-HN-S) were compared with scores on the dysphagia-specific composite MD Anderson Dysphagia Inventory (MDADI) and the EuroQol visual analog scale (EQ-VAS) in 714 patients who had received definitive radiotherapy ≥12 months before the survey. An MDASI-HN-S score ≥6 and an MDADI composite score <60 were considered representative of moderate/severe swallowing dysfunction. RESULTS: Moderate/severe dysphagia was reported by 17% and 16% of respondents on the MDASI-HN-S and the composite MDADI, respectively. Both swallow PROs were predictive of QOL, and the MDASI-HN-S model was slightly more parsimonious for the discrimination of EQ-VAS scores compared with MDADI scores (Bayesian information criteria, 6062 vs 6076, respectively). An MDASI-HN-S cutoff score of ≥6 correlated best with a declining EQ-VAS score (P < .0001) and was associated with increased radiotherapy dose to several normal swallowing structures. CONCLUSIONS: In this cohort, the single-item MDASI-HN-S performed favorably for the discrimination of QOL compared with the multi-item MDADI. A time-efficient model for PRO measurement of swallowing is proposed in which the MDADI may be reserved for patients who score ≥6 on the MDASI-HN-S.

Symptom Burden Associated With Late Lower Cranial Neuropathy in Long-term Oropharyngeal Cancer Survivors.

Importance: Lower cranial neuropathy (LCNP) is a rare but potentially disabling result of radiotherapy and other head and neck cancer therapies. Survivors who develop late LCNP may experience profound functional impairment, with deficits in swallowing, speech, and voice. Objective: To investigate the association of late LCNP with severity of cancer treatment-related symptoms and subsequent general functional impairment among oropharyngeal cancer (OPC) survivors. Design, Setting, and Participants: This cross-sectional survey study analyzed 889 OPC survivors nested within a retrospective cohort of OPC survivors treated at MD Anderson Cancer Center from January 1, 2000, to December 31, 2013. Eligible survey participants were disease free and completed OPC treatment 1 year or more before the survey. Data analysis was performed from October 10, 2017, to March 15, 2018. Exposures: Late LCNP defined by onset 3 months or more after cancer therapy. Main Outcomes and Measures: The primary outcome variable was the mean of the top 5 most severely scored symptoms of all 22 core and head and neck cancer-specific symptoms from the MD Anderson Symptom Inventory Head and Neck Cancer Module (MDASI-HN). Secondary outcomes included mean MDASI-HN interference scores and single-item scores of the most severe symptoms. Multivariate models regressed MDASI-HN scores on late LCNP status, adjusting for clinical covariates. Results: Overall, 36 of 889 OPC survivors (4.0%) (753 [84.7%] male; 821 [92.4%] white; median [range] age, 56 [32-84] years; median [range] survival time, 7 [1-16] years) developed late LCNP. Late LCNP was significantly associated with worse mean top 5 MDASI-HN symptom scores (coefficient, 1.54; 95% CI, 0.82-2.26), adjusting for age, survival time, sex, therapeutic modality, T stage, subsite, type of radiotherapy, smoking, and normal diet before treatment. Late LCNP was also significantly associated with single-item scores for difficulty swallowing or chewing (coefficient, 2.25; 95% CI, 1.33-3.18), mucus (coefficient, 1.97; 95% CI, 1.03-2.91), fatigue (coefficient, 1.35; 95% CI, 0.40-2.21), choking (coefficient, 1.53; 95% CI, 0.65-2.41), and voice or speech symptoms (coefficient, 2.30; 95% CI, 1.60-3.03) in multivariable models. Late LCNP was not significantly associated with mean interference scores after correction for multiple comparisons (mean interference coefficient, 0.72; 95% CI, 0.09-1.35). Conclusions and Relevance: In this large survey study, OPC survivors with late LCNP reported worse cancer treatment-related symptoms, a finding suggesting an association between late LCNP and symptom burden. This research may inform the development and implementation of strategies for LCNP surveillance and management.

Radiotherapy dose-volume parameters predict videofluoroscopy-detected dysphagia per DIGEST after IMRT for oropharyngeal cancer: Results of a prospective registry.

PURPOSE: Our primary aim was to prospectively validate retrospective dose-response models of chronic radiation-associated dysphagia (RAD) after intensity modulated radiotherapy (IMRT) for oropharyngeal cancer (OPC). The secondary aim was to validate a grade ≥2 cut-point of the published videofluoroscopic dysphagia severity (Dynamic Imaging Grade for Swallowing Toxicity, DIGEST) as radiation dose-dependent. MATERIAL AND METHODS: Ninety-seven patients enrolled on an IRB-approved prospective registry protocol with stage I-IV OPC underwent pre- and 3-6 month post-RT videofluoroscopy. Dose-volume histograms (DVH) for swallowing regions of interest (ROI) were calculated. Dysphagia severity was graded per DIGEST criteria (dichotomized with grade ≥2 as moderate/severe RAD). Recursive partitioning analysis (RPA) and Bayesian Information Criteria (BIC) were used to identify dose-volume effects associated with moderate/severe RAD. RESULTS: 31% developed moderate/severe RAD (i.e. DIGEST grade ≥2) at 3-6 months after RT. RPA found DVH-derived dosimetric parameters of geniohyoid/mylohyoid (GHM), superior pharyngeal constrictor (SPC), and supraglottic region were associated with DIGEST grade ≥2 RAD. V61 ≥ 18.57% of GHM demonstrated optimal model performance for prediction of DIGEST grade ≥2. CONCLUSION: The findings from this prospective longitudinal registry validate prior observations that dose to submental musculature predicts for increased burden of dysphagia after oropharyngeal IMRT. Findings also support dichotomization of DIGEST grade ≥2 as a dose-dependent split for use as an endpoint in trials or predictive dose-response analysis of videofluoroscopy results.

Symptom burden as a driver of decisional regret in long-term oropharyngeal carcinoma survivors.

BACKGROUND: The purpose of this study was to characterize decisional regret and its association with symptom burden in a large cohort of oropharyngeal carcinoma (OPC) survivors. METHODS: A cross-sectional survey was administered to 1729 OPC survivors. Survey items included a multisymptom inventory and a validated decisional regret inventory. Associations between regret and symptom scores were analyzed to determine and rank symptom drivers of decisional regret. RESULTS: Nine hundred seventy-two patients responded reporting a low level of decisional regret overall, although 15.5% communicated "moderate to strong" regret. Overall symptom score and treatment group were statistically significant predictors of decisional regret. Relative to other symptoms, difficulty swallowing and feeling sad were the strongest drivers of decisional regret. CONCLUSION: OPC survivors provide a robust description of their long-term outcomes with 15.5% expressing "moderate to high" regret that was significantly associated with late symptom burden and multimodality treatment. Difficulty swallowing was the strongest driver of decisional regret.