Framework Development: Standardizing Definition of Advanced Practice Radiation Therapy Activities for Clinical Workload Quantification.

Purpose: Advanced practice (AP) in radiation therapy (RT) is being implemented around the globe. In an effort to advance the understanding of the similarities and differences in APRT roles in Ontario, Canada, a community of practice (CoP) sought ways to provide quantitative data on the nature of APRT clinical activities and the frequency with which these activities were being executed. Methods: In 2017, a consensus building project involving 20 APRTs and 14 radiation therapy (RT) department managers in Ontario was completed to establish a mechanism to quantify APRTs' clinical impact. In Round 1 & 2, expert feedback was gathered to generate an Advanced Practice (AP) Activity List. In Round 3: 20 APRTs completed an online survey to assess the importance and applicability of each AP Activity to their role using Likert scale (0-5). A final AP Activity List & Definitions was generated. Results & discussion: Round 1: Forty-seven AP activities were identified. Round 2: 3/14 RT managers provided 145 feedback statements on Round 1 AP Activity List. The working group used RT managers' feedback to clarify AP activities and definitions, specifically merging 33 unique AP activities to create 11 inclusive AP activities and eliminating 8 activities identified from Round 1. The most inclusive AP activity created was #1 New Patient Consultation, this AP Activity is merged from 7 unique AP activities. Incorporating RT managers' feedback with the internal AP clinical workload lists from 2 Ontario cancer centres resulted in a revised AP Activity List with 20 AP inclusive activities. Round 3: 14/20 APRTs provided Likert scores on this revised list. The most applicable AP activities (mean score) were #16 Technical Consultation (4.0), #15 Contouring Target Volume (3.8) and #2 Planning Consultation (3.8); the least applicable was #18 MR Applicator Assessment (0.9). Conclusions: This is the first systematic attempt to build consensus on AP clinical activities. Non-clinical APRT activities related to research, education, innovation, and program development were not in the scope of this project. The Final AP Activity List & Definitions serves as a framework that allows standardized and continuous monitoring of AP clinical activities and impact.

Pre- and Post-Radiotherapy Radiologic Nodal Features and Oropharyngeal Cancer Outcomes.

OBJECTIVES: To assess the prognostic value of pre-/post-radiotherapy (pre-/post-RT) radiologic lymph node (LN) features in human papillomavirus (HPV)-positive and HPV-negative oropharyngeal carcinoma (OPC) patients treated with definitive (chemo-)RT. METHODS: Clinical node-positive OPCs treated from 2011 to 2015 were reviewed. Nodal features were reviewed by a radiologist on pre-/post-RT computed tomography (CTs). Univariable analysis calculated hazard ratio (HR) for regional failure (RF), distant metastasis (DM), and deaths. Multivariable analysis estimated adjusted HR (aHR) of significant nodal features identified in univariable analysis adjusting for confounders. RESULTS: Pre-RT CT was undertaken in 344 HPV-positive and 94 HPV-negative OPC patients, of whom 242 (70%) HPV-positive and 67 (71%) HPV-negative also had a post-RT CT. Median follow-up was 4.9 years. Pre-RT LN calcification (pre-RT_LN-cal) increased the risk of RF in HPV-negative (aHR: 5.3, P = .007) but not HPV-positive patients (P = .110). Pre-RT radiologic extranodal extension (pre-RT_rENE+) increased the risk of DM and death in both HPV-negative (DM: aHR 6.6, P < .001; death: aHR 2.1, both P = .019) and HPV-positive patients (DM: aHR 4.9; death: aHR 3.0, both P < .001). Increased risk of RF occured with < 20% post-RT LN size reduction in both HPV-negative (HR 6.0, P = .002) and HPV-positive cases (HR 3.0, P = .049). Post-RT_LN-cal did not affect RF, DM, or death regardless of tumor HPV status (all P > .05). CONCLUSION: Pre-RT_LN-cal is associated with higher RF risk in HPV-negative but not in HPV-positive patients. Pre-RT_rENE increases risk of DM and death regardless of tumor HPV status. Minimal post-RT LN size reduction (< 20%) increases risk of RF in both diseases. Post-RT_LN-cal + has no apparent influence on outcomes in either disease. LEVEL OF EVIDENCE: 4 (a single institution case-control series) Laryngoscope, 131:E1162-E1171, 2021.

Sexual satisfaction in nasopharyngeal carcinoma survivors: Rates and determinants.

OBJECTIVES: Sexual health problems have been identified as an unmet need in head and neck cancer (HNC) survivors. In particular, little is known about such outcomes in survivors of nasopharyngeal cancer (NPC). MATERIALS AND METHODS: A cross-sectional study of NPC survivors with ≥4y follow-up was undertaken. Sexual satisfaction was assessed using the optional "I am satisfied with my sex life" item of the FACT-H&N. Other patient-reported outcomes measures were also captured including fatigue (FACIT-F), HNC symptom burden (MDASI-HN), emotional distress (HADS) and frontal function (FrSBE). Univariate and multivariate analyses were performed to determine factors influencing sexual satisfaction. RESULTS: The sexual satisfaction item was answered by 85/103 (83%) enrollees. Female (p < 0.001) and non-partnered (p = 0.0045) patients were more likely to abstain from answering. The distribution of responses were: "very much" (26%), "quite a bit" (21%), "somewhat" (20%), "a little bit" (13%) and "not at all" (20%). Sexual satisfaction was associated with multiple patient-reported measures on univariate analysis, including quality of life, fatigue, a priori selected HNC symptoms (pain, taste), emotional distress, frontal lobe function, body image and relationship strength. On multivariate analysis, only relationship strength and emotional distress remained significant. Sociodemographic factors (age, sex, marital status) and other selected orofacial toxicities were not significant. CONCLUSIONS: Nearly half (47%) of our sample reported being in the higher satisfaction range. While reassuring in the context of comparative population level data, a number of factors including toxicity, psychological and social factors were associated with sexual satisfaction responses. Prospective evaluation of this unmet need is required.

Privacy-preserving distributed learning of radiomics to predict overall survival and HPV status in head and neck cancer.

A major challenge in radiomics is assembling data from multiple centers. Sharing data between hospitals is restricted by legal and ethical regulations. Distributed learning is a technique, enabling training models on multicenter data without data leaving the hospitals ("privacy-preserving" distributed learning). This study tested feasibility of distributed learning of radiomics data for prediction of two year overall survival and HPV status in head and neck cancer (HNC) patients. Pretreatment CT images were collected from 1174 HNC patients in 6 different cohorts. 981 radiomic features were extracted using Z-Rad software implementation. Hierarchical clustering was performed to preselect features. Classification was done using logistic regression. In the validation dataset, the receiver operating characteristics (ROC) were compared between the models trained in the centralized and distributed manner. No difference in ROC was observed with respect to feature selection. The logistic regression coefficients were identical between the methods (absolute difference <10-7). In comparison of the full workflow (feature selection and classification), no significant difference in ROC was found between centralized and distributed models for both studied endpoints (DeLong p > 0.05). In conclusion, both feature selection and classification are feasible in a distributed manner using radiomics data, which opens new possibility for training more reliable radiomics models.

A cross sectional study in cognitive and neurobehavioral impairment in long-term nasopharyngeal cancer survivors treated with intensity-modulated radiotherapy.

PURPOSE/OBJECTIVES: To determine neurocognitive and neurobehavioral impairment in long-term nasopharyngeal cancer survivors (NPC) treated with intensity-modulated radiotherapy (IMRT). MATERIALS/METHODS: A cross-sectional cohort of NPC ≥4 years (y) following IMRT was assessed. Objective cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and patient-reported memory was assessed with the MDASI-HN problems remembering item. Patient and family ratings of patients' neurobehavioral symptoms of apathy, disinhibition and executive dysfunction were assessed with the Frontal Systems Behavior Scale (FrSBe). Other patient-reported symptoms (MDASI-HN), mood (HADS), and quality of life (FACT-H&N) were also collected. RESULTS: Among 102 participants: M:F = 66:36; median age 56y (32-77); median time since IMRT 7.5y (4.2-11.1). Impaired MoCA scores (<23) were observed in 33 (32%). Patient and family ratings of pre-illness neurobehavioral symptoms were in the normal range (total FrSBe T-scores 53.3 and 59.0 respectively). In contrast, post-treatment patient and family T-scores were clinically impaired (64.7, 71.3 respectively), with apathy, disinhibition and executive dysfunction post-treatment ratings all significantly worse than pre-treatment (p < 0.001). Prevalence of clinically significant post-treatment disturbance was high by patient and family ratings (48%/66% apathy, 35%/53% disinhibition, 39%/56% executive dysfunction). Post-treatment neurobehavioral symptoms strongly correlated with lower quality of life (r = -0.62) and higher anxiety (r = 0.62) and depression scores (r = 0.67, all p < 0.001). Total MoCA scores did not correlate with RT dose. However, greater declines in apathy, disinhibition and executive dysfunction were associated with receiving >75 Gy to temporal lobes. CONCLUSION: NPC treated with IMRT had moderate to high rates of neurocognitive impairment and clinically significant apathy, disinhibition, and executive dysfunction.

Long-Term Late Toxicity, Quality of Life, and Emotional Distress in Patients With Nasopharyngeal Carcinoma Treated With Intensity Modulated Radiation Therapy.

PURPOSE: To report long-term (>4 years) toxicity and quality of life (QoL) among patients with nasopharyngeal carcinoma (NPC) treated with intensity modulated radiation therapy (IMRT) in a nonendemic center. METHODS AND MATERIALS: A cross-sectional cohort study enrolled patients with NPC who were disease-free and ≥4 years after IMRT ± chemotherapy. Physician-reported adverse events (Common Terminology Criteria for Adverse Events, version 4.03) and patient-reported QoL (Functional Assessment of Cancer Therapy-Head and Neck, Functional Assessment of Chronic Illness Therapy-Fatigue), utilities (EuroQOL-5D), head and neck symptoms (MD Anderson Symptom Inventory-Head and Neck), and emotional distress (Hospital Anxiety and Depression Scale) were collected. Consenting patients also underwent endocrine screening and audiometry. RESULTS: Among 107 patients enrolled, median age at enrollment and time since treatment were 57 (32-81) and 7.5 years (4.2-11.1), respectively. Most patients (99%) received 70 Gy in 35 fractions; the majority (93%) received concurrent chemotherapy. Mean scores for the Functional Assessment of Cancer Therapy-Head and Neck, Functional Assessment of Chronic Illness Therapy-Fatigue, and EuroQOL-5D were 105.0 (46-148), 116.6 (44-160), and 0.85 (0.29-1.00), respectively. Dry mouth, mucus, swallowing/chewing, memory, and teeth/gum problems were scored highest on the MD Anderson Symptom Inventory-Head and Neck; mean symptom severity and symptom interference scores were 2.3 and 2.4, respectively. Grade 3 or higher physician-reported adverse events were noted in 50 patients (47%), most frequently hearing problems (46, 43%). Audiometry revealed significant bilateral hearing loss (grade ≥3) in 68 patients (72%). Depression (25%), anxiety (37%), and fatigue (28%) were common and strongly correlated with QoL. Most patients (69%) developed hypothyroidism; 1 patient (1%) developed pituitary dysfunction requiring hormone replacement. V50 >90 and V45 >99 to the thyroid correlated with significantly higher rates of hypothyroidism. CONCLUSIONS: Despite the implementation of IMRT, survivors of NPC still experience many physical symptoms that affect long-term QoL many years after treatment. Depression, anxiety, and fatigue remain common in long-term survivors and are highly correlated with QoL.

Partial Laryngeal IMRT for T2N0 Glottic Cancer: Impact of Image Guidance and Radiation Therapy Intensification.

PURPOSE: To assess the impact of the radiation therapy (RT) regimen and image guidance (image guided radiation therapy [IGRT]) protocol on local control (LC) for T2N0 glottic cancer treated with partial laryngeal intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: All patients with T2N0 glottic cancer treated with IMRT from 2006 to 2013 at a single institution were retrospectively reviewed. The gross tumor volume (GTV), delineated from endoscopic and/or radiologic findings, was expanded 0.5 cm for the high-dose clinical target volume and an additional 0.5 cm for the lower-dose clinical target volume (total of 1.0 cm from GTV). The planning target volume margin was 0.5 cm radially and 1 cm superiorly and inferiorly. RT regimens evolved from hypofractionated IMRT (RT-hypo, 60 Gy in 25 fractions over a period of 5 weeks) to moderately accelerated IMRT (RT-acc, 66-70 Gy in 33-35 fractions over a period of 5.5-6 weeks) since 2010. The IGRT matching surrogate changed from cervical vertebral bone (IGRT-bone) to laryngeal soft tissue (IGRT-larynx) in 2008. LC was compared between 3 sequential cohorts: RT-hypo/IGRT-bone, RT-hypo/IGRT-larynx, and RT-acc/IGRT-larynx. Multivariable analysis assessed the relative impact of RT regimen and IGRT technique on local failure separately. RESULTS: Among 139 eligible patients (median follow-up period, 5.03 years [range, 0.8-10.5 years]), we identified 28 local, 6 regional, and 2 distant failures. A higher 3-year LC rate was observed for RT-acc/IGRT-larynx (89% [95% CI: 78%-95%]) versus RT-hypo/IGRT-larynx (80% [95% CI: 54%-91%]) and RT-hypo/IGRT-bone (70% [95% CI: 53%-80%]) (P = .02). Multivariable analysis adjusted for GTV (in cubic centimeters) and smoking status confirmed that IGRT-larynx versus IGRT-bone (hazard ratio, 0.40; P = .019) and RT-acc versus RT-hypo (hazard ratio, 0.34; P = .012) both reduced the risk of local failure. CONCLUSIONS: This single-institution cohort study shows a high LC rate (89%) for T2N0 glottic cancer following moderately accelerated partial laryngeal IMRT with daily laryngeal soft tissue matching IGRT. These results appear to represent an improvement attributable to changes in both IGRT matching and dose delivered, but their independent significance is unknown and further confirmation in a larger cohort is warranted.

Radiomic Biomarkers to Refine Risk Models for Distant Metastasis in HPV-related Oropharyngeal Carcinoma.

PURPOSE: Distant metastasis (DM) is the main cause of death for patients with human papillomavirus (HPV)-related oropharyngeal cancers (OPCs); yet, there are few reliable predictors of DM in this disease. The role of quantitative imaging (ie, radiomic) analysis was examined to determine whether there are primary tumor features discernible on imaging studies that are associated with a higher risk of DM developing. METHODS AND MATERIALS: Radiation therapy planning computed tomography scans were retrieved for all nonmetastatic p16-positive OPC patients treated with radiation therapy or chemoradiation therapy at a single institution between 2005 and 2010. Radiomic biomarkers were derived from each gross tumor volume. The biomarkers included 4 representative radiomic features from tumor first-order statistics, shape, texture, and wavelet groups, as well as a combined 4-feature signature. Univariable Cox proportional hazards models for DM risk were identified. The discriminative performance of prognostic univariable and multivariable models was compared using the concordance index (C-index). Subgroup analyses were performed. RESULTS: There were 300 HPV-related OPC patients who were eligible for the analysis. A total of 36 DM events occurred within a median follow-up period of 5 years. On univariable analysis, top results included the 4 representative radiomic features (C-index, 0.670-0.686; P < .001), the radiomic signature (C-index, 0.670; P < .001), tumor stage (C-index, 0.633; P < .001), tumor diameter (C-index, 0.653; P < .001), and tumor volume (C-index, 0.674; P < .001), which demonstrated moderate discrimination of DM risk. Combined clinical-radiomic models yielded significantly improved performance (C-index, 0.701-0.714; P < .05). In subgroup analyses, the radiomic biomarkers consistently stratified patients for DM risk, particularly for those cohorts with greater risks (C-index, 0.663-0.796), such as patients with stage III disease. CONCLUSIONS: Radiomic biomarkers appear to classify DM risk for patients with nonmetastatic HPV-related OPC. Radiomic biomarkers could be used either alone or with other clinical characteristics in the assignment of DM risk in future HPV-related OPC clinical trials.

Development and validation of a radiomic signature to predict HPV (p16) status from standard CT imaging: a multicenter study.

OBJECTIVES: Human papillomavirus (HPV) positive oropharyngeal cancer (oropharyngeal squamous cell carcinoma, OPSCC) is biologically and clinically different from HPV negative OPSCC. Here, we evaluate the use of a radiomic approach to identify the HPV status of OPSCC. METHODS: Four independent cohorts, totaling 778 OPSCC patients with HPV determined by p16 were collected. We randomly assigned 80% of all data for model training (N = 628) and 20% for validation (N = 150). On the pre-treatment CT images, 902 radiomic features were calculated from the gross tumor volume. Multivariable modeling was performed using least absolute shrinkage and selection operator. To assess the impact of CT artifacts in predicting HPV (p16), a model was developed on all training data (Mall) and on the artifact-free subset of training data (Mno art). Models were validated on all validation data (Vall), and the subgroups with (Vart) and without (Vno art) artifacts. Kaplan-Meier survival analysis was performed to compare HPV status based on p16 and radiomic model predictions. RESULTS: The area under the receiver operator curve for Mall and Mno art ranged between 0.70 and 0.80 and was not significantly different for all validation data sets. There was a consistent and significant split between survival curves with HPV status determined by p16 [p = 0.007; hazard ratio (HR): 0.46], Mall (p = 0.036; HR: 0.55) and Mno art (p = 0.027; HR: 0.49). CONCLUSION: This study provides proof of concept that molecular information can be derived from standard medical images and shows potential for radiomics as imaging biomarker of HPV status. Advances in knowledge: Radiomics has the potential to identify clinically relevant molecular phenotypes.

Clinical outcomes in patients with T4 laryngeal cancer treated with primary radiotherapy versus primary laryngectomy.

BACKGROUND: The purpose of this study was to determine the clinical outcomes of T4 laryngeal cancers. METHODS: T4 laryngeal cancers treated with curative intent from January 2003 to December 2010 were analyzed. Outcomes were evaluated in both primary radiotherapy (+/- chemotherapy) (RT/CRT) and primary surgery cohorts. RESULTS: Among the 65 primary RT/CRT and 42 primary surgery patients included, median follow-up was 4.4 years. There was a trend for improved locoregional control with surgery (74% vs 88%; p = .08). In the RT/CRT group the 3-year laryngectomy-free survival was 67%. The 2-year gastrostomy dependency rate was 23% with RT/CRT versus 6% with primary surgery (p = .07). Overall survival (OS) at 3 years was significantly lower in the RT/CRT versus primary surgery group (41% vs 70%; p < .01). CONCLUSION: Laryngeal preservation is achieved in over two thirds of patients with primary RT/CRT. Patients with low volume minimal cartilage involvement T4 disease may be best suited to RT/CRT. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2035-E2040, 2016.

Outcomes and prognostic factors for major salivary gland carcinoma following postoperative radiotherapy.

PURPOSE: To report outcomes of postoperative radiotherapy (PORT) for major salivary gland carcinoma (SGC) and identify patients at high risk of distant metastases (DM). METHODS AND MATERIALS: Patients with major SGC treated between 2000-2012 were identified. All patients underwent initial primary resection, with neck dissection (ND) therapeutically (if N+) or electively in high risk N0 patients. PORT was delivered using 3D-CRT or IMRT. Multivariable analysis (MVA) assessed predictors for DM, cause-specific (CSS) and overall survival. RESULTS: Overall 304 patients were identified: 48% stage III-IVB, 22% lymphovascular invasion (LVI), 50% involved margins and 64% high risk pathology. ND was performed in 154 patients (51%). Adjuvant chemotherapy was used in 10 patients (3%). IMRT was delivered in 171 patients (56%) and 3D-CRT in 133 (44%). With a median follow-up of 82 months, the 5-(10-) year local, regional, distant control, CSS and OS were 96% (96%), 95% (94%), 80% (77%), 83% (82%) and 78% (75%), respectively. DM was the most frequent treatment failure (n=62). On MVA, stage III-IVB and LVI significantly correlated with DM, CSS and OS, while positive margins predicted DM and CSS, and high risk pathology predicted DM. No grade ⩾ 4 RTOG late toxicity was reported; 9 patients had grade 3, including osteoradionecrosis (n=4), neck fibrosis (n=3), trismus (n=1) and dysphagia (n=1). CONCLUSIONS: Surgery and PORT with 3D-CRT/IMRT produced excellent long-term outcomes. Further research is required for patients with stage III-IVB, LVI, positive margins and high risk pathology to determine the incremental benefit of systemic therapy in management of SGC.

Outcomes after reirradiation for recurrent nasopharyngeal carcinoma: North American experience.

BACKGROUND: The purpose of this article was to report outcomes of reirradiation for locoregionally recurrent nasopharyngeal carcinoma (NPC). METHODS: A retrospective review was conducted of all patients with locoregionally recurrent NPC who received reirradiation between 2001 and 2012. Overall survival (OS), local control, regional control, distant control, and Radiation Therapy Oncology Group (RTOG) grades 3 to 4 late toxicity were examined. RESULTS: A total of 42 recurrent cases treated with intensity-modulated radiotherapy (IMRT; 27 patients) or non-IMRT (stereotactic radiotherapy [RT], 12 patients; 3D conformal RT, 3 patients) were identified. Median time from initial RT to recurrence was 4.6 years. Hyperfractionation with 1.1 to 1.4 Gy/fraction twice daily to a total of 40 to 60 Gy was used in 27 IMRT and 5 non-IMRT patients. The remaining 10 patients received conventional fractionation 1.8 to 2.0 Gy/fraction to 50 to 60 Gy. Median follow-up was 3.0 years. The 3-year OS, local control, regional control, distant control, and late toxicity rates were 49%, 46%, 71%, 79%, and 37%, respectively. CONCLUSION: Reirradiation for recurrent NPC, delivered mostly with hyperfractionated IMRT, can result in durable disease control with acceptable late toxicity. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1102-E1109, 2016.

External validation of a prognostic CT-based radiomic signature in oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is one of the fastest growing disease sites of head and neck cancers. A recently described radiomic signature, based exclusively on pre-treatment computed tomography (CT) imaging of the primary tumor volume, was found to be prognostic in independent cohorts of lung and head and neck cancer patients treated in the Netherlands. Here, we further validate this signature in a large and independent North American cohort of OPSCC patients, also considering CT artifacts. METHODS: A total of 542 OPSCC patients were included for which we determined the prognostic index (PI) of the radiomic signature. We tested the signature model fit in a Cox regression and assessed model discrimination with Harrell's c-index. Kaplan-Meier survival curves between high and low signature predictions were compared with a log-rank test. Validation was performed in the complete cohort (PMH1) and in the subset of patients without (PMH2) and with (PMH3) visible CT artifacts within the delineated tumor region. RESULTS: We identified 267 (49%) patients without and 275 (51%) with visible CT artifacts. The calibration slope (ß) on the PI in a Cox proportional hazards model was 1.27 (H0: ß = 1, p = 0.152) in the PMH1 (n = 542), 0.855 (H0: ß = 1, p = 0.524) in the PMH2 (n = 267) and 1.99 (H0: ß = 1, p = 0.002) in the PMH3 (n = 275) cohort. Harrell's c-index was 0.628 (p = 2.72e-9), 0.634 (p = 2.7e-6) and 0.647 (p = 5.35e-6) for the PMH1, PMH2 and PMH3 cohort, respectively. Kaplan-Meier survival curves were significantly different (p < 0.05) between high and low radiomic signature model predictions for all cohorts. CONCLUSION: Overall, the signature validated well using all CT images as-is, demonstrating a good model fit and preservation of discrimination. Even though CT artifacts were shown to be of influence, the signature had significant prognostic power regardless if patients with CT artifacts were included.