Transoral Robotic Surgery and Radiation Volume Deintensification in Unknown Primary Squamous Cell Carcinoma of the Neck: The Phase 2 FIND Nonrandomized Controlled Trial.

Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects. Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control. Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022. Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0. Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings. Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%). Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.

Contralateral nodal failures in oropharyngeal cancers after TORS and unilateral neck management: a retrospective study.

BACKGROUND: Report the incidence of contralateral nodal failure rates in well-lateralized oropharyngeal carcinoma treated with upfront surgery and unilateral neck management. METHODS: Lateralized oropharyngeal carcinomas treated with upfront surgery using transoral robotic surgery (TORS) and unilateral neck management (unilateral neck dissection ± unilateral radiation treatment) were identified. Primary endpoint was contralateral regional control (CRC). Secondary endpoints were local control (LC), and overall survival (OS). RESULTS: Thirty-two patients were included. Pathologic T categories included 66% pT1, 31% pT2 and 3% pT3. Nodal diseases comprised 41% N0 and 47% N1 (AJCC 8th). Twenty-three (72%) patients had HPV related tumors. 3-years CRC, LC and OS were 100%, 96% (89-100) and 96% (CI 89-100). One patient developed a second primary with contralateral nodal disease. Only one patient died from another primary cancer. CONCLUSION: In selected patients with lateralized oropharyngeal cancer, treatment with TORS and ipsilateral management of the neck may be oncologically safe without significant risk of contralateral failure. LEVEL OF EVIDENCE: Level 2.

Acceptability of Routine Evaluations Using Patient-Reported Outcomes of Common Terminology Criteria for Adverse Events and Other Patient-Reported Symptom Outcome Tools in Cancer Outpatients: Princess Margaret Cancer Centre Experience.

BACKGROUND: Recent studies have demonstrated improved outcomes with real-time patient-reported outcome questionnaires (PRO questionnaires) using questions adapted for patient use from the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). Outside of the clinical trial setting, limited information exists on factors affecting the completion of PRO questionnaires in routine practice. The primary aim of this prospective cross-sectional study was to evaluate patient willingness to complete PRO questionnaires on a regular basis and to better understand responder biases to improve patient feedback. MATERIALS AND METHODS: Patients performing PRO-CTCAE toxicity and symptom PRO questionnaires in oncology clinics at Princess Margaret Cancer Centre from 2013 to 2016 were assessed for their willingness to complete PRO questionnaires using a nine-item, tablet-based acceptability survey. Patient-reported characteristics (i.e., age, sex, language, marital status, education, occupation, etc.), cancer type, treatment modalities, and health metrics (i.e., Eastern Cooperative Oncology Group) were also collected. Characteristics were evaluated by logistic regression (odds ratios [OR]) using the primary outcome with prespecified levels of significance for univariate (p ≤ .10), and additional multivariate (p ≤ .05) testing. RESULTS: A total of 1,792 patients (median age 60 years; range 18-97) with various cancer diagnoses were assessed. A greater proportion of female (56%) and white (74%) respondents with an annual household income of <$100,000 (69%) participated. More than half (58%) of respondents were willing to complete PRO questionnaires at every clinic visit, and a high proportion (77%) found utility in reporting physical and emotional feelings to clinicians using PRO questionnaires. In general, patients did not find that PRO questionnaires made clinic visits more difficult (93%). In uni- and multivariable testing, patients were more willing to complete sleep- and fatigue-related PRO questionnaires relative to chemotoxicity-based PRO questionnaires (OR 1.52; p = .012). Patients aged 40-65 versus 18-40 years were also more likely to report high PRO questionnaire acceptability (OR 1.49; p = .025). Additional patient characteristics such as white ethnicity (OR 1.76), Canada as country of birth (OR 1.66), and English language (OR 2.15) relative to other had higher acceptability on uni- (p < .001) and multivariable (p < .001) analyses. Patients reporting treatment intent as palliative (OR 0.69; p = .0013) or hematological (OR 0.73; p = .027) were less likely to report high PRO questionnaire acceptability on univariable analysis; however, only palliative patients (OR 0.72) maintained this effect on multivariable testing (p = .012). Patients reporting higher health utility scores (per change in .05) also had significantly increased PRO questionnaire acceptability in uni- (OR 1.06; p < .001) and multivariable (OR 1.05; p = .008) analyses. No significant differences in PRO questionnaire acceptability were seen between cancer types, education level, household income, employment status, or treatment modality. CONCLUSION: Routine assessment using PRO questionnaires is associated with moderate acceptability by patients with cancer. Specific patient characteristics are associated with higher completion willingness. Additional research is necessary to identify factors associated with low acceptability of PRO questionnaires and to develop site-, ethnicity-, and treatment-specific instruments to assess the value of PRO questionnaires for symptom monitoring in clinical practice. IMPLICATIONS FOR PRACTICE: This study will help to identify the clinical, demographic, and survey characteristics associated with willingness to complete patient-reported outcome questionnaires regularly in the cancer outpatient setting.

Occult Nodal Disease and Occult Extranodal Extension in Patients With Oropharyngeal Squamous Cell Carcinoma Undergoing Primary Transoral Robotic Surgery With Neck Dissection.

IMPORTANCE: The historically reported rates of subclinical cervical nodal metastases in oropharyngeal squamous cell carcinoma (OPSCC) predate the emergence of human papillomavirus as the predominant causative agent. The rate of occult nodal disease with changing etiology of OPSCC is not known, and it is challenging to anticipate which patients will be upstaged postoperatively and will require adjuvant therapy. OBJECTIVE: To assess the rate of nodal upstaging and occult extranodal extension (ENE) in a multi-institutional population of patients with pathologic (p)T1-2 OPSCC treated by transoral robotic surgery and neck dissection. DESIGN, SETTING AND PARTICIPANTS: This retrospective, multicenter cohort study of 92 participants at 2 US institutions (Albert Einstein College of Medicine, Bronx, New York [n = 38], and Icahn School of Medicine at Mount Sinai, New York, New York [n = 39]) and 1 Canadian institution (Princess Margaret Hospital, Toronto [n = 15]) examined the rate of postoperative pathologic upstaging for 92 patients with pT1-2 OPSCC undergoing transoral robotic surgery with neck dissection from August 2007 to December 2016. A neuroradiologist at each site blinded to final pathologic diagnosis reviewed preoperative imaging; these findings were compared with operative pathology and applied for tumor staging using the eighth edition of the American Joint Committee on Cancer Cancer Staging Manual. The statistical analysis was performed on December 18, 2018. MAIN OUTCOMES AND MEASURES: Occult pathologic nodal disease and change in nodal category postoperatively. RESULTS: Of 92 patients who met the inclusion criteria, 76 (83%) were male, and they had a mean (SD) age at surgery of 59.5 (10.5) years; 70 patients (84%) with available p16 status were positive. Five of 18 patients (28%) who had no evidence of nodal disease on imaging had occult pathologic nodal disease. Seven of 32 patients (22%) presenting with no nodal disease or with a single metastatic node on imaging received pathologic upstaging because of multiple positive nodes, indicating implementation of additional adjuvant treatment not anticipated after a priori imaging. Changes included 12 patients (13%) who had pathologic nodal upstaging and 12 (13%) with pathologic nodal downstaging in the eighth edition of staging. In the cohort, 24 patients (27%) had pathologic ENE, and 5 of 39 patients (13%) had occult ENE in the absence of radiographic evidence. CONCLUSIONS AND RELEVANCE: Predicting pathologic staging preoperatively for patients with OPSCC undergoing transoral robotic surgery and neck dissection remains a challenge. Although nodal size, tumor size, and location do not help predict ENE, the presence of nodes on imaging and nodal category may help predict ENE. Our findings suggest a small proportion of patients might benefit from further adjuvant therapies not predicted by preoperative imaging based on occult nodal upstaging and ENE.

Occult contralateral nodal disease in oropharyngeal squamous cell carcinoma patients undergoing primary TORS with bilateral neck dissection.

BACKGROUND: Knowledge of the rate of occult contralateral nodal disease for oropharynx cancers (OPSCC) in the era of Human Papillomavirus-dominated disease would inform practitioners as to who may be a candidate for unilateral neck management. The objective of this study was to determine the rate of pathologic contralateral positive nodes in patients in OPSCC patients with pT1 and pT2 disease treated with TORS and bilateral neck dissections (BND). METHODS: Retrospective review of medical records was performed at Princess Margaret Cancer Center, Toronto; Icahn School of Medicine at Mount Sinai, New York City; and Montefiore Medical Center, New York City. Patients with pT1-2 N0-3 (AJCC 8th Edition) OPSCC disease treated with TORS and BND were included. RESULTS: Thirty-two patients met inclusion criteria. Twelve patients (37.5%) had a tonsil primary site, 19 (59.4%) patients had a base of tongue primary site, and 1 (3.1%) patient had a pharyngeal wall primary. Twenty-four (75%) patients were known to be p16+. Twenty-seven patients (84.4%) were radiographically negative in the contralateral neck preoperatively, and two of these patients had pathologic contralateral positive nodes. The occult pathologic contralateral nodal metastasis rate was 7.4% (2/27). The sensitivity, specificity, positive predictive value, and negative predictive value of suspicious contralateral nodes on preoperative imaging for pathologically positive nodes were 33.3%, 86.2%, 20% and 93% respectively. In the p16+ subgroup, the occult nodal positive rate in the contralateral neck was 5%. CONCLUSIONS: pT1-2 OPSCC patients undergoing TORS and elective contralateral neck dissection have a low rate of pathologic contralateral nodal positivity.

Proteomic Analysis of Cancer-Associated Fibroblasts Reveals a Paracrine Role for MFAP5 in Human Oral Tongue Squamous Cell Carcinoma.

Bidirectional communication between cells and their microenvironment is crucial for both normal tissue homeostasis and tumor growth. During the development of oral tongue squamous cell carcinoma (OTSCC), cancer-associated fibroblasts (CAFs) create a supporting niche by maintaining a bidirectional crosstalk with cancer cells, mediated by classically secreted factors and various nanometer-sized vesicles, termed as extracellular vesicles (EVs). To better understand the role of CAFs within the tumor stroma and elucidate the mechanism by which secreted proteins contribute to OTSCC progression, we isolated and characterized patient-derived CAFs from resected tumors with matched adjacent tissue fibroblasts (AFs). Our strategy employed shotgun proteomics to comprehensively characterize the proteomes of these matched fibroblast populations. Our goals were to identify CAF-secreted factors (EVs and soluble) that can functionally modulate OTSCC cells in vitro and to identify novel CAF-associated biomarkers. Comprehensive proteomic analysis identified 4247 proteins, the most detailed description of a pro-tumorigenic stroma to date. We demonstrated functional effects of CAF secretomes (EVs and conditioned media) on OTSCC cell growth and migration. Comparative proteomics identified novel proteins associated with a CAF-like state. Specifically, MFAP5, a protein component of extracellular microfibrils, was enriched in CAF secretomes. Using in vitro assays, we demonstrated that MFAP5 activated OTSCC cell growth and migration via activation of MAPK and AKT pathways. Using a tissue microarray of richly annotated primary human OTSCCs, we demonstrated an association of MFAP5 expression with patient survival. In summary, our proteomics data of patient-derived stromal fibroblasts provide a useful resource for future mechanistic and biomarker studies.

EQ-5D Health Utility Scores: Data from a Comprehensive Canadian Cancer Centre.

BACKGROUND: To improve the precision of health economics analyses in oncology, reference datasets of health utility (HU) scores are needed from cancer survivors across different disease sites. These data are particularly sparse amongst Canadian survivors. METHODS: A survey was completed by 1759 ambulatory cancer survivors at the Princess Margaret Cancer Centre which contained demographic questions and the EuroQol-5D (EQ-5D) instrument. Clinical information was abstracted from electronic records and HU scores were calculated using Canadian health state valuations. Construct validity was assessed through correlation of HU and visual analog scale (VAS) scores (Spearman) and by comparing HU scores between performance status groups (effect size). The influence of socio-demographic clinical variables on HU was analyzed by non-parametric between-group comparisons and multiple linear regression. RESULTS: Mean EQ-5D HU scores were derived for 26 cancers. Among all survivors, the mean ± standard error of the mean EQ-5D utility score was 0.81 ± 0.004. Scores varied significantly by performance status (p < 0.0001) and correlated with VAS (Spearman r = 0.61). The cancer sites with the lowest mean HU scores were acute lymphoblastic leukemia (0.70 ± 0.03) and pancreatic cancer (0.76 ± 0.03); testicular cancer (0.89 ± 0.02) and chronic lymphocytic leukemia (0.90 ± 0.05) had the highest mean scores. A multiple regression model showed that scores were influenced by disease site (p < 0.001), education level (p < 0.001), partner status (p < 0.001), disease extent (p = 0.0029), and type of most recent treatment (p = 0.0061). CONCLUSIONS: This work represents the first set of HU scores for numerous cancer sites derived using Canadian preference weights. The dataset demonstrated construct validity and HU scores varied by general socio-demographic and clinical parameters.

Salvage surgery for locally recurrent oropharyngeal cancer.

BACKGROUND: There are limited data on whether recurrent human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) is associated with higher surgical salvage rates. The purpose of this study was to determine the success rate of salvage surgery for locally recurrent oropharyngeal cancer and factors influencing the outcome, including p16 status. METHODS: All patients who underwent salvage surgery for locally recurrent or persistent oropharyngeal cancer after (chemo)radiotherapy between 2000 and 2012 were included. The Kaplan-Meier analysis was used to determine overall survival (OS) and recurrence-free survival (RFS). Univariable analysis was performed using Cox proportional hazards regression. RESULTS: Thirty-four patients underwent salvage surgery. Five patients (14.7%) were tracheostomy dependent and 22 (64.7%) were gastrostomy tube dependent after salvage surgery. Postoperative complications occurred in 15 patients. RFS after salvage surgery was 28% and 19% at 3 and 5 years, respectively. The presence of nodal disease at the time of local recurrence, close or positive margins, and lymphovascular invasion were the only factors associated with worse survival on univariable analysis. HPV status based on p16 testing was not associated with either OS or RFS. CONCLUSION: Surgical salvage for oropharyngeal SCC after failure of radiotherapy (+/- chemotherapy) is feasible. Patients who may benefit from surgery include those without regional recurrence and/or those in whom negative margins can be obtained. However, patients may be tracheotomy or gastrostomy tube dependent. The p16 status did not seem to have prognostic impact in the salvage setting; however, larger series are required to assess this relationship. © 2015 Wiley Periodicals, Inc. Head Neck 38: E658-E664, 2016.

Predictors of breast radiotherapy plan modifications: quality assurance rounds in a large cancer centre.

BACKGROUND AND PURPOSE: This study describes the process and outcomes of breast radiotherapy (RT) quality assurance (QA) rounds, seeking to identify variables associated with plan modifications. MATERIALS AND METHODS: Real-time data were prospectively collected over 2 years. Descriptive statistics determined the proportion of cases requiring no (A), minor (B), or major (C) modifications, which were then subjected to univariate and multivariate analyses. RESULTS: A total of 2223 breast cancer QA cases were reviewed; 47 cases (2.1%) underwent a minor, and 52 cases (2.3%) required a major modification. Common changes included boost, volume, seroma, and bolus. On univariate analysis, regional nodal irradiation (RNI), tumour size, and axillary node dissection were significantly associated with major modifications. Upon multivariate analysis, the only independent predictor was RNI (OR 2.12, p=0.0075). For patients with no RNI, <2 cm tumours, no axillary lymph node dissection, and no boosts (n=420); the likelihood of category C was only 1.4%. CONCLUSIONS: It is feasible to conduct QA review for all breast cancer cases prior to commencing RT. Patients undergoing RNI had a higher likelihood of plan modifications; a group with low risk of modification was identified, which could direct future re-structuring of QA rounds.

Integrated omic analysis of oropharyngeal carcinomas reveals human papillomavirus (HPV)-dependent regulation of the activator protein 1 (AP-1) pathway.

HPV-positive oropharyngeal carcinoma (OPC) patients have superior outcomes relative to HPV-negative patients, but the underlying mechanisms remain poorly understood. We conducted a proteomic investigation of HPV-positive (n = 27) and HPV-negative (n = 26) formalin-fixed paraffin-embedded OPC biopsies to acquire insights into the biological pathways that correlate with clinical behavior. Among the 2,633 proteins identified, 174 were differentially abundant. These were enriched for proteins related to cell cycle, DNA replication, apoptosis, and immune response. The differential abundances of cortactin and methylthioadenosine phosphorylase were validated by immunohistochemistry in an independent cohort of 29 OPC samples (p = 0.023 and p = 0.009, respectively). An additional 1,124 proteins were independently corroborated through comparison to a published proteomic dataset of OPC. Furthermore, utilizing the Cancer Genome Atlas, we conducted an integrated investigation of OPC, attributing mechanisms underlying differential protein abundances to alterations in mutation, copy number, methylation, and mRNA profiles. A key finding of this integration was the identification of elevated cortactin oncoprotein levels in HPV-negative OPCs. These proteins might contribute to reduced survival in these patients via their established role in radiation resistance. Through interrogation of Cancer Genome Atlas data, we demonstrated that activation of the ß1-integrin/FAK/cortactin/JNK1 signaling axis and associated differential regulation of activator protein 1 transcription factor target genes are plausible consequences of elevated cortactin protein levels.

Potentially novel candidate biomarkers for head and neck squamous cell carcinoma identified using an integrated cell line-based discovery strategy.

Head and neck squamous cell carcinomas (HNSCC) can arise from the oral cavity, oropharynx, larynx or hypopharynx, and is the sixth leading cancer by incidence worldwide. The 5-year survival rate of HNSCC patients remains static at 40-60%. Hence, biomarkers which can improve detection of HNSCC or early recurrences should improve clinical outcome. Mass spectrometry-based proteomics methods have emerged as promising approaches for biomarker discovery. As one approach, mass-spectrometric identification of proteins shed or secreted from cancer cells can contribute to the identification of potential biomarkers for HNSCC and our understanding of tumor behavior. In the current study, mass spectrometry-based proteomic profiling was performed on the conditioned media (i.e. secretome) of head and neck cancer (HNC) cell lines (FaDu, UTSCC8 and UTSCC42a) in addition to gene expression microarrays to identify over-expressed transcripts in the HNSCC cells in comparison to a normal control cell line. This integrated data set was systematically mined using publicly available resources (Human Protein Atlas and published proteomic/transcriptomic data) to prioritize putative candidates for validation. Subsequently, quantitative real-time PCR (qRT-PCR), Western blotting, immunohistochemistry (IHC), and ELISAs were performed to verify selected markers. Our integrated analyses identified 90 putative protein biomarkers that were secreted or shed to the extracellular space and over-expressed in HNSCC cell lines, relative to controls. Subsequently, the over-expression of five markers was verified in vitro at the transcriptional and translational levels using qRT-PCR and Western blotting, respectively. IHC-based validation conducted in two independent cohorts comprising of 40 and 39 HNSCC biopsies revealed that high tumor expression of PLAU, IGFBP7, MMP14 and THBS1 were associated with inferior disease-free survival, and increased risk of disease progression or relapse. Furthermore, as demonstrated using ELISAs, circulating levels of PLAU and IGFBP7 were significantly higher in the plasma of HNSCC patients compared with healthy individuals.