Flavonoids Induce Migration Arrest and Apoptosis in Detroit 562 Oropharynx Squamous Cell Carcinoma Cells

Despite advances in the treatment of head and neck squamous cell carcinoma (HNSCC), the morbidity remains at a high level due to the resistance of SCC cells to chemotherapeutics. This study aimed to determine and compare the magnitude of the flavonoids’ effectiveness in activating apoptosis and migration arrest in HNSCC cells in vitro. Methods: Head and neck SCC cells of the Detroit 562 line were exposed to a range of concentrations (5-100 μM) of quercetin (Que), hesperidin (Hes) and rutin (Rut) for 24 and 48 h. The SCC cell viability and migration rate were investigated using cytotoxicity and migration inhibition assays. Muse Cell Analyzer flow cytometry was utilized to quantitatively assess the apoptosis rate of Detroit 562 cells exposed to Que, Hes and Rut. The morphology of the SCC cells was evaluated via hematoxylin-eosin staining. Results: The viability diminishment of the Detroit 562-line cells treated with Que, Hes and Rut for 48 h revealed a significant dose-dependent trend, relatively equal for three substances, whereas the most noticeable cytotoxic effect observed for Hes. Exposure to Hes and Rut exhibited a dose-dependent increased proportion of apoptotic SCC cells, at either necrosis or late apoptosis stage. Detroit 562 SCC migration rate and cells motility were halted for the 100 µM dose of Hes and Que. The comparative results elucidated that Hesperidin and Quercetin achieved a more potent reduction of Detroit 562 migration at 24 h. Conclusions: Hesperidin, rutin and quercetin are capable of inducing apoptosis and migration arrest in the Detroit 562 cell line to various extents, resulting in proapoptotic attenuating effects at different magnitudes.

Phase I trial of dose-escalated stereotactic radiosurgery (SRS) boost for unfavorable locally advanced oropharyngeal cancer

Background and purpose Patients with locally advanced oropharynx squamous cell carcinoma have suboptimal outcomes with standard chemoradiation. Here, we evaluated toxicity and oncologic outcomes of dose escalation using radiosurgical boost for patients with unfavorable oropharynx squamous cell carcinoma. Materials and methods Between 2010–2017, Thirty four patients with intermediate- or high-risk oropharynx squamous cell carcinoma were enrolled onto this prospective phase I trial. Each patient received concurrent cisplatin and fractionated radiotherapy totaling 60 Gy or 66 Gy followed by radiosurgery boost to areas of residual gross tumor: single fraction of 8 Gy or 10 Gy, or two fractions of 5 Gy each. Primary endpoint was treatment toxicity. Secondary endpoints were local, regional, and distant disease control. Results Eleven, sixteen and seven patients received radiosurgery boost with 8 Gy in 1 fraction, 10 Gy in 1 fraction, and 10 Gy in 2 fractions respectively. Acute toxicities include 4 patients with tumor necrosis causing grade 3 dysphagia, of which 3 developed grade 4 pharyngeal hemorrhage requiring surgical intervention. At 24 months after treatment, 7%, 9%, and 15% had grade 2 dysgeusia, xerostomia, and dysphagia, respectively, and two patients remained feeding tube dependent. No grade 5 toxicities occurred secondary to treatment. Local, regional, and distant control at a median follow up of 4.2 years were 85.3%, 85.3% and 88.2%, respectively. Five patients died resulting in overall survival of 85.3%. Conclusions This study is the first to report the use of radiosurgery boost dose escalation in patients with unfavorable oropharynx squamous cell carcinoma. Longer follow-up, larger cohorts, and further refinement of boost methodology are needed prior to implementation in routine clinical practice. Trial Registration: Northwell Health Protocol #09-309A (NCT02703493) (https://clinicaltrials.gov/ct2/show/NCT02703493)

Phase I Trial of Dose-Escalated Stereotactic Radiosurgery (SRS) Boost for Unfavorable Locally Advanced Oropharyngeal Cancer

Background and Purpose: Patients with locally advanced oropharynx squamous cell carcinoma have suboptimal outcomes with standard chemoradiation. Here, we evaluated toxicity and oncological outcomes of dose escalation using radiosurgical boost for patients with unfavorable oropharynx squamous cell carcinoma.Materials and Methods: Between 2010-2017, Thirty four patients with intermediate- or high-risk oropharynx squamous cell carcinoma were enrolled onto this prospective phase I trial. Each patient received concurrent cisplatin and fractionated radiotherapy totaling 60 Gy or 66 Gy followed by radiosurgery boost to areas of residual gross tumor: single fraction of 8 Gy or 10 Gy, or two fractions of 5 Gy each. Primary endpoint was treatment toxicity. Secondary endpoints were local, regional, and distant disease control.Results: Eleven, sixteen and seven patients received radiosurgery boost with 8 Gy in 1 fraction, 10 Gy in 1 fraction, and 10 Gy in 2 fractions respectively. Acute toxicities include 4 patients with tumor necrosis causing grade 3 dysphagia, of which 3 developed grade 4 pharyngeal hemorrhage requiring surgical intervention. At 24 months after treatment, 7%, 9%, and 15% had grade 2 dysgeusia, xerostomia, and dysphagia, respectively, and two patients remained feeding tube dependent. No grade 5 toxicities occurred secondary to treatment. Local, regional, and distant control at a median follow up of 4.2 years were 85.3%, 85.3% and 88.2%, respectively. Five patients died resulting in overall survival of 85.3%.Conclusions: This study is the first to report the use of radiosurgery boost dose escalation in patients with unfavorable oropharynx squamous cell carcinoma. Longer follow-up, larger cohorts, and further refinement of boost methodology are needed prior to implementation in routine clinical practice.

Patterns of Nodal Metastases and Predictors of Occult Disease in HPV-Associated Oropharynx Cancer

Objective For human papilloma virus–associated oropharynx squamous cell carcinoma (HPV+ OPSCC), we evaluated the distribution of neck-level lymph node (LN) metastasis, based on postsurgical histopathology, and the incidence of and risk factors for occult LN metastases, as these patterns need clarification for this newer cancer subset. Study Design Retrospective cohort study. Setting National Cancer Database (NCDB). Methods We analyzed 2358 patients in the NCDB with HPV+ OPSCC who underwent neck dissection (ND) from 2010 to 2015. Incidence and distribution of LN metastases were calculated for neck levels I to V. Variables associated with occult LN metastasis were assessed by multivariate logistic regression. Results In therapeutic NDs (n = 1935), the following proportions of positive LNs were found: level I, 9.0% (n = 175); level II, 81.0% (n = 1568); level III, 29.6% (n = 573); level IV, 11.9% (n = 230); and level V, 4.9% (n = 95). In elective NDs (n = 423), occult-positive LNs were found in 35.8% (n = 152), with the following proportions by level: level I, 3.3% (n = 14); level II, 26.9% (n = 114); level III, 8.7% (n = 37); level IV, 4.0% (n = 17); and level V, 0.2% (n = 1). The presence of occult LNs was independently associated with a Charlson-Deyo score of 1 (odds ratio, 2.26; 95% CI, 1.18-4.31; P = .014) and lymphovascular invasion (odds ratio, 5.91; 95% CI, 3.21-11.18; P < .001). Occult LN metastases were not significantly associated with pT classification, primary site, or number of LNs resected. Conclusion For HPV+ OPSCC, occult nodal disease is common. Therapeutic NDs should encompass at least levels II, III, and IV and possibly I, whereas elective NDs could possibly encompass levels II and III. Level of Evidence 4.

Phase I Trial of Dose-Escalated Stereotactic Radiosurgery (SRS) Boost for Unfavorable Locally Advanced Oropharyngeal Cancer

Background and Purpose: Patients with locally advanced oropharynx squamous cell carcinoma have suboptimal outcomes with standard chemoradiation. Here, we evaluated toxicity and oncologic outcomes of dose escalation using radiosurgical boost for patients with unfavorable oropharynx squamous cell carcinoma. Materials and Methods: Between 2010-2017, Thirty four patients with intermediate- or high-risk oropharynx squamous cell carcinoma were enrolled onto this prospective phase I trial. Each patient received concurrent cisplatin and fractionated radiotherapy totaling 60 Gy or 66 Gy followed by radiosurgery boost to areas of residual gross tumor: single fraction of 8 Gy or 10 Gy, or two fractions of 5 Gy each. Primary endpoint was treatment toxicity. Secondary endpoints were local, regional, and distant disease control.Results: Eleven, sixteen and seven patients received radiosurgery boost with 8 Gy in 1 fraction, 10 Gy in 1 fraction, and 10 Gy in 2 fractions respectively. Acute toxicities include 4 patients with tumor necrosis causing grade 3 dysphagia, of which 3 developed grade 4 pharyngeal hemorrhage requiring surgical intervention. At 24 months after treatment, 7%, 9%, and 15% had grade 2 dysgeusia, xerostomia, and dysphagia, respectively, and two patients remained feeding tube dependent. No grade 5 toxicities occurred secondary to treatment. Local, regional, and distant control at a median follow up of 4.2 years were 85.3%, 85.3% and 88.2%, respectively. Five patients died resulting in overall survival of 85.3%. Conclusions: This study is the first to report the use of radiosurgery boost dose escalation in patients with unfavorable oropharynx squamous cell carcinoma. Longer follow-up, larger cohorts, and further refinement of boost methodology are needed prior to implementation in routine clinical practice.Trial Registration: Northwell Health Protocol #09-309A (NCT02703493) (https://clinicaltrials.gov/ct2/show/NCT02703493)