A Phase I Study of the CDK4/6 Inhibitor Palbociclib in Combination with Cetuximab and Radiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma.

PURPOSE: Palbociclib, a cyclin D kinase 4 (CDK4)/6 inhibitor, has shown radiosensitizing effects in preclinical studies. There is a strong rationale for adding palbociclib to cetuximab and radiotherapy in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), especially in p16-negative HNSCC. PATIENTS AND METHODS: We conducted a phase I dose-escalation study (NCT03024489) using a classical 3+3 design to determine safety, tolerability, and MTD of palbociclib, cetuximab, and intensity-modulated radiotherapy (IMRT) combination. At the recommended phase II dose (RP2D), additional p16-negative patients were enrolled. RESULTS: Twenty-seven patients with LA-HNSCC (13 in dose escalation, 14 in expansion) with oropharyngeal (41%) and hypopharyngeal (30%) cancers were enrolled. The MTD was not reached, and the RP2D of palbociclib was established at the full standard palbociclib dose of 125 mg/day for 21 days per cycle, administered for two cycles during IMRT. The most common grade 3-4 toxicities were mucositis (59%), radiation dermatitis (22%), and neutropenia (22%), with a febrile neutropenia rate of 7%. Common genomic alterations included mutations in TP53 (57%), GNAQ (35%), and PIK3CA (17%), and copy-number gains in CCND1 (22%), CCND2 (9%), and EGFR (9%). Overall, p16 expression was positive in 15% of patients. No correlation was observed between p16 status, genomic alterations, and preliminary efficacy. The objective response rate was 84%. The rates for 2-year locoregional control, event-free survival, and overall survival were 73%, 48%, and 71%, respectively. CONCLUSIONS: The palbociclib, cetuximab, and IMRT combination was well tolerated. The RP2D was established, while no MTD was determined. The regimen demonstrated promising preliminary efficacy, suggesting further investigation is warranted in patients with cisplatin-ineligible p16/human papilloma virus-unrelated LA-HNSCC.

Nasopharyngeal Carcinoma Radiomic Evaluation with Serial PET/CT: Exploring Features Predictive of Survival in Patients with Long-Term Follow-Up.

PURPOSE: We aim determine the value of PET and CT radiomic parameters on survival with serial follow-up PET/CT in patients with nasopharyngeal carcinoma (NPC) for which curative intent therapy is undertaken. METHODS: Patients with NPC and available pre-treatment as well as follow up PET/CT were included from 2005 to 2006 and were followed to 2021. Baseline demographic, radiological and outcome data were collected. Univariable Cox proportional hazard models were used to evaluate features from baseline and follow-up time points, and landmark analyses were performed for each time point. RESULTS: Sixty patients were enrolled, and two-hundred and seventy-eight (278) PET/CT were at baseline and during follow-up. Thirty-eight percent (38%) were female, and sixty-two patients were male. All patients underwent curative radiation or chemoradiation therapy. The median follow-up was 11.72 years (1.26-14.86). Five-year and ten-year overall survivals (OSs) were 80.0% and 66.2%, and progression-free survival (PFS) was 90.0% and 74.4%. Time-dependent modelling suggested that, among others, PET gray-level zone length matrix (GLZLM) gray-level non-uniformity (GLNU) (HR 2.74 95% CI 1.06, 7.05) was significantly associated with OS. Landmark analyses suggested that CT parameters were most predictive at 15 month, whereas PET parameters were most predictive at time points 3, 6, 9 and 15 month. CONCLUSIONS: This study with long-term follow up data on NPC suggests that mainly PET-derived radiomic features are predictive for OS but not PFS in a time-dependent evaluation. Furthermore, CT radiomic measures may predict OS and PFS best at initial and long-term follow-up time points and PET measures may be more predictive in the interval. These modalities are commonly used in NPC surveillance, and prospective validation should be considered.

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.

Machine Learning Applications for Head and Neck Imaging.

The head and neck (HN) consists of a large number of vital anatomic structures within a compact area. Imaging plays a central role in the diagnosis and management of major disorders affecting the HN. This article reviews the recent applications of machine learning (ML) in HN imaging with a focus on deep learning approaches. It categorizes ML applications in HN imaging into deep learning and traditional ML applications and provides examples of each category. It also discusses the main challenges facing the successful deployment of ML-based applications in the clinical setting and provides suggestions for addressing these challenges.

Dual Energy Computed Tomography in Head and Neck Imaging: Pushing the Envelope.

Multiple applications of dual energy computed tomography (DECT) have been described for the evaluation of disorders in the head and neck, especially in oncology. We review the body of evidence suggesting advantages of DECT for the evaluation of the neck compared with conventional single energy computed tomography scans, but the full potential of DECT is still to be realized. There is early evidence suggesting significant advantages of DECT for the extraction of quantitative biomarkers using radiomics and machine learning, representing a new horizon that may enable this technology to reach its full potential.