The Utility of Interim Positron Emission Tomography Imaging to Inform Adaptive Radiotherapy for Head and Neck Squamous Cell Carcinoma.

ABSTRACT: In this article, as part of this special issue on biomarkers of early response, we review the current evidence to support the use of positron emission tomography (PET) imaging during chemoradiation therapy to inform biologically adaptive radiotherapy for head and neck squamous cell carcinoma. We review literature covering this topic spanning nearly 3 decades, including the use of various radiotracers and discoveries of novel predictive PET biomarkers. Through understanding how observational trials have informed current interventional clinical trials, we hope that this review will encourage researchers and clinicians to incorporate PET response criteria in new trial designs to advance biologically optimized radiotherapy.

Initial Feasibility and Acute Toxicity Outcomes From a Phase 2 Trial of 18F-Fluorodeoxyglucose Positron Emission Tomography Response-Based De-escalated Definitive Chemoradiotherapy for p16+ Oropharynx Cancer: A Planned Interim Analysis.

PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) parameters are prognostic of oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). We used FDG-PET imaging biomarkers to select patients for de-escalated chemoradiotherapy (CRT), hypothesizing that acute toxicity will be improved with de-escalation. METHODS AND MATERIALS: This is a planned interim initial feasibility and acute toxicity report from a phase 2, prospective, nonrandomized study, which enrolled patients with stage I-II p16+ OPSCC. All patients started definitive CRT to 70 Gy in 35 fractions, and those who met de-escalation criteria on midtreatment FDG-PET at fraction 10 completed treatment at 54 Gy in 27 fractions. We report the acute toxicity and patient-reported outcomes for 59 patients with a minimum follow-up of 3 months. RESULTS: There were no statistically significant differences between baseline patient characteristics in the standard and de-escalated cohorts. There were 28 of 59 (47.5%) patients who met FDG-PET de-escalation criteria and collectively received 20% to 30% less dose to critical organs at risk known to affect toxicity. At 3 months posttreatment, patients who received de-escalated CRT lost significantly less weight (median, 5.8% vs 13.0%; P < .001), had significantly less change from baseline in penetration-aspiration scale score (median, 0 vs 1; P = .018), and had significantly fewer aspiration events on repeat swallow study (8.0% vs 33.3%, P = .037) compared with patients receiving standard CRT. CONCLUSIONS: Approximately half of patients with early-stage p16+ OPSCC are selected for de-escalation of definitive CRT using midtreatment FDG-PET biomarkers, which resulted in significantly improved rates of observed acute toxicity. Further follow-up is ongoing and will be required to determine whether this de-escalation approach preserves the favorable oncologic outcomes for patients with p16+ OPSCC before adoption.

Magnetic Resonance Guided Radiotherapy for Head and Neck Cancers.

Radiotherapy is an integral component of head/neck squamous cell carcinomas (HNSCCs) treatment, and technological developments including advances in image-guided radiotherapy over the past decades have offered improvements in the technical treatment of these cancers. Integration of magnetic resonance imaging (MRI) into image guidance through the development of MR-guided radiotherapy (MRgRT) offers further potential for refinement of the techniques by which HNSCCs are treated. This article provides an overview of the literature supporting the current use of MRgRT for HNSCC, challenges with its use, and developing research areas.

Development and Assessment of a Model for Predicting Individualized Outcomes in Patients With Oropharyngeal Cancer.

Importance: Recent insights into the biologic characteristics and treatment of oropharyngeal cancer may help inform improvements in prognostic modeling. A bayesian multistate model incorporates sophisticated statistical techniques to provide individualized predictions of survival and recurrence outcomes for patients with newly diagnosed oropharyngeal cancer. Objective: To develop a model for individualized survival, locoregional recurrence, and distant metastasis prognostication for patients with newly diagnosed oropharyngeal cancer, incorporating clinical, oncologic, and imaging data. Design, Setting, and Participants: In this prognostic study, a data set was used comprising 840 patients with newly diagnosed oropharyngeal cancer treated at a National Cancer Institute-designated center between January 2003 and August 2016; analysis was performed between January 2019 and June 2020. Using these data, a bayesian multistate model was developed that can be used to obtain individualized predictions. The prognostic performance of the model was validated using data from 447 patients treated for oropharyngeal cancer at Erasmus Medical Center in the Netherlands. Exposures: Clinical/oncologic factors and imaging biomarkers collected at or before initiation of first-line therapy. Main Outcomes and Measures: Overall survival, locoregional recurrence, and distant metastasis after first-line cancer treatment. Results: Of the 840 patients included in the National Cancer Institute-designated center, 715 (85.1%) were men and 268 (31.9%) were current smokers. The Erasmus Medical Center cohort comprised 300 (67.1%) men, with 350 (78.3%) current smokers. Model predictions for 5-year overall survival demonstrated good discrimination, with area under the curve values of 0.81 for the model with and 0.78 for the model without imaging variables. Application of the model without imaging data in the independent Dutch validation cohort resulted in an area under the curve of 0.75. This model possesses good calibration and stratifies patients well in terms of likely outcomes among many competing events. Conclusions and Relevance: In this prognostic study, a multistate model of oropharyngeal cancer incorporating imaging biomarkers appeared to estimate and discriminate locoregional recurrence from distant metastases. Providing personalized predictions of multiple outcomes increases the information available for patients and clinicians. The web-based application designed in this study may serve as a useful tool for generating predictions and visualizing likely outcomes for a specific patient.

Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination.

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.

CT and FDG-PET radiologic biomarkers in p16+ oropharyngeal squamous cell carcinoma patients treated with definitive chemoradiotherapy.

PURPOSE: To assess associations between imaging biomarkers from standard of care pre-treatment CT and FDG-PET scans and locoregional (LR) and distant metastatic (DM) recurrences in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiotherapy (CRT). METHODS: An institutional database from a single NCI-designated cancer center identified 266 patients with p16+ OPSCC treated with definitive CRT in our department from 2005 to 2016 with evaluable pre-treatment FDG-PET scans. Quantitative SUV metrics and qualitative imaging metrics were determined from FDG-PET and CT scans, while clinical characteristics were abstracted from the medical record. Associations between clinical/imaging features and time to LR (TTLRF) or DM (TTDMF) failure and overall survival (OS) were assessed using univariable Cox regression and penalized stepwise regression for multivariable analyses (MVA). RESULTS: There were 27 LR and 32 DM recurrences as incident failures. Imaging biomarkers were significantly associated with TTLRF, TTDMF and OS. FDG-PET metrics outperformed CT and clinical metrics for TTLRF, with metabolic tumor volume being the only significant feature selected on MVA: C-index = 0.68 (p = 0.01). Radiographic extranodal extension (rENE), positive retropharyngeal nodes (RPN+), and clinical stage were significant on MVA for TTDMF: C-index = 0.84 (p < 0.001). rENE, group stage, and RPN+ were significant on MVA for OS: C-index = 0.77 (p < 0.001). CONCLUSIONS: In the largest study to date of uniformly treated patients with CRT to evaluate both pretreatment CT and FDG-PET, radiographic biomarkers were significantly associated with TTLRF, TTDMF and OS among patients with p16+ OPSCC treated with CRT. CT metrics performed best to predict TTDMF, while FDG-PET metrics showed improved prediction for LRRFS. These metrics may help identify candidates for treatment intensification or de-escalation of therapy. STATEMENT OF TRANSLATIONAL RELEVANCE: Pre-treatment imaging features from standard-of-care PET/CT imaging show promise for predicting long-term outcomes following HPV-associated oropharynx cancer (HPV-OPC) therapy. This study comprehensively characterizes qualitative and quantitative pre-treatment imaging metrics associated with time to pattern-specific failure in a cohort of 266 patients treated uniformly with definitive chemoradiation. Multivariate analysis (MVA) for time to locoregional failure (TTLRF), time to distant metastatic failure (TTDMF), and overall survival (OS) was performed. FDG-PET metrics outperformed CT and clinical metrics for TTLRF. CT radiographic extranodal extension, positive retropharyngeal nodes, and stage strongly predicted TTDMF (combined C-index = 0.84, log rank p < 0.001). Number of smoking pack-years complemented clinical and imaging features only in patients without radiographic extranodal extension or positive retropharyngeal nodes. Time to pattern-specific failure is important for guiding treatment de-escalation strategies, which intend to reduce treatment-related toxicity in patients with relatively long expected survival times. This study suggests that PET/CT features should play a crucial role in future de-escalation trials and management of HPV-OPC patients.

Predicting late radiation-induced xerostomia with parotid gland PET biomarkers and dose metrics.

PURPOSE: To assess associations between parotid gland PET biomarkers and late radiation-induced xerostomia, and to validate improvement of xerostomia predictive models by adding pre-treatment PET features to models based on dose and pre-treatment xerostomia. MATERIALS AND METHODS: Intensity PET features from 47 patients treated on institutional prospective clinical trials for HPV-associated oropharyngeal squamous cell carcinoma with uniform chemoRT were analyzed. Associations between 90th percentile of the parotid gland standardized uptake values (P90) from pre-treatment and post-treatment PET scans, mean parotid gland doses, and late xerostomia defined by the Xerostomia Questionnaire (XQ) and salivary flow rates were quantified. Multivariable analysis was applied for dose and PET features using penalized logistic regression for feature selection and generation of predictive models using the LASSO technique, and optimism bias was estimated by bootstrap resampling. RESULTS: Significant associations between late xerostomia and both mean parotid gland dose and P90 were demonstrated, and were generally stronger for post-treatment PET scans. The addition of P90 from pre-treatment PET scans improved the prediction model for late moderate or severe xerostomia compared to the base model, from AUC = 0.74 to 0.78 (p-value <0.001) for XQ summary score and from 0.77 to 0.84 (p-value <0.001) for the single eating-related XQ item with the largest inter-patient variability; however, only the latter remained significant on cross validation (AUC = 0.69 to 0.70 and 0.73 to 0.80, respectively). CONCLUSIONS: The addition of pre-treatment parotid gland PET biomarkers improved a predictive model for late patient-reported xerostomia over dose and pre-treatment xerostomia.

Development and comprehensive commissioning of an automated brachytherapy plan checker.

PURPOSE: To present on the commissioning of an automated brachytherapy plan checker (BPC) for the evaluation of high-dose-rate brachytherapy treatment plans in support of standardized workflows and patient safety. METHODS AND MATERIALS: A BPC was developed using an applications programming interface in a commercial treatment planning system based on different inputs (e.g., regulations, professional society recommendations, and user feedback) and leveraged our experience with an in-house developed external beam plan checker. The BPC was commissioned using a comprehensive suite of test plans with known errors and anonymized clinical plans. RESULTS: During commissioning, the BPC was successfully executed on a total of 87 test plans. Commissioning tests spanned a range of treatment sites and evaluated that pass and fail states were correct. Administration settings were changed in a nonclinical database to evaluate tests involving the source and afterloader. Clinical testing of the BPC was then performed in parallel with a manual review process before clinical implementation. CONCLUSIONS: To commission the BPC for clinical use, a comprehensive suite of test plans was developed and used to ensure the BPC correctly detected and reported errors. A summary of the test plans is presented to help guide users developing similar automated tools. The BPC represents a process-improvement initiative designed to reduce errors and improve safety for brachytherapy patients. By using a comprehensive test suite for commissioning, tests are available for periodic quality assurance and after software upgrades.

Predictive Models to Determine Clinically Relevant Deviations in Delivered Dose for Head and Neck Cancer.

PURPOSE: This study aimed to improve the understanding of deviations between planned and accumulated doses and to establish metrics to predict clinically significant dosimetric deviations midway through treatment to evaluate the potential need to re-plan during fractionated radiation therapy (RT). METHODS AND MATERIALS: A total of 100 patients with head and neck cancer were retrospectively evaluated. Contours were mapped from the planning computed tomography (CT) scan to each fraction cone beam CT via deformable image registration. The dose was calculated on each cone beam CT and evaluated based on the mapped contours. The mean dose at each fraction was averaged to approximate the accumulated dose for structures with mean dose constraints, and the daily maximum dose was summed to approximate the accumulated dose for structures with maximum dose constraints. A threshold deviation value was calculated to predict for patients needing midtreatment re-planning. This predictive model was applied to 52 patients treated at a separate institution. RESULTS: Dose was accumulated on 10 organs over 100 patients. To generate a threshold deviation that predicted the need to re-plan with 100% sensitivity, the submandibular glands required re-planning if the delivered dose was at least 3.5 Gy higher than planned by fraction 15. This model predicts the need to re-plan the submandibular glands with 98.7% specificity. In the independent evaluation cohort, this model predicts the need to re-plan the submandibular glands with 100% sensitivity and 98.0% specificity. The oral cavity, intermediate clinical target volume, left parotid, and inferior constrictor patient groups each had 1 patient who exceeded the threshold deviation by the end of RT. By fraction 15 of 30 to 35 total fractions, the left parotid gland, inferior constrictor, and intermediate clinical target volume had a dose deviation of 3.1 Gy, 5.9 Gy, and 4.8 Gy, respectively. When a deformable image registration failure was observed, the dose deviation exceeded the threshold for at least 1 organ, demonstrating that an automated deformable image registration-based dose assessment process could be developed with user evaluation for cases that result in dose deviations. CONCLUSIONS: A midtreatment threshold deviation was determined to predict the need to replan for the submandibular glands by fraction 15 of 30 to 35 total fractions of RT.

Volumetric 18 F-FDG-PET parameters as predictors of locoregional failure in low-risk HPV-related oropharyngeal cancer after definitive chemoradiation therapy.

BACKGROUND: We sought to investigate the prognostic value of volumetric positron emission tomography (PET) parameters in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and a ≤10 pack-year smoking history treated with chemoradiation. METHODS: A total of 142 patients were included. Maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of the primary tumor, involved regional lymph nodes, and total lesion were calculated. Cox proportional hazard modeling was used to evaluate associations of clinical and PET parameters with locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS: On univariate analysis, volumetric PET parameters were significantly associated with all endpoints, and 8th edition American Joint Committee on Cancer/Union Internationale Contre le Cancer staging was significantly associated with DMFS and OS. On multivariate analysis, total lesion TLG was significantly associated with LRFFS, while staging was most significantly prognostic for DMFS and OS. CONCLUSION: Volumetric PET parameters are uniquely prognostic of LRFFS in low-risk HPV-related OPSCC and may be useful for directing de-intensification strategies.

Early Changes in Serial CBCT-Measured Parotid Gland Biomarkers Predict Chronic Xerostomia After Head and Neck Radiation Therapy.

PURPOSE: To determine whether serial cone beam computed tomography (CBCT) images taken during head and neck radiation therapy (HNR) can improve chronic xerostomia prediction. METHODS AND MATERIALS: In a retrospective analysis, parotid glands (PGs) were delineated on daily kV CBCT images using deformable image registration for 119 HNR patients (60 or 70 Gy in 2 Gy fractions over 6 or 7 weeks). Deformable image registration accuracy for a subset of deformed contours was quantified using the Dice similarity coefficient and mean distance to agreement in comparison with manually drawn contours. Average weekly changes in CBCT-measured mean Hounsfield unit intensity and volume were calculated for each PG relative to week 1. Dose-volume histogram statistics were extracted from each plan, and interactions among dose, volume, and intensity were investigated. Univariable analysis and penalized logistic regression were used to analyze association with observer-rated xerostomia at 1 year after HNR. Models including CBCT delta imaging features were compared with clinical and dose-volume histogram-only models using area under the receiver operating characteristic curve (AUC) for grade ≥1 and grade ≥2 xerostomia prediction. RESULTS: All patients experienced end-treatment PG volume reduction with mean (range) ipsilateral and contralateral PG shrinkage of 19.6% (0.9%-58.4%) and 17.7% (4.4%-56.3%), respectively. Midtreatment volume change was highly correlated with mean PG dose (r = -0.318, P < 1e-6). Incidence of grade ≥1 and grade ≥2 xerostomia was 65% and 16%, respectively. For grade ≥1 xerostomia prediction, the delta-imaging model had an AUC of 0.719 (95% confidence interval [CI], 0.603-0.830), compared with 0.709 (95% CI, 0.603-0.815) for the dose/clinical model. For grade ≥2 xerostomia prediction, the dose/clinical model had an AUC of 0.692 (95% CI, 0.615-0.770), and the addition of contralateral PG changes modestly improved predictive performance, with an AUC of 0.776 (0.643-0.912). CONCLUSIONS: The rate of CBCT-measured PG image feature changes improves prediction over dose alone for chronic xerostomia prediction. Analysis of CBCT images acquired for treatment positioning may provide an inexpensive monitoring system to support toxicity-reducing adaptive radiation therapy.