Magnetic resonance linear accelerator technology and adaptive radiation therapy: An overview for clinicians.

Radiation therapy (RT) continues to play an important role in the treatment of cancer. Adaptive RT (ART) is a novel method through which RT treatments are evolving. With the ART approach, computed tomography or magnetic resonance (MR) images are obtained as part of the treatment delivery process. This enables the adaptation of the irradiated volume to account for changes in organ and/or tumor position, movement, size, or shape that may occur over the course of treatment. The advantages and challenges of ART maybe somewhat abstract to oncologists and clinicians outside of the specialty of radiation oncology. ART is positioned to affect many different types of cancer. There is a wide spectrum of hypothesized benefits, from small toxicity improvements to meaningful gains in overall survival. The use and application of this novel technology should be understood by the oncologic community at large, such that it can be appropriately contextualized within the landscape of cancer therapies. Likewise, the need to test these advances is pressing. MR-guided ART (MRgART) is an emerging, extended modality of ART that expands upon and further advances the capabilities of ART. MRgART presents unique opportunities to iteratively improve adaptive image guidance. However, although the MRgART adaptive process advances ART to previously unattained levels, it can be more expensive, time-consuming, and complex. In this review, the authors present an overview for clinicians describing the process of ART and specifically MRgART.

Post-radiotherapy PET/CT for predicting treatment outcomes in head and neck cancer after postoperative radiotherapy.

PURPOSE: The purpose of this study was to retrospectively review the role of post-treatment (post-tx) FDG-PET/CT scans in patients receiving postoperative intensity-modulated radiotherapy (IMRT) for head and neck squamous cell carcinomas (HNSCC). MATERIALS AND METHODS: Eighty-two patients with HNSCC treated with surgery and postoperative IMRT with or without chemotherapy from October 15, 2008 to December 31, 2014 that had post-tx PET/CT within 6 months of completing IMRT were included. PET/CT was considered positive based on multi-disciplinary review integrating clinical information. Survival analysis was performed using the Kaplan-Meier method. Categorical and continuous predictors of positive post-tx PET/CT were evaluated using Fisher's exact test and logistic regression, respectively. Predictors for survival outcomes were evaluated with log-rank testing. A p ≤ 0.05 was considered statistically significant. RESULTS: Median follow-up was 3.88 years. For all patients, 3-year overall survival (OS) and recurrence-free survival (RFS) were 71.8% and 61.3%, respectively. Patients with positive post-tx PET/CT had worse OS compared to those with negative post-tx PET/CT (log rank p < 0.001). For patients with positive post-tx PET/CT, 3-year OS was 11.2% compared to 89.9% for patients with negative post-tx PET/CT. The positive predictive value (PPV) of PET/CT was 100% for local recurrence (LR), regional recurrence (RR) and distant metastasis (DM). The negative predictive values (NPV) for LR, RR and DM were 89.0%, 89.2%, and 85.9%, respectively. Perineural invasion (p = 0.009), p16 status (p = 0.009), non-oropharyngeal primary site (p = 0.002), and the use of chemotherapy (p = 0.01) were independent predictors of positive PET/CT. CONCLUSIONS: Post-tx PET/CT after postoperative radiation is prognostic for survival outcomes. The PPV of post-tx PET for recurrence was excellent, allowing for early detection of recurrent disease. Post-tx PET/CT should be considered after postoperative radiation.

Intermediate-grade carcinoma of the parotid and the impact of adjuvant radiation.

PURPOSE: To determine the influence of adjuvant radiotherapy on survival in surgically-managed early stage intermediate-grade mucoepidermoid and acinic cell carcinoma of the parotid. MATERIALS AND METHODS: The National Cancer Database was reviewed between 2004 and 2015 to identify patients with intermediate-grade, early T-stage, node-negative parotid carcinoma who underwent parotidectomy ± radiotherapy. RESULTS: There were 744 patients identified of which 81% had mucoepidermoid carcinoma and 19% had acinic cell carcinoma. Positive surgical margins were identified in 21% and adjuvant radiotherapy was administered in 38% of cases. Of the 159 patients with positive margins, 113 (71%) received adjuvant radiotherapy. Of the 585 patients with negative margins, 173 (30%) underwent adjuvant radiotherapy. In multivariable analysis, age (over 52 years: HR 5.19, 95%CI 2.33-11.57), insurance status (private insurance: HR 0.24 95%CI 0.13-0.43), and extent of parotidectomy (total parotidectomy: HR 2.02 95%CI 1.23-3.31) were significantly associated with overall survival, while adjuvant radiotherapy was not a significant predictive factor (HR 0.81, 95%CI 0.49-1.36). In patients with positive margin resections, however, adjuvant radiation was an independent predictor of improved survival when adjusted for age, insurance status, and extent of parotidectomy (HR 0.34, 95%CI 0.13-0.88). Conversely, in patients with negative margin resections, adjuvant radiation did not influence survival outcomes when adjusted for these covariates (HR 1.02, 95%CI 0.53-1.93). CONCLUSIONS AND RELEVANCE: In patients with early stage intermediate-grade parotid carcinoma, adjuvant radiotherapy significantly and independently improves survival in those with post-operative positive margins. Adjuvant therapy, however, does not appear to improve survival outcomes in those with negative margin resections.

Comparative analysis for renal stereotactic body radiotherapy using Cyberknife, VMAT and proton therapy based treatment planning.

PURPOSE: We conducted this dosimetric analysis to evaluate the feasibility of a multi-center stereotactic body radiation therapy (SBRT) trial for renal cell carcinoma (RCC) using different SBRT platforms. MATERIALS/METHODS: The computed tomography (CT) simulation images of 10 patients with unilateral RCC previously treated on a Phase 1 trial at Institution 1 were anonymized and shared with Institution 2 after IRB approval. Treatment planning was generated through five different platforms aiming a total dose of 48 Gy in three fractions. These platforms included: Cyberknife and volumetric modulated arc therapy (VMAT) at institution 1, and Cyberknife, VMAT, and pencil beam scanning (PBS) Proton Therapy at institution 2. Dose constraints were based on the Phase 1 approved trial. RESULTS: Compared to Cyberknife, VMAT and PBS plans provided overall an equivalent or superior coverage to the target volume, while limiting dose to the remaining kidney, contralateral kidney, liver, spinal cord, and bowel. CONCLUSION: This dosimetric study supports the feasibility of a multi-center trial for renal SBRT using PBS, VMAT and Cyberknife.

Post-treatment PET/CT and p16 status for predicting treatment outcomes in locally advanced head and neck cancer after definitive radiation.

PURPOSE: To retrospectively review post-treatment (post-tx) FDG-PET/CT scans in patients with advanced head and neck squamous cell carcinoma (HNSCC) and known p16 status, treated with definitive (chemo)radiation (RT). METHODS: A total of 108 eligible patients had N2A or greater HNSCC treated with chemoRT from August 1, 2008, to February 28, 2015, with post-tx PET/CT within 6 months after RT. Kaplan-Meier curves, log-rank statistics, and Cox proportional hazards regression were used for statistical analysis. RESULTS: Median follow-up was 2.38 years. Sixty-eight (63.0%) patients had p16+ and 40 (37.0%) had p16- status. Two-year overall survival and recurrence-free survival were 93.4% and 77.8%, respectively. The negative predictive value (NPV) of PET/CT for local recurrence (LR) was 100%. The NPV for regional recurrence (RR) was 96.5% for all patients, 100% for p16+ patients, and 88.5% for p16- patients. The positive predictive value (PPV) of PET/CT for recurrence was 77.3% for all patients, 50.0% for p16+, and 78.6% for p16-. The PPV for LR was 72.7% for all patients, 50.0% for p16+ patients, and 72.7% for p16- patients. The PPV for RR was 50.0% for all patients, 33% for p16+, and 66.6% for p16-. Post-tx PET/CT and p16 status were independent predictors of recurrence-free survival (p < 0.01). CONCLUSIONS: Post-tx PET/CT predicts treatment outcomes in both p16 + and p16- patients, and does so independently of p16 status. P16- patients with negative PET have a 10% risk of nodal recurrence, and closer follow-up in these patients is warranted.

Outcomes of microvascular free tissue transfer in twice-irradiated patients.

BACKGROUND: Patients may require microvascular free tissue transfer (MFTT) following re-irradiation for recurrent cancer or radiation complications. The objective of this study was to describe the indications for and outcomes of free flaps performed in twice-radiated patients. METHODS: A retrospective chart review identified the indications for and outcomes of 36 free flaps performed on 29 twice-irradiated patients. RESULTS: The free flap success rate was 92%. The most common indications requiring MFTT were cancer recurrence and osteoradionecrosis. Sixty-one percent experienced postoperative complications, most commonly wound infection (33%). Twenty-five percent of the procedures required return to the operating room due to postoperative complication. CONCLUSIONS: MFTT can be successfully performed in the twice-irradiated patient population with a success rate comparable to singly-radiated patients. Despite a high success rate, there is also a high rate of surgical site complications, especially infection.

Quality assurance assessment of diagnostic and radiation therapy-simulation CT image registration for head and neck radiation therapy: anatomic region of interest-based comparison of rigid and deformable algorithms.

PURPOSE: To develop a quality assurance (QA) workflow by using a robust, curated, manually segmented anatomic region-of-interest (ROI) library as a benchmark for quantitative assessment of different image registration techniques used for head and neck radiation therapy-simulation computed tomography (CT) with diagnostic CT coregistration. MATERIALS AND METHODS: Radiation therapy-simulation CT images and diagnostic CT images in 20 patients with head and neck squamous cell carcinoma treated with curative-intent intensity-modulated radiation therapy between August 2011 and May 2012 were retrospectively retrieved with institutional review board approval. Sixty-eight reference anatomic ROIs with gross tumor and nodal targets were then manually contoured on images from each examination. Diagnostic CT images were registered with simulation CT images rigidly and by using four deformable image registration (DIR) algorithms: atlas based, B-spline, demons, and optical flow. The resultant deformed ROIs were compared with manually contoured reference ROIs by using similarity coefficient metrics (ie, Dice similarity coefficient) and surface distance metrics (ie, 95% maximum Hausdorff distance). The nonparametric Steel test with control was used to compare different DIR algorithms with rigid image registration (RIR) by using the post hoc Wilcoxon signed-rank test for stratified metric comparison. RESULTS: A total of 2720 anatomic and 50 tumor and nodal ROIs were delineated. All DIR algorithms showed improved performance over RIR for anatomic and target ROI conformance, as shown for most comparison metrics (Steel test, P < .008 after Bonferroni correction). The performance of different algorithms varied substantially with stratification by specific anatomic structures or category and simulation CT section thickness. CONCLUSION: Development of a formal ROI-based QA workflow for registration assessment demonstrated improved performance with DIR techniques over RIR. After QA, DIR implementation should be the standard for head and neck diagnostic CT and simulation CT allineation, especially for target delineation.

Estimation of daily interfractional larynx residual setup error after isocentric alignment for head and neck radiotherapy: quality assurance implications for target volume and organs-at-risk margination using daily CT on- rails imaging.

Larynx may alternatively serve as a target or organs at risk (OAR) in head and neck cancer (HNC) image-guided radiotherapy (IGRT). The objective of this study was to estimate IGRT parameters required for larynx positional error independent of isocentric alignment and suggest population-based compensatory margins. Ten HNC patients receiving radiotherapy (RT) with daily CT on-rails imaging were assessed. Seven landmark points were placed on each daily scan. Taking the most superior-anterior point of the C5 vertebra as a reference isocenter for each scan, residual displacement vectors to the other six points were calculated postisocentric alignment. Subsequently, using the first scan as a reference, the magnitude of vector differences for all six points for all scans over the course of treatment was calculated. Residual systematic and random error and the necessary compensatory CTV-to-PTV and OAR-to-PRV margins were calculated, using both observational cohort data and a bootstrap-resampled population estimator. The grand mean displacements for all anatomical points was 5.07 mm, with mean systematic error of 1.1 mm and mean random setup error of 2.63 mm, while bootstrapped POIs grand mean displacement was 5.09 mm, with mean systematic error of 1.23 mm and mean random setup error of 2.61 mm. Required margin for CTV-PTV expansion was 4.6 mm for all cohort points, while the bootstrap estimator of the equivalent margin was 4.9 mm. The calculated OAR-to-PRV expansion for the observed residual setup error was 2.7 mm and bootstrap estimated expansion of 2.9 mm. We conclude that the interfractional larynx setup error is a significant source of RT setup/delivery error in HNC, both when the larynx is considered as a CTV or OAR. We estimate the need for a uniform expansion of 5 mm to compensate for setup error if the larynx is a target, or 3 mm if the larynx is an OAR, when using a nonlaryngeal bony isocenter.

Development of a software for quantitative evaluation radiotherapy target and organ-at-risk segmentation comparison.

Modern radiotherapy requires accurate region of interest (ROI) inputs for plan optimization and delivery. Target delineation, however, remains operator-dependent and potentially serves as a major source of treatment delivery error. In order to optimize this critical, yet observer-driven process, a flexible web-based platform for individual and cooperative target delineation analysis and instruction was developed in order to meet the following unmet needs: (1) an open-source/open-access platform for automated/semiautomated quantitative interobserver and intraobserver ROI analysis and comparison, (2) a real-time interface for radiation oncology trainee online self-education in ROI definition, and (3) a source for pilot data to develop and validate quality metrics for institutional and cooperative group quality assurance efforts. The resultant software, Target Contour Testing/Instructional Computer Software (TaCTICS), developed using Ruby on Rails, has since been implemented and proven flexible, feasible, and useful in several distinct analytical and research applications.

Type I interferon signaling promotes radioresistance in head and neck cancer.

Despite the promise of concurrent radiotherapy (RT) and immunotherapy in head and neck cancer (HNC), multiple randomized trials of this combination have had disappointing results. To evaluate potential immunologic mechanisms of RT resistance, we compared pre-treatment HNCs that developed RT resistance to a matched cohort that achieved curative status. Gene set enrichment analysis demonstrated that a pre-treatment pro-immunogenic tumor microenvironment (TME), including type II interferon [interferon gamma (IFNγ)] and tumor necrosis factor alpha (TNFα) signaling, predicted cure while type I interferon [interferon alpha (IFNα)] enrichment was associated with an immunosuppressive TME found in tumors that went on to recur. We then used immune deconvolution of RNA sequencing datasets to evaluate immunologic cell subset enrichment. This identified M2 macrophage signaling associated with type I IFN pathway expression in RT-recurrent disease. To further dissect mechanism, we then evaluated differential gene expression between pre-treatment and RT-resistant HNCs from sampled from the same patients at the same anatomical location in the oral cavity. Here, recurrent samples exhibited upregulation of type I IFN-stimulated genes (ISGs) including members of the IFN-induced protein with tetratricopeptide repeats (IFIT) and IFN-induced transmembrane (IFITM) gene families. While several ISGs were upregulated in each recurrent cancer, IFIT2 was significantly upregulated in all recurrent tumors when compared with the matched pre-RT specimens. Based on these observations, we hypothesized sustained type I IFN signaling through ISGs, such as IFIT2, may suppress the intra-tumoral immune response thereby promoting radiation resistance.

Tumor-specific T cells in head and neck cancer have rescuable functionality and can be identified through single-cell co-culture.

BACKGROUND: Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a treatment-resistance disease with limited response to immunotherapy. While T cells in HNSCC are known to display phenotypic dysfunction, whether they retain rescuable functional capacity and tumor-killing capability remains unclear. METHODS: To investigate the functionality and tumor-specificity of tumor-infiltrating lymphocytes (TILs) across HNSCCs, malignant cell lines and TILs were derived from 31 HPV-negative HNSCCs at the time of standard surgical resection. T cell functional capacity was evaluated through ex vivo expansion, immunophenotyping, and IsoLight single-cell proteomics. Tumor-specificity was investigated through both bulk and single-cell tumor-TIL co-culture. RESULTS: TILs could be successfully generated from 24 patients (77%), including both previously untreated and radiation recurrent HNSCCs. We demonstrate that across HNSCCs, TILs express multiple exhaustion markers but maintain a predominantly effector memory phenotype. After ex vivo expansion, TILs retain immunogenic functionality even from radiation-resistant, exhausted, and T cell-depleted disease. We further demonstrate tumor-specificity of T cells across HNSCC patients through patient-matched malignant cell-T cell co-culture. Finally, we use optofluidic technology to establish an autologous single tumor cell-single T cell co-culture platform for HNSCC. Cells derived from three HNSCC patients underwent single-cell co-culture which enabled identification and visualization of individual tumor-killing TILs in real-time in all patients. CONCLUSIONS: These studies show that cancer-specific T cells exist across HNSCC patients with rescuable immunogenicity and can be identified on a single-cell level. These data lay the foundation for development of patient-specific T cell immunotherapies in HNSCC.

Changes in Daily Apparent Diffusion Coefficient on Fully Quantitative Magnetic Resonance Imaging Correlate With Established Genomic Pathways of Radiation Sensitivity and Reveal Novel Biologic Associations.

PURPOSE: Changes in quantitative magnetic resonance imaging (qMRI) are frequently observed during chemotherapy or radiation therapy (RT). It is hypothesized that qMRI features are reflective of underlying tissue responses. It's unknown what underlying genomic characteristics underly qMRI changes. We hypothesized that qMRI changes may correlate with DNA damage response (DDR) capacity within human tumors. Therefore, we designed the current study to correlate qMRI changes from daily RT treatment with underlying tumor transcriptomic profiles. METHODS AND MATERIALS: Study participants were prospectively enrolled (National Clinical Trial 03500081). RNA expression levels for 757 genes from pretreatment biopsies were obtained using a custom panel that included signatures of radiation sensitivity and DDR. Daily qMRI data were obtained from a 1.5 Tesla MR linear accelerator. Using these images, d-slow, d-star, perfusion, and apparent diffusion coefficient-mean values in tumors were plotted per-fraction, over time, and associated with genomic pathways. RESULTS: A total of 1022 qMRIs were obtained from 39 patients and both genomic data and qMRI data from 27 total patients. For 20 of those patients, we also generated normal tissue transcriptomic data. Radio sensitivity index values most closely associated with tissue of origin. Multiple genomic pathways including DNA repair, peroxisome, late estrogen receptor responses, KRAS signaling, and UV response were significantly associated with qMRI feature changes (P < .001). CONCLUSIONS: Genomic pathway associations across metabolic, RT sensitivity, and DDR pathways indicate common tumor biology that may correlate with qMRI changes during a course of treatment. Such data provide hypothesis-generating novel mechanistic insight into the biologic meaning of qMRI changes during treatment and enable optimal selection of imaging biomarkers for biologically MR-guided RT.

Intensity-Modulated Reirradiation Therapy With Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial.

Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS). Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation. Design, Setting, and Participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023. Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks. Main Outcomes and Measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers. Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed. Conclusions and Relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT03521570.

Obtaining organ-specific radiobiological parameters from clinical data for radiation therapy planning of head and neck cancers.

Objective.Different radiation therapy (RT) strategies, e.g. conventional fractionation RT (CFRT), hypofractionation RT (HFRT), stereotactic body RT (SBRT), adaptive RT, and re-irradiation are often used to treat head and neck (HN) cancers. Combining and/or comparing these strategies requires calculating biological effective dose (BED). The purpose of this study is to develop a practical process to estimate organ-specific radiobiologic model parameters that may be used for BED calculations in individualized RT planning for HN cancers.Approach.Clinical dose constraint data for CFRT, HFRT and SBRT for 5 organs at risk (OARs) namely spinal cord, brainstem, brachial plexus, optic pathway, and esophagus obtained from literature were analyzed. These clinical data correspond to a particular endpoint. The linear-quadratic (LQ) and linear-quadratic-linear (LQ-L) models were used to fit these clinical data and extract relevant model parameters (alpha/beta ratio, gamma/alpha,dTand BED) from the iso-effective curve. The dose constraints in terms of equivalent physical dose in 2 Gy-fraction (EQD2) were calculated using the obtained parameters.Main results.The LQ-L and LQ models fitted clinical data well from the CFRT to SBRT with the LQ-L representing a better fit for most of the OARs. The alpha/beta values for LQ-L (LQ) were found to be 2.72 (2.11) Gy, 0.55 (0.30) Gy, 2.82 (2.90) Gy, 6.57 (3.86) Gy, 5.38 (4.71) Gy, and the dose constraint EQD2 were 55.91 (54.90) Gy, 57.35 (56.79) Gy, 57.54 (56.35) Gy, 60.13 (59.72) Gy and 65.66 (64.50) Gy for spinal cord, optic pathway, brainstem, brachial plexus, and esophagus, respectively. Additional two LQ-L parametersdTwere 5.24 Gy, 5.09 Gy, 7.00 Gy, 5.23 Gy, and 6.16 Gy, and gamma/alpha were 7.91, 34.02, 8.67, 5.62 and 4.95.Significance.A practical process was developed to extract organ-specific radiobiological model parameters from clinical data. The obtained parameters can be used for biologically based radiation planning such as calculating dose constraints of different fractionation regimens.

Photoactivated HPPH-Liposomal therapy for the treatment of HPV-Negative head and neck cancer.

OBJECTIVES: Human Papillomavirus (HPV)-negative head and neck cancer (HNC) is an aggressive malignancy with a poor prognosis. To improve outcomes, we developed a novel liposomal targeting system embedded with 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a chlorin-based photosensitizer. Upon exposure to 660 nm light, HPPH phototriggering generates reactive oxygen species. The objective of this study was to evaluate biodistribution and test efficacy of HPPH-liposomal therapy in a patient-derived xenograft (PDX) model of chemoradioresistant HNC. MATERIALS AND METHODS: PDX models were developed from two surgically resected HNCs (P033 and P038) recurrent after chemoradiation. HPPH-liposomes were created including trace amounts of DiR (Ex/Em 785/830 nm), a near infrared lipid probe. Liposomes were injected via tail vein into PDX models. Biodistribution was assessed at serial timepoints in tumor and end-organs through in vivo DiR fluorescence. To evaluate efficacy, tumors were treated with a cw-diode 660 nm laser (90 mW/cm2, 5 min). This experimental arm was compared to appropriate controls, including HPPH-liposomes without laser or vehicle with laser alone. RESULTS: HPPH-liposomes delivered via tail vein exhibited selective tumor penetration, with a peak concentration at 4 h. No systemic toxicity was observed. Treatment with combined HPPH-liposomes and laser resulted in improved tumor control relative to either vehicle or laser alone. Histologically, this manifested as both increased cellular necrosis and decreased Ki-67 staining in the tumors treated with combined therapy. CONCLUSIONS: These data demonstrate tumor-specific anti-neoplastic efficacy of HPPH-liposomal treatment for HNC. Importantly, this platform can be leveraged in future studies for targeted delivery of immunotherapies which can be packaged within HPPH-liposomes.

Chronic stress promotes an immunologic inflammatory state and head and neck cancer growth in a humanized murine model.

BACKGROUND: Despite the importance of immune response and environmental stress on head and neck cancer (HNC) outcomes, no current pre-clinical stress model includes a humanized immune system. METHODS: We investigated the effects of chronic stress induced by social isolation on tumor growth and human immune response in subcutaneous HNC tumors grown in NSG-SGM3 mice engrafted with a human immune system. RESULTS: Tumor growth (p < 0.0001) and lung metastases (p = 0.035) were increased in socially isolated versus control animals. Chronic stress increased intra-tumoral CD4+ T-cell infiltrate (p = 0.005), plasma SDF-1 (p < 0.0001) expression, and led to tumor cell dedifferentiation toward a cancer stem cell phenotype (CD44+ /ALDHhigh , p = 0.025). CONCLUSIONS: Chronic stress induced immunophenotypic changes, increased tumor growth, and metastasis in HNC in a murine model with a humanized immune system. This model system may provide further insight into the immunologic and oncologic impact of chronic stress on patients with HNC.

General and custom deep learning autosegmentation models for organs in head and neck, abdomen, and male pelvis.

PURPOSE: To reduce workload and inconsistencies in organ segmentation for radiation treatment planning, we developed and evaluated general and custom autosegmentation models on computed tomography (CT) for three major tumor sites using a well-established deep convolutional neural network (DCNN). METHODS: Five CT-based autosegmentation models for 42 organs at risk (OARs) in head and neck (HN), abdomen (ABD), and male pelvis (MP) were developed using a full three-dimensional (3D) DCNN architecture. Two types of deep learning (DL) models were separately trained using either general diversified multi-institutional datasets or custom well-controlled single-institution datasets. To improve segmentation accuracy, an adaptive spatial resolution approach for small and/or narrow OARs and a pseudo scan extension approach, when CT scan length is too short to cover entire organs, were implemented. The performance of the obtained models was evaluated based on accuracy and clinical applicability of the autosegmented contours using qualitative visual inspection and quantitative calculation of dice similarity coefficient (DSC), mean distance to agreement (MDA), and time efficiency. RESULTS: The five DL autosegmentation models developed for the three anatomical sites were found to have high accuracy (DSC ranging from 0.8 to 0.98) for 74% OARs and marginally acceptable for 26% OARs. The custom models performed slightly better than the general models, even with smaller custom datasets used for the custom model training. The organ-based approaches improved autosegmentation accuracy for small or complex organs (e.g., eye lens, optic nerves, inner ears, and bowels). Compared with traditional manual contouring times, the autosegmentation times, including subsequent manual editing, if necessary, were substantially reduced by 88% for MP, 80% for HN, and 65% for ABD models. CONCLUSIONS: The obtained autosegmentation models, incorporating organ-based approaches, were found to be effective and accurate for most OARs in the male pelvis, head and neck, and abdomen. We have demonstrated that our multianatomical DL autosegmentation models are clinically useful for radiation treatment planning.

A volume-independent conformity index for stereotactic radiosurgery.

PURPOSE: To develop a volume-independent conformity metric called the Gaussian Weighted Conformity Index (GWCI) to evaluate stereotactic radiosurgery/radiotherapy (SRS/SRT) plans for small brain tumors. METHODS: A signed bi-directional local distance (BLD) between the prescription isodose line and the target contour is determined for each point along the tumor contour (positive distance represents under-coverage). A similarity score function (SF) is derived from Gaussian function, penalizing under- and over-coverage at each point by assigning standard deviations of the Gaussian function. Each point along the dose line contour is scored with this SF. The average of the similarity scores determines the GWCI. A total of 40 targets from 18 patients who received Gamma-Knife SRS/SRT treatments were analyzed to determine appropriate penalty criteria. The resulting GWCIs for test cases already deemed clinically acceptable are presented and compared to the same cases scored with the New Conformity Index to determine the influence of tumor volumes on the two conformity indices (CIs). RESULTS: A total of four penalty combinations were tested based on the signed BLDs from the 40 targets. A GWCI of 0.9 is proposed as a cutoff for plan acceptability. The GWCI exhibits no target volume dependency as designed. CONCLUSION: A limitation of current CIs, volume dependency, becomes apparent when applied to SRS/SRT plans. The GWCI appears to be a more robust index, which penalizes over- and under-coverage of tumors and is not skewed by the tumor volume.

A phase 2 trial of a topical antiseptic bundle in head and neck cancer surgery: Effects on surgical site infection and the oral microbiome.

BACKGROUND: Head and neck cancer (HNC) surgery remains an important component of management but is associated with a high rate of surgical site infection (SSI). We aimed to assess the safety and efficacy of a topical mucosal antiseptic bundle in preventing SSI and evaluate microbial predictors of infection through a genomic sequencing approach. METHODS: This study was an open-label, single-arm, single-center, phase 2 trial of a topical mucosal antiseptic bundle in patients with HNC undergoing aerodigestive tract resection and reconstruction. Patients underwent topical preparation of the oral mucosa with povidone-iodine (PI) and chlorhexidine gluconate (CHG) pre- and intra-operatively followed by oral tetracycline ointment every 6 hours for 2 days post-operatively. The primary outcome was change in bacterial bioburden at the oral surgical site. Secondary outcomes included safety, SSI, and microbial predictors of infection. FINDINGS: Of 27 patients screened between January 8, 2021, and May 14, 2021, 26 were enrolled and 25 completed the study. There were no antiseptic-related adverse events. The topical mucosal antiseptic bundle significantly decreased oral bacterial colony-forming units from pre-operative levels (log10 mean difference 4·03, 95%CI 3·13-4·;92). There were three SSI (12%) within 30 days. In correlative genomic studies, a distinct set of amplicon sequence variants in the post-operative microbiome was associated with SSI. Further, despite no instance of post-operative orocervical fistula, metagenomic sequence mapping revealed the oral cavity as the origin of the infectious organism in two of the three SSI. INTERPRETATION: The bacterial strains which subsequently caused SSI were frequently identified in the pre-operative oral cavity. Accordingly, a topical antiseptic bundle decreased oral bacterial bioburden throughout the peri-operative period and was associated with a low rate of SSI, supporting further study of topical antisepsis in HNC surgery. FUNDING: Alliance Oncology.

Tumor Control Probability Modeling for Radiation Therapy of Keratinocyte Carcinoma.

SUMMARY: Skin cancer patients may be treated definitively using radiation therapy (RT) with electrons, kilovoltage, or megavoltage photons depending on tumor stage and invasiveness. This study modeled tumor control probability (TCP) based on the pooled clinical outcome data of RT for primary basal and cutaneous squamous cell carcinomas (BCC and cSCC, respectively). Four TCP models were developed and found to be potentially useful in developing optimal treatment schemes based on recommended ASTRO 2020 Skin Consensus Guidelines for primary, keratinocyte carcinomas (i.e. BCC and cSCC). BACKGROUND: Radiotherapy (RT) with electrons or photon beams is an excellent primary treatment option for keratinocyte carcinoma (KC), particularly for non-surgical candidates. Our objective is to model tumor control probability (TCP) based on the pooled clinical data of primary basal and cutaneous squamous cell carcinomas (BCC and cSCC, respectively) in order to optimize treatment schemes. METHODS: Published reports citing crude estimates of tumor control for primary KCs of the head by tumor size (diameter: ≤2 cm and >2 cm) were considered in our study. A TCP model based on a sigmoidal function of biological effective dose (BED) was proposed. Three-parameter TCP models were generated for BCCs ≤2 cm, BCCs >2cm, cSCCs ≤2 cm, and cSCCs >2 cm. Equivalent fractionation schemes were estimated based on the TCP model and appropriate parameters. RESULTS: TCP model parameters for both BCC and cSCC for tumor sizes ≤2 cm and >2cm were obtained. For BCC, the model parameters were found to be TD50 = 56.62 ± 6.18 × 10-3 Gy, k = 0.14 ± 2.31 × 10-2 Gy-1 and L = 0.97 ± 4.99 × 10-3 and TD50 = 55.78 ± 0.19 Gy, k = 1.53 ± 0.20 Gy-1 and L = 0.94 ± 3.72 × 10-3 for tumor sizes of ≤2 cm and >2 cm, respectively. For SCC the model parameters were found to be TD50 = 56.81 ± 19.40 × 104 Gy, k = 0.13 ± 7.92 × 104 Gy-1 and L = 0.96 ± 1.31 × 10-2 and TD50 = 58.44 ± 0.30 Gy, k = 2.30 ± 0.43 Gy-1 and L = 0.91± 1.22 × 10-2 for tumors ≤2cm and >2 cm, respectively. The TCP model with the derived parameters predicts that radiation regimens with higher doses, such as increasing the number of fractions and/or dose per fraction, lead to higher TCP, especially for KCs >2 cm in size. CONCLUSION: Four TCP models for primary KCs were developed based on pooled clinical data that may be used to further test the recommended kV and MV x-ray and electron RT regimens from the 2020 ASTRO guidelines. Increasing both number of fractions and dose per fraction may have clinically significant effects on tumor control for tumors >2 cm in size for both BCC and cSCC.