Holly McMillan’s research while affiliated with University of Texas MD Anderson Cancer Center and other places

Radiation-induced fibrosis (RIF) is a common side effect of cancer treatment, but can manifest into a devastating syndrome for which there is no preventive measure or cure. In rats who perform a repetitive work task, who left untreated develop signs and symptoms that resemble repetitive motion disorders in humans, we have shown that manual therapy prevents the development of fibrosis and other key biomarkers. The fibrosis of RIF and repetitive motion disorders has similar biomarkers. In rats, we sought to determine if manual therapy would alter key biomarkers of post-irradiation fibrosis following X-ray irradiation given to the rat forelimb. One limb of rats was given a damaging dose of X-ray irradiation. Some limbs were massaged using a protocol previously described and characterized. Serum inflammatory markers, histological assays of tissue fibrosis and nerve pathology, and electrophysiology for neuropathic discharge were assayed after 8 weeks. We also tested if an experienced therapist could identify the irradiated limb using blinded palpation at the 8 week end-point. While preliminary assays showed robust changes compared to control limbs, the other assays did not show similar pathology. Our therapist could detect each irradiated limb. Serum inflammatory markers were reduced by massage to the irradiated limb. We conclude that blinded palpation is sensitive to detect subtle changes in tissue following irradiation. In contrast to the preliminary studies, the dose of irradiation used was insufficient to induce long-lasting deep fibrosis or nerve degeneration. We suspect that a difference in housing, and thus physical activity, was the plausible reason for this difference.

Background Radiation-associated lymphedema and fibrosis (LEF) is a significant toxicity following radiation therapy (RT) for head and neck cancer (HNC) patients. Recently, the CT Lymphedema and Fibrosis Assessment Tool (CT-LEFAT) was developed to standardize LEF diagnosis through fat stranding visualized on CT. This study aims to evaluate the inter-observer reliability and diagnostic accuracy of the CT-LEFAT criteria. Materials and Methods This study retrospectively evaluated 26 HNC patients treated with RT that received a minimum of two contrast-enhanced CT scans. Qualitative review was conducted by five physician raters to assess the fat stranding observed on CT according to the CT-LEFAT criteria. Fleiss' kappa analysis was used to assess the inter- and intra-rater reliability, and Receiver Operating Characteristic (ROC) Area Under the Curve (AUC) analysis was used to evaluate diagnostic accuracy. Results The inter-rater reliability across the six CT-LEFAT regions generally indicated a slight to fair agreement across all raters (0.04 ≤ kappa ≤ 0.36). Intra-observer agreement was generally fair to moderate (overall kappa=0.44). The ROC AUC analysis varied based on aggregation method used (0.60 ≤ average AUC ≤ 0.70). Conclusion This specific use-case evaluating CT-LEFAT criteria displays limited performance. This suggests that additional materials, such as further training, refinement of imaging methods, or other processes may be required before achieving clinically-ready diagnostic performance of LEF diagnosis.

Importance Quantifying Head and Neck Lymphedema and Fibrosis (HN-LEF) is crucial in the investigation and management of this highly prevalent treatment sequelae in head and neck cancer (HNC). The HN-LEF grading system classifies physically palpable soft-tissue injury categorically. Imaging biomarkers from MRI may serve to complement or validate physical HN-LEF grading when assessing the effectiveness of therapeutic interventions or toxicity profiles of patients. Objective To explore the relationship between 1) physical HN-LEF classification in submental and oral regions of interest (ROI) and the MRI T1- and T2-weighted signal intensity (SI) in close proximity regions, and 2) a novel HN-LEF score and MRI T1 and T2 structural volumes. Design Post hoc analysis of pilot single arm MANTLE trial ( NCT03612531 ). Setting Single institution, NCI-designated comprehensive cancer center. Participants A total of 16 individuals (mean [SD] age, 68.28 [7.0] years; 3[19%] female) enrolled in the MANTLE trial underwent MRI. All participants were disease-free at least two years post radiotherapy with grade ≥2 fibrosis (in any cervical ROI) and grade ≥2 dysphagia (per DIGEST). Over a 12-week period, participants engaged in manual therapy sessions accompanied by concurrent standardized multiparametric, serial MRI examinations and palpation-based HN-LEF evaluations at 3 time points: baseline, post-manual therapy, and post-washout. Exposures The independent variable HN-LEF included its categorical classification (No-LEF, A-B = edema, C= edema + fibrosis, D=fibrosis) and a novel metric (10-point scale) derived from the HN-LEF categories (considering both type and severity classification). Main Outcomes and Measures The T1- and T2-weighted MRI SI was examined by Kruskal-Wallis tests in relation to HN-LEF categories and the novel HN-LEF score. We hypothesized higher T2 SI in edema states, higher T1 SI in fibrotic states, and decreasing structural volume as HN-LEF score increased. Results We identified differences in mean ranks among HN-LEF categories in relation to the MRI SI (A-B and C are higher than D and No-LEF for T2 SI, and A-B is the highest for T1). Furthermore, six pairs of FOM volumes on MRI demonstrated a strong negative correlation (p<0.05) with the HN-LEF score at adjacent palpable sites: digastric vs. submental left ( ρ = -0.421; 95% CI, -0.65∼ -0.10, T1), mylohyoid vs. submental left ( ρ = -0.36; 95% CI, -0. 62∼ 0.03, T1), digastric vs. submental left (ρ = --0.45; 95% CI, -0. 72∼ -0.06, T2), genioglossus vs. Intraoral left (ρ = -0.47; 95% CI, -0. 74∼ -0.07, T2), mylohyoid vs. Intraoral left (ρ = -0.48; 95% CI, -0. 75∼ -0.09, T2), tongue base vs. Intraoral left (r = -0.42; 95% CI, -0. 71∼ -0.01, T2). Conclusions and Relevance This exploratory analysis provides hypothesis generating data supporting further study of MRI SI as an imaging biomarker of edematous soft tissue states after RT in HNC, but does not support the hypothesized T2 SI relationship with fibrotic tissue states. The inverse correlation between the novel HN-LEF scores and structural volumes points to the potential validity of this novel metric assuming structural volume diminishes as patients move from edema to fibrotic states. This study highlights the potential for enhancing the LEF quantification using imaging metrics, which might further aid in the early detection and precise measurement of lymphedema and fibrosis severity in post-radiation HNC patients.

Clinical implementation of evidence-based practice (EBP) tools is a healthcare priority. The Dynamic Grade of Swallowing Toxicity (DIGEST) is an EBP tool developed in 2016 for videofluoroscopy in head and neck (H&N) oncology with clinical implementation as a goal. We sought to examine: (1) feasibility of clinical implementation of DIGEST in a national comprehensive cancer center, and (2) fidelity of DIGEST adoption in real-world practice. A retrospective implementation evaluation was conducted in accordance with the STARI framework. Electronic health record (EHR) databases were queried for all consecutive modified barium swallow (MBS) studies conducted at MD Anderson Cancer Center from 2016 to 2021. Implementation outcomes included: feasibility as measured by DIGEST reporting in EHR (as a marker of clinical use) and fidelity as measured by accuracy of DIGEST reporting relative to the decision-tree logic (penetration-aspiration scale [PAS], residue, and Safety [S] and Efficiency [E] grades). Contextual factors examined included year, setting, cancer type, MBS indication, and provider. 13,055 MBS were conducted by 29 providers in 7,842 unique patients across the lifespan in diverse oncology populations (69% M; age 1–96 years; 58% H&N cancer; 10% inpatient, 90% outpatient). DIGEST was reported in 12,137/13,088 exams over the 6-year implementation period representing 93% (95% CI: 93–94%) adoption in all exams and 99% (95% CI: 98–99%) of exams excluding the total laryngectomy population (n = 730). DIGEST reporting varied modestly by year, cancer type, and setting/provider (> 91% in all subgroups, p < 0.001). Accuracy of DIGEST reporting was high for overall DIGEST (incorrect SE profile 1.6%, 200/12,137), DIGEST-safety (incorrect PAS 0.4% 51/12,137) and DIGEST-efficiency (incorrect residue 1.2%, 148/12,137). Clinical implementation of DIGEST was feasible with high fidelity in a busy oncology practice across a large number of providers. Adoption of the tool across the lifespan in diverse cancer diagnoses may motivate validation beyond H&N oncology.

Purpose of Review Delayed onset of communication and swallowing dysfunction due to radiation-associated neuromuscular injury is one of the most challenging clinical presentations in head and neck cancer rehabilitation. This review details the current literature and describes an evidence-based process for evaluating and treating this unique clinical entity. Recent Findings Radiation-fibrosis syndrome (RFS) is associated with lower cranial nerve palsy, dysphagia, trismus, dysarthria, dysphonia, and dyspnea. Sequelae of dysfunction can include feeding tube dependence, tracheostomy, depression, anxiety, and poor quality of life. While there is limited research evaluating rehabilitation efficacy explicitly in this population, the broader evidence base supports a multidimensional evaluation process and interventions that include compensatory approaches, skill-based training, and restorative exercises. Further evidence is forthcoming, with several ongoing randomized clinical trials exploring this topic. Summary Communication and swallowing dysfunction associated with RFS is debilitating, and treatment is intensive, often involving a phased approach with multiple specialties.

Introduction Following the COVID-19 directive to cease non-essential services, a rapid shift was made in the delivery of Speech Language Pathology (SLP) dysphagia management in the 3-arm, randomized PRO-ACTIVE trial. To inform future programs, this study explored patients’ experiences with telehealth when the planned in-person SLP intervention was moved to a telehealth modality. Methods A theory-guided qualitative descriptive approach was used. Willing participants who had received at least one telehealth swallowing therapy session participated in a one-time semi-structured interview. Interview transcripts were subjected to a standard qualitative content/theme analysis. Researchers reviewed all transcripts and used a multi-step analysis process to build a coding framework through consensus discussion. Summaries and key messages were generated for each code. Results Eleven participants recounted their telehealth experiences and reported feeling satisfied, comfortable and confident with the session(s). They identified that previous experience with teleconferencing, access to optimal technical equipment, clinician skill, and caregiver assistance facilitated their telehealth participation. Participants highlighted that telehealth was beneficial as it reduced commuting time, COVID-19 exposure and fatigue from travel; and also allowed caregiver participation particularly during COVID. In comparing their in-person SLP sessions to telehealth sessions, limitations were also identified, including: lack of previous experience with and/or poor access to technology, and less opportunity for personalization. Participants indicated that use of phone alone was less preferred than an audio/video platform. Discussion Patients reported that overall, telehealth sessions did not compromise their learning experience when compared to in-person sessions. Patients benefited from use of telehealth in several ways despite some limitations of the use of technology. Patient feedback about telehealth provides an important perspective that may be critical to inform best practices for care delivery.

This book was inadvertently published with the incorrect affiliation of Dr. Jaimie Payne Anderson in Chapter 11. This has been changed to:

Skull base and sinonasal neoplasms threaten basic functions, appearance, and quality of life. These tumors arise in close proximity to vital structures including the brainstem, cerebral cortex, cervical spine, nasal cavity, orbit, and pituitary gland. Patients presenting with skull base tumors report high symptom burden at presentation (prior to treatment) relative to other malignancies in the head and neck region. Surgical morbidity can also be substantial, as may be both acute and late effects of radiotherapy on normal tissues in this functionally critical region. Treatment advances and interdisciplinary supportive care help to lessen the functional impairments and the resultant loss of quality of life (QOL) that were once accepted as inevitable tradeoffs for cure. This chapter reviews functional and quality of life outcomes among patients treated for sinonasal and skull base malignancies. Evaluation and management protocols for swallowing and communication impairments will be presented, as well as considerations for management of lymphedema as it relates to both body image and functional outcomes. Recent progress in QOL and patient-reported outcome (PRO) measurement methods for this population will also be covered.KeywordsDysphagiaLymphedemaCranial nerveQuality of lifeDysphoniaCognitionDysarthria

Importance: Trismus is highly prevalent in head and neck cancer (HNC) survivorship. Current standards for trismus treatment include various stretch-based exercise protocols as a primary and single treatment modality with limited evidence regarding the role of manual therapy (MT) for this indication. Objective: To assess the effect size and associations of response to MT to increase oral opening in the setting of radiation-associated trismus. Design, setting, and participants: This retrospective case series was conducted at the University of Texas MD Anderson Cancer Center between 2016 and March 2020 (before COVID-19 interruption) and included 49 disease-free survivors of HNC who were referred for treatment of radiation-associated trismus. Intervention: Intraoral MT (including or excluding external head and neck) targeting the muscles of mastication. Main outcomes and measures: Maximum interincisal opening (MIO) before and after the initial MT session compared with serial MT sessions. Covariates were examined to determine the association with response to MT for trismus. Results: A total of 49 survivors of HNC (13 women [27%]; 24 [49%] 64 years or younger; 25 [51%] 65 years or older; mean [range] of 6.6 [0-33] years postradiotherapy were included, 9 [18.4%] of whom underwent a single MT session; 40 [81.6%] who underwent multiple sessions [mean, 6; median (range), 3 (2-48)]). The MIO improved after a single session by a mean (SD) of 4.1 (1.9) mm (0.45 effect size) and after serial MT sessions by a mean (SD) of 6.4 (4.8) mm with an effect size of 0.7. No covariates were found to be clinically meaningfully associated with MIO improvement following MT. Conclusions and relevance: The findings of this case series study suggest that MT improved MIO with a medium to large effect size in survivors of HNC with radiation-associated trismus. The results suggest that the largest increase in oral opening was achieved after the initial treatment and although gains were more modest, oral opening continued to improve with serial treatment. Covariates were not associated with MT response, suggesting that patients with clinical features often considered treatment refractory (eg, advanced disease, multiple lines of oncology treatment, ≥5 years posttreatment) may benefit from treatment with MT. Manual therapy may be a beneficial frontline or adjuvant treatment when combined with traditional stretching therapy. A clinically meaningful increase in oral opening has the potential to improve swallow function, speech, pain, and quality of life.