A Review of Contemporary Image Guidance Techniques in Head and Neck Cancer.

BACKGROUND: Traditional head and neck cancer treatment involves open surgery, cytotoxic chemotherapy, and conventional radiotherapy planning. Emerging techniques aim to improve precision and reduce associated toxicity and functional impairment in current practice. This review article describes four such adaptations in image guidance, tailored to next generation therapies. METHODS: This is a review of current literature, including feasibility studies from our cancer center, relating to: saline-aided intra-oral ultrasound-guided retropharyngeal biopsy; intra-oral ultrasound guided trans-oral robotic surgery (TORS); ultrasound-guided injection of "directly injected therapies"; and magnetic resonance imaging-guided radiotherapy. RESULTS: Presented within the context of the wider literature, initial local experience and data indicate good technical outcomes and patient tolerance, and low technical complications in all four image guidance techniques. CONCLUSION: Initial findings suggest a potentially important future role for these four image guidance techniques, on which next generation therapies are reliant. The broader implications on cross-disciplinary collaboration are also explored herein.

Measurement and Incorporation of Laryngeal Motion Using cine-MRI on an MR-Linear Accelerator to Generate Radiation Therapy Plans for Early-stage Squamous Cell Cancers of the Glottis.

Purpose: Swallow-related motion of the larynx is most significant in the cranio-caudal directions and of` short duration. Conventional target definition for radical radiation therapy includes coverage of the whole larynx. This study longitudinally examined respiration- and swallow-related laryngeal motions using cine-magnetic resonance imaging. We further analyzed the dosimetry to organs at risk by comparing 3D-conformal radiation therapy (3D-CRT), volumetric modulated arc therapy (VMAT), and intensity modulated radiation therapy (IMRT) techniques. Methods: Fifteen patients with T1-2 N0 glottic squamous cell carcinomas were prospectively recruited for up to 3 cine-MRI scans on the Elekta Unity MR-Linear accelerator, at the beginning, middle, and end of a course of radical radiation therapy. Swallow frequency and motion of the hyoid bone, cricoid and thyroid cartilages, and vocal cords were recorded during swallow and rest. Adapted treatment volumes consisted of gross tumor volume + 0.5-1 cm to a clinical target volume with an additional internal target volume (ITV) for personalized resting-motion. Swallow-related motion was deemed infrequent and was not accounted for in the ITV. We compared radiation therapy plans for 3D-CRT (whole larynx), VMAT (whole larynx), and VMAT and IMRT (ITV for resting motion). Results: Resting- and swallow-related motions were most prominent in the cranio-caudal plane. There were no significant changes in the magnitude of motion over the course of radiation therapy. There was a trend of a progressive reduction in the frequency of swallow. Treatment of partial larynx volumes with intensity modulated methods significantly reduced the dose to carotid arteries, compared with treatment of whole larynx volumes. Robustness analysis demonstrated that when accounting for intrafraction swallow, the total dose delivered to the ITV/planning target volume was maintained at above 95%. Conclusions: Swallow-related motions are infrequent and accounting for resting motion in an ITV is sufficient. VMAT/IMRT techniques that treat more conformal targets can significantly spare critical organs at risk such as the carotid arteries and thyroid gland, potentially reducing the risk of carotid artery stenosis-related complications and other long-term complications.

Clinical acceptance and dosimetric impact of automatically delineated elective target and organs at risk for head and neck MR-Linac patients.

Background: MR-Linac allows for daily online treatment adaptation to the observed geometry of tumor targets and organs at risk (OARs). Manual delineation for head and neck cancer (HNC) patients takes 45-75 minutes, making it unsuitable for online adaptive radiotherapy. This study aims to clinically and dosimetrically validate an in-house developed algorithm which automatically delineates the elective target volume and OARs for HNC patients in under a minute. Methods: Auto-contours were generated by an in-house model with 2D U-Net architecture trained and tested on 52 MRI scans via leave-one-out cross-validation. A randomized selection of 684 automated and manual contours (split half-and-half) was presented to an oncologist to perform a blind test and determine the clinical acceptability. The dosimetric impact was investigated for 13 patients evaluating the differences in dosage for all structures. Results: Automated contours were generated in 8 seconds per MRI scan. The blind test concluded that 114 (33%) of auto-contours required adjustments with 85 only minor and 15 (4.4%) of manual contours required adjustments with 12 only minor. Dosimetric analysis showed negligible dosimetric differences between clinically acceptable structures and structures requiring minor changes. The Dice Similarity coefficients for the auto-contours ranged from 0.66 ± 0.11 to 0.88 ± 0.06 across all structures. Conclusion: Majority of auto-contours were clinically acceptable and could be used without any adjustments. Majority of structures requiring minor adjustments did not lead to significant dosimetric differences, hence manual adjustments were needed only for structures requiring major changes, which takes no longer than 10 minutes per patient.

Online adaptive radiotherapy for head and neck cancers on the MR linear Accelerator: Introducing a novel modified Adapt-to-Shape approach.

INTRODUCTION: The Elekta Unity MR-Linac (MRL) has enabled adaptive radiotherapy (ART) for patients with head and neck cancers (HNC). Adapt-To-Shape-Lite (ATS-Lite) is a novel Adapt-to-Shape strategy that provides ART without requiring daily clinician presence to perform online target and organ at risk (OAR) delineation. In this study we compared the performance of our clinically-delivered ATS-Lite strategy against three Adapt-To-Position (ATP) variants: Adapt Segments (ATP-AS), Optimise Weights (ATP-OW), and Optimise Shapes (ATP-OS). METHODS: Two patients with HNC received radical-dose radiotherapy on the MRL. For each fraction, an ATS-Lite plan was generated online and delivered and additional plans were generated offline for each ATP variant. To assess the clinical acceptability of a plan for every fraction, twenty clinical goals for targets and OARs were assessed for all four plans. RESULTS: 53 fractions were analysed. ATS-Lite passed 99.9% of mandatory dose constraints. ATP-AS and ATP-OW each failed 7.6% of mandatory dose constraints. The Planning Target Volumes for 54 Gy (D95% and D98%) were the most frequently failing dose constraint targets for ATP. ATS-Lite median fraction times for Patient 1 and 2 were 40 mins 9 s (range 28 mins 16 s - 47 mins 20 s) and 32 mins 14 s (range 25 mins 33 s - 44 mins 27 s), respectively. CONCLUSIONS: Our early data show that the novel ATS-Lite strategy produced plans that fulfilled 99.9% of clinical dose constraints in a time frame that is tolerable for patients and comparable to ATP workflows. Therefore, ATS-Lite, which bridges the gap between ATP and full ATS, will be further utilised and developed within our institute and it is a workflow that should be considered for treating patients with HNC on the MRL.

Early-Stage Glottic Squamous Cell Carcinoma in the Era of Image-Guided Radiotherapy.

Early-stage squamous cell cancer (SCC) of the glottis has a good prognosis. Therefore, patients have long survival outcomes and may potentially suffer from late toxicities of radiotherapy. Radiotherapy with a conventional parallel-opposed-pair or anterior-oblique beam arrangements for stage 1 and 2 glottic SCC have field borders that traditionally cover the entire larynx, exposing organs-at-risk (e.g. carotid arteries, contralateral vocal cord, contralateral arytenoid and inferior pharyngeal constrictor muscles) to high radiation doses. The potential long-term risk of cerebrovascular events has attracted much attention to the dose that carotid arteries receive. Swallow and respiratory motion of laryngeal structures has been an important factor that previously limited reduction of the radiation treatment volume. Motion has been evaluated using multiple imaging modalities and this information has been used to calculate PTV margins for generation of more limited target volumes. This review discusses the current literature surrounding dose-effect relationships for various organs-at-risk and the late toxicities that are associated with them. This article also reviews the currently available data and effects of laryngeal motions on dosimetry to the primary target. We also review the current limitations and benefits of a more targeted approach of radiotherapy for early-stage glottic SCCs and the evolution of CT-based IGRT and MR-guided radiotherapy techniques that may facilitate a shift away from a conventional 3D-conformal radiotherapy approach.

On-treatment immune prognostic score for patients with relapsed and/or metastatic head and neck squamous cell carcinoma treated with immunotherapy.

BACKGROUND: Previous studies have suggested that inflammatory markers (neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH) and fibrinogen) are prognostic biomarkers in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors (ICIs). We aimed to develop a model that predicts response and survival in patients with relapsed and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy. METHODS: Analysis of 100 consecutive patients with unresectable R/M HNSCC who were treated with ICI. Baseline and on-treatment (day 28) NLR, fibrinogen and LDH were calculated and correlated with response, progression-free survival (PFS) and overall survival (OS) using univariate and multivariate analyses. The optimal cut-off values were derived using maximally selected log-rank statistics. RESULTS: Low baseline NLR and fibrinogen levels were associated with response. There was a statistically significant correlation between on-treatment NLR and fibrinogen and best overall response. On-treatment high NLR and raised fibrinogen were significantly associated with poorer outcome. In multivariate analysis, on-treatment NLR (≥4) and on-treatment fibrinogen (≥4 ng/mL) showed a significant negative correlation with OS and PFS. Using these cut-off points, we generated an on-treatment score for OS and PFS (0-2 points). The derived scoring system shows appropriate discrimination and suitability for OS (HR 2.4, 95% CI 1.7 to 3.4, p<0.0001, Harrell's C 0.67) and PFS (HR 1.8, 95% CI 1.4 to 2.3, p<0.0001, Harrell's C 0.68). In the absence of an external validation cohort, results of fivefold cross-validation of the score and evaluation of median OS and PFS on the Kaplan-Meier survival distribution between trained and test data exhibited appropriate accuracy and concordance of the model. CONCLUSIONS: NLR and fibrinogen levels are simple, inexpensive and readily available biomarkers that could be incorporated into an on-treatment scoring system and used to help predict survival and response to ICI in patients with R/M HNSCC.

Safety and Treatment Outcomes of Nivolumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Retrospective Multicenter Cohort Study.

Nivolumab is an anti-PD-1 monoclonal antibody currently used as immunotherapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with evidence of disease progression after platinum-based chemotherapy. This study evaluates real-world safety and treatment outcomes of non-trial nivolumab use. A retrospective multicenter cohort study of patients with recurrent/metastatic HNSCC treated with nivolumab between January 2017 and March 2020 was performed. Overall, 123 patients were included. The median age was 64 years, the majority of patients were male (80.5%) and had a smoking history (69.9%). Primary outcomes included overall response rate (ORR) of 19.3%, median progression-free survival (PFS) of 3.9 months, 1-year PFS rate of 16.8%, a median overall survival (OS) of 6.5 months and 1-year OS rate of 28.6%. These results are comparable to the CHECKMATE-141 study. Of 27 patients who had PD-L1 status tested, positive PD-L1 status did not significantly affect PFS (p = 0.86) or OS (p = 0.84). Nivolumab was well tolerated with only 15.1% experiencing immune-related toxicities (IRT) and only 6.7% of patients stopping due to toxicity. The occurrence of IRT appeared to significantly affect PFS (p = 0.01) but not OS (p = 0.07). Nivolumab in recurrent/metastatic HNSCC is well tolerated and may be more efficacious in patients who develop IRT.

Taste dysfunction following radiotherapy to the head and neck: A systematic review.

BACKGROUND: An intact sense of taste provides pleasure, supports sustenance and alerts the body to toxins. Head and neck cancer (HNC) patients who receive radiotherapy (RT) are high-risk for developing radiation-induced taste dysfunction. Advances in RT offer opportunities for taste-preserving strategies by reducing dose to the gustatory organs-at-risk. METHODS: PubMed, Medline and EMBASE were searched for publications reporting on taste, RT and HNC. Randomised trials, cohort studies and cross-sectional studies were included. RESULTS: 31 studies were included in this review. Meta-analysed prevalence of acute taste dysfunction following RT was approximately 96% (95% CI 64 to 100%) by objective measures and 79% (95% CI 65 to 88%) by subjective measures, with the majority of patients showing at least partial recovery. Long-term dysfunction was seen in ~25% of patients. Taste dysfunction was associated with sequalae including weight loss and reduced quality-of-life (QoL). Taste dysfunction was more common when the oral cavity, and specifically the anterior two-thirds of the tongue, was irradiated, suggesting a dose constraint for taste preservation might be feasible. Proton beam therapy and customised bite blocks reduced dose to the gustatory field and subsequent loss of taste. CONCLUSIONS: Taste dysfunction following RT is common and negatively affects patients' nutritional status and QoL. Decisions about treatment strategies, including choice of RT modality, dose distribution across the gustatory field and the use of adjuncts like bite blocks may be beneficial. However, evidence is limited. There is a pressing need for randomised studies or large prospective cohort studies with sufficient adjustment for confounders.

The impact of restricted length of treatment field and anthropometric factors on selection of head and neck cancer patients for treatment on the MR-Linac.

OBJECTIVE: This study investigates the impact of a restricted craniocaudal (CC) field length of <20 cm on the selection of head and neck cancer (HNC) patients who can be treated on the MR-Linac using a single isocentre technique. We also assess the effects of anthropometric factors and the neck position on the CC field length. METHODS: 110 HNC patients who underwent radical primary or adjuvant radiotherapy were retrospectively analysed. We assessed the proportion of treatment fields with a CC length of <20 cm and the effects of gender, height, hyo-sternal neck length (distance from superior surface of hyoid to sternal notch measured on the coronal reconstruction of the planning CT) and neck position on CC length. RESULTS: 95% of HNC patients had a CC field length <20 cm. Female patients showed a significantly shorter median CC length than male patients in both extended (p = 0.0003) and neutral (p = 0.008) neck positions. Neck position influenced the median CC length with neutral neck being significantly shorter than extended neck (p = 0.0119). Patient height and hyo-sternal neck length showed positive correlation with the CC length, with neck length in neutral position having the strongest correlation (r = 0.65, p = 0.0001 and r = 0.63, p < 0.0001, respectively for extended neck; r = 0.55, p = 0.0070 and r = 0.80, p < 0.0001, respectively for neutral neck). A hyo-sternal neck length of <14.6 cm predicted a CC length of <20 cm in neutral neck position. CONCLUSION: The majority of patients with HNC at the Royal Marsden Hospital have anthropometric features compatible with their being treated on the MR-Linac using a single isocentre technique. The absolute CC field size may vary according to primary tumour site, patient factors and neck position. A hyo-sternal neck length cut-off of 14.6 cm in the neutral neck position can be used as a surrogate marker for suitability of treatment on MR-Linac. ADVANCES IN KNOWLEDGE: This paper highlights the potential impact of a restricted CC field in HNC patient selection for the MR-Linac treatment. This is the first report to suggest the use of neck length as a surrogate marker for suitability of treatment on the MR-Linac.