A systematic review of antibody-drug conjugates and bispecific antibodies in head and neck squamous cell carcinoma and nasopharyngeal carcinoma: Charting the course of future therapies.

INTRODUCTION: There is a need to improve the outcomes of patients with head and neck squamous cell carcinoma (HNSCC) and nasopharyngeal carcinoma (NPC), especially in recurrent unresectable and metastatic (R/M) setting. Antibody-drug conjugates (ADC) and bispecific antibodies (BsAb) may deliver promising results. METHODS: We conducted a systematic literature review to identify ADC and BsAb clinical trials, involving patients with HNSCC and NPC, from database creation to December 2023. We reported trial characteristics, overall response rate (ORR), overall survival (OS), and grade ≥ 3 treatment-related adverse events (trAEs). RESULTS: 23 trials (65 % phase I) were found, involving 540 R/M patients (355 [20trials] HNSCC and 185 [5trials] NPC). There were 13 ADC (n = 343) and 10 BsAb (n = 197) trials. 96 % patients were refractory to standard of care treatments. ORR ranged from 0 to 100 %, with the highest ORR for GEN1042 plus chemoimmunotherapy. ORRs for monotherapies were 47 % for ADC, and 0-37 % for BsAb. MRG003 reached in HNSCC 43 % and NPC 47 %. BL-B01D1 54 % in NPC. Longest median OS was seen with MRG003 and KN046. Grade ≥ 3 trAEs were 28-60 % in ADC trials, and 3-33 % BsAb. Grade ≥ 3 myelosuppressive trAEs were typically seen in 8 ADC trials, while 4 BsAb showed infusion-related reactions (IRR). Four treatment-related deaths were reported (1 pneumonitis), all ADC trials. CONCLUSION: ADC and BsAb antibodies show promise in R/M HNSCC and NPC. Results are premature by small sample sizes and lack of control arm. ADC mainly caused myelosuppression and a pneumonitis case, and BsAb IRR. Further research is warranted in this setting.

The use of pembrolizumab monotherapy for the management of head and neck squamous cell carcinoma (HNSCC) in the UK.

Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.

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.

FUME-TCRseq Enables Sensitive and Accurate Sequencing of the T-cell Receptor from Limited Input of Degraded RNA.

Genomic analysis of the T-cell receptor (TCR) reveals the strength, breadth, and clonal dynamics of the adaptive immune response to pathogens or cancer. The diversity of the TCR repertoire, however, means that sequencing is technically challenging, particularly for samples with low-quality, degraded nucleic acids. Here, we developed and validated FUME-TCRseq, a robust and sensitive RNA-based TCR sequencing methodology that is suitable for formalin-fixed paraffin-embedded samples and low amounts of input material. FUME-TCRseq incorporates unique molecular identifiers into each molecule of cDNA, allowing correction for sequencing errors and PCR bias. Using RNA extracted from colorectal and head and neck cancers to benchmark the accuracy and sensitivity of FUME-TCRseq against existing methods demonstrated excellent concordance between the datasets. Furthermore, FUME-TCRseq detected more clonotypes than a commercial RNA-based alternative, with shorter library preparation time and significantly lower cost. The high sensitivity and the ability to sequence RNA of poor quality and limited amount enabled quantitative analysis of small numbers of cells from archival tissue sections, which is not possible with other methods. Spatially resolved FUME-TCRseq analysis of colorectal cancers using macrodissected archival samples revealed the shifting T-cell landscapes at the transition to an invasive phenotype and between tumor subclones containing distinct driver alterations. In summary, FUME-TCRseq represents an accurate, sensitive, and low-cost tool for the characterization of T-cell repertoires, particularly in samples with low-quality RNA that have not been accessible using existing methodology. SIGNIFICANCE: FUME-TCRseq is a TCR sequencing methodology that supports sensitive and spatially resolved detection of TCR clones in archival clinical specimens, which can facilitate longitudinal tracking of immune responses through disease course and treatment.

Circulating HPV DNA as a Biomarker for Pre-Invasive and Early Invasive Cervical Cancer: A Feasibility Study.

BACKGROUND: High-risk HPV infection is responsible for >99% of cervix cancers (CC). In persistent infections that lead to cancer, the tumour breaches the basement membrane, releasing HPV-DNA into the bloodstream (cHPV-DNA). A next-generation sequencing assay (NGS) for detection of plasma HPV circulating DNA (cHPV-DNA) has demonstrated high sensitivity and specificity in patients with locally advanced cervix cancers. We hypothesised that cHPV-DNA is detectable in early invasive cervical cancers but not in pre-invasive lesions (CIN). METHODS: Blood samples were collected from patients with CIN (n = 52) and FIGO stage 1A-1B CC (n = 12) prior to treatment and at follow-up. DNA extraction from plasma, followed by NGS, was used for the detection of cHPV-DNA. RESULTS: None of the patients with pre-invasive lesions were positive for CHPV-DNA. In invasive tumours, plasma from one patient (10%) reached the threshold of positivity for cHPV-DNA in plasma. CONCLUSION: Low detection of cHPV-DNA in early CC may be explained by small tumour size, poorer access to lymphatics and circulation, and therefore little shedding of cHPV-DNA in plasma at detectable levels. The detection rate of cHPV-DNA in patients with early invasive cervix cancer using even the most sensitive of currently available technologies lacks adequate sensitivity for clinical utility.

Predicting Response to Radical Chemoradiotherapy with Circulating HPV DNA (cHPV-DNA) in Locally Advanced Uterine Cervix Cancer.

BACKGROUND: The majority of locally advanced cervical cancers (LaCC) are causally related to HPV. We sought to investigate the utility of an ultra-sensitive HPV-DNA next generation sequencing (NGS) assay-panHPV-detect-in LaCC treated with chemoradiotherapy, as a marker of treatment response and persistent disease. METHOD: Serial blood samples were collected from 22 patients with LaCC before, during and after chemoradiation. The presence of circulating HPV-DNA was correlated with clinical and radiological outcomes. RESULTS: The panHPV-detect test demonstrated a sensitivity and specificity of 88% (95% CI-70-99%) and 100% (95% CI-30-100%), respectively, and correctly identified the HPV-subtype (16, 18, 45, 58). After a median follow up of 16 months, and three relapses all had detectable cHPV-DNA at 3 months post-CRT despite complete response on imaging. Another four patients with radiological partial or equivocal response and undetectable cHPV-DNA at the 3-month time point did not go on to develop relapse. All patients with radiological CR and undetectable cHPV-DNA at 3-months remained disease free. CONCLUSIONS: These results demonstrate that the panHPV-detect test shows high sensitivity and specificity for detecting cHPV-DNA in plasma. The test has potential applications in assessment of the response to CRT and in monitoring for relapse, and these initial findings warrant validation in a larger cohort.

Systematic review and meta-analysis of occult contralateral nodal metastases in patients with oropharyngeal squamous carcinoma undergoing elective neck dissection.

A systematic review and meta-analysis was conducted to evaluate the occult contralateral nodal metastases (OCM) in patients undergoing bilateral neck dissection for surgically treated oropharyngeal squamous cell carcinoma (OPSCC). Following PRISMA guidelines, MEDLINE, Embase and Cochrane Controlled Register of Trials databases were searched for observational and experimental studies until March 2021. Search yielded 175 articles, of which 13 were included. Overall, OCM were seen in 9.8% of patients (95% CI: [5.7, 16.4], 839 patients, 12 studies, I2 65%). For ipsilateral cN0 necks, the OCM rate was 1.7% (95% CI: [0.1, 22.4], 150 patients, 8 studies, I2 0%) and for cN + necks the OCM rate was 9.8% (95% CI: [4.4, 20.3], 429 patients, 8 studies, I2 72%). Occult contralateral nodal metastases are uncommon in OPSCC patients with clinico-radiologically negative ipsilateral necks. Occult rates are higher in the contralateral neck when the ipsilateral neck is clinico-radiologically node positive.

T-cell receptor determinants of response to chemoradiation in locally-advanced HPV16-driven malignancies.

Background: The effect of chemoradiation on the anti-cancer immune response is being increasingly acknowledged; however, its clinical implications in treatment responses are yet to be fully understood. Human papillomavirus (HPV)-driven malignancies express viral oncogenic proteins which may serve as tumor-specific antigens and represent ideal candidates for monitoring the peripheral T-cell receptor (TCR) changes secondary to chemoradiotherapy (CRT). Methods: We performed intra-tumoral and pre- and post-treatment peripheral TCR sequencing in a cohort of patients with locally-advanced HPV16-positive cancers treated with CRT. An in silico computational pipeline was used to cluster TCR repertoire based on epitope-specificity and to predict affinity between these clusters and HPV16-derived epitopes. Results: Intra-tumoral repertoire diversity, intra-tumoral and post-treatment peripheral CDR3ß similarity clustering were predictive of response. In responders, CRT triggered an increase peripheral TCR clonality and clonal relatedness. Post-treatment expansion of baseline peripheral dominant TCRs was associated with response. Responders showed more baseline clustered structures of TCRs maintained post-treatment and displayed significantly more maintained clustered structures. When applying clustering by TCR-specificity methods, responders displayed a higher proportion of intra-tumoral TCRs predicted to recognise HPV16 peptides. Conclusions: Baseline TCR characteristics and changes in the peripheral T-cell clones triggered by CRT are associated with treatment outcome. Maintenance and boosting of pre-existing clonotypes are key elements of an effective anti-cancer immune response driven by CRT, supporting a paradigm in which the immune system plays a central role in the success of CRT in current standard-of-care protocols.

Quantitative analysis of diffusion weighted imaging in rectal cancer during radiotherapy using a magnetic resonance imaging integrated linear accelerator.

Background and purpose: Magnetic resonance imaging integrated linear accelerator (MR-Linac) platforms enable acquisition of diffusion weighted imaging (DWI) during treatment providing potential information about treatment response. Obtaining DWI on these platforms is technically different from diagnostic magnetic resonance imaging (MRI) scanners. The aim of this project was to determine feasibility of obtaining DWI and calculating apparent diffusion coefficient (ADC) parameters longitudinally in rectal cancer patients on the MR-Linac. Materials and methods: Nine patients undergoing treatment on MR-Linac had DWI acquired using b-values 0, 30, 150, 500 s/mm2. Gross tumour volume (GTV) and normal tissue was delineated on DWI throughout treatment and median ADC was calculated using an in-house tool (pyOsirix ®). Results: Seven out of nine patients were included in the analysis; all demonstrated downstaging at follow-up. A total of 63 out of 70 DWI were analysed (7 excluded due to poor image quality). An increasing trend of ADC median for GTV (1.15 × 10-3 mm2/s interquartile range (IQ): 1.05-1.17 vs 1.59 × 10-3 mm2/s IQ: 1.37 - 1.64; p = 0.0156), correlating to treatment response. In comparison ADC median for normal tissue remained the same between first and last fraction (1.61 × 10-3 mm2/s IQ: 1.56-1.71 vs 1.67 × 10-3 mm2/s IQ: 1.37-2.00; p = 0.9375). Conclusions: DWI assessment in rectal cancer patients on MR-Linac is feasible. Initial results provide foundations for further studies to determine DWI use for treatment adaptation in rectal cancer.

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.

Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial.

BACKGROUND: Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. METHODS: We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. FINDINGS: Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5-60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74-1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. CONCLUSION: DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375.

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.

Next Generation Sequencing Assay for Detection of Circulating HPV DNA (cHPV-DNA) in Patients Undergoing Radical (Chemo)Radiotherapy in Anal Squamous Cell Carcinoma (ASCC).

Background: Following chemo-radiotherapy (CRT) for human papilloma virus positive (HPV+) anal squamous cell carcinoma (ASCC), detection of residual/recurrent disease is challenging. Patients frequently undergo unnecessary repeated biopsies for abnormal MRI/clinical findings. In a pilot study we assessed the role of circulating HPV-DNA in identifying "true" residual disease. Methods: We prospectively collected plasma samples at baseline (n = 21) and 12 weeks post-CRT (n = 17). Circulating HPV-DNA (cHPV DNA) was measured using a novel next generation sequencing (NGS) assay, panHPV-detect, comprising of two primer pools covering distinct regions of eight high-risk HPV genomes (16, 18, 31, 33, 35, 45, 52, and 58) to detect circulating HPV-DNA (cHPV DNA). cHPV-DNA levels post-CRT were correlated to disease response. Results: In pre-CRT samples, panHPV-detect demonstrated 100% sensitivity and specificity for HPV associated ASCC. PanHPV-detect was able to demonstrate cHPV-DNA in 100% (9/9) patients with T1/T2N0 cancers. cHPV-DNA was detectable 12 weeks post CRT in just 2/17 patients, both of whom relapsed. 1/16 patients who had a clinical complete response (CR) at 3 months post-CRT but relapsed at 9 months and 1/1 patient with a partial response (PR). PanHPV-detect demonstrated 100% sensitivity and specificity in predicting response to CRT. Conclusion: We demonstrate that panHPV-detect, an NSG assay is a highly sensitive and specific test for the identification of cHPV-DNA in plasma at diagnosis. cHPV-DNA post-treatment may predict clinical response to CRT.

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.

Transoral robotic surgery for recurrent cancers of the upper aerodigestive tract-Systematic review and meta-analysis.

BACKGROUND: Transoral robotic surgery (TORS) for recurrent head and neck (H&N) cancer is an emerging but relatively infrequent procedure. METHODS: Systematic review and meta-analysis of studies reporting survival data and functional outcomes for patients undergoing TORS for previously treated H&N cancers. RESULTS: Eight hundred seventy-eight records were identified, of which eight were eligible for inclusion, covering 161 cases (range 1-64). The pooled rates were as follows: 2-year overall survival 73.8% (4 studies, range 70.6-75.0, 95% confidence intervals (CI) 65.4 to 81.5, [I2 0.0%, P = 1.0]); 2-year disease-free survival 74.8% (4 studies, range 56.2-92.0, 95% CI 63.3 to 84.8, [I2 36.9%, P = .2]); postoperative hemorrhage 9.3% (4 studies, range 3.3-13.3, 95% CI 4.7 to 15.1, [I2 0.0%, P = .5]). CONCLUSIONS: Functional and oncological outcomes are favorable, although the follow-up is limited in the literature. Larger cohorts with longer follow-up are needed for definitive conclusions to be drawn.

Realizing the potential of magnetic resonance image guided radiotherapy in gynaecological and rectal cancer.

CT-based radiotherapy workflow is limited by poor soft tissue definition in the pelvis and reliance on rigid registration methods. Current image-guided radiotherapy and adaptive radiotherapy models therefore have limited ability to improve clinical outcomes. The advent of MRI-guided radiotherapy solutions provides the opportunity to overcome these limitations with the potential to deliver online real-time MRI-based plan adaptation on a daily basis, a true "plan of the day." This review describes the application of MRI guided radiotherapy in two pelvic tumour sites likely to benefit from this approach.

Magnetic Resonance-based Response Assessment and Dose Adaptation in Human Papilloma Virus Positive Tumors of the Oropharynx treated with Radiotherapy (MR-ADAPTOR): An R-IDEAL stage 2a-2b/Bayesian phase II trial.

BACKGROUND: Current standard radiotherapy for oropharynx cancer (OPC) is associated with high rates of severe toxicities, shown to adversely impact patients' quality of life. Given excellent outcomes of human papilloma virus (HPV)-associated OPC and long-term survival of these typically young patients, treatment de-intensification aimed at improving survivorship while maintaining excellent disease control is now a central concern. The recent implementation of magnetic resonance image - guided radiotherapy (MRgRT) systems allows for individual tumor response assessment during treatment and offers possibility of personalized dose-reduction. In this 2-stage Bayesian phase II study, we propose to examine weekly radiotherapy dose-adaptation based on magnetic resonance imaging (MRI) evaluated tumor response. Individual patient's plan will be designed to optimize dose reduction to organs at risk and minimize locoregional failure probability based on serial MRI during RT. Our primary aim is to assess the non-inferiority of MRgRT dose adaptation for patients with low risk HPV-associated OPC compared to historical control, as measured by Bayesian posterior probability of locoregional control (LRC). METHODS: Patients with T1-2 N0-2b (as per AJCC 7th Edition) HPV-positive OPC, with lymph node <3 cm and <10 pack-year smoking history planned for curative radiotherapy alone to a dose of 70 Gy in 33 fractions will be eligible. All patients will undergo pre-treatment MRI and at least weekly intra-treatment MRI. Patients undergoing MRgRT will have weekly adaptation of high dose planning target volume based on gross tumor volume response. The stage 1 of this study will enroll 15 patients to MRgRT dose adaptation. If LRC at 6 months with MRgRT dose adaptation is found sufficiently safe as per the Bayesian model, stage 2 of the protocol will expand enrollment to an additional 60 patients, randomized to either MRgRT or standard IMRT. DISCUSSION: Multiple methods for safe treatment de-escalation in patients with HPV-positive OPC are currently being studied. By leveraging the ability of advanced MRI techniques to visualize tumor and soft tissues through the course of treatment, this protocol proposes a workflow for safe personalized radiation dose-reduction in good responders with radiosensitive tumors, while ensuring tumoricidal dose to more radioresistant tumors. MRgRT dose adaptation could translate in reduced long term radiation toxicities and improved survivorship while maintaining excellent LRC outcomes in favorable OPC. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03224000; Registration date: 07/21/2017.