Assessing the quality of patient-reported outcome measurements for gynecological cancers: a systematic review.

Aim: To provide perspective on patient-reported outcome measurement (PROM) instruments to adopt in patients diagnosed with gynecological cancers. Methods: A systematic search was conducted to identify PROMs developed for or applied in gynecological cancer populations. PROMs identified in more than one study subsequently underwent assessment according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) criteria. Results: Overall, 55 PROMs were identified within the gynecological cancer setting, and 20 were assessed according to COSMIN guidelines. Most PROMs had limited information reported, but a best fit approach was adopted to recommend a number of instruments for use in patients with gynecological cancer. Conclusion: Further study to assess the methodological quality of each PROM utilized in gynecological cancers is warranted to endorse the recommendations of this review.

Gynecological cancers are cancers which occur in the reproductive system of women. The cervical cancer screening program and development of new treatments mean that women with gynecological cancers are now living longer than before. However, these new treatments may have side effects that can affect the quality of life of women with cancer. Many care providers now agree that looking at women's quality of life during their gynecological cancer journey is an important part of their treatment. Patient-reported outcome measurements (PROMs) are questionnaires that the patient completes to measure their symptoms and quality of life. There are a lot of PROMs available to choose from, and it can be difficult to select one that is relevant and understandable for all women with gynecological cancer. This article searched the literature to find all PROMs that can be completed by women with gynecological cancer and then measured each of the PROM's quality. PROM quality was measured by looking at validity (whether the questionnaire measures what it is supposed to measure), reliability (that the questionnaire is not subject to different errors in measuring), and sensitivity (that the questionnaire can measure changes in questionnaire scores over time). Overall, this study found that there were a few PROMs that were of good enough quality to be completed by women with gynecological cancers. These questionnaires are called the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Cervical Cancer Module (EORTC QLQ-CX24), the Functional Assessment of Cancer Therapy - General (FACT-G), European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Endometrial Cancer (EORTC QLQ-EN24), Functional Assessment of Cancer Therapy Gynecologic Oncology Group ­ Neurotoxicity (FACT-GOG/Ntx), Functional Assessment of Cancer Therapy ­ Ovarian (FACT-O) and Female Sexual Function Index (FSFI). Each questionnaire can be filled out by women with different types of gynecological cancer, and the FSFI measures sexual problems that women may experience after cancer treatment.

Clinical outcomes in relapsed oropharyngeal cancer after definitive (chemo) radiotherapy.

OBJECTIVES: To report clinical outcomes of relapsed oropharyngeal squamous cell carcinoma (OPSCC) after definitive intensity-modulated (chemo)radiotherapy [(C)RT]. MATERIALS AND METHODS: Data for all relapsed patients treated for OPSCC with definitive (C)RT between 2010 and 2016 were collected. Primary end-point was post-failure survival (PFS). RESULTS: Overall, 273 OPSCC patients completed definitive (C)RT. Of these, 42 cases (n = 26 human papilloma virus (HPV)-negative; n = 16 HPV-positive) had relapsed (n = 23 persistent disease; n = 19 recurrent disease) and were included in the final analysis. Two-year PFS for the entire population was 30.6%; 20.5% for HPV-negative and 43.8% for HPV-positive patients. Salvage curative surgery was associated with a significantly higher 2 years PFS rate (56.2%) compared with palliative treatment (22.9%) and best supportive care (0%) (p < 0.001). A positive trend in 2 years PFS was recorded in the early complete response cases (49.5%) versus patients who did not achieve a complete response within 3 months of the end of (C)RT (23.0%) (p = 0.11). CONCLUSION: A higher PFS rate is achieved when relapsed OPSCC cases are treated with salvage curative intent. HPV-positive disease and early complete response within 3 months from the end of (C)RT may be related to better PFS.

An assessment of the use of patient reported outcome measurements (PROMs) in cancers of the pelvic abdominal cavity: identifying oncologic benefit and an evidence-practice gap in routine clinical practice.

BACKGROUND: Patient reported outcome measurements (PROMs) are emerging as an important component of patient management in the cancer setting, providing broad perspectives on patients' quality of life and experience. The use of PROMs is, however, generally limited to the context of randomised control trials, as healthcare services are challenged to sustain high quality of care whilst facing increasing demand and financial shortfalls. We performed a systematic review of the literature to identify any oncological benefit of using PROMs and investigate the wider impact on patient experience, in cancers of the pelvic abdominal cavity specifically. METHODS: A systematic review of the literature was conducted using MEDLINE (Pubmed) and Ovid Gateway (Embase and Ovid) until April 2020. Studies investigating the oncological outcomes of PROMs were deemed suitable for inclusion. RESULTS: A total of 21 studies were included from 2167 screened articles. Various domains of quality of life (QoL) were identified as potential prognosticators for oncologic outcomes in cancers of the pelvic abdominal cavity, independent of other clinicopathological features of disease: 3 studies identified global QoL as a prognostic factor, 6 studies identified physical and role functioning, and 2 studies highlighted fatigue. In addition to improved outcomes, a number of included studies also reported that the use of PROMs enhanced both patient-clinician communication and patient satisfaction with care in the clinical setting. CONCLUSIONS: This review highlights the necessity of routine collection of PROMs within the pelvic abdominal cancer setting to improve patient quality of life and outcomes.

Clinical evaluation of tumour-infiltrating lymphocytes as a prognostic factor in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma.

Clinical evaluation of tumour-infiltrating lymphocytes as a prognostic factor in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma AIMS: The majority of patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OpSCC) have favourable survival outcomes, but a significant minority of individuals will die of their disease. There are currently no definitive criteria with which to identify HPV-associated OpSCC patients with poor outcomes. Recent reports suggest that quantitative evaluation of T-cell subpopulations in OpSCC may be of prognostic value, but the methods used have limited utility in a clinical diagnostic setting. We therefore sought to determine the clinical prognostic utility of tumour-infiltrating lymphocyte (TIL) evaluation in patients with HPV-associated OpSCC within the context of a diagnostic histopathology setting. METHODS AND RESULTS: Representative diagnostic haematoxylin and eosin (H&E)-stained slides from 232 consecutive HPV-associated OpSCC patients were classified as containing a high (TILHi ; diffuse, lymphocytes in >80% of tumour and stroma), moderate (TILMod ; patchy, present in 20-80% of tumour and stroma) or low (TILLo ; sparse or absent, present in <20% of tumour and stroma) TILs. Interobserver reliability was assessed, and TIL category was then correlated with overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses showed statistically significant differences in OS and DFS estimates when TILHi and TILMod patients were compared with TILLo patients (P < 0.0001 for TILHi versus TILLo ; P < 0.0001 for TILMod versus TILLo ). Statistical significance was retained when TILHi and TILMod patients were grouped into a single category (TILHi ) and compared with TILLo patients (P < 0.0001). CONCLUSION: We demonstrate the prognostic utility of TILs in patients with HPV-associated OpSCC in clinical practice. A binary system classifying HPV-associated OpSCC into TILHi and TILLo on the basis of routine H&E staining stratifies patients into those with potentially favourable and unfavourable survival outcomes, respectively.

Association between hypoxic volume and underlying hypoxia-induced gene expression in oropharyngeal squamous cell carcinoma.

BACKGROUND: Hypoxia imaging is a promising tool for targeted therapy but the links between imaging features and underlying molecular characteristics of the tumour have not been investigated. The aim of this study was to compare hypoxia biomarkers and gene expression in oropharyngeal squamous cell carcinoma (OPSCC) diagnostic biopsies with hypoxia imaged with 64Cu-ATSM PET/CT. METHODS: 64Cu-ATSM imaging, molecular and clinical data were obtained for 15 patients. Primary tumour SUVmax, tumour to muscle ratio (TMR) and hypoxic volume were tested for association with reported hypoxia gene signatures in diagnostic biopsies. A putative gene signature for hypoxia in OPSCCs (hypoxic volume-associated gene signature (HVS)) was derived. RESULTS: Hypoxic volume was significantly associated with a reported hypoxia gene signature (rho=0.57, P=0.045), but SUVmax and TMR were not. Immunohistochemical staining with the hypoxia marker carbonic anhydrase 9 (CA9) was associated with a gene expression hypoxia response (rho=0.63, P=0.01). Sixteen genes were positively and five genes negatively associated with hypoxic volume (adjusted P<0.1; eight genes had adjusted P<0.05; HVS). This signature was associated with inferior 3-year progression-free survival (HR=1.5 (1.0-2.2), P=0.047) in an independent patient cohort. CONCLUSIONS: 64Cu-ATSM-defined hypoxic volume was associated with underlying hypoxia gene expression response. A 21-gene signature derived from hypoxic volume from patients with OPSCCs in our study may be linked to progression-free survival.

(18)F-FDG PET/CT to assess response and guide risk-stratified follow-up after chemoradiotherapy for oropharyngeal squamous cell carcinoma.

PURPOSE: To evaluate the use of (18)F-FDG PET/CT as the principal investigation to assess tumour response, to determine the need for further surgery and to guide follow-up following radical chemoradiotherapy for stage III/IV oropharyngeal squamous cell carcinoma (OPSCC). METHODS: A retrospective analysis was undertaken in 146 patients treated at our centre with radical chemoradiotherapy for OPSCC and who had a PET/CT scan to assess response. According to the PET/CT findings, patients were divided into four groups and recommendations: (1) complete metabolic response (enter clinical follow-up); (2) low-level uptake only (follow-up PET/CT scan in 12 weeks); (3) residual uptake suspicious for residual disease (further investigation with or without neck dissection); and (4) new diagnosis of distant metastatic disease (palliative treatment options). RESULTS: The initial PET/CT scan was performed at a median of 12.4 weeks (range 4.3 - 21.7 weeks) following treatment. Overall sensitivity and specificity rates were 92.0 % (74.0 - 99.0 %) and 85 % (77.5 - 90.9 %). Of the 146 patients, 90 (62 %) had a complete response and had estimated 3-year overall and disease-free survival rates of 91.9 % (85.6 - 98.2 %) and 85.6 % (78.0 - 93.2 %), respectively, 17 (12 %) had residual low-level uptake only (with two having confirmed residual disease on subsequent PET/CT, both surgically salvaged), 30 (21 %) had suspicious residual uptake (12 proceeded to neck dissection; true positive rate at surgery 33 %). HPV-positive patients with reassuring PET/CT findings had an estimated 3-year progression-free survival rate of 91.7 % (85.2 - 98.2 %), compared with 66.2 % (41.5 - 90.9 %) of HPV-negative patients. CONCLUSION: A strategy of using PET/CT results alongside clinical examination to help select patients for salvage surgery appears successful. Despite a complete response on the 12-week PET/CT scan, HPV-negative patients have a significant risk of disease relapse in the following 2 years and further studies to assess whether surveillance imaging in this group could improve outcomes are warranted.

Factors predictive of outcome following primary total laryngectomy for advanced squamous cell carcinoma.

The increasing use of primary chemoradiation (CRT) for laryngeal squamous cell carcinoma (SCC) means that historical surgical data sets are not representative of the modern laryngectomy patient. We analyse a contemporary total laryngectomy (TL) cohort to identify factors predictive of outcome. This is a retrospective consecutive case note review in a UK tertiary referral centre. Demographic, staging, treatment and outcome data were collected. Oncological outcomes are expressed using the Kaplan-Meier method. The log-rank test was used for univariate analysis and cox regression for multivariate analysis. Sixty consecutive patients between 2003 and 2010 underwent primary TL, 28 including partial pharyngectomy. Median age was 61 years and mean follow-up was 24 months (1-78 months). Thirty six patients died during the study period, 24 of their disease. Of the disease-specific deaths, two occurred peri-operatively, four from local, two from regional and 18 from distant disease [two patients had simultaneous local and distant recurrence (DR)]. Five-year overall survival, disease-specific survival, loco-regional recurrence-free survival and distant recurrence-free survival (DRFS) were 36, 51, 87, 62 %, respectively. Of 17 parameters analysed, pN-stage, extra-capsular spread, a non-cohesive tumour front, thyroid infiltration and involvement of level 6 were significant predictors of disease-specific survival (DSS) on univariate analysis. pN > 1 and the presence of adverse histological features were found to be independent predictors of DSS and DRFS on multivariate analysis. Neither was significantly associated with loco-regional recurrence-free survival. Around half of patients who undergo TL for stage IV SCC will die of disease within 5 years, with most deaths attributable to DR. Surgery provides excellent loco-regional control but patients, especially those with advanced nodal disease and/or adverse histological features, should be thoroughly screened for occult distant disease. Level of evidence 4.

Effect of synthetic CT on dose-derived toxicity predictors for MR-only prostate radiotherapy.

Objectives: Toxicity-driven adaptive radiotherapy (RT) is enhanced by the superior soft tissue contrast of magnetic resonance (MR) imaging compared with conventional computed tomography (CT). However, in an MR-only RT pathway synthetic CTs (sCT) are required for dose calculation. This study evaluates 3 sCT approaches for accurate rectal toxicity prediction in prostate RT. Methods: Thirty-six patients had MR (T2-weighted acquisition optimized for anatomical delineation, and T1-Dixon) with same day standard-of-care planning CT for prostate RT. Multiple sCT were created per patient using bulk density (BD), tissue stratification (TS, from T1-Dixon) and deep-learning (DL) artificial intelligence (AI) (from T2-weighted) approaches for dose distribution calculation and creation of rectal dose volume histograms (DVH) and dose surface maps (DSM) to assess grade-2 (G2) rectal bleeding risk. Results: Maximum absolute errors using sCT for DVH-based G2 rectal bleeding risk (risk range 1.6% to 6.1%) were 0.6% (BD), 0.3% (TS) and 0.1% (DL). DSM-derived risk prediction errors followed a similar pattern. DL sCT has voxel-wise density generated from T2-weighted MR and improved accuracy for both risk-prediction methods. Conclusions: DL improves dosimetric and predicted risk calculation accuracy. Both TS and DL methods are clinically suitable for sCT generation in toxicity-guided RT, however, DL offers increased accuracy and offers efficiencies by removing the need for T1-Dixon MR. Advances in knowledge: This study demonstrates novel insights regarding the effect of sCT on predictive toxicity metrics, demonstrating clear accuracy improvement with increased sCT resolution. Accuracy of toxicity calculation in MR-only RT should be assessed for all treatment sites where dose to critical structures will guide adaptive-RT strategies. Clinical trial registration number: Patient data were taken from an ethically approved (UK Health Research Authority) clinical trial run at Guy's and St Thomas' NHS Foundation Trust. Study Name: MR-simulation in Radiotherapy for Prostate Cancer. ClinicalTrials.gov Identifier: NCT03238170.

Pre-operative tracheostomy does not impact on stomal recurrence and overall survival in patients undergoing primary laryngectomy.

Pre-operative tracheostomy (POT) to secure a critical airway up to several weeks before definitive laryngectomy in patients with laryngeal cancer has been proposed as a risk factor for poor oncologic outcome. Few modern papers, however, examine this question. The aim of this study is therefore to determine whether POT affects oncologic outcome with an emphasis on stomal/peristomal recurrence. This is a retrospective case note review of 60 consecutive patients undergoing curative primary total laryngectomy (TL) for advanced laryngeal squamous cell carcinoma (SCC). Demographic, staging, treatment and outcome data were collected. 27/60 (45 %) patients had POT and 33/60 did not. No patient underwent laser debulking. Median age was 62 years (39-90 years) and median follow-up of survivors was 31 months. 5-year overall survival (OS), disease-specific survival (DSS) and local recurrence-free survival (LRFS) of patients undergoing POT versus no POT was 28 versus 39 % (p = 0.947), 55 versus 46 % (p = 0.201) and 96 versus 88 % (p = 0.324) respectively. No statistically significant difference in OS, DSS and LRFS was found between patients undergoing POT and those not. Despite the relatively small case series, this evidence should reassure surgeons without the ability to perform trans-oral debulking that they should not hesitate to perform tracheostomy on a patient with airway obstruction due to laryngeal cancer. Appropriate definitive treatment meant that POT was not a risk factor for poor oncological outcome in our series.

Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study.

BACKGROUND: Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αß, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues. METHODS: We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1-4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107-1×109 T4+ T-cells, administered without prior lymphodepletion. RESULTS: Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product. CONCLUSIONS: These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.

Fully-automated, CT-only GTV contouring for palliative head and neck radiotherapy.

Planning for palliative radiotherapy is performed without the advantage of MR or PET imaging in many clinics. Here, we investigated CT-only GTV delineation for palliative treatment of head and neck cancer. Two multi-institutional datasets of palliative-intent treatment plans were retrospectively acquired: a set of 102 non-contrast-enhanced CTs and a set of 96 contrast-enhanced CTs. The nnU-Net auto-segmentation network was chosen for its strength in medical image segmentation, and five approaches separately trained: (1) heuristic-cropped, non-contrast images with a single GTV channel, (2) cropping around a manually-placed point in the tumor center for non-contrast images with a single GTV channel, (3) contrast-enhanced images with a single GTV channel, (4) contrast-enhanced images with separate primary and nodal GTV channels, and (5) contrast-enhanced images along with synthetic MR images with separate primary and nodal GTV channels. Median Dice similarity coefficient ranged from 0.6 to 0.7, surface Dice from 0.30 to 0.56, and 95th Hausdorff distance from 14.7 to 19.7 mm across the five approaches. Only surface Dice exhibited statistically-significant difference across these five approaches using a two-tailed Wilcoxon Rank-Sum test (p ≤ 0.05). Our CT-only results met or exceeded published values for head and neck GTV autocontouring using multi-modality images. However, significant edits would be necessary before clinical use in palliative radiotherapy.

The impact of Human Papilloma Virus status on the prediction of head and neck cancer chemoradiotherapy outcomes using the pre-treatment apparent diffusion coefficient.

OBJECTIVE: To determine the impact of Human Papilloma Virus (HPV) oropharyngeal cancer (OPC) status on the prediction of head and neck squamous cell cancer (HNSCC) chemoradiotherapy (CRT) outcomes with pre-treatment quantitative diffusion-weighted magnetic resonance imaging (DW-MRI). METHODS: Following ethical approval, 65 participants (53 male, age 59.9 ± 7.86) underwent pre-treatment DW-MRI in this prospective cohort observational study. There were 46 HPV OPC and 19 other HNSCC cases with Stage III/IV HNSCC. Regions of interest (ROIs) (volume, largest area, core) at the primary tumour (n = 57) and largest pathological node (n = 59) were placed to analyse ADCmean and ADCmin. Unpaired t-test or Mann-Whitney test evaluated the impact of HPV OPC status and clinical parameters on their prediction of post-CRT 2 year locoregional and disease-free survival (LRFS and DFS). Multivariate logistic regression compared significant variables with 2 year outcomes. RESULTS: On univariate analysis of all participants, the primary tumour area ADCmean was predictive of 2 year LRFS (p = 0.04). However, only the HPV OPC diagnosis (LFRS p = 0.03; DFS p = 0.02) predicted outcomes on multivariate analysis. None of the pre-treatment ADC values were predictive of 2 year DFS in the HPV OPC subgroup (p = 0.21-0.68). Amongst participants without 2 year disease-free survival, HPV-OPC was found to have much lower primary tumour ADCmean values than other HNSCC. CONCLUSION: Knowledge of HPV OPC status is required in order to determine the impact of the pre-treatment ADC values on post-CRT outcomes in HNSCC. ADVANCES IN KNOWLEDGE: Pre-treatment ADCmean and ADCmin values acquired using different ROI methods are not predictive of 2 year survival outcomes in HPV OPC.

Neural network dose prediction for rectal spacer stratification in dose-escalated prostate radiotherapy.

PURPOSE: To develop a knowledge-based decision-support system capable of stratifying patients for rectal spacer (RS) insertion based on neural network predicted rectal dose, reducing the need for time- and resource-intensive radiotherapy (RT) planning. METHODS: Forty-four patients treated for prostate cancer were enrolled into a clinical trial (NCT03238170). Dose-escalated prostate RT plans were manually created for 30 patients with simulated boost volumes using a conventional treatment planning system (TPS) and used to train a hierarchically dense 3D convolutional neural network to rapidly predict RT dose distributions. The network was used to predict rectal doses for 14 unseen test patients, with associated toxicity risks calculated according to published data. All metrics obtained using the network were compared to conventionally planned values. RESULTS: The neural network stratified patients with an accuracy of 100% based on optimal rectal dose-volume histogram constraints and 78.6% based on mandatory constraints. The network predicted dose-derived grade 2 rectal bleeding risk within 95% confidence limits of -1.9% to +1.7% of conventional risk estimates (risk range 3.5%-9.9%) and late grade 2 fecal incontinence risk within -0.8% to +1.5% (risk range 2.3%-5.7%). Prediction of high-resolution 3D dose distributions took 0.7 s. CONCLUSIONS: The feasibility of using a neural network to provide rapid decision support for RS insertion prior to RT has been demonstrated, and the potential for time and resource savings highlighted. Directly after target and healthy tissue delineation, the network is able to (i) risk stratify most patients with a high degree of accuracy to prioritize which patients would likely derive greatest benefit from RS insertion and (ii) identify patients close to the stratification threshold who would require conventional planning.

The microbiota and radiotherapy for head and neck cancer: What should clinical oncologists know?

Radiotherapy is a linchpin in head and neck squamous cell carcinoma (HN-SCC) treatment. Modulating tumour and/or normal tissue biology offers opportunities to further develop HN-SCC radiotherapy. The microbiota, which can exhibit homeostatic properties and be a modulator of immunity, has recently received considerable interest from the Oncology community. Microbiota research in head and neck oncology has also flourished. However, available data are difficult to interpret for clinical and radiation oncologists. In this review, we focus on how microbiota research can contribute to the improvement of radiotherapy for HN-SCC, focusing on how current and future research can be translated back to the clinic. We include in-depth discussions about the microbiota, its multiple habitats and relevance to human physiology, mechanistic interactions with HN-SCC, available evidence on microbiota and HNC oncogenesis, efficacy and toxicity of treatment. We discuss clinically-relevant areas such as the role of the microbiota as a predictive and prognostic biomarker, as well as the potential of leveraging the microbiota and its interactions with immunity to improve treatment results. Importantly, we draw parallels with other cancers where research is more mature. We map out future directions of research and explain clinical implications in detail.

Comparison of machine learning methods for prediction of osteoradionecrosis incidence in patients with head and neck cancer.

OBJECTIVES: Mandible osteoradionecrosis (ORN) is one of the most severe toxicities in patients with head and neck cancer (HNC) undergoing radiotherapy (RT). The existing literature focuses on the correlation of mandible ORN and clinical and dosimetric factors. This study proposes the use of machine learning (ML) methods as prediction models for mandible ORN incidence. METHODS: A total of 96 patients (ORN incidence ratio of 1:1) treated between 2011 and 2015 were selected from the local HNC toxicity database. Demographic, clinical and dosimetric data (based on the mandible dose-volume histogram) were considered as model variables. Prediction accuracy (measured using a stratified fivefold nested cross-validation), sensitivity, specificity, precision and negative predictive value were used to evaluate the prediction performance of a multivariate logistic regression (LR) model, a support vector machine (SVM) model, a random forest (RF) model, an adaptive boosting (AdaBoost) model and an artificial neural network (ANN) model. The different models were compared based on their prediction accuracy and using the McNemar's hypothesis test. RESULTS: The ANN model (77% accuracy), closely followed by the SVM (76%), AdaBoost (75%) and LR (75%) models, showed the highest overall prediction accuracy. The RF model (71%) showed the lowest prediction accuracy. However, based on the McNemar's test applied to all model pair combinations, no statistically significant difference between the models was found. CONCLUSION: Based on our results, we encourage the use of ML-based prediction models for ORN incidence as has already been done for other HNC toxicity end points. ADVANCES IN KNOWLEDGE: This research opens a new path towards personalised RT for HNC using ML to predict mandible ORN incidence.

Risk stratified follow up for head and neck cancer patients - An evidence based proposal.

Head and neck squamous cell carcinoma (HNSCC) has a significant impact on patients' quality of life and treatment can be associated with severe morbidity. Following completion of treatment, patients are followed up in order to detect potentially salvageable recurrences and to manage long-term toxicities. In recent years, a growing interest has been given to risk stratified follow-up interventions to prevent and detect recurrences and manage treatment toxicities in other tumour sites as well as to transfer some of that care to community services. We review the literature for HNSCC and propose a risk stratified follow up protocol to address these issues and assist clinicians in decision making. A shift in patterns of care is suggested in order to provide a basis to improve care for HNSCC patients after complete response to primary treatment.

TNM 8 staging is a better prognosticator than TNM 7 for patients with locally advanced oral cavity squamous cell carcinoma treated with surgery and post-operative radiotherapy.

PURPOSE: To assess TNM 8 staging in discriminating overall survival (OS) amongst patients with locally advanced oral cavity squamous cell carcinoma (OCSCC) treated with surgery and post-operative radiotherapy (PORT), compared to TNM 7. MATERIAL AND METHODS: Data from OCSCC patients treated with surgery and PORT between January 2010 and December 2018 were reviewed. Demographics, tumour characteristics and treatment response data were collected, and patients staged according to both TNM 7 and TNM 8. OS and disease free survival (DFS) were estimated using the Kaplan Meier method. Univariate and multivariable analyses were conducted for factors affecting OS, DFS and early disease recurrence within 12 months. RESULTS: Overall 172 patients were analyzed. Median follow up was 32 months for all patients and 48 months for surviving patients. TNM 8 staging demonstrated significant stratification of OS and DFS amongst the entire cohort, whereas TNM 7 staging did not. On multivariable analysis, TNM 8 stage, performance status (PS) and a positive surgical margin were prognostic for OS. Looking at disease recurrence within 12 months, TNM 8 stage IVB, presence of lymphovascular invasion (LVSI), younger age and lesser smoking history were predictive factors on multivariable analysis. CONCLUSION: TNM 8 is a good development of its predecessor in terms of predicting survival for patients with locally advanced OCSCC. We have also identified younger age (<60 years) and a smoking history of <10 pack years as risk factors for early disease recurrence, potentially representing a separate biological cohort within OCSCC patients.

Guidance on the use of MRI for treatment planning in radiotherapy clinical trials.

The aim of this article is to propose meaningful guidance covering the technical and safety issues involved when designing or conducting radiotherapy clinical trials that use MRI for treatment planning. The complexity of imaging requirements will depend on the trial aims, design and MRI methods used.The use of MRI within the RT pathway is becoming more prevalent and clinically appropriate as access to MRI increases, treatment planning systems become more versatile and potential indications for MRI-planning in RT are documented. Novel MRI-planning opportunities are often initiated and validated within clinical trials.The guidance in this document is intended to assist researchers designing RT clinical trials involving MRI, so that they may provide sufficient information about the appropriate methods to be used for image acquisition, post-processing and quality assurance such that participating sites complete MRI to consistent standards. It has been produced in collaboration with the National Radiotherapy Trials Quality Assurance Group (RTTQA).As the use of MRI in RT is developed, it is highly recommended for researchers writing clinical trial protocols to include imaging guidance as part of their clinical trial documentation covering the trial-specific requirements for MRI procedures. Many of the considerations and recommendations in this guidance may well apply to MR-guided treatment machines, where clinical trials will be crucial. Similarly, many of these recommendations will apply to the general use of MRI in RT, outside of clinical trials.This document contains a large number of recommendations, not all of which will be relevant to any particular trial. Designers of RT clinical trials must therefore take this into account. They must also use their own judgement as to the appropriate compromise between accessibility of the trial and its technical rigour.

Analyzing oropharyngeal cancer survival outcomes: a decision tree approach.

OBJECTIVES: To analyze survival outcomes in patients with oropharygeal cancer treated with primary intensity modulated radiotherapy (IMRT) using decision tree algorithms. METHODS: A total of 273 patients with newly diagnosed oropharyngeal cancer were identified between March 2010 and December 2016. The data set contained nine predictor variables and a dependent variable (overall survival (OS) status). The open-source R software was used. Survival outcomes were estimated by Kaplan-Meier method. Important explanatory variables were selected using the random forest approach. A classification tree that optimally partitioned patients with different OS rates was then built. RESULTS: The 5 year OS for the entire population was 78.1%. The top three important variables identified were HPV status, N stage and early complete response to treatment. Patients were partitioned in five groups on the basis of these explanatory variables. CONCLUSION: The proposed classification tree could help to guide future research in oropharyngeal cancer field. ADVANCES IN KNOWLEDGE: Decision tree method seems to be an appropriate tool to partition oropharyngeal cancer patients.

Pre-radiotherapy dental status of oropharyngeal cancer patients based on HPV status in a novel radiation era.

Objectives Among common head and neck cancers (HNCs), oropharyngeal cancer (OPC) patients have been identified as having a better dentition than many other tumour subsites. OPC consists of human papillomavirus (HPV)-positive and negative groups with different prognosis. The purpose of this study is to explore the presenting dental status of OPC patients based on HPV status at the pre-radiotherapy phase.Materials and methods The study reviewed the dental panoramic radiographs of OPC patients seen at a dedicated pre-radiotherapy dental assessment clinic from 2011-2017. Only patients planned for intensity-modulated radiotherapy treatment were included within this study. Relevant dental and oncological data were collected.Results A total of 316 patients with known HPV status (215 positive; 101 negative) were included for analysis. HPV-positive patients had significantly more teeth on attendance than HPV-negative patients (22.3 vs 19.0, p = 0.0000) and horizontal bone loss was less severe compared to HPV-negative patients (p = 0.0000). HPV-positive males and patients in the 55-64 decade presented with the best and most complex dentition.Conclusion The rise of OPC with the prospect of long survival, particularly in HPV-positive patients, requires a dentition with adequate function and subsequent maintenance. The current study demonstrated that these patients have a complex dentition presenting new challenges to the dentist. This may explain in part the elevated osteoradionecrosis rate seen in this tumour group.