Dynamic nomogram for long-term survival in patients with locally advanced oropharyngeal cancer after (chemo)radiotherapy.

PURPOSE: This study aimed to establish a nomogram for predicting overall survival (OS) in oropharyngeal cancer patients treated with curative (chemo)radiotherapy. MATERIALS AND METHODS: The dynamic nomogram was constructed on 273 patients with oropharyngeal squamous cell carcinoma treated in a Tertiary Head and Neck Cancer Unit. The clinical features that were previously reported to be associated with OS were analyzed. The performance of the nomogram was assessed using concordance index (C-index) and calibration curves. RESULTS: The nomogram incorporated three explanatory variables derived from a decision tree approach including HPV status, N classification according to 8th edition TNM and early response to (chemo)radiotherapy. The nomogram was capable to predict OS with a validation C-index of 0.768. The proposed stratification in risk groups allowed significant distinction between Kaplan-Meier curves for OS outcome (p < 0.0001). CONCLUSIONS: The nomogram provided an accurate evaluation of OS for oropharyngeal cancer patients treated with curative (chemo)radiotherapy.

Palatine tonsil SUVmax on FDG PET-CT as a discriminator between benign and malignant tonsils in patients with and without head and neck squamous cell carcinoma of unknown primary.

AIM: To analyse the maximum standardised uptake value (SUVmax) ratio between tonsils in patients with and without tonsillar carcinoma to determine useful diagnostic thresholds. MATERIALS AND METHODS: Positron-emission tomography (PET)/computed tomography (CT) examinations of patients with suspected head and neck squamous cell carcinoma (SCC) and controls from April 2013 to September 2016 were reviewed retrospectively. Tonsillar SUVmax ratios (ipsilateral/contralateral for malignant tonsils, maximum/minimum for patients without [controls]) were calculated and used to construct a receiver operating characteristic (ROC) curve. RESULTS: Twenty-five patients had tonsillar carcinoma (mean SUVmax ratio of 2, range 0.89-5.4) and 86 patients acted as controls (mean SUVmax ratio of 1.1, range 1-1.5). Using the ROC, the most accurate SUVmax ratio for identifying malignancy was >1.2 (77% sensitivity, 86% specificity). A potentially more clinically useful SUVmax ratio is ≥1.6 with 62% sensitivity and 100% specificity. CONCLUSION: An SUVmax ratio between tonsils of ≥1.6 is highly suspicious for SCC and could be used to direct site of biopsy. Some malignant tonsils had normal FDG uptake; therefore, PET/CT should not be used to exclude tonsillar cancer. Minor asymmetrical uptake is frequently seen in non-malignant tonsils and does not necessarily require further investigation. Due to the single centre nature of this study and the recognised variation in SUV measurements between PET scans, other centres may need to develop their own cut-offs.

Outcomes of intensity-modulated radiotherapy as primary treatment for oropharyngeal squamous cell carcinoma - a European singleinstitution analysis.

OBJECTIVES: To analyse survival and toxicity outcomes in patients treated with primary intensity-modulated radiotherapy (IMRT) for oropharyngeal squamous cell carcinoma (OPSCC) in the era of routine human papilloma virus (HPV) testing. DESIGN: Single-institution case series. SETTING: Tertiary Head and Neck Cancer Unit. PARTICIPANTS: A total of 186 patients received IMRT (+/- chemotherapy) for radical primary treatment of OPSCC between March 2010 and December 2013. HPV status was available for 88% of cases. Median radiation dose was 65 Gy in 30 daily fractions. 90% of stage III/IV patients received concurrent chemotherapy or cetuximab. MAIN OUTCOME MEASURES: Overall, disease-free and disease-specific survival; rates of late xerostomia and dysphagia. RESULTS: A total of 177 patients completed treatment (Stage I/II: 23; Stage III/IV: 154), with median follow-up of 26 months. Estimated 3-year overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS) rates were 77.2% (70.5-83.9), 72.3% (65.4-79.2) and 80.2% (74.1-86.3). Estimated 3-year OS, DFS and DSS for HPV-positive patients were 90.9% (85.2-96.6), 87.9% (81.4-94.4) and 91.8% (86.3-97.3). A previously identified risk stratification method was validated, showing improved OS for low-risk over high-risk patients (HR 0.09, P < 0.001). The 2-year feeding tube retention rate was 6%, and 2-year grade ≥2 xerostomia rate was 38% (23% if mean contralateral parotid dose <24 Gy). CONCLUSIONS: Outcomes with IMRT are favourable, particularly in the HPV-positive patient group. This data further supports the use of a previously described prognostication model that can be used to select patients for escalation/de-escalation clinical trials.

The Impact of Interactive MRI-Based Radiologist Review on Radiotherapy Target Volume Delineation in Head and Neck Cancer.

BACKGROUND AND PURPOSE: Peer review of head and neck cancer radiation therapy target volumes by radiologists was introduced in our center to optimize target volume delineation. Our aim was to assess the impact of MR imaging-based radiologist peer review of head and neck radiation therapy gross tumor and nodal volumes, through qualitative and quantitative analysis. MATERIALS AND METHODS: Cases undergoing radical radiation therapy with a coregistered MR imaging, between April 2019 and March 2020, were reviewed. The frequency and nature of volume changes were documented, with major changes classified as per the guidance of The Royal College of Radiologists. Volumetric alignment was assessed using the Dice similarity coefficient, Jaccard index, and Hausdorff distance. RESULTS: Fifty cases were reviewed between April 2019 and March 2020. The median age was 59 years (range, 29-83 years), and 72% were men. Seventy-six percent of gross tumor volumes and 41.5% of gross nodal volumes were altered, with 54.8% of gross tumor volume and 66.6% of gross nodal volume alterations classified as "major." Undercontouring of soft-tissue involvement and unidentified lymph nodes were predominant reasons for change. Radiologist review significantly altered the size of both the gross tumor volume (P = .034) and clinical target tumor volume (P = .003), but not gross nodal volume or clinical target nodal volume. The median conformity and surface distance metrics were the following: gross tumor volume Dice similarity coefficient = 0.93 (range, 0.82-0.96), Jaccard index = 0.87 (range, 0.7-0.94), Hausdorff distance = 7.45 mm (range, 5.6-11.7 mm); and gross nodular tumor volume Dice similarity coefficient = 0.95 (0.91-0.97), Jaccard index = 0.91 (0.83-0.95), and Hausdorff distance = 20.7 mm (range, 12.6-41.6). Conformity improved on gross tumor volume-to-clinical target tumor volume expansion (Dice similarity coefficient = 0.93 versus 0.95, P = .003). CONCLUSIONS: MR imaging-based radiologist review resulted in major changes to most radiotherapy target volumes and significant changes in volume size of both gross tumor volume and clinical target tumor volume, suggesting that this is a fundamental step in the radiotherapy workflow of patients with head and neck cancer.

The ability of post-chemoradiotherapy DWI ADCmean and 18F-FDG SUVmax to predict treatment outcomes in head and neck cancer: impact of human papilloma virus oropharyngeal cancer status.

OBJECTIVES: To evaluate the ability of post-chemo-radiotherapy (CRT) diffusion-weighted-MRI apparent diffusion coefficient (ADCmean) and 18F-FDG PET maximum standardized uptake value (SUVmax) to predict disease-free survival (DFS) in head and neck squamous cell carcinoma (HNSCC), and to determine whether this ability is influenced by human papillomavirus oropharyngeal cancer (HPV-OPC) status. METHODS: This prospective cohort observational study included 65 participants (53 male, mean ± SD age 59.9 ± 7.9 years, 46 HPV-OPC) with stage III or IV HNSCC. Primary tumour and nodal ADCmean (pre-treatment, 6- and 12-weeks post-CRT) and SUVmax (12-weeks post-CRT) were measured. Variables were compared with 2-year DFS (independent t-test/Mann-Whitney test) and overall DFS (Cox regression), before and after accounting for HPV-OPC status. Variables were also compared between HPV-OPC and other HNSCC subgroups after stratifying for DFS. RESULTS: Absolute post-CRT ADCmean values predicted 2-year DFS and overall DFS for all participants (p = 0.03/0.03, 6-week node; p = 0.02/0.03 12-week primary tumour) but not in the HPV-OPC subgroup. In participants with DFS, percentage interval changes in primary tumour ADCmean at 6- and 12-weeks were higher in HPV-OPC than other HNSCC (p = 0.01, 6 weeks; p = 0.005, 12 weeks). The 12-week post-CRT SUVmax did not predict DFS. CONCLUSION: Absolute post-CRT ADCmean values predicted DFS in HNSCC but not in the HPV-OPC subgroup. Amongst participants with DFS, post-CRT percentage interval changes in primary tumour ADCmean were significantly higher in HPV-OPC than in other HNSCC. Knowledge of HPV-OPC status is crucial to the clinical utilisation of post-CRT DWI-MRI for the prediction of outcomes.

18F-FDG-PET in guided dose-painting with intensity modulated radiotherapy in oropharyngeal tumours: A phase I study (FiGaRO).

BACKGROUND AND PURPOSE: The FiGaRO trial assessed the feasibility and safety of using an FDG-PET-based dose-painting technique to deliver a radiotherapy (RT) boostto the FDG-avid primary tumour in patients with locally advanced high and intermediate risk oropharyngeal cancer. MATERIALS AND METHOD: Patients underwent a planning 18FDG-PET-CT scan, immobilised in the treatment position, after one cycle of induction chemotherapy. The volume of persistent FDG-avidity in the primary tumour was escalated to 71.5 Gy in30 fractions delivered using a simultaneous integrated boost Intensity Modulated RT (SIB-IMRT) technique. RT was delivered with concomitant Cisplatin following 2 cycles of induction chemotherapy. The primary outcome was the incidence of grade ≥ 3 late mucosal toxicity 12 months post-treatment, with an excess rate of >10% regarded as unacceptable. RESULTS: Twenty-nine patients were included and twenty-four were treated between 2014 and 2018, in two UK centres. Median follow-up was 36 months (range 4-56 months). Pre-defined planning target volume objectives and organ at risk dose constraints were met in all cases. There were no incidents of acute grade 4 toxicity. There were 4 cases of grade ≥ 3 mucosal toxicity at 12 months post-treatment (19.1%). There were no cases of persistent mucosal ulceration at 12 months. Overall survival at 3-years was 87.5%, 92.9% for intermediate and 70.0% for high risk patients. CONCLUSION: Late toxicity rates, although higher than anticipated, are comparable to contemporary published data for standard dose chemo-IMRT. Results suggest improved 3y survival rates for high risk patients. This approach merits further investigation. ClinicalTrials.gov Identifier: NCT02953197.

Radical (chemo)radiotherapy in oropharyngeal squamous cell carcinoma: Comparison of TNM 7th and 8th staging systems.

PURPOSE: To evaluate whether the 8th staging system is a better discriminator of overall survival (OS) than the 7th edition for oropharyngeal cancer patients after definitive (chemo)radiotherapy (CRT). MATERIAL AND METHODS: Data from oropharyngeal cancer patients treated with CRT with curative intent between 2010 and 2016 at Guy's and St Thomas' Hospitals were reviewed. Human papillomavirus (HPV) status was ascertained in all cases. Patients were staged using the 7th edition and the 8th edition TNM staging system. Demographics, tumor characteristics and treatment response data were included in univariate and multivariate analysis for OS. OS and disease-free survival (DFS) were estimated using the Kaplan-Meier method. In addition, a multivariate survival Cox regression analysis of several clinical variables was performed. RESULTS: A total of 273 patients were included. The median follow-up was 4.7 years. Overall 63 patients died. In multivariate analysis, HPV status, complete response at 3 months and ≤21 units/week alcohol were prognostic for OS. For the entire cohort, the 5-year OS and DFS rates were 78.1% (95% confidence interval CI 0.719-0.831) and 73.9% (95% CI 0.677-0.792), respectively. Better stratification of OS and DFS was recorded by 8th edition for the entire cohort. In HPV-positive cases, risk stratification based on tobacco smoking and nodal stage resulted in statistically higher discrimination in OS rates (5-year OS 90.7% in low risk patients and 84.6% in intermediate risk, p = 0.05) and DFS rates (5-year DFS 91.5% in low risk and 76.1% in intermediate risk, p = 0.001). CONCLUSION: The 8th edition TNM staging system provides better OS stratification in oropharyngeal cancer after definitive CRT compared with the 7th edition. Other clinical variables, such as complete response at 3 months, alcohol and tobacco smoking, should also be considered in future classifications as they provide additional risk stratification information in both HPV-positive and HPV-negative disease.

Accelerated chemotherapy in the treatment of urothelial cancer.

To evaluate an alternative treatment for advanced or metastatic urothelial cancers, a dose-intensive combination chemotherapy regimen using carboplatin, methotrexate, vincristine and cisplatin was given to 60 patients over a 3-year period (1990 to 1993). There were 26 patients with locally advanced disease and 34 with metastatic disease; 49 patients were evaluable for response. A complete response was noted in four patients (8%) and a partial response in 15 (31%), for an overall response rate of 39%. The median survival was 12 months. Two- and 5-year survival rates were 25.5% (95% confidence interval CI) 15.2-37.0) and 7.3% (95% CI 2.2-16.4) respectively. Failure-free survival was 15.3% (95% CI 7.5-25.6) at 2 years and 5.9% (95% CI 1.6-14.4) at 5 years, with a median of 8 months. For the responders, the median duration of response was 14 months, with a range of 2-59+ months. Toxicity included myelosuppression (28% grade 4/5 neutropenia, 19% grade 4 thrombocytopenia), peripheral neuropathy (54% grade 1 and 23% grade 2/3) and ototoxicity (21% grade 1, 19% grade 2). This schedule of dose-intensified platinum-based chemotherapy for bladder cancer resulted in significant neurotoxicity without evidence of enhanced response rates or survival. Regimens such as methotrexate, vinblastine, doxorubicin and cisplatin should remain standard. Accelerated regimens may be useful in situations were it is necessary to administer chemotherapy over a short time (e.g. as part of combined modality treatment).

Clinical update on cancer: molecular oncology of head and neck cancer.

Head and neck cancers encompass a heterogeneous group of tumours that, in general, are biologically aggressive in nature. These cancers remain difficult to treat and treatment can cause severe, long-term side effects. For patients who are not cured by surgery and/or (chemo)radiotherapy, there are few effective treatment options. Targeted therapies and predictive biomarkers are urgently needed in order to improve the management and minimise the treatment toxicity, and to allow selection of patients who are likely to benefit from both nonselective and targeted therapies. This clinical update aims to provide an insight into the current understanding of the molecular pathogenesis of the disease, and explores the novel therapies under development and in clinical trials.

Co-registration of cone beam CT and planning CT in head and neck IMRT dose estimation: a feasible adaptive radiotherapy strategy.

OBJECTIVE: To investigate if cone beam CT (CBCT) can be used to estimate the delivered dose in head and neck intensity-modulated radiotherapy (IMRT). METHODS: 15 patients (10 without replan and 5 with replan) were identified retrospectively. Weekly CBCT was co-registered with original planning CT. Original high-dose clinical target volume (CTV1), low-dose CTV (CTV2), brainstem, spinal cord, parotids and external body contours were copied to each CBCT and modified to account for anatomical changes. Corresponding planning target volumes (PTVs) and planning organ-at-risk volumes were created. The original plan was applied and calculated using modified per-treatment volumes on the original CT. Percentage volumetric, cumulative (planned dose delivered prior to CBCT + adaptive dose delivered after CBCT) and actual delivered (summation of weekly adaptive doses) dosimetric differences between each per-treatment and original plan were calculated. RESULTS: There was greater volumetric change in the parotids with an average weekly difference of between -4.1% and -27.0% compared with the CTVs/PTVs (-1.8% to -5.0%). The average weekly cumulative dosimetric differences were as follows: CTV/PTV (range, -3.0% to 2.2%), ipsilateral parotid volume receiving ≥26 Gy (V26) (range, 0.5-3.2%) and contralateral V26 (range, 1.9-6.3%). In patients who required replan, the average volumetric reductions were greater: CTV1 (-2.5%), CTV2 (-6.9%), PTV1 (-4.7%), PTV2 (-11.5%), ipsilateral (-10.4%) and contralateral parotids (-12.1%), but did not result in significant dosimetric changes. CONCLUSION: The dosimetric changes during head and neck simultaneous integrated boost IMRT do not necessitate adaptive radiotherapy in most patients. ADVANCES IN KNOWLEDGE: Our study shows that CBCT could be used for dose estimation during head and neck IMRT.

What is the quality of economic evaluations of non-drug therapies? A systematic review and critical appraisal of economic evaluations of radiotherapy for cancer.

BACKGROUND: Breast, cervical and colorectal cancers are the three most frequent cancers in women, while lung, prostate and colorectal cancers are the most frequent in men. Much attention has been given to the economic evaluation of pharmaceuticals for treatment of cancer by the National Institute for Health and Care Excellence (NICE) in the UK and similar authorities internationally, while economic analysis developed for other types of anti-cancer interventions, including radiotherapy and surgery, are less common. OBJECTIVES: Our objective was to review methods used in published cost-effectiveness studies evaluating radiotherapy for breast, cervical, colorectal, head and neck and prostate cancer, and to compare the economic evaluation methods applied with those defined in the guidelines used by the NICE technology appraisal programme. METHODS: A systematic search of seven databases (MEDLINE, EMBASE, CDSR, NHSEED, HTA, DARE, EconLit) as well as research registers, the NICE website and conference proceedings was conducted in July 2012. Only economic evaluations of radiotherapy interventions in individuals diagnosed with cancer that included quality-adjusted life-years (QALYs) or life-years (LYs) were included. Included studies were appraised on the basis of satisfying essential, preferred and UK-specific methods requirements, building on the NICE Reference Case for economic evaluations and on other methods guidelines. RESULTS: A total of 29 studies satisfied the inclusion criteria (breast 14, colorectal 2, prostate 10, cervical 0, head and neck 3). Only two studies were conducted in the UK (13 in the USA). Among essential methods criteria, the main issue was that only three (10%) of the studies used clinical-effectiveness estimates identified through systematic review of the literature. Similarly, only eight (28%) studies sourced health-related quality-of-life data directly from patients with the condition of interest. Other essential criteria (e.g. clear description of comparators, patient group indication and appropriate time horizon) were generally fulfilled, while most of the UK-specific requirements were not met. CONCLUSION: Based on this review there is a dearth of up-to-date, robust evidence on the cost effectiveness of radiotherapy in cancer suitable to support decision making in the UK. Studies selected did not fully satisfy essential method standards currently recommended by NICE.

Should elective neck dissection be routinely performed in patients undergoing salvage total laryngectomy?

BACKGROUND: The prevalence of occult neck metastasis in patients undergoing salvage total laryngectomy remains unclear, and there is controversy regarding whether elective neck dissection should routinely be performed. METHOD: A retrospective case note review of 32 consecutive patients undergoing salvage total laryngectomy in a tertiary centre was performed, in order to correlate pre-operative radiological staging with histopathological staging. RESULTS: The median patient age was 61 years (range, 43-84 years). With regard to lymph node metastasis, 28 patients were pre-operatively clinically staged (following primary radiotherapy or chemoradiotherapy) as node-negative, 1 patient was staged as N1, two patients as N2c and one patient as N3. Fifty-two elective and seven therapeutic neck dissections were performed. Pathological analysis up-staged two patients from clinically node-negative (following primary radiotherapy or chemoradiotherapy) to pathologically node-positive (post-surgery). No clinically node-positive patients were down-staged. More than half of the patients suffered a post-operative fistula. CONCLUSION: Pre-operative neck staging had a negative predictive value of 96 per cent. Given the increased complications associated with neck dissection in the salvage setting, consideration should be given to conservative management of the neck in clinically node-negative patients (staged following primary radiotherapy or chemoradiotherapy).

The effect of 6 and 15 MV on intensity-modulated radiation therapy prostate cancer treatment: plan evaluation, tumour control probability and normal tissue complication probability analysis, and the theoretical risk of secondary induced malignancies.

OBJECTIVE: The aim of this study was to investigate the effect of 6 and 15-MV photon energies on intensity-modulated radiation therapy (IMRT) prostate cancer treatment plan outcome and to compare the theoretical risks of secondary induced malignancies. METHODS: Separate prostate cancer IMRT plans were prepared for 6 and 15-MV beams. Organ-equivalent doses were obtained through thermoluminescent dosemeter measurements in an anthropomorphic Aldersen radiation therapy human phantom. The neutron dose contribution at 15 MV was measured using polyallyl-diglycol-carbonate neutron track etch detectors. Risk coefficients from the International Commission on Radiological Protection Report 103 were used to compare the risk of fatal secondary induced malignancies in out-of-field organs and tissues for 6 and 15 MV. For the bladder and the rectum, a comparative evaluation of the risk using three separate models was carried out. Dose-volume parameters for the rectum, bladder and prostate planning target volume were evaluated, as well as normal tissue complication probability (NTCP) and tumour control probability calculations. RESULTS: There is a small increased theoretical risk of developing a fatal cancer from 6 MV compared with 15 MV, taking into account all the organs. Dose-volume parameters for the rectum and bladder show that 15 MV results in better volume sparing in the regions below 70 Gy, but the volume exposed increases slightly beyond this in comparison with 6 MV, resulting in a higher NTCP for the rectum of 3.6% vs 3.0% (p=0.166). CONCLUSION: The choice to treat using IMRT at 15 MV should not be excluded, but should be based on risk vs benefit while considering the age and life expectancy of the patient together with the relative risk of radiation-induced cancer and NTCPs.

Intensity-modulated radiotherapy allows escalation of the radiation dose to the pelvic lymph nodes in patients with locally advanced prostate cancer: preliminary results of a phase I dose escalation study.

AIM: Pelvic irradiation in addition to prostate irradiation may improve outcome in locally advanced prostate cancer, but is associated with dose-limiting bowel toxicity. We report the preliminary results of a dose escalation study using intensity-modulated radiotherapy. MATERIALS AND METHODS: Eligible patients had high-risk (T3, Gleason > or =8 or prostate-specific antigen > or =20 ng/ml) or lymph node-positive disease. Intensity-modulated radiotherapy was inverse planned giving 70 Gy/35 fractions to the prostate and 50 Gy/55 Gy/60 Gy in sequential cohorts to the pelvis with a 5 Gy boost to positive lymph nodes. Acute and late toxicity were recorded with Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue - Subjective Objective Management LENT-SOM scales. Neoadjuvant androgen suppression was given for 3 years. This report concerns the 50 and 55 Gy cohorts. RESULTS: Seventy-nine men were recruited (25 to 50 Gy/54 to 55 Gy) with a median follow-up of 2 years. Patients were divided into two groups according to the total bowel volume outlined (median 450 cm(3)). Acute RTOG (> or =2) bowel toxicity was 40 and 50% for the 50 and 55 Gy groups and 38 and 51% for bowel volume <450 cm(3) and > or =450 cm(3), respectively, suggesting both volume and dose relationships for acute effects. Late RTOG diarrhoea > or =grade 2 was only seen with bowel volume > or =450 cm(3), but no dose effect was apparent (12%/50 Gy and 10%/55 Gy). LENT-SOM bowel > or =grade 2 toxicity occurred in 22%/50 Gy and 15%/55 Gy. Only one patient had grade 3 toxicity. A dose volume histogram analysis showed increased late RTOG diarrhoea > or =grade 2 with larger bowel volume irradiated, significant for BV40 >124 cm(3) (P=0.04), BV45 >71 cm(3) (P=0.03) and BV60 >2 cm(3) (P=0.01). CONCLUSIONS: Acute and late bowel toxicity was acceptably low using a pelvic dose of up to 55 Gy over 7 weeks. Both relate to total pelvic bowel volume and dose volume constraints have been defined.