A proposed framework for the implementation of head and neck cancer treatment at a new cancer center from a radiation oncology perspective.

BACKGROUND: Establishing a new head and neck cancer (HNC) treatment center requires multidisciplinary team management and expertise. To our knowledge, there are no clear recommendations or guidelines in the literature for the commencement of HNC radiation therapy (RT) at a new cancer center. We propose a novel framework outlining the necessary components required to set-up a new radiation therapy HNC treatment. METHODS: We reviewed the infrastructure and methodology in the commencement of HNC radiation therapy in our cancer care center and invited several external, experienced metropolitan head and neck radiation oncologists to develop a novel consensus guideline that may be used by new RT centers to treat HNC. Recommendations were presented to our internal and external staff specialists using a survey questionnaire with ratings utilized to determine consensus using pre-defined thresholds as per the American Society of Clinical Oncology Guidelines Methodology Manual. CONCLUSION: This consensus recommendation aims to improve RT utilization whilst advocating for optimal patient outcomes by presenting a framework for new radiation therapy centers ready to step up and manage the treatment of head and neck cancer patients. We propose these evidence-based consensus guidelines endorsed by external HNC radiation oncologists.

Changes in serial multiparametric MRI and FDG-PET/CT functional imaging during radiation therapy can predict treatment response in patients with head and neck cancer.

OBJECTIVES: To test if tumour changes measured using combination of diffusion-weighted imaging (DWI) MRI and FDG-PET/CT performed serially during radiotherapy (RT) in mucosal head and neck carcinoma can predict treatment response. METHODS: Fifty-five patients from two prospective imaging biomarker studies were analysed. FDG-PET/CT was performed at baseline, during RT (week 3), and post RT (3 months). DWI was performed at baseline, during RT (weeks 2, 3, 5, 6), and post RT (1 and 3 months). The ADCmean from DWI and FDG-PET parameters SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were measured. Absolute and relative change (%∆) in DWI and PET parameters were correlated to 1-year local recurrence. Patients were categorised into favourable, mixed, and unfavourable imaging response using optimal cut-off (OC) values of DWI and FDG-PET parameters and correlated to local control. RESULTS: The 1-year local, regional, and distant recurrence rates were 18.2% (10/55), 7.3% (4/55), and 12.7% (7/55), respectively. ∆Week 3 ADCmean (AUC 0.825, p = 0.003; OC ∆ > 24.4%) and ∆MTV (AUC 0.833, p = 0.001; OC ∆ > 50.4%) were the best predictors of local recurrence. Week 3 was the optimal time point for assessing DWI imaging response. Using a combination of ∆ADCmean and ∆MTV improved the strength of correlation to local recurrence (p ≤ 0.001). In patients who underwent both week 3 MRI and FDG-PET/CT, significant differences in local recurrence rates were seen between patients with favourable (0%), mixed (17%), and unfavourable (78%) combined imaging response. CONCLUSIONS: Changes in mid-treatment DWI and FDG-PET/CT imaging can predict treatment response and could be utilised in the design of future adaptive clinical trials. CLINICAL RELEVANCE STATEMENT: Our study shows the complementary information provided by two functional imaging modalities for mid-treatment response prediction in patients with head and neck cancer. KEY POINTS: •FDG-PET/CT and DWI MRI changes in tumour during radiotherapy in head and neck cancer can predict treatment response. •Combination of FDG-PET/CT and DWI parameters improved correlation to clinical outcome. •Week 3 was the optimal time point for DWI MRI imaging response assessment.

Mid-treatment 18F-FDG PET imaging changes in parotid gland correlates to radiation-induced xerostomia.

BACKGROUND: The aim of this study was to measure functional changes in parotid glands using mid-treatment FDG-PET/CT and correlate early imaging changes to subsequent xerostomia in mucosal head and neck squamous cell carcinoma patients undergoing radiotherapy. MATERIALS AND METHODS: 56 patients from two prospective imaging biomarker studies underwent FDG-PET/CT at baseline and during radiotherapy (week 3). Both parotid glands were volumetrically delineated at each time point. PET parameter SUVmedian were calculated for ipsilateral and contralateral parotid glands. Absolute and relative change (Δ) in SUVmedian were correlated to moderate-severe xerostomia (CTCAE grade ≥ 2) at 6 months. Four predictive models were subsequently created using multivariate logistic regression using clinical and radiotherapy planning parameters. Model performance was calculated using ROC analysis and compared using Akaike information criterion (AIC) RESULTS: 29 patients (51.8%) developed grade ≥ 2 xerostomia. Compared to baseline, there was an increase in SUVmedian at week 3 in ipsilateral (8.4%) and contralateral (5.5%) parotid glands. Increase in ipsilateral parotid Δ SUVmedian (p = 0.04) and contralateral mean parotid dose (p = 0.04) were correlated to xerostomia. The reference 'clinical' model correlated to xerostomia (AUC 0.667, AIC 70.9). Addition of ipsilateral parotid Δ SUVmedian to the clinical model resulted in the highest correlation to xerostomia (AUC 0.777, AIC 65.4). CONCLUSION: Our study shows functional changes occurring in the parotid gland early during radiotherapy. We demonstrate that integration of baseline and mid-treatment FDG-PET/CT changes in the parotid gland with clinical factors has the potential to improve xerostomia risk prediction which could be utilised for personalised head and neck radiotherapy.

Prognostic and predictive values of baseline and mid-treatment FDG-PET in oropharyngeal carcinoma treated with primary definitive (chemo)radiation and impact of HPV status: Review of current literature and emerging roles.

BACKGROUND AND PURPOSE: This study provides a review of the literature assessing whether semiquantitative PET parameters acquired at baseline and/or during definitive (chemo)radiotherapy ("prePET" and "iPET") can predict survival outcomes in patients with oropharyngeal squamous cell carcinoma (OPC), and the impact of human papilloma virus (HPV) status. MATERIAL AND METHODS: A literature search was carried out using PubMed and Embase between 2001 to 2021 in accordance with PRISMA. RESULTS: The analysis included 22 FDG-PET/CT studies [1-22], 19 pre-PET and 3 both pre-PET and iPET, The analysis involved 2646 patients, of which 1483 are HPV-positive (17 studies: 10 mixed and 7 HPV-positive only), 589 are HPV-negative, and 574 have unknown HPV status. Eighteen studies found significant correlations of survival outcomes with pre-PET parameters, most commonly primary or "Total" (combined primary and nodal) metabolic tumour volume and/or total lesional glycolysis. Two studies could not establish significant correlations and both employed SUVmax only. Two studies also could not establish significant correlations when taking into account of the HPV-positive population only. Because of the heterogeneity and lack of standardized methodology, no conclusions on optimal cut-off values can be drawn. Ten studies specifically evaluated HPV-positive patients: five showed positive correlation of pre-PET parameters and survival outcomes, but four of these studies did not include advanced T or N staging in multivariate analysis, and two studies only showed positive correlations after excluding high risk patients with smoking history or adverse CT features. Two studies found that prePET parameters predicted treatment outcomes only in HPV-negative but not HPV-positive patients. Two studies found that iPET parameters could predict outcomes in HPV-positive patients but not prePET parameters. CONCLUSION: The current literature supports high pre-treatment metabolic burden prior to definitive (chemo)radiotherapy can predict poor treatment outcomes for HPV-negative OPC patients. Evidence is conflicting and currently does not support correlation in HPV-positive patients.

Impact of tumour region of interest delineation method for mid-treatment FDG-PET response prediction in head and neck squamous cell carcinoma undergoing radiotherapy.

Background: The aim of this study was to evaluate the impact of tumour region of interest (ROI) delineation method on mid-treatment 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) response prediction in mucosal head and neck squamous cell carcinoma during radiotherapy. Methods: A total of 52 patients undergoing definitive radiotherapy with or without systemic therapy from two prospective imaging biomarker studies were analysed. FDG-PET was performed at baseline and during radiotherapy (week 3). Primary tumour was delineated using a fixed SUV 2.5 threshold (MTV2.5), relative threshold (MTV40%) and a gradient based segmentation method (PET Edge). PET parameters SUVmax, SUVmean, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were calculated using different ROI methods. Absolute and relative change (∆) in PET parameters were correlated to 2-year locoregional recurrence. Strength of correlation was tested using receiver operator characteristic analysis using area under the curve (AUC). Response was categorized using optimal cut-off (OC) values. Correlation and agreement between different ROI methods was determined using Bland-Altman analysis. Results: A significant difference in SUVmean, MTV and TLG values were noted between ROI delineation methods. When measuring relative change at week 3, a greater agreement was seen between PET Edge and MTV2.5 methods with average difference in ∆SUVmax, ∆SUVmean, ∆MTV and ∆TLG of 0.0%, 3.6%, 10.3% and 13.6% respectively. A total of 12 patients (22.2%) experienced locoregional recurrence. ∆MTV using PET Edge was the best predictor of locoregional recurrence (AUC =0.761, 95% CI: 0.573-0.948, P=0.001; OC ∆>50%). The corresponding 2-year locoregional recurrence rate was 7% vs. 35%, P=0.001. Conclusions: Our findings suggest that it is preferable to use gradient based method to assess volumetric tumour response during radiotherapy and offers advantage in predicting treatment outcomes compared with threshold-based methods. This finding requires further validation and can assist in future response-adaptive clinical trials.

Identifying the location of locoregional recurrences after definitive radiotherapy for head and neck cancer using metabolic parameters of baseline and mid-treatment 18F-FDG-PET scans.

INTRODUCTION: Tumour recurrences after treatment of head and neck squamous cell carcinoma (HNSCC) are more likely to originate from regions of high-baseline FDG-PET uptake. Mid-treatment functional imaging can potentially predict for higher risk of tumour recurrence. The aim of this study is to correlate the location of locoregional tumour recurrence with baseline FDG-PET metabolic volumes and mid-treatment FDG-PET metabolic volumes in patients with HNSCC following definitive radiotherapy. METHODS: A total of 23 patients with 26 local and/or regional recurrences underwent baseline (W0-PET) and mid-treatment (W3-PET) 18F-FDG PET scans as part of their radiotherapy. FDG-PET-based metabolic volumes (MTV20%, MTV40%, MTV60%, MTV80%, SUV2.5, SUVpeak and PET_EDGE) were delineated onto the FDG-PET scans. The recurrence nidus was identified on FDG-PET at the time of recurrence (REC-PET). DIR-based fusion was performed for REC-PET to W0-PET, and REC-PET to W3-PET. The location of the recurrence nidus was correlated with the FDG-PET volumes. Further analysis included a comparison of the recurrence density to FDG-PET metabolic volumes. RESULTS: Most recurrences occurred within the MTV20%, MTV40% and SUV 2.5 volumes. Sixty-nine per cent of recurrences (18 of 26) occurred within both the W0 MTV40% and W3 MTV40% volumes. A higher recurrence density was seen for iso-SUV contours closer to the maximum SUV for both W0 and W3. For a number of the FDG-PET volumes, including MTV20%, MTV40% and SUV2.5, the recurrence density was improved for W3 compared to W0, however, this improvement was small in magnitude. The average volume of MTV40% contours was considerably smaller than MTV20% and SUV2.5 contours. CONCLUSION: The metabolic parameters of SUV2.5, MTV20% and MTV40% delineated on the baseline and mid-treatment FDG-PET scans encompassed the majority of recurrences. The MTV40% is significantly smaller, hence, we prefer this volume for future dose escalation studies.

Nodal metastasis size predicts disease-free survival in cutaneous head and neck squamous cell carcinoma involving the parotid but not cervical nodes.

BACKGROUND: The 8th edition American Joint Committee on Cancer nodal (N) staging of cutaneous squamous cell carcinoma of the head and neck (cSCCHN) is largely based on lymph node metastasis size, despite conflicting data in the literature. This study aimed to investigate the prognostic significance of largest node size in cSCCHN. METHODS: Retrospective analysis of 94 patients undergoing curative-intent treatment for nodal cSCCHN with surgery ± radiotherapy at Liverpool Hospital, Sydney, Australia was conducted. Survival outcomes were assessed using multivariate Cox regression. The primary end point was disease-free survival (DFS). Objective measures of model performance were used in exploratory analyses to identify optimal size thresholds for predicting survival. RESULTS: Nodal metastasis size significantly predicted DFS on multivariate analysis (hazard ratio 1.24; 95% confidence interval 1.06-1.46; P = 0.008). This prognostic impact occurred predominantly in parotid metastases (hazard ratio 1.27; 95% confidence interval 1.07-1.51; P = 0.006); each 1 cm increase in size increased the risk of recurrence or death by 27%, irrespective of the number of involved nodes. In parotid metastases, size thresholds of ≤3, 3-4.5 and >4.5 cm optimized prognostic discrimination. Extranodal extension (ENE) was associated with decreased DFS in nodes ≤3 cm in size (P = 0.025), but not in those >3 cm (P = 0.744). CONCLUSION: Size is an important prognostic factor in cSCCHN with parotid metastases, with optimal thresholds of ≤3, >3-4.5 and >4.5 cm. The prognostic impact of ENE was seen only in nodal metastases ≤3 cm in size. These results may have important implications for node size thresholds and inclusion of ENE in the American Joint Committee on Cancer N staging categories.

Number of nodal metastases and prognosis in metastatic cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Existing prognostic systems for metastatic cutaneous squamous cell carcinoma of the head and neck (cSCCHN) do not discriminate between the number of involved nodes beyond single versus multiple. This study aimed to determine if the number of metastatic lymph nodes is an independent prognostic factor in metastatic cSCCHN and whether it provides additional prognostic information to the American Joint Committee on Cancer (AJCC) staging. METHODS: We retrospectively analysed 101 patients undergoing curative intent treatment for metastatic cSCCHN to parotid and/or neck nodes by surgery +/- radiotherapy at Liverpool Hospital, Sydney, Australia. The impact of number of nodal metastases on disease-free survival (DFS) and risk of distant metastases was assessed using multivariate Cox regression. RESULTS: The mean number of nodal metastases was 2.5 (range 1-12). On multivariate analysis, increasing number of nodal metastases significantly predicted reduced DFS (hazard ratio 1.17; 95% confidence interval 1.05-1.30; P = 0.004), with a 17% increased risk of recurrence or death for each additional node. This remained significant in multivariate models adjusted for AJCC 8th edition nodal and TNM stages. Number of nodal metastases was also associated with risk of distant metastatic failure (hazard ratio 1.21; 95% confidence interval 1.05-1.39; P = 0.009). CONCLUSION: Increasing number of nodal metastases is associated with decreased DFS and increased risk of distant metastases in metastatic cSCCHN, with a cumulative risk increase with each additional node. It provides additional prognostic information to the AJCC staging, which may be improved by incorporating information on the number of nodal metastases beyond the current single versus multiple distinction.

Evaluating diffusion-weighted magnetic resonance imaging for target volume delineation in head and neck radiotherapy.

INTRODUCTION: Inter-observer variability (IOV) in target volume delineation is a source of error in head and neck radiotherapy. Diffusion-weighted imaging (DWI) has been shown to be useful in detecting recurrent head and neck cancer. This study aims to determine whether DWI improves target volume delineation and IOV. METHODS: Four radiation oncologists delineated the gross tumour volume (GTV) for ten head and neck cancer patients. Delineation was performed on CT alone as well as fused image sets which incorporated fluorodeoxyglucose (FDG)-positron emission tomography (PET) and magnetic resonance imaging (MRI) in the form of CT/PET, CT/PET/T2W and CT/PET/T2W/DWI image sets. Analysis of the variability of contour volumes was completed by comparison to the simultaneous truth and performance level estimation (STAPLE) volumes. The DICE Similarity Coefficient (DSC) and other IOV metrics for each observer's contour were compared to the STAPLE for each patient and image dataset. A DWI usability scoresheet for delineation was completed. RESULTS: The CT/PET/T2W/DWI mean GTV volume of 13.37 (10.35-16.39)cm3 was shown to be different to the mean GTV of 10.92 (8.32-13.51)cm3 when using CT alone (P < 0.001). The GTV DSC amongst observers for CT alone was 0.72 (0.65-0.79), CT/PET was 0.73 (0.67-0.80), CT/PET/T2W was 0.71 (0.64-0.77) and CT/PET/T2W/DWI was 0.69 (0.61-0.75). CONCLUSION: Mean GTVs with the addition of DWI had slightly larger volumes compared to standard CT and CT/PET volumes. DWI may add supplemental visual information for GTV delineation while having a small impact on IOV, therefore potentially improving target volume delineation.

A critical analysis of the prognostic performance of the 8th edition American Joint Committee on Cancer staging for metastatic cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: The 8th edition AJCC staging of cutaneous squamous cell carcinoma of the head and neck (cSCCHN) incorporated extranodal extension (ENE) for the first time. This study compared the prognostic performance of the 7th and 8th edition staging for cSCCHN with nodal metastases. METHODS: Retrospective analysis of 96 patients with metastatic cSCCHN, comparing the ability of staging systems to predict disease-specific and overall survival (OS) using the proportion of variation explained and Harrell's C-index. RESULTS: In AJCC8, the N classification was upstaged in 77% of patients due to the presence of ENE and 88% of patients were classified as TNM stage IV. AJCC8 was inferior to AJCC7 in predicting disease-specific survival for both N and TNM stages, and OS by TNM stage. CONCLUSIONS: The majority of patients with metastatic cSCCHN have ENE and are classified as TNM stage IV based on the 8th edition staging, resulting in poor prognostic performance.

Multiparametric magnetic resonance imaging in mucosal primary head and neck cancer: a prospective imaging biomarker study.

BACKGROUND: Radical radiotherapy, with or without concomitant chemotherapy forms the mainstay of organ preservation approaches in mucosal primary head and neck cancer. Despite technical advances in cancer imaging and radiotherapy administration, a significant proportion of patients fail to achieve a complete response to treatment. For those patients who do achieve a complete response, acute and late toxicities remain a cause of morbidity. A critical need therefore exists for imaging biomarkers which are capable of informing patient selection for both treatment intensification and de-escalation strategies. METHODS/DESIGN: A prospective imaging study has been initiated, aiming to recruit patients undergoing radical radiotherapy (RT) or chemoradiotherapy (CRT) for mucosal primary head and neck cancer (MPHNC). Eligible patients are imaged using FDG-PET/CT before treatment, at the end of week 3 of treatment and 12 weeks after treatment completion according to local imaging policy. Functional MRI using diffusion weighted (DWI), blood oxygen level-dependent (BOLD) and dynamic contrast enhanced (DCE) sequences is carried out prior to, during and following treatment. Information regarding treatment outcomes will be collected, as well as physician-scored and patient-reported toxicity. DISCUSSION: The primary objective is to determine the correlation of functional MRI sequences with tumour response as determined by FDG-PET/CT and clinical findings at 12 weeks post-treatment and with local control at 12 months post-treatment. Secondary objectives include prospective correlation of functional MRI and PET imaging with disease-free survival and overall survival, defining the optimal time points for functional MRI assessment of treatment response, and determining the sensitivity and specificity of functional MRI sequences for assessment of potential residual disease following treatment. If the study is able to successfully characterise tumours based on their functional MRI scan characteristics, this would pave the way for further studies refining treatment approaches based on prognostic and predictive imaging data. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12616000534482 (26 April 2016).

A review of the predictive role of functional imaging in patients with mucosal primary head and neck cancer treated with radiation therapy.

Advanced radiotherapy techniques, such as intensity-modulated radiotherapy, have been reported to reduce toxicities by improving the dose conformity in mucosal primary head and neck cancer (MPHNC). However, to further optimize the therapeutic ratio, details on individual patient and disease characteristics may be necessary to tailor treatments. This is likely to include identifying poor responders for treatment intensification and good responders for de-escalation strategies. Non-invasive, repeatable imaging biomarkers are attractive modalities in both pre-treatment and intra-treatment response prediction with a view to individualized treatment options. This review has assessed the current literature on the prognostic/predictive role of widely available functional imaging (FI) studies such as fMRI(functional magnetic resonance imaging), functional computed tomography (fCT) and positron-emission-tomography(PET). A literature search was carried out using Medline, Embase and PubMed. Studies were included if imaging was undertaken pre and/or during radiotherapy (with or without the addition of chemotherapy and/or surgery). A total of 99 relevant studies were identified: 14 fMRI, 10 fCT, 59 FDG-PET and 16 non-FDG-PET studies. These articles were reviewed to identify imaging parameters demonstrating a correlation with patient outcome or a factor considered to impact on patient outcome and thus likely to be of potential predictive value in MPHNC and associated future radiotherapy treatment directions. Several studies have demonstrated that both pre-treatment and mid-treatment FDG-PET is predictive of outcomes. However, further studies are required to confirm the role of other imaging studies including fMRI and PET using other tracers. There is large heterogeneity within and between published studies, including tumour sites, treatment options, outcome endpoints and parameters assessed. We propose a minimum set of factors that should be reported and make recommendations for studies evaluating the predictive utility in MPHNC.

Nodal parameters of FDG PET/CT performed during radiotherapy for locally advanced mucosal primary head and neck squamous cell carcinoma can predict treatment outcomes: SUVmean and response rate are useful imaging biomarkers.

PURPOSE: To evaluate the prognostic utility of nodal metabolic parameters derived from FDG PET/CT performed before radiotherapy (prePET) and during the third week of radiotherapy (iPET) in patients with mucosal primary head and neck squamous cell carcinoma (MPHNSCC). METHODS: This analysis included 75 patients with newly diagnosed locally advanced node-positive MPHNSCC treated with radical radiotherapy and concurrent systemic therapy who underwent prePET and iPET: N1 11 patients, N2a 38, N2b 12, N2c 9, N3 5. The median follow-up was 28 months (9 - 70 months). The maximum and mean standardized uptake values (SUVmax and SUVmean), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) of the index lymph node (node with the highest TLG) and the combined total lymph nodes, and their percentage reductions on iPET were determined, and the results were correlated with 3-year Kaplan-Meier locoregional, regional and distant metastatic failure-free survival (FFS), disease-free survival (DFS) and overall survival (OS). Optimal cut-off values were derived from receiver operating characteristic curves. Cox regression univariate and multivariate analyses with clinical covariates were performed. RESULTS: Based on assessment of residual nodal metabolic burden during treatment, the iPET index node SUVmean (optimal cut-off value 2.95 g/ml) and the total node SUVmean (optimal cut-off value 3.25) were the best independent predictors of outcome in the multivariate analysis: index node SUVmean for DFS and OS p = 0.033 and 0.003, respectively, and the total node SUVmean for locoregional FFS, DFS and OS p = 0.028, 0.025 and 0.014, respectively. Based on the assessment of response rates during treatment, a reduction of more than 50 % in the total node TLG was the best biomarker for locoregional and regional FFS, DFS and OS in the multivariate analysis (p = 0.001, 0.016, 0.001 and 0.004, respectively), and reduction in the total node MTV for locoregional FFS, DFS and OS (p = 0.026, 0.003 and 0.014, respectively). There were no significant correlations between oncological outcomes and prePET nodal parameters. CONCLUSION: We demonstrated that the index node and total node SUVmean on iPET and a reduction of more than 50 % in MTV and TLG are useful imaging biomarkers, and can potentially identify those patients with MPHNSCC who have a high risk of locoregional metastatic failure and death.

Prognostic utility of (18)F-FDG PET-CT performed prior to and during primary radiotherapy for nasopharyngeal carcinoma: Index node is a useful prognostic imaging biomarker site.

PURPOSE: To evaluate the prognostic value of (18)F-FDG-PET-CT performed prior to (prePET) and during the third week (iPET) of radiation therapy (RT) in nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Thirty-patients with newly diagnosed loco-regionally advanced NPC treated with radical RT underwent prePET and iPET. The median follow-up was 26months (8-66.9). The maximum-standardised-uptake-value (SUVmax), metabolic-tumour-volume (MTV) and total-lesional-glycolysis (TLG) of the primary tumour (PT), index-node (IN) (lymph node with highest TLG), total-lymph-nodes (TN) and combined primary-tumour and nodal (PTN), and their % reductions in iPET were analysed, and results were correlated with 2-year Kaplan-Meier loco-recurrence-free-survival (LRFS), regional-failure-free-survival (RFFS), distant-metastatic-failure-free-survival (DMFFS), disease-free-survival (DFS), and overall-survival (OS). Optimal-cutoffs (OC) were derived from Receiver-Operating-Characteristic curves. RESULTS: For LRFS, the only predictor was reduction in PT MTV by >50%: 95.2% vs. 75.0%, p=0.024. For other treatment outcomes, only nodal or PTN predicted outcomes. The IN SUVmax (pre-PET-OC=10.45g/mL and iPET-OC=8.15) and TLG (prePET-OC=90g and iPET-OC=33.4) were the best predictors of outcome: RFFS (iPET SUVmax/TLG): 100% vs. 50%, p<0.001 and 100% vs. 44%, p=0.032; DMFFS (prePET SUVmax/TLG); 100% vs. 51.9%, p=0.004 and 100% vs. 47.6%, p=0.002; DFS (prePET TLG and iPET SUVmax): 87.5% vs. 33%, p=0.045 and 78.7% vs. 20%, p=0.01; and OS (prePET TLG): 100% vs 66.3%, p=0.036. CONCLUSIONS: We have demonstrated IN of prePET and iPET to be a feasible and potentially useful novel imaging biomarker to predict for patients with NPC who have a high risk of regional or distant metastatic failure. Future work is required to validate our findings in a well-powered, prospective study with a standardised treatment protocol, and their potential use to guide individualised therapy for NPC.

18F-FDG PET-CT performed before and during radiation therapy of head and neck squamous cell carcinoma: Are they independent or complementary to each other?

INTRODUCTION: The aims of this study are to evaluate the prognostic value of metabolic parameters derived from (18) F-FDG PET-CT performed before definitive radiation therapy (RT) (prePET) in patients with mucosal primary head and neck squamous cell carcinoma (MPHNSCC) and to assess the additive prognostic values of FDG PET-CT performed during RT (iPET). METHODS: One hundred patients with MPHNSCC treated with radical RT underwent staging prePET and iPET performed during the third week of treatment. The maximum standardized uptake value (SUVmax ), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) of primary tumour were analysed for both prePET and iPET, and results were correlated with loco-regional recurrence-free survival (LRFS), disease-free survival (DFS), metastatic failure-free survival (MFFS) and overall survival (OS), using Kaplan-Meier analysis. Optimal cut-offs (OC) for prePET and iPET were derived from Receiver Operating Characteristic curves. Patients with metabolic parameters above/below the individual OC of prePET as well as iPET (i.e. combined prePET and iPET (comPET)) were evaluated against their outcomes. RESULTS: Median age was 61 years (range 39-81), median follow-up of 20 months (range 4-70, mean 27), and AJCC 7th Edition clinical stage II, III and IV were 8, 24 and 68 patients respectively. Metabolic values below individual OC in comPET were found to be associated with statistically significant improvements (P < 0.05) in DFS, LRFS and OS. In addition, patients with SUVmax above the OC in comPET were associated with worse MFFS (P = 0.011) and confirmed on both univariate (P = 0.019) and multivariate analyses (P = 0.04). CONCLUSION: Addition of iPET significantly improves the prognostic values of all three metabolic parameters and can potentially be used in future adaptive local and systemic therapy trials.

Assessment of serial multi-parametric functional MRI (diffusion-weighted imaging and R2*) with (18)F-FDG-PET in patients with head and neck cancer treated with radiation therapy.

OBJECTIVE: To evaluate the serial changes and correlations between readout-segmented technique with navigated phase correction diffusion-weighted MRI (DWI), R2*-MRI and (18)F-FDG positron emission tomography (PET) CT performed before and during radiation therapy (RT) in patients with mucosal primary head and neck cancer. METHODS: The mean apparent diffusion coefficient (ADCmean) from DWI (at b = 50 and 800 s mm(-2)), the mean R2* values derived from T2(*)-MRI, and PET metabolic parameters, including maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) were measured for the primary tumour. Spearman correlation coefficients were calculated to evaluate correlations between ADCmean, R2*, SUVmax, MTV and TLG. A paired t-test was performed to assess the MRI changes and the slope of serial MRI changes during RT. RESULTS: Pre-treatment scans were performed in 28 patients and mid-treatment scans in 20 patients. No significant correlation was found between ADCmean and either R2* values or PET parameters. There were significant negative correlations of R2* values with pre-treatment PET parameters but not with mid-RT PET parameters: pre-SUVmax (p = 0.008), pre-MTV (p = 0.006) and pre-TLG (p = 0.008). A significant rise in ADCmean was found during the first half (p < 0.001) of RT but not in the second half (p = 0.215) of the treatment. There was an increase of the ADCmean values of 279.4 [95% confidence interval (95% CI): 210-348] in the first half of the treatment (Weeks 0-3). However, during the second-half period of treatment, the mean ADC value (Weeks 3-6) was 24.0 and the 95% CI (-40 to 88) included zero. This suggests that there was no significant change in ADC values during the second half of the treatment. CONCLUSION: A significant negative correlation was found between pre-treatment R2*-MRI and PET parameters. DWI appeared to demonstrate potentially predictable changes during RT. ADVANCES IN KNOWLEDGE: Understanding the correlation and changes that occur with time between potential imaging biomarkers may help us establish the most appropriate biomarkers to consider in future research.

Prognostic role of metabolic parameters of (18)F-FDG PET-CT scan performed during radiation therapy in locally advanced head and neck squamous cell carcinoma.

PURPOSE: To evaluate the prognostic value of (18)F-FDG PET-CT performed in the third week (iPET) of definitive radiation therapy (RT) in patients with newly diagnosed locally advanced mucosal primary head and neck squamous-cell-carcinoma (MPHNSCC). METHODOLOGY: Seventy-two patients with MPHNSCC treated with radical RT underwent staging PET-CT and iPET. The maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV) and total lesional glycolysis (TLG) of primary tumour (PT) and index node (IN) [defined as lymph node(s) with highest TLG] were analysed, and results were correlated with loco-regional recurrence-free survival (LRFS), disease-free survival (DFS), metastatic failure-free survival(MFFS) and overall survival (OS), using Kaplan-Meier analysis. RESULTS: Optimal cutoffs (OC) were derived from receiver operating characteristic curves: SUVmax-PT = 4.25 g/mL, MTVPT = 3.3 cm(3), TLGPT = 9.4 g, for PT, and SUVmax-IN = 4.05 g/mL, MTVIN = 1.85 cm(3) and TLGIN = 7.95 g for IN. Low metabolic values in iPET for PT below OC were associated with statistically significant better LRFS and DFS. TLG was the best predictor of outcome with 2-year LRFS of 92.7 % vs. 71.1% [p = 0.005, compared with SUVmax (p = 0.03) and MTV (p = 0.022)], DFS of 85.9% vs. 60.8% [p = 0.005, compared with SUVmax (p = 0.025) and MTV (p = 0.018)], MFFS of 85.9% vs. 83.7% [p = 0.488, compared with SUVmax (p = 0.52) and MTV (p = 0.436)], and OS of 81.1% vs. 75.0% [p = 0.279, compared with SUVmax (p = 0.345) and MTV (p = 0.512)]. There were no significant associations between the percentage reduction of primary tumour metabolic parameters and outcomes. In patients with nodal disease, metabolic parameters below OC (for both PT and IN) were significantly associated with all oncological outcomes, while TLG was again the best predictor: LRFS of 84.0% vs. 55.3% (p = 0.017), DFS of 79.4% vs. 38.6% (p = 0.001), MFFS 86.4% vs. 68.2% (p = 0.034) and OS 80.4% vs. 55.7% (p = 0.045). CONCLUSION: The metabolic parameters of iPET can be useful predictors of patient outcome and potentially have a role in adaptive therapy for MPHNSCC. Among the three parameters, TLG was found to be the best prognostic indicator of oncological outcomes.

Impact of FDG-PET on lung cancer delineation for radiotherapy.

PURPOSE: The purpose of this study is to assess the impact of fused diagnostic F-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) and planning FDG-PET/CT scans on voluming of lung cancer for radiotherapy. METHODS: Five radiation oncologists (ROs), five radiation oncology trainees and a radiologist contoured five cases of non-small cell lung cancer. The CT alone, the diagnostic FDG-PET/CT and planning FDG-PET/CT each registered to the CT, were used to contour three volumes. The concordance index (CI) was used to compare each volume with a reference RO. RESULTS: Although there was considerable inter-observer variability in CT contouring, there was no significant difference between mean volumes of the gross tumour volume for the RO and radiation oncology trainees using any technique. There was no increase in CI with the addition of PET/CT, either diagnostic or planning, for the RO. However, the volumes of the radiation oncology trainees showed a significant increase in CI from 65.8% with CT alone to 68.0% and 72.3% with diagnostic PET/CT and planning PET/CT, respectively (P = 0.028). Mean variation at the tumour/mediastinum interface was significantly reduced with addition of registered PET/CT. CONCLUSIONS: The concordance of RO with the reference RO did not significantly increase with use of integrated FDG PET/CT images. However, the contouring of radiation oncology trainees' became more concordant with the reference.

A comparison of ICRU point doses and volumetric doses of organs at risk (OARs) in brachytherapy for cervical cancer.

INTRODUCTION: In brachytherapy for cervix cancer, doses to organs at risk (OARs) are traditionally calculated using the ICRU-38 point doses to rectum and bladder. Three-dimensional image-guided brachytherapy allows assessment of OAR dose with dose volume histograms (DVHs). The purpose of this study was to analyse the correlation between DVHs and ICRU point doses. METHODS: Using the PLATO™ planning system, the bladder, rectum and sigmoid were retrospectively contoured on 62 CT datasets for 20 patients treated with definitive radiotherapy. The median external beam radiotherapy dose was 45 Gy. Brachytherapy was delivered using a CT-MRI compatible tandem and ovoids to a median dose of 24 Gy in three fractions. DVHs were calculated, and the minimum dose to 2 cc of tissue receiving the highest dose (D(2cc) ) was recorded and compared with the ICRU point doses (D(ICRU) ). RESULTS: The mean rectal D(ICRU) was 4.01 Gy compared with D(2cc) of 4.28 Gy. The mean bladder D(ICRU) was 6.74 Gy compared with D(2cc) of 8.65 Gy. The mean sigmoid D(2cc) was 4.58 Gy. The mean dose ratios (D(2cc) /D(ICRU) ) were 1.08 for rectum and 1.39 for bladder. D(ICRU) correlated with D(2cc) for rectum (r = 0.76, P = 0.001) and for bladder (r = 0.78, P = 0.01). CONCLUSION: OAR doses assessed by DVH criteria were higher than ICRU point doses. The significant correlation between D(2cc) and D(ICRU) has allowed us to set DVH dose constraints for CT-based brachytherapy and thus begin the transition from two-dimensional to three-dimensional image-guided brachytherapy planning.