Tumour Size and Overall Survival in a Cohort of Patients with Unifocal Glioblastoma: A Uni- and Multivariable Prognostic Modelling and Resampling Study.

Published models inconsistently associate glioblastoma size with overall survival (OS). This study aimed to investigate the prognostic effect of tumour size in a large cohort of patients diagnosed with GBM and interrogate how sample size and non-linear transformations may impact on the likelihood of finding a prognostic effect. In total, 279 patients with a IDH-wildtype unifocal WHO grade 4 GBM between 2014 and 2020 from a retrospective cohort were included. Uni-/multivariable association between core volume, whole volume (CV and WV), and diameter with OS was assessed with (1) Cox proportional hazard models +/- log transformation and (2) resampling with 1,000,000 repetitions and varying sample size to identify the percentage of models, which showed a significant effect of tumour size. Models adjusted for operation type and a diameter model adjusted for all clinical variables remained significant (p = 0.03). Multivariable resampling increased the significant effects (p < 0.05) of all size variables as sample size increased. Log transformation also had a large effect on the chances of a prognostic effect of WV. For models adjusted for operation type, 19.5% of WV vs. 26.3% log-WV (n = 50) and 69.9% WV and 89.9% log-WV (n = 279) were significant. In this large well-curated cohort, multivariable modelling and resampling suggest tumour volume is prognostic at larger sample sizes and with log transformation for WV.

Impact of 18F-fluciclovine PET/CT on plans for androgen deprivation therapy in patients with biochemical recurrence of prostate cancer: data analysis from two prospective clinical trials.

INTRODUCTION: Despite early detection and primary therapy improvements, biochemical recurrence (BCR) of prostate cancer remains common. The advent of highly sensitive molecular imaging has facilitated identification of men with limited metastatic disease burden that might be more optimally treated with metastases-directed therapy than with androgen deprivation therapy (ADT). The LOCATE (NCT02680041) and FALCON (NCT02578940) trials assessed the impact of 18F-fluciclovine PET/CT on the management of patients with BCR after curative-intent primary therapy. We performed a secondary analysis of LOCATE and FALCON data to characterize sites of recurrence and management decisions for BCR patients who had an intended management plan including ADT prior to undergoing 18F-fluciclovine PET/CT. METHODS: Data from 317 LOCATE/FALCON patients who underwent 18F-fluciclovine PET/CT were analyzed and those with a prescan plan for ADT (± another treatment) were selected. 18F-Fluciclovine detection rates were determined at the patient level and for the prostate/prostate bed region, pelvic and extra-pelvic lymph nodes (LN), soft tissues, and bones. The patients' pre- and postscan treatment plans were compared and were stratified by imaging results. RESULTS: A total of 146 patients had a prescan plan for ADT (60 as monotherapy and 86 in combination with another modality). 18F-Fluciclovine detected lesions in 85 of 146 (58%) patients planned for ADT. Detection rates in the prostate/bed, pelvic LN, extra-pelvic LN, soft tissues and bone were 30%, 25%, 13%, 2.1%, and 13%, respectively. Twenty-five (17%) patients had positivity confined to the prostate/bed, 21 (14%) had 18F-fluciclovine-positive pelvic LN (±prostate/bed) but no other involvement and 39 (27%) had involvement outside the prostate/bed and pelvic LN. Postscan, 93 of 146 (64%) patients had a management change, 55 (59%) of which were to abort ADT. Only 25% of the patients originally planned for ADT monotherapy still had an unaltered plan for ADT monotherapy postscan. Patients with a postscan plan for ADT monotherapy had the most disseminated disease. Disease in the prostate/bed only was most common in those whose plan was altered to abort ADT. CONCLUSIONS: 18F-Fluciclovine-PET/CT influenced management plans for the majority of patients with a prescan plan for ADT. Plans were commonly amended to target salvage therapy for lesions identified with 18F-fluciclovine PET/CT, and consequently likely spared/delayed patients the morbidity associated with ADT.

A Road Map for Designing Phase I Clinical Trials of Radiotherapy-Novel Agent Combinations.

Radiotherapy has proven efficacy in a wide range of cancers. There is growing interest in evaluating radiotherapy-novel agent combinations and a drive to initiate this earlier in the clinical development of the novel agent, where the scientific rationale and preclinical evidence for a radiotherapy combination approach are high. Optimal design, delivery, and interpretation of studies are essential. In particular, the design of phase I studies to determine safety and dosing is critical to an efficient development strategy. There is significant interest in early-phase research among scientific and clinical communities over recent years, at a time when the scrutiny of the trial methodology has significantly increased. To enhance trial design, optimize safety, and promote efficient trial conduct, this position paper reviews the current phase I trial design landscape. Key design characteristics extracted from 37 methodology papers were used to define a road map and a design selection process for phase I radiotherapy-novel agent trials. Design selection is based on single- or dual-therapy dose escalation, dose-limiting toxicity categorization, maximum tolerated dose determination, subgroup evaluation, software availability, and design performance. Fifteen of the 37 designs were identified as being immediately accessible and relevant to radiotherapy-novel agent phase I trials. Applied examples of using the road map are presented. Developing these studies is intensive, highlighting the need for funding and statistical input early in the trial development to ensure appropriate design and implementation from the outset. The application of this road map will improve the design of phase I radiotherapy-novel agent combination trials, enabling a more efficient development pathway.

Discovery of Pre-Treatment FDG PET/CT-Derived Radiomics-Based Models for Predicting Outcome in Diffuse Large B-Cell Lymphoma.

BACKGROUND: Approximately 30% of patients with diffuse large B-cell lymphoma (DLBCL) will have recurrence. The aim of this study was to develop a radiomic based model derived from baseline PET/CT to predict 2-year event free survival (2-EFS). METHODS: Patients with DLBCL treated with R-CHOP chemotherapy undergoing pre-treatment PET/CT between January 2008 and January 2018 were included. The dataset was split into training and internal unseen test sets (ratio 80:20). A logistic regression model using metabolic tumour volume (MTV) and six different machine learning classifiers created from clinical and radiomic features derived from the baseline PET/CT were trained and tuned using four-fold cross validation. The model with the highest mean validation receiver operator characteristic (ROC) curve area under the curve (AUC) was tested on the unseen test set. RESULTS: 229 DLBCL patients met the inclusion criteria with 62 (27%) having 2-EFS events. The training cohort had 183 patients with 46 patients in the unseen test cohort. The model with the highest mean validation AUC combined clinical and radiomic features in a ridge regression model with a mean validation AUC of 0.75 ± 0.06 and a test AUC of 0.73. CONCLUSIONS: Radiomics based models demonstrate promise in predicting outcomes in DLBCL patients.

Intensity standardization of MRI prior to radiomic feature extraction for artificial intelligence research in glioma-a systematic review.

OBJECTIVES: Radiomics is a promising avenue in non-invasive characterisation of diffuse glioma. Clinical translation is hampered by lack of reproducibility across centres and difficulty in standardising image intensity in MRI datasets. The study aim was to perform a systematic review of different methods of MRI intensity standardisation prior to radiomic feature extraction. METHODS: MEDLINE, EMBASE, and SCOPUS were searched for articles meeting the following eligibility criteria: MRI radiomic studies where one method of intensity normalisation was compared with another or no normalisation, and original research concerning patients diagnosed with diffuse gliomas. Using PRISMA criteria, data were extracted from short-listed studies including number of patients, MRI sequences, validation status, radiomics software, method of segmentation, and intensity standardisation. QUADAS-2 was used for quality appraisal. RESULTS: After duplicate removal, 741 results were returned from database and reference searches and, from these, 12 papers were eligible. Due to a lack of common pre-processing and different analyses, a narrative synthesis was sought. Three different intensity standardisation techniques have been studied: histogram matching (5/12), limiting or rescaling signal intensity (8/12), and deep learning (1/12)-only two papers compared different methods. From these studies, histogram matching produced the more reliable features compared to other methods of altering MRI signal intensity. CONCLUSION: Multiple methods of intensity standardisation have been described in the literature without clear consensus. Further research that directly compares different methods of intensity standardisation on glioma MRI datasets is required. KEY POINTS: • Intensity standardisation is a key pre-processing step in the development of robust radiomic signatures to evaluate diffuse glioma. • A minority of studies compared the impact of two or more methods. • Further research is required to directly compare multiple methods of MRI intensity standardisation on glioma datasets.

Combined PET-CT and MRI for response evaluation in patients with squamous cell anal carcinoma treated with curative-intent chemoradiotherapy.

OBJECTIVES: To assess the effectiveness of fluorine-18 fluorodeoxyglucose (FDG) positron-emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI) for response assessment post curative-intent chemoradiotherapy (CRT) in anal squamous cell carcinoma (ASCC). METHODS: Consecutive ASCC patients treated with curative-intent CRT at a single centre between January 2018 and April 2020 were retrospectively identified. Clinical meta-data including progression-free survival (PFS) and overall survival (OS) outcomes were collated. Three radiologists evaluated PET-CT and MRI using qualitative response assessment criteria and agreed in consensus. Two-proportion z test was used to compare diagnostic performance metrics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy). Kaplan-Meier analysis (Mantel-Cox log-rank) was performed. RESULTS: MRI (accuracy 76%, PPV 44.8%, NPV 95.7%) and PET-CT (accuracy 69.3%, PPV 36.7%, NPV 91.1%) performance metrics were similar; when combined, there were statistically significant improvements (accuracy 94.7%, PPV 78.9%, NPV 100%). Kaplan-Meier analysis demonstrated significant differences in PFS between responders and non-responders at PET-CT (p = 0.007), MRI (p = 0.005), and consensus evaluation (p < 0.001). Cox regression analysis of PFS demonstrated a lower hazard ratio (HR) and narrower 95% confidence intervals for consensus findings (HR = 0.093, p < 0.001). Seventy-five patients, of which 52 (69.3%) were females, with median follow-up of 17.8 months (range 5-32.6) were included. Fifteen of the 75 (20%) had persistent anorectal and/or nodal disease after CRT. Three patients died, median time to death 6.2 months (range 5-18.3). CONCLUSION: Combined PET-CT and MRI response assessment post-CRT better predicts subsequent outcome than either modality alone. This could have valuable clinical benefits by guiding personalised risk-adapted patient follow-up. KEY POINTS: • MRI and PET-CT performance metrics for assessing response following chemoradiotherapy (CRT) in patients with anal squamous cell carcinoma (ASCC) were similar. • Combined MRI and PET-CT treatment response assessment 3 months after CRT in patients with ASCC was demonstrated to be superior to either modality alone. • A combined MRI and PET-CT assessment 3 months after CRT in patients with ASCC has the potential to improve accuracy and guide optimal patient management with a greater ability to predict outcome than either modality alone.

Impact of 18F-fluciclovine PET/CT on salvage radiotherapy plans for men with recurrence of prostate cancer postradical prostatectomy.

OBJECTIVES: Imaging options to localize biochemical recurrence (BCR) of prostate cancer after radical prostatectomy (RP) are limited, especially at low prostate-specific antigen (PSA) levels. The FALCON study evaluated the impact of 18F-fluciclovine PET/CT on management plans for patients with BCR. Here, we evaluate salvage radiotherapy decisions in patients post-RP. METHODS: We conducted a subgroup analysis of post-RP patients enrolled in FALCON who had a prescan plan for salvage radiotherapy (± androgen-deprivation therapy). Patients' treatment plans post-18F-fluciclovine PET/CT were compared with their prescan plans. Fisher exact test was used to determine the impact of PSA and Gleason sum on positivity and anatomical patterns of uptake. RESULTS: Sixty-five (63%) FALCON patients had undergone RP. Of these, 62 (median PSA, 0.32 ng/mL) had a prescan plan for salvage radiotherapy. Twenty-one (34%) had 18F-fluciclovine-avid lesions. Disease was confined to the prostate bed in 11 patients (52%) and to the pelvis in a further 5 (24%), while 5 (24%) had extrapelvic findings. Trends towards more disseminated disease with increasing PSA or Gleason sum were observed but did not reach statistical significance. Postscan, 25 (40%) patients had a management change; 17 (68%) were changed to the treatment modality (8 to systemic therapy, 8 to active surveillance, 1 other) and 8 (32%) were radiotherapy field modifications. CONCLUSIONS: Incorporating 18F-fluciclovine PET/CT into treatment planning may help identify patients suitable for salvage radiotherapy, help augment planned radiotherapy to better target lesions and support the clinician to optimise patient management.

Salvage Reirradiation Options for Locally Recurrent Prostate Cancer: A Systematic Review.

BACKGROUND: Reirradiation using brachytherapy (BT) and external beam radiation therapy (EBRT) are salvage strategies with locally radiorecurrent prostate cancer. This systematic review describes the oncologic and toxicity outcomes for salvage BT and EBRT [including Stereotactic Body Radiation Therapy (SBRT)]. METHODS: An International Prospective Register of Systematic Reviews (PROSPERO) registered (#211875) study was conducted using Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. EMBASE and MEDLINE databases were searched from inception to December 2020. For BT, both low dose rate (LDR) and high dose rate (HDR) BT techniques were included. Two authors independently assessed study quality using the 18-item Modified Delphi technique. RESULTS: A total of 39 eligible studies comprising 1967 patients were included (28 BT and 11 SBRT). In 35 studies (90%), the design was single centre and/or retrospective and no randomised prospective studies were found. Twelve BT studies used LDR only, 11 HDR only, 4 LDR or HDR and 1 pulsed-dose rate only. All EBRT studies used SBRT exclusively, four with Cyberknife alone and 7 using both Cyberknife and conventional linear accelerator treatments. Median (range) modified Delphi quality score was 15 (6-18). Median (range) follow-up was 47.5 months (13-108) (BT) and 25.4 months (21-44) (SBRT). For the LDR-BT studies, the median (range) 2-year and 5-year bRFS rates were 71% (48-89.5) and 52.5% (20-79). For the HDR-BT studies, the median (range) 2-year and 5-year bRFS rates were 74% (63-89) and 51% (45-65). For the SBRT studies, the median (range) 2-year bRFS for the SBRT group was 54.9% (40-80). Mean (range) acute and late grade≥3 GU toxicity rates for LDR-BT/HDR-BT/SBRT were 7.4%(0-14)/2%(0-14)/2.7%(0-8.7) and 13.6%(0-30)/7.9%(0-21.3%)/2.7%(0-8%). Mean (range) acute and late grade≥3 GI toxicity rates for LDR-BT/HDR-BT/SBRT were 6.5%(0-19)/0%/0.5%(0-4%) and 6.4%(0-20)/0.1%(0-0.9)/0.2%(0-1.5). One third of studies included Patient Reported Outcome Measures (PROMs). CONCLUSIONS: Salvage reirradiation of radiorecurrent prostate cancer using HDR-BT or SBRT provides similar biochemical control and acceptable late toxicity. Salvage LDR-BT is associated with higher late GU/GI toxicity. Challenges exist in comparing BT and SBRT from inconsistencies in reporting with missing data, and prospective randomised trials are needed.

18F-Fluciclovine PET/CT performance in biochemical recurrence of prostate cancer: a systematic review.

BACKGROUND: A systematic literature review of the performance of 18Fluorine-fluciclovine PET/CT for imaging of men with recurrent prostate cancer was performed. METHODS: Scientific literature databases (MEDLINE, ScienceDirect and Cochrane Libraries) were searched systematically during Oct 2020 using PRISMA criteria. No limit was put on the date of publication. Prospective studies reporting a patient-level 18F-fluciclovine detection rate (DR) from ≥25 patients with recurrent prostate cancer were sought. Proceedings of relevant meetings held from 2018 through Oct 2020 were searched for abstracts meeting criteria. RESULTS: Searches identified 321 unique articles. In total, nine articles (six papers and three conference abstracts), comprising a total of 850 patients met inclusion criteria. Most studies (n = 6) relied on ASTRO-Phoenix Criteria, EAU-ESTRO-SIOG, and/or ASTRO-AUA guidelines to identify patients with biochemical recurrence. Patients' PSA levels ranged from 0.02-301.7 ng/mL (median level per study, 0.34-4.10 ng/mL [n = 8]). Approximately 64% of patients had undergone prostatectomy, but three studies focused solely on post-prostatectomy patients. Adherence to imaging protocol guidelines was heterogeneous, with variance seen in administered activity, uptake and scan times. Overall patient-level DR varied between studies from 26% to 83%, with 78% of studies reporting a DR > 50%. DR was proportional to PSA, but even at PSA < 0.5 ng/mL DR of up to 53% were reported. Prostate/bed DR (n = 7) ranged from 18% to 78% and extra-prostatic rates (n = 6) from 8% to 72%. Pelvic node and bone lesion DR ranged from 8% to 47% and 0% to 26%, respectively (n = 5). 18F-Fluciclovine PET/CT was shown to impact patient management and outcomes. Two studies reported 59-63% of patients to have a management change post-scan. A further study showed significant increase in failure-free survival following 18F-fluciclovine-guided compared with conventional imaging-guided radiotherapy planning. CONCLUSIONS: 18F-Fluciclovine PET/CT shows good performance in patients with recurrent prostate cancer leading to measurable clinical benefits. Careful adherence to recommended imaging protocols may help optimize DR.

Effect of 18F-Fluciclovine Positron Emission Tomography on the Management of Patients With Recurrence of Prostate Cancer: Results From the FALCON Trial.

PURPOSE: Early and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, 18F-Fluciclovine PET/CT in biochemicAL reCurrence Of Prostate caNcer (FALCON; NCT02578940), aimed to evaluate the effect of 18F-fluciclovine on management of men with BCR of prostate cancer. METHODS AND MATERIALS: Men with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent 18F-fluciclovine positron emission tomography/computed tomography (PET/CT) according to standardized procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as major and changes within a modality as other. The primary outcome measure was record of a revised management plan postscan. Secondary endpoints were evaluation of optimal prostate specific antigen (PSA) threshold for detection, salvage treatment outcome assessment based on 18F-fluciclovine-involvement, and safety. RESULTS: 18F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA = 0.79 ng/mL). Lesions were detected in 58 out of 104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1 out of 3 of scans were positive, and 93% scans were positive at PSA >2.0 ng/mL. Sixty-six (64%) patients had a postscan management change (80% after a positive result). Major changes (43 out of 66; 65%) were salvage or systemic therapy to watchful waiting (16 out of 66; 24%); salvage therapy to systemic therapy (16 out of 66; 24%); and alternative changes to treatment modality (11 out of 66, 17%). The remaining 23 out of 66 (35%) management changes were modifications of the prescan plan: most (22 out of 66; 33%) were adjustments to planned brachytherapy/radiation therapy to include a 18F-fluciclovine-guided boost. Where 18F-fluciclovine guided salvage therapy, the PSA response rate was higher than when 18F-fluciclovine was not involved (15 out of 17 [88%] vs 28 out of 39 [72%]). CONCLUSIONS: 18F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating 18F-fluciclovine PET/CT into treatment planning may optimize targeting of recurrence sites and avoid futile salvage therapy.

Incidence and patterns of retropharyngeal lymph node involvement in oropharyngeal carcinoma.

INTRODUCTION: The aim was to evaluate in oropharyngeal carcinoma the: (1) incidence and predictors of retropharyngeal (RP) lymph node (LN) involvement, (2) pattern of ipsilateral/bilateral/contralateral-only RP LNs (3) location of RP LNs in relation to contouring guidelines. METHODS: Single centre retrospective analysis of 402 patients with oropharyngeal carcinoma treated non-surgically between 2010 and 2017. All patients had a baseline FDG PET-CT and contrast-enhanced MRI and/or CT. All cases with reported abnormal RP LNs underwent radiology review. RESULTS: Abnormal RP LNs were identified in 40/402 (10%) of patients. On multivariate analysis, RP LN involvement was associated with posterior pharyngeal wall/soft palate primaries (OR 10.13 (95% CI 2.29-19.08), p = 0.002) and contralateral cervical LN involvement (OR 2.26 (95% CI 1.05-4.86), p = 0.036). T stage, largest LN size, levels of ipsilateral LN level involvement, HPV and smoking status did not predict risk. 5/402 (1.2%) patients had bilateral RP involvement. 3/402 patients (0.7%) had contralateral-only RP LNs. All patients with contralateral RP LNs had contralateral neck nodes or primary cancers extending across midline. In 5/40 (12.5%) cases with involved RP LNs, the RP LNs were superior to hard palate/upper edge of body of C1 vertebra. CONCLUSIONS: RP LNs were identified in 10% of oropharyngeal carcinoma patients, and were associated with contralateral neck disease and/or posterior pharyngeal wall/soft palate primary. Contralateral RP LN involvement was rare and associated with contralateral neck disease and/or primary crossing midline, suggesting potential for omission from target volumes for selected patients. Involvement of RP LNs close to the skull base highlights the need for generous elective outlining.

Second-look PET-CT following an initial incomplete PET-CT response to (chemo)radiotherapy for head and neck squamous cell carcinoma.

OBJECTIVES: The limited positive predictive value of an incomplete response on PET-CT following (chemo)radiotherapy for head and neck squamous cell carcinoma (HNSCC) means that the optimal management strategy remains uncertain. The aim of the study is to assess the utility of a 'second-look' interval PET-CT. METHODS: Patients with HNSCC who were treated with (chemo)radiotherapy between 2008 and 2017 and underwent (i) baseline and (ii) response assessment PET-CT and (iii) second-look PET-CT following incomplete (positive or equivocal scan) response were included. Endpoints were conversion rate to complete response (CR) and test characteristics of the second-look PET-CT. RESULTS: Five hundred sixty-two patients with HNSCC underwent response assessment PET-CT at a median of 17 weeks post-radiotherapy. Following an incomplete response on PET-CT, 40 patients underwent a second-look PET-CT at a median of 13 weeks (range 6-25) from the first response PET-CT. Thirty-four out of 40 (85%) patients had oropharyngeal carcinoma. Twenty-four out of 40 (60%) second-look PET-CT scans converted to a complete locoregional response. The primary tumour conversion rate was 15/27 (56%) and the lymph node conversion rate was 14/19 (74%). The sensitivity, specificity, positive predictive value and negative predictive value (NPV) of the second-look PET-CT were 75%, 75%, 25% and 96% for the primary tumour and 100%, 92%, 40% and 100% for lymph nodes. There were no cases of progression following conversion to CR in the primary site or lymph nodes. CONCLUSIONS: The majority of patients who undergo a second-look PET-CT convert to a CR. The NPV of a second-look PET-CT is high, suggesting the potential to avoid surgical intervention. KEY POINTS: • PET-CT is a useful tool for response assessment following (chemo)radiotherapy for head and neck squamous cell carcinoma. • An incomplete response on PET-CT has a limited positive predictive value and optimal management is uncertain. • These data show that with a 'second-look' interval PET-CT, the majority of patients convert to a complete metabolic response. When there is doubt about clinical and radiological response, a 'second-look' PET-CT can be used to spare patients unnecessary surgical intervention.

Retropharyngeal Lymph Node Involvement in Oropharyngeal Carcinoma: Impact upon Risk of Distant Metastases and Survival Outcomes.

The influence of retropharyngeal lymph node (RPLN) involvement on prognosis in oropharyngeal carcinoma remains poorly defined. The aim of this study was to assess the impact of RPLN involvement upon outcomes. A single-centre retrospective analysis of 402 patients with oropharyngeal carcinoma treated nonsurgically between 2010 and 2017 was performed. All had a baseline 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) PET-CT and contrast-enhanced MRI and/or CT. RPLN status was determined by radiology review of cases with reported abnormal RPLN. Multivariate backwards logistic regression was used to examine impact on outcomes of factors. Abnormal RPLNs were identified in 40/402 (10%) of patients. Median follow up was 42.9 months. RPLN involvement was associated with inferior 3 year outcomes for overall survival (OS) (67.1% vs. 79.1%, p = 0.006) and distant metastases-free survival (DMFS) (73.9% versus 88.0%, p = 0.011), with no significant difference in local control (81.6% vs. 87.7%, p = 0.154) or regional control (80.7% vs. 85.4%, p = 0.252). On multivariate analysis abnormal RPLN, no concurrent chemotherapy and ongoing smoking were associated with inferior DMFS and OS, while advanced T stage was also associated with inferior OS. In summary, RPLN involvement, present in 10% of patients, was an independent prognostic factor for the development of distant disease failure translating into inferior OS. These findings need confirmation in future studies.

Accuracy of [18Fluorine]-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography-Computed Tomography Response Assessment Following (Chemo)radiotherapy for Locally Advanced Laryngeal/Hypopharyngeal Carcinoma.

INTRODUCTION: The accuracy of response assessment positron emission tomography (PET)-computed tomography (CT) following radiotherapy with or without chemotherapy for laryngeal/hypopharyngeal squamous cell carcinoma is uncertain. METHODS: In all, 35 patients with laryngeal or hypopharyngeal squamous cell carcinoma who were treated between 2009 and 2014 with (chemo)radiotherapy were identified. The accuracy of response assessment PET-CT was made by correlation with clinical follow-up and pathological findings. RESULTS: Of the 35 patients, 20 (57%) had an overall complete metabolic response. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for response assessment [18Fluorine]-fluoro-2-deoxy-d-glucose (FDG) PET-CT for primary and nodal sites, respectively, were 100%, 73%, 46%, and 100% and 83%, 95%, 83%, and 95%. CONCLUSIONS: Response assessment FDG PET-CT following (chemo)radiotherapy for laryngeal and hypopharyngeal carcinomas has a high NPV for both primary site and lymph nodes and can be used to guide treatment decisions. The PPV of residual FDG uptake at the primary tumour site is limited and requires examination and biopsy confirmation.

Evaluation of clinical target volume expansion required for involved site neck radiotherapy for lymphoma to account for the absence of a pre-chemotherapy PET-CT in the radiotherapy treatment position.

BACKGROUND AND PURPOSE: Involved site radiotherapy clinical target volume (CTV) for lymphoma requires an expansion to account for the absence of radiotherapy treatment-position pre-chemotherapy imaging, which is not widely implemented. This prospective imaging study aims to quantify CTV expansion required for neck radiotherapy. MATERIALS AND METHODS: 10 patients from a prospective single centre imaging study underwent a pre-chemotherapy FDG-PET-CT in both the diagnostic and radiotherapy treatment position, and subsequently received neck radiotherapy post-chemotherapy. CTVINRT and CTVdiagPET were delineated on the planning CT, following co-registration of the radiotherapy position PET-CT and side-by-side assessment of diagnostic PET-CT respectively. RESULTS: Intra-observer variability was limited, with delineation of CTVINRT highly reproducible and slightly lower for CTVdiagPET (mean DICE 0.88 and 0.8 respectively). Superiorly, CTVdiagPET varied by -10 to +15mm from CTVINRT. Inferiorly, CTVdiagPET varied by -18 to +6mm from CTVINRT. Comparing CTVINRT and CTVdiagPET in the axial plane, the mean DICE was 0.74. Mean sensitivity index was 0.75 (range 0.59-0.91), showing that on average 75% of the CTVINRT was encompassed by the CTVdiagPET. CONCLUSIONS: In the absence of treatment-position PET-CT, CTV expansion cranially and caudally by 10mm and 18mm respectively, along with generous contouring in the axial plane, was required to encompass pre-chemotherapy disease.

Multimodality imaging with CT, MR and FDG-PET for radiotherapy target volume delineation in oropharyngeal squamous cell carcinoma.

BACKGROUND: This study aimed to quantify the variation in oropharyngeal squamous cell carcinoma gross tumour volume (GTV) delineation between CT, MR and FDG PET-CT imaging. METHODS: A prospective, single centre, pilot study was undertaken where 11 patients with locally advanced oropharyngeal cancers (2 tonsil, 9 base of tongue primaries) underwent pre-treatment, contrast enhanced, FDG PET-CT and MR imaging, all performed in a radiotherapy treatment mask. CT, MR and CT-MR GTVs were contoured by 5 clinicians (2 radiologists and 3 radiation oncologists). A semi-automated segmentation algorithm was used to contour PET GTVs. Volume and positional analyses were undertaken, accounting for inter-observer variation, using linear mixed effects models and contour comparison metrics respectively. RESULTS: Significant differences in mean GTV volume were found between CT (11.9 cm(3)) and CT-MR (14.1 cm(3)), p < 0.006, CT-MR and PET (9.5 cm(3)), p < 0.0009, and MR (12.7 cm(3)) and PET, p < 0.016. Substantial differences in GTV position were found between all modalities with the exception of CT-MR and MR GTVs. A mean of 64 %, 74 % and 77 % of the PET GTVs were included within the CT, MR and CT-MR GTVs respectively. A mean of 57 % of the MR GTVs were included within the CT GTV; conversely a mean of 63 % of the CT GTVs were included within the MR GTV. CT inter-observer variability was found to be significantly higher in terms of position and/or volume than both MR and CT-MR (p < 0.05). Significant differences in GTV volume were found between GTV volumes delineated by radiologists (9.7 cm(3)) and oncologists (14.6 cm(3)) for all modalities (p = 0.001). CONCLUSIONS: The use of different imaging modalities produced significantly different GTVs, with no single imaging technique encompassing all potential GTV regions. The use of MR reduced inter-observer variability. These data suggest delineation based on multimodality imaging has the potential to improve accuracy of GTV definition. TRIAL REGISTRATION: ISRCTN Registry: ISRCTN34165059 . Registered 2nd February 2015.

Alterations in anatomic and functional imaging parameters with repeated FDG PET-CT and MRI during radiotherapy for head and neck cancer: a pilot study.

BACKGROUND: The use of imaging to implement on-treatment adaptation of radiotherapy is a promising paradigm but current data on imaging changes during radiotherapy is limited. This is a hypothesis-generating pilot study to examine the changes on multi-modality anatomic and functional imaging during (chemo)radiotherapy treatment for head and neck squamous cell carcinoma (HNSCC). METHODS: Eight patients with locally advanced HNSCC underwent imaging including computed tomography (CT), Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT and magnetic resonance imaging (MRI) (including diffusion weighted (DW) and dynamic contrast enhanced (DCE)) at baseline and during (chemo)radiotherapy treatment (after fractions 11 and 21). Regions of interest (ROI) were drawn around the primary tumour at baseline and during treatment. Imaging parameters included gross tumour volume (GTV) assessment, SUVmax, mean ADC value and DCE-MRI parameters including Plasma Flow (PF). On treatment changes and correlations between these parameters were analysed using a Wilcoxon rank sum test and Pearson's linear correlation coefficient respectively. A p-value <0.05 was considered statistically significant. RESULTS: Statistically significant reductions in GTV-CT, GTV-MRI and GTV-DW were observed between all imaging timepoints during radiotherapy. Changes in GTV-PET during radiotherapy were heterogeneous and non-significant. Significant changes in SUVmax, mean ADC value, Plasma Flow and Plasma Volume were observed between the baseline and the fraction 11 timepoint, whilst only changes in SUVmax between baseline and the fraction 21 timepoint were statistically significant. Significant correlations were observed between multiple imaging parameters, both anatomical and functional; 20 correlations between baseline to the fraction 11 timepoint; 12 correlations between baseline and the fraction 21 timepoints; and 4 correlations between the fraction 11 and fraction 21 timepoints. CONCLUSIONS: Multi-modality imaging during radiotherapy treatment demonstrates early changes (by fraction 11) in both anatomic and functional imaging parameters. All functional imaging modalities are potentially complementary and should be considered in combination to provide multi-parametric tumour assessment, to guide potential treatment adaptation strategies. TRIAL REGISTRATION: ISRCTN Registry: ISRCTN34165059 . Registered 2nd February 2015.

Functional imaging for radiation treatment planning, response assessment, and adaptive therapy in head and neck cancer.

Patients with squamous cell carcinomas (SCCs) of the head and neck are increasingly treated nonsurgically. Imaging plays a critical role in helping define the targets for radiation therapy, especially intensity-modulated radiation therapy, in which the dose gradients are steep. Anatomic imaging with conventional modalities, particularly computed tomography (CT), has been used in patients with head and neck SCCs, but this approach has limitations. Functional imaging techniques, including positron emission tomography (PET) combined with CT or magnetic resonance (MR) imaging, offer complementary information and can be used noninvasively to assess a range of biomarkers in patients with head and neck SCCs, including hypoxia, cell proliferation and apoptosis, and epidermal growth factor receptor status. These biologic markers can be monitored before, during, and after treatment to improve patient selection for specific therapeutic strategies, guide adaptation of therapy, and potentially facilitate more accurate assessment of disease response. This article discusses the practical aspects of integrating functional imaging into head-and-neck radiation therapy planning and reviews the potential of molecular imaging biomarkers for response assessment and therapy adaptation. The uses of PET tracers for imaging cellular processes such as metabolism, proliferation, hypoxia, and cell membrane synthesis are explored, and applications for MR techniques such as dynamic contrast material-enhanced imaging, diffusion-weighted imaging, blood oxygenation level-dependent imaging, and MR spectroscopy are reviewed. The potential of integrated PET/CT perfusion imaging and hybrid PET/MR imaging also is highlighted. These developments may allow more individualized treatment planning in patients with head and neck SCCs in the emerging era of personalized medicine.

Clinical impact of (18)F-FDG PET-CT in recurrent stage III/IV melanoma: a tertiary centre Specialist Skin Cancer Multidisciplinary Team (SSMDT) experience.

OBJECTIVES: To assess the clinical impact of (18)F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) compared with contrast-enhanced computed tomography (CECT) in patients referred via the Specialist Skin Cancer Multidisciplinary Team (SSMDT) with recurrent stage III/IV malignant melanoma (MM). METHODS: Forty-five patients were referred for further evaluation with FDG PET-CT. Findings on FDG PET-CT were compared with prior CECT and the clinical impact on subsequent management decisions was determined retrospectively. A major clinical impact was defined as a change in treatment plan resulting from identification of additional sites of disease or by characterisation of indeterminate findings on prior imaging. A minor impact was defined as confirmation of known sites of disease as identified on prior CECT. RESULTS: Fifty-one PET-CT examinations were performed. FDG PET-CT had a major clinical impact in 21 cases (41.2 %), of which 18 examinations were performed in patients with proven or suspected stage IV MM. FDG PET-CT had a minor impact in 23 cases (45.1 %), and there were five false-positive cases (9.8 %) and two false-negative cases (3.9 %). CONCLUSION: FDG PET-CT is an effective tool in recurrent stage III/IV MM with a significant clinical impact on management decisions in patients who are appropriately referred via the highly specialised forum of the SSMDT. KEY POINTS: • FDG PET-CT is an effective tool in recurrent stage III/IV malignant melanoma. • FDG PET-CT has a significant clinical impact on management decisions. • Effective use of FDG PET-CT is via referral from the Specialist Skin Cancer Multidisciplinary Team.