18F-FDG PET baseline radiomics features improve the prediction of treatment outcome in diffuse large B-cell lymphoma.

PURPOSE: Accurate prognostic markers are urgently needed to identify diffuse large B-Cell lymphoma (DLBCL) patients at high risk of progression or relapse. Our purpose was to investigate the potential added value of baseline radiomics features to the international prognostic index (IPI) in predicting outcome after first-line treatment. METHODS: Three hundred seventeen newly diagnosed DLBCL patients were included. Lesions were delineated using a semi-automated segmentation method (standardized uptake value ≥ 4.0), and 490 radiomics features were extracted. We used logistic regression with backward feature selection to predict 2-year time to progression (TTP). The area under the curve (AUC) of the receiver operator characteristic curve was calculated to assess model performance. High-risk groups were defined based on prevalence of events; diagnostic performance was assessed using positive and negative predictive values. RESULTS: The IPI model yielded an AUC of 0.68. The optimal radiomics model comprised the natural logarithms of metabolic tumor volume (MTV) and of SUVpeak and the maximal distance between the largest lesion and any other lesion (Dmaxbulk, AUC 0.76). Combining radiomics and clinical features showed that a combination of tumor- (MTV, SUVpeak and Dmaxbulk) and patient-related parameters (WHO performance status and age > 60 years) performed best (AUC 0.79). Adding radiomics features to clinical predictors increased PPV with 15%, with more accurate selection of high-risk patients compared to the IPI model (progression at 2-year TTP, 44% vs 28%, respectively). CONCLUSION: Prediction models using baseline radiomics combined with currently used clinical predictors identify patients at risk of relapse at baseline and significantly improved model performance. TRIAL REGISTRATION NUMBER AND DATE: EudraCT: 2006-005,174-42, 01-08-2008.

Comparing lesion and feature selections to predict progression in newly diagnosed DLBCL patients with FDG PET/CT radiomics features.

PURPOSE: Biomarkers that can accurately predict outcome in DLBCL patients are urgently needed. Radiomics features extracted from baseline [18F]-FDG PET/CT scans have shown promising results. This study aims to investigate which lesion- and feature-selection approaches/methods resulted in the best prediction of progression after 2 years. METHODS: A total of 296 patients were included. 485 radiomics features (n = 5 conventional PET, n = 22 morphology, n = 50 intensity, n = 408 texture) were extracted for all individual lesions and at patient level, where all lesions were aggregated into one VOI. 18 features quantifying dissemination were extracted at patient level. Several lesion selection approaches were tested (largest or hottest lesion, patient level [all with/without dissemination], maximum or median of all lesions) and compared to the predictive value of our previously published model. Several data reduction methods were applied (principal component analysis, recursive feature elimination (RFE), factor analysis, and univariate selection). The predictive value of all models was tested using a fivefold cross-validation approach with 50 repeats with and without oversampling, yielding the mean cross-validated AUC (CV-AUC). Additionally, the relative importance of individual radiomics features was determined. RESULTS: Models with conventional PET and dissemination features showed the highest predictive value (CV-AUC: 0.72-0.75). Dissemination features had the highest relative importance in these models. No lesion selection approach showed significantly higher predictive value compared to our previous model. Oversampling combined with RFE resulted in highest CV-AUCs. CONCLUSION: Regardless of the applied lesion selection or feature selection approach and feature reduction methods, patient level conventional PET features and dissemination features have the highest predictive value. Trial registration number and date: EudraCT: 2006-005174-42, 01-08-2008.

Machine learning-based analysis of [18F]DCFPyL PET radiomics for risk stratification in primary prostate cancer.

PURPOSE: Quantitative prostate-specific membrane antigen (PSMA) PET analysis may provide for non-invasive and objective risk stratification of primary prostate cancer (PCa) patients. We determined the ability of machine learning-based analysis of quantitative [18F]DCFPyL PET metrics to predict metastatic disease or high-risk pathological tumor features. METHODS: In a prospective cohort study, 76 patients with intermediate- to high-risk PCa scheduled for robot-assisted radical prostatectomy with extended pelvic lymph node dissection underwent pre-operative [18F]DCFPyL PET-CT. Primary tumors were delineated using 50-70% peak isocontour thresholds on images with and without partial-volume correction (PVC). Four hundred and eighty standardized radiomic features were extracted per tumor. Random forest models were trained to predict lymph node involvement (LNI), presence of any metastasis, Gleason score ≥ 8, and presence of extracapsular extension (ECE). For comparison, models were also trained using standard PET features (SUVs, volume, total PSMA uptake). Model performance was validated using 50 times repeated 5-fold cross-validation yielding the mean receiver-operator characteristic curve AUC. RESULTS: The radiomics-based machine learning models predicted LNI (AUC 0.86 ± 0.15, p < 0.01), nodal or distant metastasis (AUC 0.86 ± 0.14, p < 0.01), Gleason score (0.81 ± 0.16, p < 0.01), and ECE (0.76 ± 0.12, p < 0.01). The highest AUCs reached using standard PET metrics were lower than those of radiomics-based models. For LNI and metastasis prediction, PVC and a higher delineation threshold improved model stability. Machine learning pre-processing methods had a minor impact on model performance. CONCLUSION: Machine learning-based analysis of quantitative [18F]DCFPyL PET metrics can predict LNI and high-risk pathological tumor features in primary PCa patients. These findings indicate that PSMA expression detected on PET is related to both primary tumor histopathology and metastatic tendency. Multicenter external validation is needed to determine the benefits of using radiomics versus standard PET metrics in clinical practice.

The quantitative assessment of interstitial lung disease with positron emission tomography scanning in systemic sclerosis patients.

OBJECTIVES: The reversibility of interstitial lung disease (ILD) in SSc is difficult to assess by current diagnostic modalities and there is clinical need for imaging techniques that allow for treatment stratification and monitoring. 18F-Fluorodeoxyglucose (FDG) PET/CT scanning may be of interest for this purpose by detection of metabolic activity in lung tissue. This study aimed to investigate the potential role of 18F-FDG PET/CT scanning for the quantitative assessment of SSc-related active ILD. METHODS: 18F-FDG PET/CT scans and high resolution CT scans of eight SSc patients, including five with ILD, were analysed. For comparison, reference groups were included: eight SLE patients and four primary Sjögren's syndrome (pSS) patients, all without ILD. A total of 22 regions of interest were drawn in each patient at apical, medial and dorsobasal lung levels. 18F-FDG uptake was measured as mean standardized uptake value (SUVmean) in each region of interest. Subsequently, basal/apical (B/A) and medial/apical (M/A) ratios were calculated at patient level (B/A-p and M/A-p) and at tissue level (B/A-t and M/A-t). RESULTS: SUVmean values in dorsobasal ROIs and B/A-p ratios were increased in SSc with ILD compared with SSc without ILD (P = 0.04 and P = 0.07, respectively), SLE (P = 0.003 and P = 0.002, respectively) and pSS (P = 0.03 and P = 0.02, respectively). Increased uptake in the dorsobasal lungs and increased B/A-t ratios corresponded to both ground glass and reticulation on high resolution CT. CONCLUSION: Semi-quantitative assessment of 18F-FDG PET/CT is able to distinguish ILD from non-affected lung tissue in SSc, suggesting that it may be used as a new biomarker for SSc-ILD disease activity.

Outcome-based interpretation of early interim PET in advanced-stage Hodgkin lymphoma.

The HD18 study for patients with newly diagnosed advanced-stage Hodgkin lymphoma (HL) used positron emission tomography (PET) after 2 cycles (PET-2) of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses (eBEACOPP) to guide further treatment. Here, we analyzed the impact of PET-2 results in the context of eBEACOPP according to the Deauville score (DS) in patients treated within the HD18 trial. Residual tissue was visually compared with reference regions according to DS. We analyzed the association between PET-2 uptake and baseline characteristics, progression-free survival (PFS), and overall survival (OS). One thousand five patients (52%) had DS1 or DS2, 471 (24%) had DS3, and 469 (24%) DS4. PET-2 uptake was associated with baseline risk factors large mediastinal mass, extranodal disease, and high International Prognostic Score (P < .0001 each). Among 722 patients receiving standard therapy with 6 cycles of eBEACOPP, 3-year PFS rates were 92.2%, 95.9%, and 87.6% with DS1-2, DS3, and DS4, respectively. Univariate hazard ratio (HR) for PFS in patients with DS4 vs DS1-3 was 2.3 (1.3-3.8; P = .002). DS4 was the only factor remaining significant for PFS in a multivariate analysis including the associated baseline risk factors. Three-year OS rates were 97.6% for DS1-2, 99.0% for DS3, and 96.8% for DS4, with a univariate HR for DS4 vs DS1-3 of 2.6 (1.0-6.6; P = .04). Residual uptake above that in the liver at PET-2 (ie, DS4) is an important risk factor regarding survival outcomes for patients treated with eBEACOPP upfront. We thus recommend DS4 as the cutoff value for PET-2 positivity. This trial was registered at www.clinicaltrials.gov as #NCT00515554.

Treatment of patients with MYC rearrangement positive large B-cell lymphoma with R-CHOP plus lenalidomide: results of a multicenter HOVON phase II trial.

Patients with MYC-rearrangement positive large B-cell lymphoma (MYC+ LBCL) have an inferior prognosis following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) as compared to patients without MYC rearrangement. Although intensive chemotherapy regimens yield higher remission rates, toxicity remains a concern. Lenalidomide is an oral immunomodulatory drug which downregulates MYC and its target genes thereby providing support using lenalidomide as additional therapeutic option for MYC+ LBCL. A phase II trial was conducted evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients identified through a nationwide MYC-FISH screening program. The primary endpoint was complete metabolic response (CMR) on centrally reviewed 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-computer tomography (CT)-scan at end-of-treatment. Secondary endpoints were overall survival (OS), disease-free survival (DFS) and event-free survival (EFS). Eighty-two patients with stage II-IV MYC+ LBCL were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 25.4 months, 2-year estimates (95% CI) for OS, DFS, EFS were 73% (62-82%), 75% (63-84%) and 63% (52-73%) respectively. In this prospective trial for newly diagnosed MYC+ LBCL patients, we found that administering R2CHOP was safe, and yields comparable CMR and survival rates as in studies applying more intensive chemotherapy regimens. Hence, these findings offer new prospects for MYC+ LBCL patients and warrant comparison in prospective randomized clinical trials. This trial was registered at www.clinicaltrialsregister.eu (#2014-002654-39).

Quantification of 18F-fluorodeoxyglucose uptake to detect residual nodal disease in locally advanced head and neck squamous cell carcinoma after chemoradiotherapy: results from the ECLYPS study.

BACKGROUND: The Hopkins criteria were introduced for nodal response evaluation after therapy in head and neck cancer, but its superiority over quantification is not yet confirmed. METHODS: SUVbody weight thresholds and lesion-to-background ratios were explored in a prospective multicenter study of standardized FDG-PET/CT 12 weeks after CRT in newly diagnosed locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients (ECLYPS). Reference standard was histology, negative FDG-PET/CT at 12 months after treatment or ≥ 2 years of negative follow-up. Area under the receiver operator characteristics curves (AUROC) were estimated and obtained thresholds were validated in an independent cohort of HNSCC patients (n = 127). RESULTS: In ECLYPS, 124 patients were available for quantification. With a median follow-up of 20.4 months, 23 (18.5%) nodal neck recurrences were observed. A SUV70 threshold of 2.2 (AUROC = 0.89; sensitivity = 79.7%; specificity = 80.8%) was identified as optimal metric to identify nodal recurrence within 1 year after therapy. For lesion-to-background ratios, an SUV50/SUVliver threshold of 0.96 (AUROC = 0.89; sensitivity = 79.7%; specificity = 82.8%) had the best performance. Compared with Hopkins criteria (AUROC = 0.81), SUV70 and SUV50/SUVliver provided a borderline significant (p = 0.040 and p = 0.094, respectively) improvement. Validation of thresholds yielded similar AUROC values (SUV70 = 0.93, SUV50/SUVliver = 0.95), and were comparable to the Hopkins score (AUROC = 0.91; not statistically significant). CONCLUSION: FDG quantification detects nodal relapse in LAHNSCC patients. When using EARL standardized PET acquisitions and reconstruction, absolute SUV metrics (SUV70 threshold 2.2) prove robust, yet ratios (SUV50/SUVliver, threshold 0.96) may be more useful in routine clinical care. In this setting, the diagnostic value of quantification is comparable to the Hopkins criteria. TRIAL REGISTRATION: US National Library for Medicine, NCT01179360. Registered 11 August 2010, https://clinicaltrials.gov/ct2/show/NCT01179360.

Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study.

BACKGROUND: Retrospective studies suggest that low molecular weight heparin may delay the development of metastasis in patients with resected NSCLC. METHODS: Multicentre phase 3 study with patients with completely resected NSCLC who were randomised after surgery to receive chemotherapy with or without nadroparin. The main exclusion criteria were R1/2 and wedge/segmental resection. FDG-PET was required. The primary endpoint was recurrence-free survival (RFS). RESULTS: Among 235 registered patients, 202 were randomised (nadroparin: n = 100; control n = 102). Slow accrual enabled a decrease in the number of patients needed from 600 to 202, providing 80% power to compare RFS with 94 events (α = 0.05; 2-sided). There were no differences in bleeding events between the two groups. The median RFS was 65.2 months (95% CI, 36-NA) in the nadroparin arm and 37.7 months (95% CI, 22.7-NA) in the control arm (HR 0.77 (95% CI, 0.53-1.13, P = 0.19). FDG-PET SUVmax ≥10 predicted a greater likelihood of recurrence in the first year (HR 0.48, 95% CI 0.22-0.9, P = 0.05). CONCLUSIONS: Adjuvant nadroparin did not improve RFS in patients with resected NSCLC. In this study, a high SUVmax predicted a greater likelihood of recurrence in the first year. CLINICAL TRIAL REGISTRATION: Netherlands Trial registry: NTR1250/1217.

Predictive value of interim positron emission tomography in diffuse large B-cell lymphoma: a systematic review and meta-analysis.

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma. Most relapses occur in the first 2 years after diagnosis. Early response assessment with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) may facilitate early change of treatment, thereby preventing ineffective treatment and unnecessary side effects. We aimed to assess the predictive value of visually-assessed interim 18F-FDG PET on progression-free survival (PFS) or event-free survival (EFS) in DLBCL patients treated with first-line immuno-chemotherapy regimens. METHODS: For this systematic review and meta-analysis Pubmed, Embase, and the Cochrane Library were searched until July 11, 2017. Prospective and retrospective studies investigating qualitative interim PET response assessment without treatment adaptation based on the interim PET result were eligible. The primary outcome was two-year PFS or EFS. Prognostic and diagnostic measures were extracted and analysed with pooled hazard ratios and Hierarchical Summary Receiver Operator Characteristic Curves, respectively. Meta-regression was used to study covariate effects. RESULTS: The pooled hazard ratio for 18 studies comprising 2,255 patients was 3.13 (95%CI 2.52-3.89) with a 95% prediction interval of 1.68-5.83. In 19 studies with 2,366 patients, the negative predictive value for progression generally exceeded 80% (64-95), but sensitivity (33-87), specificity (49-94), and positive predictive values (20-74) ranged widely. CONCLUSIONS: These findings showed that interim 18F-FDG PET has predictive value in DLBCL patients. However, (subgroup) analyses were limited by lack of information and small sample sizes. Some diagnostic test characteristics were not satisfactory, especially the positive predictive value should be improved, before a successful risk stratified treatment approach can be implemented in clinical practice.

Interobserver reproducibility of tumor uptake quantification with 89Zr-immuno-PET: a multicenter analysis.

PURPOSE: In-vivo quantification of tumor uptake of 89-zirconium (89Zr)-labelled monoclonal antibodies (mAbs) with PET provides a potential tool in strategies to optimize tumor targeting and therapeutic efficacy. A specific challenge for 89Zr-immuno-PET is low tumor contrast. This is expected to result in interobserver variation in tumor delineation. Therefore, the aim of this study was to determine interobserver reproducibility of tumor uptake measures by tumor delineation on 89Zr-immuno-PET scans. METHODS: Data were obtained from previously published clinical studies performed with 89Zr-rituximab, 89Zr-cetuximab and 89Zr-trastuzumab. Tumor lesions on 89Zr-immuno-PET were identified as focal uptake exceeding local background by a nuclear medicine physician. Three observers independently manually delineated volumes of interest (VOI). Maximum, peak and mean standardized uptake values (SUVmax, SUVpeak and SUVmean) were used to quantify tumor uptake. Interobserver variability was expressed as the coefficient of variation (CoV). The performance of semi-automatic VOI delineation using 50% of background-corrected ACpeak was described. RESULTS: In total, 103 VOI were delineated (3-6 days post injection (D3-D6)). Tumor uptake (median, interquartile range) was 9.2 (5.2-12.6), 6.9 (4.0-9.6) and 5.5 (3.3-7.8) for SUVmax, SUVpeak and SUVmean. Interobserver variability was 0% (0-12), 0% (0-2) and 7% (5-14), respectively (n = 103). The success rate of the semi-automatic method was 45%. Inclusion of background was the main reason for failure of semi-automatic VOI. CONCLUSIONS: This study shows that interobserver reproducibility of tumor uptake quantification on 89Zr-immuno-PET was excellent for SUVmax and SUVpeak using a standardized manual procedure for tumor segmentation. Semi-automatic delineation was not robust due to limited tumor contrast.

Lesion detection by [89Zr]Zr-DFO-girentuximab and [18F]FDG-PET/CT in patients with newly diagnosed metastatic renal cell carcinoma.

PURPOSE: The main objective of this preliminary analysis of the IMaging PAtients for Cancer drug selecTion (IMPACT)-renal cell cancer (RCC) study is to evaluate the lesion detection of baseline contrast-enhanced CT, [89Zr]Zr-DFO-girentuximab-PET/CT and [18F]FDG-PET/CT in detecting ccRCC lesions in patients with a good or intermediate prognosis metastatic clear cell renal cell carcinoma (mccRCC) according to the International Metastatic Database Consortium (IMDC) risk model. METHODS: Between February 2015 and March 2018, 42 newly diagnosed mccRCC patients with good or intermediate prognosis, eligible for watchful waiting, were included. Patients underwent CT, [89Zr]Zr-DFO-girentuximab-PET/CT and [18F]FDG-PET/CT at baseline. Scans were independently reviewed and lesions of ≥10 mm and lymph nodes of ≥15 mm at CT were analyzed. For lesions with [89Zr]Zr-DFO-girentuximab or [18F]FDG-uptake visually exceeding background uptake, maximum standardized uptake values (SUVmax) were measured. RESULTS: A total of 449 lesions were detected by ≥1 modality (median per patient: 7; ICR 4.25-12.75) of which 42% were in lung, 22% in lymph nodes and 10% in bone. Combined [89Zr]Zr-DFO-girentuximab-PET/CT and CT detected more lesions than CT alone: 91% (95%CI: 87-94) versus 56% (95%CI: 50-62, p = 0.001), respectively, and more than CT and [18F]FDG-PET/CT combined (84% (95%CI:79-88, p < 0.005). Both PET/CTs detected more bone and soft tissue lesions compared to CT alone. CONCLUSIONS: The addition of [89Zr]Zr-DFO-girentuximab-PET/CT and [18F]FDG-PET/CT to CT increases lesion detection compared to CT alone in newly diagnosed good and intermediate prognosis mccRCC patients eligible for watchful waiting.

F8-IL10: A New Potential Antirheumatic Drug Evaluated by a PET-Guided Translational Approach.

Antibody fragment F8-mediated interleukin 10 (IL10) delivery is a novel treatment for rheumatoid arthritis (RA). F8 binds to the extra-domain-A of fibronectin (ED-A). In this study, in vivo biodistribution and arthritis targeting of radiolabeled F8-IL10 were investigated in RA patients, followed by further animal studies. Therefore, three RA patients (DAS28 > 3.2) received 0.4 mg of 30-74 megabecquerel [124I]I-F8-IL10 for PET-CT and blood sampling. In visually identified PET-positive joints, target-to-background was calculated. Healthy mice, rats, and arthritic rats were injected with iodinated F8-IL10 or KSF-IL10 control antibody. Various organs were excised, weighed, and counted for radioactivity. Tissue sections were stained for fibronectin ED-A. In RA patients, [124I]I-F8-IL10 was cleared rapidly from the circulation with less than 1% present in blood after 5 min. PET-CT showed targeting in 38 joints (11-15 per patient) and high uptake in the liver and spleen. Mean target-to-background ratios of PET-positive joints were 2.5 ± 1.2, 1.5 times higher for clinically active than clinically silent joints. Biodistribution of radioiodinated F8-IL10 in healthy mice showed no effect of the radioiodination method. [124I]I-F8-IL10 joint uptake was also demonstrated in arthritic rats, ∼14-fold higher than that of the control antibody [124I]I-KSF-IL10 ( p < 0.001). Interestingly, liver and spleen uptake were twice as high in arthritic than in healthy rats and were related to increased (∼7×) fibronectin ED-A expression in these tissues. In conclusion, [124I]I-F8-IL10 uptake was observed in arthritic joints in RA patients holding promise for visualization of inflamed joints by PET-CT imaging and therapeutic targeting. Patient observations and, subsequently, arthritic animal studies pointed to awareness of increased [124I]I-F8-IL10 uptake in the liver and spleen associated with moderate systemic inflammation. This translational study demonstrated the value of in vivo biodistribution and PET-CT-guided imaging in development of new and potential antirheumatic drugs'.

Is C-11 Methionine PET an alternative to 18-F FDG-PET for identifying recurrent laryngeal cancer after radiotherapy?

OBJECTIVE: 18F FDG-PET is superior to other imaging techniques in revealing residual laryngeal cancer after radiotherapy. Unfortunately, its specificity is low, due to FDG uptake in inflammation and in anaerobic conditions. PET imaging with the amino acid-based radiopharmaceutical C11-methionine (MET) should be less influenced by post-radiation conditions. The aim of this study was to investigate the potential of MET in diagnosing recurrent laryngeal cancer after radiotherapy as compared to 18F-FDG. METHODS: Forty-eight patients with a clinical suspicion of local residual disease at least 3 months after completion of radiotherapy or chemoradiotherapy for a T2-4 laryngeal carcinoma, along with an indication for direct laryngoscopy, were included. They received MET-PET and FDG-PET prior to the direct laryngoscopy. One senior nuclear medicine physician assessed both the FDG-PET and MET-PET images visually for the degree of abnormal uptake. The gold standard was a biopsy-proven recurrence 12 months after PET. The nuclear physician had no access to the medical charts and was blinded to the results of the other PET. Sensitivity, specificity and positive and negative predictive value were calculated. RESULTS: The sensitivity of FDG was 77.3% and the specificity 56.0% after the conservative reading, with these values equalling 54.5% and 76.0% for MET. The positive predictive value of FDG was 60.7% and the negative predictive value 73.7%. The PPV of MET was 66.7%, and the NPV was 65.5%. The McNemar test within diseased (sensitivity comparison) shows a p-value of 0.125, and the McNemar test within non-diseased (specificity comparison) shows a P-value of 0.180. CONCLUSION: MET-PET is not superior to FDG-PET in terms of identifying recurrent laryngeal cancer.

Use of modern imaging methods to facilitate trials of metastasis-directed therapy for oligometastatic disease in prostate cancer: a consensus recommendation from the EORTC Imaging Group.

Oligometastatic disease represents a clinical and anatomical manifestation between localised and polymetastatic disease. In prostate cancer, as with other cancers, recognition of oligometastatic disease enables focal, metastasis-directed therapies. These therapies potentially shorten or postpone the use of systemic treatment and can delay further metastatic progression, thus increasing overall survival. Metastasis-directed therapies require imaging methods that definitively recognise oligometastatic disease to validate their efficacy and reliably monitor response, particularly so that morbidity associated with inappropriately treating disease subsequently recognised as polymetastatic can be avoided. In this Review, we assess imaging methods used to identify metastatic prostate cancer at first diagnosis, at biochemical recurrence, or at the castration-resistant stage. Standard imaging methods recommended by guidelines have insufficient diagnostic accuracy for reliably diagnosing oligometastatic disease. Modern imaging methods that use PET-CT with tumour-specific radiotracers (choline or prostate-specific membrane antigen ligand), and increasingly whole-body MRI with diffusion-weighted imaging, allow earlier and more precise identification of metastases. The European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group suggests clinical algorithms to integrate modern imaging methods into the care pathway at the various stages of prostate cancer to identify oligometastatic disease. The EORTC proposes clinical trials that use modern imaging methods to evaluate the benefits of metastasis-directed therapies.

Bone formation in ankylosing spondylitis during anti-tumour necrosis factor therapy imaged by 18F-fluoride positron emission tomography.

Objectives: Excessive bone formation is an important hallmark of AS. Recently it has been demonstrated that axial bony lesions in AS patients can be visualized using 18F-fluoride PET-CT. The aim of this study was to assess whether 18F-fluoride uptake in clinically active AS patients is related to focal bone formation in spine biopsies and is sensitive to change during anti-TNF treatment. Methods: Twelve anti-TNF-naïve AS patients [female 7/12; age 39 years (SD 11); BASDAI 5.5 ± 1.1] were included. 18 F-fluoride PET-CT scans were performed at baseline and in two patients, biopsies were obtained from PET-positive and PET-negative spine lesions. The remaining 10 patients underwent a second 18F-fluoride PET-CT scan after 12 weeks of anti-TNF treatment. PET scans were scored visually by two blinded expert readers. In addition, 18F-fluoride uptake was quantified using the standardized uptake value corrected for individual integrated whole blood activity concentration (SUVAUC). Clinical response to anti-TNF was defined according to a ⩾ 20% improvement in Assessment of SpondyloArthritis international Society criteria at 24 weeks. Results: At baseline, all patients showed at least one axial PET-positive lesion. Histological analysis of PET-positive lesions in the spine confirmed local osteoid formation. PET-positive lesions were found in the costovertebral joints (43%), facet joints (23%), bridging syndesmophytes (20%) and non-bridging vertebral lesions (14%) and in SI joints (75%). After 12 weeks of anti-TNF treatment, 18F-fluoride uptake in clinical responders decreased significantly in the costovertebral (mean SUVAUC -1.0; P < 0.001) and SI joints (mean SUVAUC -1.2; P = 0.03) in contrast to non-responders. Conclusions: 18F-fluoride PET-CT identified bone formation, confirmed by histology, in the spine and SI joints of AS patients and demonstrated alterations in bone formation during anti-TNF treatment.

iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics.

Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies.

Impact of partial-volume correction in oncological PET studies: a systematic review and meta-analysis.

PURPOSE: Positron-emission tomography can be useful in oncology for diagnosis, (re)staging, determining prognosis, and response assessment. However, partial-volume effects hamper accurate quantification of lesions <2-3× the PET system's spatial resolution, and the clinical impact of this is not evident. This systematic review provides an up-to-date overview of studies investigating the impact of partial-volume correction (PVC) in oncological PET studies. METHODS: We searched in PubMed and Embase databases according to the PRISMA statement, including studies from inception till May 9, 2016. Two reviewers independently screened all abstracts and eligible full-text articles and performed quality assessment according to QUADAS-2 and QUIPS criteria. For a set of similar diagnostic studies, we statistically pooled the results using bivariate meta-regression. RESULTS: Thirty-one studies were eligible for inclusion. Overall, study quality was good. For diagnosis and nodal staging, PVC yielded a strong trend of increased sensitivity at expense of specificity. Meta-analysis of six studies investigating diagnosis of pulmonary nodules (679 lesions) showed no significant change in diagnostic accuracy after PVC (p = 0.222). Prognostication was not improved for non-small cell lung cancer and esophageal cancer, whereas it did improve for head and neck cancer. Response assessment was not improved by PVC for (locally advanced) breast cancer or rectal cancer, and it worsened in metastatic colorectal cancer. CONCLUSIONS: The accumulated evidence to date does not support routine application of PVC in standard clinical PET practice. Consensus on the preferred PVC methodology in oncological PET should be reached. Partial-volume-corrected data should be used as adjuncts to, but not yet replacement for, uncorrected data.

The added value of SPECT-CT for the identification of sentinel lymph nodes in early stage oral cancer.

PURPOSE: To assess the role of single-photon emission computed tomography with computed tomography (SPECT-CT) for the identification of sentinel lymph nodes (SLNs) in patients with early stage (T1-T2) oral cancer and a clinically negative neck (cN0). METHODS: In addition to planar lymphoscintigraphy, SPECT-CT was performed in 66 consecutive patients with early stage oral cancer and a clinically negative neck. The addition of SPECT-CT to planar images was retrospectively analyzed for the number of additional SLNs, more precise localization of SLNs, and importance of anatomical information by a team consisting of a nuclear physician, surgeon, and investigator. RESULTS: Identification rate for both imaging modalities combined was 98% (65/66). SPECT-CT identified 15 additional SLNs in 14 patients (22%). In 2/15 (13%) of these additional SLNs, the only metastasis was found, resulting in an upstaging rate of 3% (2/65). In 20% of the patients with at least one positive SLN, the only positive SLN was detected due to the addition of SPECT-CT. SPECT-CT was considered to add important anatomical information in two patients (3%). In 5/65 (8%) of the patients initially scored SLNs on planar lymphoscintigrams were scored as non-SLNs when SPECT-CT was added. There were four false-negative SLN biopsy procedures in this cohort. CONCLUSIONS: The addition of SPECT-CT to planar lymphoscintigraphy is recommended for the identification of more (positive) SLNs and better topographical orientation for surgery in sentinel lymph node biopsy for early stage oral cancer.

[18F]FDG PET/CT-based response assessment of stage IV non-small cell lung cancer treated with paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches.

PURPOSE: Nitroglycerin (NTG) is a vasodilating drug, which increases tumor blood flow and consequently decreases hypoxia. Therefore, changes in [18F] fluorodeoxyglucose positron emission tomography ([18F]FDG PET) uptake pattern may occur. In this analysis, we investigated the feasibility of [18F]FDG PET for response assessment to paclitaxel-carboplatin-bevacizumab (PCB) treatment with and without NTG patches. And we compared the [18F]FDG PET response assessment to RECIST response assessment and survival. METHODS: A total of 223 stage IV non-small cell lung cancer (NSCLC) patients were included in a phase II study (NCT01171170) randomizing between PCB treatment with or without NTG patches. For 60 participating patients, a baseline and a second [18F]FDG PET/computed tomography (CT) scan, performed between day 22 and 24 after the start of treatment, were available. Tumor response was defined as a 30 % decrease in CT and PET parameters, and was compared to RECIST response at week 6. The predictive value of these assessments for progression free survival (PFS) and overall survival (OS) was assessed with and without NTG. RESULTS: A 30 % decrease in SUVpeak assessment identified more patients as responders compared to a 30 % decrease in CT diameter assessment (73 % vs. 18 %), however, this was not correlated to OS (SUVpeak30 p = 0.833; CTdiameter30 p = 0.557). Changes in PET parameters between the baseline and the second scan were not significantly different for the NTG group compared to the control group (p value range 0.159-0.634). The CT-based (part of the [18F]FDG PET/CT) parameters showed a significant difference between the baseline and the second scan for the NTG group compared to the control group (CT diameter decrease of 7 ± 23 % vs. 19 ± 14 %, p = 0.016, respectively). CONCLUSIONS: The decrease in tumoral FDG uptake in advanced NSCLC patients treated with chemotherapy with and without NTG did not differ between both treatment arms. Early PET-based response assessment showed more tumor responders than CT-based response assessment (part of the [18F]FDG PET/CT); this was not correlated to survival. This might be due to timing of the [18F]FDG PET shortly after the bevacizumab infusion.

A randomised, phase II study of repeated rhenium-188-HEDP combined with docetaxel and prednisone versus docetaxel and prednisone alone in castration-resistant prostate cancer (CRPC) metastatic to bone; the Taxium II trial.

BACKGROUND: Rhenium-188-HEDP is a beta-emitting radiopharmaceutical used for palliation of metastatic bone pain. We investigated whether the addition of rhenium-188-HEDP to docetaxel/prednisone improved efficacy of chemotherapy in patients with CRPC. METHODS: Patients with progressive CRPC and osteoblastic bone metastases were randomised for first-line docetaxel 75 mg/m2 3-weekly plus prednisone with or without 2 injections of rhenium-188-HEDP after the third (40 MBq/kg) and after the sixth (20 MBq/kg) cycle of docetaxel. Primary endpoint was progression-free survival (PFS), defined as either PSA, radiographic or clinical progression. Patients were stratified by extent of bone metastases and hospital. RESULTS: Forty-two patients were randomised for standard treatment and 46 patients for combination therapy. Median number of cycles of docetaxel was 9 in the control group and 8 in the experimental group. Median follow-up was 18.4 months. Two patients from the experimental group did not start treatment after randomisation. In the intention to treat analysis no differences in PFS, survival and PSA became apparent between the two groups. In an exploratory per-protocol analysis median overall survival was significantly longer in the experimental group (33.8 months (95%CI 31.75-35.85)) than in the control group (21.0 months (95%CI 13.61-28.39); p 0.012). Also median PFS in patients with a baseline phosphatase >220U/L was significantly better with combination treatment (9.0 months (95%CI 3.92-14.08) versus 6.2 months (95%CI 3.08-9.32); log rank p 0.005). As expected, thrombocytopenia (grade I/II) was reported more frequently in the experimental group (25% versus 0%). CONCLUSION: Combined treatment with rhenium-188-HEDP and docetaxel did not prolong PFS in patients with CRPC. The observed survival benefit in the per-protocol analysis warrants further studies in the combined treatment of chemotherapy and radiopharmaceuticals.