Using PET for therapy monitoring in oncological clinical trials: challenges ahead.

Molecular imaging with PET has emerged as a powerful imaging tool in the clinical care of oncological patients. Assessing therapy response is a prime application of PET and so the integration of PET into multicentre trials can offer valuable scientific insights and shape future clinical practice. However, there are a number of logistic and methodological challenges that have to be dealt with. These range from availability and regulatory compliance of the PET radiopharmaceutical to availability of scan time for research purposes. Standardization of imaging and reconstruction protocols, quality control, image processing and analysis are of paramount importance. Strategies for harmonization of the final image and the quantification result are available and can be implemented within the scope of multicentre accreditation programmes. Data analysis can be performed either locally or by centralized review. Response assessment can be done visually or using more quantitative approaches, depending on the research question. Large-scale real-time centralized review can be achieved using web-based solutions. Specific challenges for the future are inclusion of PET/MRI scanners in multicentre trials and the incorporation of radiomic analyses. Inclusion of PET in multicentre trials is a necessity to guarantee the further development of PET for routine clinical care and may yield very valuable scientific insights.

Comparison of diagnostic accuracy of (111)In-pentetreotide SPECT and (68)Ga-DOTATOC PET/CT: A lesion-by-lesion analysis in patients with metastatic neuroendocrine tumours.

OBJECTIVES: To compare the diagnostic accuracy of (111)In-pentetreotide-scintigraphy with (68)Ga-DOTATOC-positron emission tomography (PET)/computed tomography (CT) in patients with metastatic-neuroendocrine tumour (NET) scheduled for peptide receptor radionuclide therapy (PRRT). Incremental lesions (ILs) were defined as lesions observed on only one modality. METHODS: Fifty-three metastatic-NET-patients underwent (111)In-pentetreotide-scintigraphy (24 h post-injection; planar+single-photon emission CT (SPECT) abdomen) and whole-body (68)Ga-DOTATOC-PET/CT. SPECT and PET were compared in a lesion-by-lesion and organ-by-organ analysis, determining the total lesions and ILs for both modalities. RESULTS: Significantly more lesions were detected on (68)Ga-DOTATOC-PET/CT versus (111)In-pentetreotide-scintigraphy. More specifically, we observed 1,098 lesions on PET/CT (range: 1-105; median: 15) versus 660 on SPECT (range: 0-73, median: 9) (p<0.0001), with 439 PET-ILs (42/53 patients) and one SPECT-IL (1/53 patients). The sensitivity for PET/CT was 99.9 % (95 % CI, 99.3-100.0), for SPECT 60.0 % (95 % CI, 48.5-70.2). The organ-by-organ analysis showed that the PET-ILs were most frequently visualized in liver and skeleton. CONCLUSION: Ga-DOTATOC-PET/CT is superior for the detection of NET-metastases compared to (111)In-pentetreotide SPECT. KEY POINTS: Somatostatin receptor PET is superior to SPECT in detecting NET metastases. PET is the scintigraphic method for accurate depiction of NET tumour burden. The sensitivity of PET is twofold higher than the sensitivity of SPECT.

Fulminant ectopic Cushing's syndrome caused by metastatic small intestine neuroendocrine tumour - a case report and review of the literature.

Cushing's syndrome (CS) secondary to adrenocorticotropic hormone (ACTH) producing tumours is a severe condition with a challenging diagnosis. Ectopic ACTH-secretion often involves neuroendocrine tumours (NET) in the respiratory tract. ACTH-secreting small intestine neuro-endocrine tumours (siNET) are extremely rare entities barely reported in literature. This review is illustrated by the case of a 75-year old woman with fulminant ectopic CS caused by a ACTH-secreting metastatic siNET. Severe hypokalemia, fluid retention and refractory hypertension were the presenting symptoms. Basal and dynamic laboratory studies were diagnostic for ACTH-dependent CS. Extensive imaging studies of the pituitary and thorax-abdomen areas were normal, while [68Ga]Ga-DOTATATE PET-CT revealed increased small intestine uptake in the left iliac fossa. The hypercortisolism was well controlled with somatostatin analogues, after which a debulking resection of the tumour was performed. Pathological investigation confirmed a well-differentiated NET with sporadic ACTH immunostaining and post-operative treatment with somatostatin analogues was continued with favourable disease control.

Does 11C-choline PET-CT contribute to multiparametric MRI for prostate cancer localisation?

BACKGROUND AND PURPOSE: The aim of this work was to determine whether 11C-choline positron emission tomography (PET)-computed tomography (CT) makes a positive contribution to multiparametric magnetic resonance imaging (MRI) for localisation of intraprostatic tumour nodules. PATIENTS AND METHODS: A total of 73 patients with biopsy-proven intermediate- and high-risk prostate cancer were enrolled in a prospective imaging study consisting of T2-weighted (T2w), dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MRI and 11C-choline PET-CT before radical prostatectomy. Cancerous regions were delineated on the whole-mount prostatectomy sections and on the different MRI modalities and analysed in 24 segments per patient (3 sections, 8 segments each). To analyse PET-CT images, standardized uptake values (SUV) were calculated per segment. RESULTS: In total, 1,752 segments were analyzed of which 708 (40.4%) were found to be malignant. A high specificity (94.7, 93.6 and 92.2%) but relatively low sensitivity (31.2, 24.9 and 44.1%) for tumour localisation was obtained with T2w, DCE and DW MRI, respectively. Sensitivity values significantly increased when combining all MRI modalities (57.2%). For PET-CT, mean SUVmax of malignant octants was significantly higher than mean SUVmax of benign octants (3.68±1.30 vs. 3.12±1.02, p<0.0001). In terms of accuracy, the benefit of adding PET-CT to (multiparametric) MRI was less than 1%. CONCLUSION: The additional value of 11C-choline PET-CT to MRI in localising intraprostatic tumour nodules is limited, especially when multiparametric MRI is used.

PET/CT in the staging of patients with a pelvic mass suspicious for ovarian cancer.

OBJECTIVE: To prospectively assess the value of PET/CT for staging, diagnosis and operability of ovarian cancer, with special attention to the peritoneal spread. METHODS: From June 2009 to March 2011, 69 patients with suspicion of having an ovarian cancer underwent an (18)F-FDG PET/CT. To identify the diagnostic value of PET/CT, the results were compared with the findings at diagnostic laparoscopy and/or debulking surgery. RESULTS: There were 56 patients with malignant tumors and 13 with benign tumors. We observed a sensitivity and specificity of 93% and 77%, respectively for malignant tumors with PET/CT. CT alone had a sensitivity and specificity of 96% and 38%, respectively. The overall FIGO classification evaluation for PET/CT and CT were the same. For the evaluation of metastases, the sensitivity of PET/CT was worse, while the specificity was better than CT. Retroperitoneal lymph node metastases were diagnosed better with PET/CT, while there was no difference for peritoneal spread and for the intestines. PET/CT detected another unknown primary tumor in 3 (4.3%) cases. CONCLUSION: PET/CT is better than CT in detecting retroperitoneal lymph node metastases, but not for peritoneal metastases.

Semi-Quantitative Characterization of Post-Transplant Lymphoproliferative Disorder Morphological Subtypes with [18F]FDG PET/CT.

Background: Post-transplant lymphoproliferative disorder (PTLD) is a complication of organ transplantation classified according to the WHO as nondestructive, polymorphic, monomorphic, and classic Hodgkin Lymphoma subtypes. In this retrospective study, we investigated the potential of semi-quantitative 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) PET/computed tomography (CT)-based parameters to differentiate between the PTLD morphological subtypes. Methods: 96 patients with histopathologically confirmed PTLD and baseline [18F]FDG PET/CT between 2009 and 2019 were included. Extracted semi-quantitative measurements included: Maximum, peak, and mean standardized uptake value (SUVmax, SUVpeak, and SUVmean). Results: Median SUVs were highest for monomorphic PTLD followed by polymorphic and nondestructive subtypes. The median SUVpeak at the biopsy site was significantly higher in monomorphic PTLD (17.8, interquartile range (IQR):16) than in polymorphic subtypes (9.8, IQR:13.4) and nondestructive (4.1, IQR:6.1) (p = 0.04 and p ≤ 0.01, respectively). An SUVpeak ≥ 24.8 was always indicative of a monomorphic PTLD in our dataset. Nevertheless, there was a considerable overlap in SUV across the different morphologies. Conclusion: The median SUVpeak at the biopsy site was significantly higher in monomorphic PTLD than polymorphic and nondestructive subtypes. However, due to significant SUV overlap across the different subtypes, these values may only serve as an indication of PTLD morphology, and SUV-based parameters cannot replace histopathological classification.

Prognostic superiority of International Prognostic Index over [18F]FDG PET/CT volumetric parameters in post-transplant lymphoproliferative disorder.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLDs) are a spectrum of hematological malignancies occurring after solid organ and hematopoietic stem cell transplantation. [18F]FDG PET/CT is routinely performed at PTLD diagnosis, allowing for both staging of the disease and quantification of volumetric parameters, such as whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG). In this retrospective study, we aimed to determine the prognostic value of MTV and TLG in PTLD patients, together with other variables of interest, such as the International Prognostic Index (IPI), organ transplant type, EBV tumor status, time after transplant, albumin levels and PTLD morphology. RESULTS: A total of 88 patients were included. The 1-, 3-, 5- year overall survival rates were 67%, 58% and 43% respectively. Multivariable analysis indicated that a high IPI (HR: 1.56, 95% CI: 1.13-2.16) and an EBV-negative tumor (HR: 2.71, 95% CI: 1.38-5.32) were associated with poor overall survival. Patients with a kidney transplant had a longer overall survival than any other organ recipients (HR: 0.38 95% CI: 0.16-0.89). IPI was found to be the best predicting parameter of overall survival in our cohort. Whole-body MTV, TLG, time after transplant, hypoalbuminemia and PTLD morphology were not associated with overall survival. CONCLUSION: [18F]FDG PET/CT whole-body volumetric quantitative parameters were not predictive of overall survival in PTLD. In our cohort, high IPI and an EBV-negative tumor were found to predictors of worse overall survival while kidney transplant patients had a longer overall survival compared to other organ transplant recipients.

Intra-Arterial Therapies for Liver Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Performing a systematic review and meta-analysis to assess the evidence of intra-arterial therapies in liver metastatic breast cancer (LMBC) patients. METHODS: A systemic literature search was performed in PubMed, EMBASE, SCOPUS for studies regarding intra-arterial therapies in LMBC patients. Full text studies of LMBC patients (n ≥ 10) published between January 2010 and December 2020 were included when at least one outcome among response rate, adverse events or survival was available. Response rates were pooled using generalized linear mixed models. A weighted estimate of the population median overall survival (OS) was obtained under the assumption of exponentially distributed survival times. RESULTS: A total of 26 studies (1266 patients) were included. Eleven articles reported on transarterial radioembolization (TARE), ten on transarterial chemoembolization (TACE) and four on chemo-infusion. One retrospective study compared TARE and TACE. Pooled response rates were 49% for TARE (95%CI 32-67%), 34% for TACE (95%CI 22-50%) and 19% for chemo-infusion (95%CI 14-25%). Pooled median survival was 9.2 months (range 6.1-35.4 months) for TARE, 17.8 months (range 4.6-47.0) for TACE and 7.9 months (range 7.0-14.2) for chemo-infusion. No comparison for OS was possible due to missing survival rates at specific time points (1 and 2 year OS) and the large heterogeneity. CONCLUSION: Although results have to be interpreted with caution due to the large heterogeneity, the superior response rate of TARE and TACE compared to chemo-infusion suggests first choice of TARE or TACE in chemorefractory LMBC patients. Chemo-infusion could be considered in LMBC patients not suitable for TARE or TACE. LEVEL OF EVIDENCE: 3a.

Disseminated histoplasmosis in a kidney liver transplant patient from a non-endemic area: A diagnostic challenge.

Disseminated histoplasmosis is a rare opportunistic infection in non-endemic areas, where the disease is often diagnosed late. The spectrum of clinical manifestations is broad and life-threatening complications occur. We present a detailed case of a kidney liver transplant patient with disseminated histoplasmosis in a non-endemic area. Our case highlights the wide range of pathogens to consider in the immunocompromised patient, the delayed diagnosis of Histoplasmosis Capsulatum in non-endemic areas and the possibility of severe gastrointestinal disease. We also briefly review diagnostic tests and treatment options.

Radioembolization with 90Y Resin Microspheres of Neuroendocrine Liver Metastases After Initial Peptide Receptor Radionuclide Therapy.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) and radioembolization are increasingly used in neuroendocrine neoplasms patients. However, concerns have been raised on cumulative hepatotoxicity. The aim of this sub-analysis was to investigate hepatotoxicity of yttrium-90 resin microspheres radioembolization in patients who were previously treated with PRRT. METHODS: Patients treated with radioembolization after systemic radionuclide treatment were retrospectively analysed. Imaging response according to response evaluation criteria in solid tumours (RECIST) v1.1 and clinical response after 3 months were collected. Clinical, biochemical and haematological toxicities according to common terminology criteria for adverse events (CTCAE) v4.03 were also collected. Specifics on prior PRRT, subsequent radioembolization treatments, treatments after radioembolization and overall survival (OS) were collected. RESULTS: Forty-four patients were included, who underwent a total of 58 radioembolization procedures, of which 55% whole liver treatments, at a median of 353 days after prior PRRT. According to RECIST 1.1, an objective response rate of 16% and disease control rate of 91% were found after 3 months. Clinical response was seen in 65% (15/23) of symptomatic patients after 3 months. Within 3 months, clinical toxicities occurred in 26%. Biochemical and haematological toxicities CTCAE grade 3-4 occurred in ≤ 10%, apart from lymphocytopenia (42%). Radioembolization-related complications occurred in 5% and fatal radioembolization-induced liver disease in 2% (one patient). A median OS of 3.5 years [95% confidence interval 1.8-5.1 years] after radioembolization for the entire study population was found. CONCLUSION: Radioembolization after systemic radionuclide treatments is safe, and the occurrence of radioembolization-induced liver disease is rare. LEVEL OF EVIDENCE: 4, case series.

Current practice in approaching controversial diagnostic and therapeutic topics in gastroenteropancreatic neuroendocrine neoplasm management. Belgian multidisciplinary expert discussion based on a modified Delphi method.

BACKGROUND AND STUDY AIMS: Neuroendocrine neoplasms (NENs) are relatively rare, with marked clinical and biological heterogeneity. Consequently, many controversial areas remain in diagnosis and optimal treatment stratification for NEN patients. We wanted to describe current clinical practice regarding controversial NEN topics and stimulate critical thinking and mutual learning among a Belgian multidisciplinary expert panel. PATIENTS AND METHODS: A 3-round, Delphi method based project, coordinated by a steering committee (SC), was applied to a predefined multidisciplinary NEN expert panel studying the following controversial topics : factors guiding therapeutic decision making, the use of somatostatin analogues (SSA) in adjuvant setting, the interference between non-radioactive and radioactive SSAs, challenging small intestine neuroendocrine tumor (NET) cases, the approach of the carcinoid syndrome, the role of chemotherapy in well differentiated NET, the relevance of NET G3 and neuroendocrine carcinoma subclassification and the role of imaging techniques in NEN management. RESULTS: A high level of consensus exists regarding the necessary diagnostic work-up, use of imaging techniques and interference between non-radioactive and radioactive SSAs. However, the prognostic impact of tumor functionality might be overrated and adequate diarrhea differential diagnostic work-up in these patients is underused. Significant differences are seen between individual experts and centers regarding treatment preferences both on the treatment modality level, as well as the choice of specific drugs (e.g. chemotherapy regimen). CONCLUSIONS: A Delphi-like multi-round expert discussion proves useful to boost critical thinking and discussion among experts of different background, as well as to describe current clinical practice and stimulate mutual learning in the absence of high-level scientific guidance.

Radioembolization with 90Y Resin Microspheres of Neuroendocrine Liver Metastases: International Multicenter Study on Efficacy and Toxicity.

PURPOSE: Radioembolization of liver metastases of neuroendocrine neoplasms (NEN) has shown promising results; however, the current literature is of limited quality. A large international, multicentre retrospective study was designed to address several shortcomings of the current literature. MATERIALS: 244 NEN patients with different NEN grades were included. METHODS: Primary outcome parameters were radiologic response 3 and 6 months after treatment according to RECIST 1.1 and mRECIST. Secondary outcome parameters included clinical response, clinical and biochemical toxicities. RESULTS: Radioembolization resulted in CR in 2%, PR in 14%, SD in 75% and PD 9% according to RECIST 1.1 and in CR in 8%, PR in 35%, SD in 48% and PD in 9% according to mRECIST. Objective response rates improved over time in 20% and 26% according to RECIST 1.1. and mRECIST, respectively. Most common new grade 3-4 biochemical toxicity was lymphocytopenia (6.7%). No unexpected clinical toxicities occurred. Radioembolization-specific complications occurred in < 4%. In symptomatic patients, improvement and resolution of symptoms occurred in 44% and 34%, respectively. Median overall survival from first radioembolization was 3.7, 2.7 and 0.7 years for G1, G2 and G3, respectively. Objective response is independent of NEN grade or primary tumour origin. Significant prognostic factors for survival were NEN grade/Ki67 index, ≥ 75% intrahepatic tumour load, the presence of extrahepatic disease and disease control rate according to RECIST 1.1. CONCLUSION: Safety and efficacy of radioembolization in NEN patients was confirmed with a high disease control rate of 91% in progressive patients and alleviation of NEN-related symptoms in 79% of symptomatic patients. LEVEL OF EVIDENCE: 4.