Combined use of 177Lu-DOTATATE and metronomic capecitabine (Lu-X) in FDG-positive gastro-entero-pancreatic neuroendocrine tumors.

PURPOSE: FDG-positive neuroendocrine tumors (NETs) have a poorer prognosis and exhibit shorter response duration to peptide receptor radionuclide therapy (PRRT). The aim of this prospective phase II study was to evaluate the efficacy and toxicity of PRRT with 177Lu-DOTATATE associated with metronomic capecitabine as a radiosensitizer agent in patients with advanced progressive FDG-positive gastro-entero-pancreatic (GEP) NETs. PATIENTS AND METHODS: Patients with advanced somatostatin receptor- and FDG-positive G1-G3 GEP-NETs (Ki67 < 55%) were treated with a cumulative activity of 27.5 GBq of 177Lu-DOTATATE divided in five cycles of 5.5 GBq each every 8 weeks. Capecitabine (1000-1500 mg daily) was administered orally in the inter-cycle period between 177Lu-DOTATATE treatments. Prior to commencing capecitabine, all patients were triaged with the dihydropyrimidine dehydrogenase (DPD) test. Only DPD-proficient individuals were enrolled. The primary objectives were disease control rate (DCR) and safety. Secondary aims included progression-free (PFS) and overall survival (OS). Treatment response was assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. RESULTS: From August 2015 to December 2016, 37 subjects were consecutively enrolled. A total of 25 (68%) were affected by pancreatic neuroendocrine tumors (P-NETs), and 12 (32%) had gastrointestinal neuroendocrine tumors (GI-NETs). By grading (WHO 2010 classification), 12 patients (32%) had G1 (Ki67 ≤ 2%), 22 (59%) had G2 (3% < Ki67 ≤ 20%), and 3 patients (9%) had G3 (Ki67 > 20%) NETs. Grade 3 (G3) or 4 (G4) hematological toxicity occurred in 16.2% of patients. Other G3-G4 adverse events were diarrhea in 5.4% of cases and asthenia in 5.4%. No renal toxicity was observed for the duration of follow-up. In 37 patients, 33 were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%) and stable disease (SD) in 18 patients (55%), with a DCR of 85%. The median follow-up was 38 months (range 4.6-51.1 months). The median PFS was 31.4 months (17.6-45.4), and mOS was not reached. CONCLUSIONS: This study demonstrated that the combination of PRRT with 177Lu-DOTATATE and metronomic capecitabine is active and well tolerated in patients with aggressive FDG-positive G1-G3 GEP-NETs. These data constitute the basis for a randomized study of PPRT alone vs. PRRT plus metronomic capecitabine.

Theragnostic in neuroendocrine tumors.

In the last few decades, the incidence and prevalence of neuroendocrine tumors has been increasing. The theragnostic approach, that allows the diagnosis and treatment of different neoplasms with the same ligand, is a typical nuclear medicine tool. Applied for years, is also pivotal in neuroendocrine tumors (NETs) where it has improved the diagnostic accuracy and the therapeutic efficacy with impact on patient's survival. Theragnostic also allows the identification of important prognostic factors such as tumor location and burden, presence of liver metastases and intensity of somatostatin receptors (SSTR) expression to consider in new and possibly combined studies to ameliorate patient's outcome. Moreover, the possibility to evaluate receptor expression even in non-NET malignancies has de facto widened the possible indications for PRRT. We believe that this innovative therapeutic approach will be implemented in next years by radiomics and biological tumors characterization to better address PRRT applications.

Prognostic value of 18F-choline PET/CT metabolic parameters in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide.

PURPOSE: The role of 18F-choline positron emission tomography/computed tomography (FCH-PET/CT) in patients with metastatic castration-resistant prostate cancer (mCRPC) has been firmly established in recent years. We analyzed the prognostic value of functional parameters such as mean standardized uptake volume (SUVmean), maximum standardized uptake volume (SUVmax), metabolic total volume (MTV; the volume of interest consisting of all spatially connected voxels within a fixed threshold of 40% of the SUVmax), and total lesion activity (TLA: the product of MTV and mean standardized uptake value) estimated with FCH-PET/CT in mCRPC patients in progression after docetaxel and treated with new antiandrogen receptor therapies, abiraterone or enzalutamide. METHODS: We retrospectively studied 94 mCRPC patients, mean age 74 years (range 42-90), previously treated with docetaxel who were treated with either abiraterone (n = 52) or enzalutamide (n = 42). An FCH-PET/CT was performed at baseline, and patients were evaluated on a monthly basis for serological PSA response and every 3 months for radiological response. We measured MTV, SUVmean, SUVmax and TLA for each lesion and analyzed the sum of MTV (SMTV), SUVmean (SSUVmean), SUVmax (SSUVmax) and TLA (STLA) values for a maximum of 20 lesions. Univariate analysis was used to correlate these data with PFS and OS. RESULTS: We observed a median SMTV of 130 cm3, median SSUVmax of 106.5 and a median STLA of 495,070. All of these parameters were significant for PFS and OS in univariate analysis, while only STLA was significant for PFS and OS in multivariate analysis after adjusting for lesion and age (p < 0.0001 and p = 0.001, respectively). Baseline PSA values maintained a certain reliability for OS (p = 0.034). CONCLUSIONS: Semiquantitative parameters of FCH-PET/CT play a prognostic role in mCRCP patients treated with abiraterone or enzalutamide.

68Ga-PSMA PET/CT in patients with recurrent prostate cancer after radical treatment: prospective results in 314 patients.

PURPOSE: We studied the usefulness of 68Ga-prostate-specific membrane antigen (PSMA) PET/CT for detecting relapse in a prospective series of patients with biochemical recurrence (BCR) of prostate cancer (PCa) after radical treatment. METHODS: Patients with BCR of PCa after radical surgery and/or radiotherapy with or without androgen-deprivation therapy were included in the study. 68Ga-PSMA PET/CT scans performed from the top of the head to the mid-thigh 60 min after intravenous injection of 150 ± 50 MBq of 68Ga-PSMA were interpreted by two nuclear medicine physicians. The results were correlated with prostate-specific antigen (PSA) levels at the time of the scan (PSApet), PSA doubling time, Gleason score, tumour stage, postsurgery tumour residue, time from primary therapy to BCR, and patient age. When available, 68Ga-PSMA PET/CT scans were compared with negative 18F-choline PET/CT scans routinely performed up to 1 month previously. RESULTS: From November 2015 to October 2017, 314 PCa patients with BCR were evaluated. Their median age was 70 years (range 44-92 years) and their median PSApet was 0.83 ng/ml (range 0.003-80.0 ng/ml). 68Ga-PSMA PET/CT was positive (one or more suspected PCa lesions detected) in 197 patients (62.7%). Lesions limited to the pelvis, i.e. the prostate/prostate bed and/or pelvic lymph nodes (LNs), were detected in 117 patients (59.4%). At least one distant lesion (LNs, bone, other organs, separately or combined with local lesions) was detected in 80 patients (40.6%). PSApet was higher in PET-positive than in PET-negative patients (P < 0.0001). Of 88 patients negative on choline PET/CT scans, 59 (67%) were positive on 68Ga-PSMA PET/CT. CONCLUSION: We confirmed the value of 68Ga-PSMA PET/CT in restaging PCa patients with BCR, highlighting its superior performance and safety compared with choline PET/CT. Higher PSApet was associated with a higher relapse detection rate.

Reduction of 68Ga-PSMA renal uptake with mannitol infusion: preliminary results.

PURPOSE: Urea-based prostate-specific membrane antigen (PSMA) ligands labelled with 68Ga or 177Lu are new tracers with great potential for theranostic approaches in prostate cancer. However, clinical studies have shown that the kidneys are one of the off-target organs along with the salivary and lacrimal glands. In the kidneys, PSMA is physiologically expressed in the apical epithelium of the proximal tubules, and mannitol acts as an osmotic diuretic in these tubules. We investigated the potential of mannitol to reduce renal uptake of 68Ga-PSMA. METHODS: Kidney uptake (SUVmax) was calculated in nine patients undergoing 68Ga-PSMA PET/CT at baseline (b-PET/CT) and after intravenous infusion of 500 ml of 10% mannitol (m-PET/CT). Two different infusion schemes for mannitol were used: (1) 500 ml mannitol was infused over 40 min after 68Ga-PSMA administration (A-infusion) and (2) 250 ml mannitol was infused over 15 min before and again after 68Ga-PSMA administration (B-infusion). RESULTS: In patients receiving the A-infusion, mean SUVmax increased by 11.9% and 7.4% in the right and left kidney, respectively. In patients receiving the B-infusion, mean SUVmax decreased by 24.3% and 22.4% in the right and left kidney, respectively. CONCLUSION: Our preliminary findings indicate that mannitol may play a role in reducing off-target 68Ga-PSMA renal uptake. Administration of the osmotic diuretic should be rapid and start before 68Ga-PSMA injection. These results warrant dosimetric studies in patients treated with 177Lu-PSMA to find the best scheme for mannitol administration.

Peptide receptor radionuclide therapy with (177)Lu-DOTATATE in advanced bronchial carcinoids: prognostic role of thyroid transcription factor 1 and (18)F-FDG PET.

PURPOSE: Typical and atypical carcinoids (TC and AC) represent 20 - 25 % of all neuroendocrine tumours. No standard therapeutic approach is available for patients with advanced disease. The aim of this phase II study was to investigate the efficacy and safety of peptide receptor radionuclide therapy with (177)Lu-DOTATATE (Lu-PRRT) and the role of thyroid transcription factor 1 (TTF-1) and (18)F-FDG PET as prognostic factors in patients with advanced TC or AC. METHODS: A total of 34 consecutive patients with radiologically documented progressive disease were treated with Lu-PRRT at a therapeutic cumulative activity of 18.5 or 27.8 GBq in four or five cycles according to the patient's kidney function and bone marrow reserve. Information on TTF-1 was available in all patients. FDG PET studies prior to Lu-PRRT were available in 29 patients. RESULTS: The median follow-up was 29 months (range 7 - 69 months). The disease control rate (DCR) in patients with TC was 80 %: 6 % complete response, 27 % partial response and 47 % stable disease. The median progression-free survival (mPFS) was 20.1 months (95 % CI 11.8 - 26.8 months). Stable disease was achieved in 47 % of patients with AC with a mPFS of 15.7 months (95 % CI 10.6 - 25.9 months). No major acute or delayed toxicity occurred in either group or with either cumulative activity. mPFS in patients with TTF-1-negative TC was 26.3 months (95 % CI 12.9 - 45.2 months), but in patients with TTF-1-positive TC mPFS was 7.2 months (4.2 - 14.0 months; p = 0.0009). FDG PET was negative in 13 patients (10 TC and 3 AC) and positive in 16 patients (4 TC and 12 AC). The mPFS in the FDG PET-negative group was 26.4 months (95 % CI 14.2 - 48.9 months) and 15.3 months (11.7 - 31.1 months) in the FDG PET-positive group. CONCLUSION: Lu-PRRT showed antitumour activity in terms of DCR and PFS and proved safe, even in patients with a higher risk of side effects. TTF-1 would appear to be a prognostic factor. FDG PET positivity in bronchial carcinoids is a hallmark of aggressive tumour and is more frequent in patients with AC than in those with TC.

Feasibility and utility of re-treatment with (177)Lu-DOTATATE in GEP-NENs relapsed after treatment with (90)Y-DOTATOC.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is a valid therapy for grade 1/2 gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). Although a median progression-free survival (PFS) of more than 20 months is frequently observed, the majority of patients relapse after 2 - 3 years. In the present study, we investigated the use of low dosage re-treatment with (177)Lu-DOTATATE (Lu-PRRT) in patients with GEP-NENs who relapsed after treatment with (90)Y-DOTATOC (Y-PRRT). METHODS: Upon tumour progression, 26 patients with a PFS of at least 12 months after Y-PRRT were consecutively enrolled in a phase II study of re-treatment with Lu-PRRT. All patients had preserved kidney and haematological parameters and received 14.8 - 18.5 GBq of Lu-PRRT in four or five cycles. The disease control rate (DCR), toxicity, PFS and prognostic factors were evaluated. RESULTS: Median total activity of Lu-PRRT was 16.5 GBq in five cycles. The DCR was 84.6%, median PFS was 22 months (95% CI 16 months - not reached) compared to 28 months (95% CI 20 - 36 months) after Y-PRRT. Tumour burden and number of liver metastases were important prognostic factors. Toxicity was mild after Lu-PRRT re-treatment in the majority of patients, with only two patients with grade 2 and one with grade 3 bone marrow toxicity; one patient had grade 2 and one grade 3 renal toxicity. CONCLUSION: Patients with GEP-NEN who have previously responded to Y-PRRT are suitable candidates for Lu-PRRT re-treatment on progression. Although our sample size was limited, low-dosage Lu-PRRT was safe, and led to DCR and PFS rates comparable with those observed when Y-PRRT was used as primary treatment.

(18)F-Fluorocholine PET/CT for early response assessment in patients with metastatic castration-resistant prostate cancer treated with enzalutamide.

PURPOSE: We investigated the role of (18)F-methylcholine (FCH) PET/CT in the early evaluation of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide. METHODS: The study group comprised 36 patients with a median age of 72 years (range 48-90 years) who were treated with enzalutamide 160 mg once daily after at least one chemotherapeutic regimen with docetaxel. Patients were evaluated monthly for serological prostate-specific antigen (PSA) response. FCH PET/CT was performed at baseline and repeated after 3-6 weeks. Univariate and multivariate Cox regression models addressed potential predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: At a median follow-up of 24.2 months (range 1.8-27.3 months), 34 patients were evaluable for early FCH PET/CT evaluation of response, and of these 17 showed progressive disease (PD) and 17 had stable disease or a partial response. A decrease in PSA level of more than 50% was observed in 21 patients. Early FCH PET/CT PD predicted radiological PD 3 months in advance of CT in 12 of 18 patients (66%) and was discordant with the decrease in PSA level in 13 patients. In 6 of these, biochemical PD was confirmed in 2 months. In multivariate analysis, only decrease in PSA level and FCH PET/CT were significant predictors of PFS (p = 0.0005 and p = 0.029, respectively), whereas decrease in PSA level alone was predictive of OS (p = 0.007). CONCLUSION: This is one of the first studies to evaluate the role of FCH PET/CT as an early predictor of outcome in mCRPC patients treated with enzalutamide. Our preliminary results suggest that the combination of FCH PET/CT and decrease in PSA level could be a valid tool to predict PFS in mCRPC patients. PSA remains the single most important prognostic factor, while FCH PET/CT does not add more information on OS beyond that obtained from PSA. Further studies in larger populations are needed to confirm these data and to clarify the role of FCH PET/CT in predicting response to enzalutamide in mCRPC patients.

ITA-IMMUNO-PET: The Role of [18F]FDG PET/CT for Assessing Response to Immunotherapy in Patients with Some Solid Tumors.

AIM: To examine the role of [18F]FDG PET/CT for assessing response to immunotherapy in patients with some solid tumors. METHODS: Data recorded in a multicenter (n = 17), retrospective database between March and November 2021 were analyzed. The sample included patients with a confirmed diagnosis of a solid tumor who underwent serial [18F]FDG PET/CT (before and after one or more cycles of immunotherapy), who were >18 years of age, and had a follow-up of at least 12 months after their first PET/CT scan. Patients enrolled in clinical trials or without a confirmed diagnosis of cancer were excluded. The authors classified cases as having a complete or partial metabolic response to immunotherapy, or stable or progressive metabolic disease, based on a visual and semiquantitative analysis according to the EORTC criteria. Clinical response to immunotherapy was assessed at much the same time points as the serial PET scans, and both the obtained responses were compared. RESULTS: The study concerned 311 patients (median age: 67; range: 31-89 years) in all. The most common neoplasm was lung cancer (56.9%), followed by malignant melanoma (32.5%). Nivolumab was administered in 46.3%, and pembrolizumab in 40.5% of patients. Baseline PET and a first PET scan performed at a median 3 months after starting immunotherapy were available for all 311 patients, while subsequent PET scans were obtained after a median 6, 12, 16, and 21 months for 199 (64%), 102 (33%), 46 (15%), and 23 (7%) patients, respectively. Clinical response to therapy was recorded at around the same time points after starting immunotherapy for 252 (81%), 173 (56%), 85 (27%), 40 (13%), and 22 (7%) patients, respectively. After a median 18 (1-137) months, 113 (36.3%) patients had died. On Kaplan-Meier analysis, metabolic responders on the first two serial PET scans showed a better prognosis than non-responders, while clinical response became prognostically informative from the second assessment after starting immunotherapy onwards. CONCLUSIONS: [18F]FDG PET/CT could have a role in the assessment of response to immunotherapy in patients with some solid tumors. It can provide prognostic information and thus contribute to a patient's appropriate treatment. Prospective randomized controlled trials are mandatory.

Can Baseline [18F]FDG PET/CT Predict Response to Immunotherapy After 6 Months and Overall Survival in Patients with Lung Cancer or Malignant Melanoma? A Multicenter Retrospective Study.

Aim: To assess the role of baseline 18F-fluorodeoxyglucose ([18F]FDG)-positron emission tomography/computed tomography (PET/CT) in predicting response to immunotherapy after 6 months and overall survival (OS) in patients with lung cancer (LC) or malignant melanoma (MM). Materials and Methods: Data from a multicenter, retrospective study conducted between March and November 2021 were analyzed. Patients >18 years old with a confirmed diagnosis of LC or MM, who underwent a baseline [18F]FDG-PET/CT within 1-2 months before starting immunotherapy and had a follow-up of at least 12 months were included. PET scans were examined visually and semiquantitatively by physicians at peripheral centers. The metabolic tumor burden (number of lesions with [18F]FDG-uptake) and other parameters were recorded. Clinical response was assessed at 3 and 6 months after starting immunotherapy, and OS was calculated as the time elapsing between the PET scan and death or latest follow-up. Results: The study concerned 177 patients with LC and 101 with MM. Baseline PET/CT was positive in primary or local recurrent lesions in 78.5% and 9.9% of cases, in local/distant lymph nodes in 71.8% and 36.6%, in distant metastases in 58.8% and 84%, respectively, in LC and in MM patients. Among patients with LC, [18F]FDG-uptake in primary/recurrent lung lesions was more often associated with no clinical response to immunotherapy after 6 months than in cases without any tracer uptake. After a mean 21 months, 46.5% of patients with LC and 37.1% with MM had died. A significant correlation emerged between the site/number of [18F]FDG foci and death among patients with LC, but not among those with MM. Conclusions: In patients with LC who are candidates for immunotherapy, baseline [18F]FDG-PET/CT can help to predict response to this therapy after 6 months, and to identify those with a poor prognosis based on their metabolic parameters. For patients with MM, there was only a weak correlation between baseline PET/CT parameters, response to therapy, and survival.

Radiomics Analysis on [68Ga]Ga-PSMA-11 PET and MRI-ADC for the Prediction of Prostate Cancer ISUP Grades: Preliminary Results of the BIOPSTAGE Trial.

Prostate cancer (PCa) risk categorization based on clinical/PSA testing results in a substantial number of men being overdiagnosed with indolent, early-stage PCa. Clinically non-significant PCa is characterized as the presence of ISUP grade one, where PCa is found in no more than two prostate biopsy cores.MRI-ADC and [68Ga]Ga-PSMA-11 PET have been proposed as tools to predict ISUP grade one patients and consequently reduce overdiagnosis. In this study, Radiomics analysis is applied to MRI-ADC and [68Ga]Ga-PSMA-11 PET maps to quantify tumor characteristics and predict histology-proven ISUP grades. ICC was applied with a threshold of 0.6 to assess the features' stability with variations in contouring. Logistic regression predictive models based on imaging features were trained on 31 lesions to differentiate ISUP grade one patients from ISUP two+ patients. The best model based on [68Ga]Ga-PSMA-11 PET returned a prediction efficiency of 95% in the training phase and 100% in the test phase whereas the best model based on MRI-ADC had an efficiency of 100% in both phases. Employing both imaging modalities, prediction efficiency was 100% in the training phase and 93% in the test phase. Although our patient cohort was small, it was possible to assess that both imaging modalities add information to the prediction models and show promising results for further investigations.

Combining liquid biopsy and functional imaging analysis in metastatic castration-resistant prostate cancer helps predict treatment outcome.

Plasma tumour DNA (ptDNA) is a potential early noninvasive biomarker of treatment outcome in metastatic castration-resistant prostate cancer (mCRPC). Herein, we investigated whether pretreatment ptDNA levels reflect metabolic tumour burden in mCRPC and better predict treatment outcome in combination with functional imaging. Targeted next-generation sequencing was performed to estimate the ptDNA fraction from 102 mCRPC patients receiving abiraterone or enzalutamide. The maximum standardized uptake value (SUVmax), total lesion activity (TLA) and metabolic tumour volume (MTV) were evaluated on 18 F-fluorocholine positron emission tomography/computed tomography. We assessed a Weibull multiple regression model to determine the combined impact of clinical, molecular and imaging characteristics on overall survival (OS) and progression-free survival (PFS), and to obtain prognostic scores. A significant association was seen between ptDNA and SUVmax, MTV and TLA. For survival analysis, patients were randomly allocated into a training (n = 68) and a validation (n = 34) set. In the training set, multivariable analyses showed that ptDNA, MTV and serum lactate dehydrogenase together with visceral metastasis were independent predictors of both OS and PFS. Prognostic scores were generated, with the identification of three groups of patients with significantly different median OS (29.2, 15.9 and 8.7 months) and PFS (13.3, 7.7 and 3.2 months) probabilities. The differences in median survival between risk groups were confirmed in the validation cohort for both OS and PFS. In our study, we showed that integrating plasma DNA analysis with functional imaging may improve prognostic risk stratification and treatment selection in mCRPC.

PSMA PET for the Evaluation of Liver Metastases in Castration-Resistant Prostate Cancer Patients: A Multicenter Retrospective Study.

Background: To evaluate the diagnostic performance of PSMA-PET compared to conventional imaging/liver biopsy in the detection of liver metastases in CRPC patients. Moreover, we evaluated a PSMA-PET/CT-based radiomic model able to identify liver metastases. Methods: Multicenter retrospective study enrolling patients with the following inclusion criteria: (a) proven CRPC patients, (b) PSMA-PET and conventional imaging/liver biopsy performed in a 6 months timeframe, (c) no therapy changes between PSMA-PET and conventional imaging/liver biopsy. PSMA-PET sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for liver metastases were calculated. After the extraction of radiomic features, a prediction model for liver metastases identification was developed. Results: Sixty CRPC patients were enrolled. Within 6 months before or after PSMA-PET, conventional imaging and liver biopsy identified 24/60 (40%) patients with liver metastases. PSMA-PET sensitivity, specificity, PPV, NPV, and accuracy for liver metastases were 0.58, 0.92, 0.82, 0.77, and 0.78, respectively. Either number of liver metastases and the maximum lesion diameter were significantly associated with the presence of a positive PSMA-PET (p < 0.05). On multivariate regression analysis, the radiomic feature-based model combining sphericity, and the moment of inverse difference (Idm), had an AUC of 0.807 (95% CI:0.686-0.920). Conclusion: For liver metastases assessment, [68Ga]Ga-PSMA-11-PET demonstrated moderate sensitivity while high specificity, PPV, and inter-reader agreement compared to conventional imaging/liver biopsy in CRPC patients.

Diagnostic and Prognostic Potential of 18F-FET PET in the Differential Diagnosis of Glioma Recurrence and Treatment-Induced Changes After Chemoradiation Therapy.

BACKGROUND: MRI-based differential diagnosis of glioma recurrence (GR) and treatment-induced changes (TICs) remain elusive in up to 30% of treated glioma patients. We aimed to determine 18F-FET PET diagnostic performance in this clinical scenario, its outcome dependency on established prognostic factors, optimal 18F-FET semi-quantitative thresholds, and whether 18F-FET parameters may instantly predict progression-free survival (PFS) and overall survival (OS). METHODS: We retrospectively analyzed 45 glioma patients treated with chemoradiation therapy (32 males; mean age: 51 years, glioma grade: n=26 WHO4; n=15 WHO3; n=4 WHO2) who underwent 18F-FET PET to resolve differential diagnosis of GR and TICs raised by MRI performed in the preceding 2 weeks and depicting any of the following changes in their radiation field: volumetric increase of contrast-enhancing lesions; new contrast-enhancing lesion; significant increase in T2/FLAIR non-enhancing lesion without reducing corticosteroids. 18F-FET PET outcome relied on evaluation of maximum tumor-to-brain ratio (TBRmax), time-to-peak (TTP), and time-activity curve pattern (TAC). Metabolic tumor volume (MTV) and total tumor metabolism (TTM) were calculated for prognostic purposes. Standard of reference was repeat MRI performed 4-6 weeks after the previous MRI. Non-parametric statistics tested 18F-FET-based parameters for dependency on established prognostic markers. ROC curve analysis determined optimal cutoff values for 18F-FET semi-quantitative parameters. 18F-FET parameters and prognostic factors were evaluated for PFS and OS by Kaplan-Meier, univariate, and multivariate analyses. RESULTS: 18F-FET PET sensitivity, specificity, positive predictive value, negative predictive value were 86.2, 81.3, 89.3, 76.5%, respectively; higher diagnostic accuracy was yielded in IDH-wild-type glioma patients compared to IDH-mutant glioma patients (sensitivity: 81.8 versus 88.9%; specificity: 80.8 versus 81.8%). KPS was the only prognostic factor differing according to 18F-FET PET outcome (negative versus positive). Optimal 18F-FET cutoff values for GR were TBRmax ≥ 2.1, SUVmax ≥ 3.5, and TTP ≤ 29 min. PFS differed based on 18F-FET outcome and related metrics and according to KPS; a different OS was observed according to KPS only. On multivariate analysis, 18F-FET PET outcome was the only significant PFS factor; KPS and age the only significant OS factors. CONCLUSION: 18F-FET PET demonstrated good diagnostic performance. 18F-FET PET outcome and metrics were significantly predictive only for PFS.

Flare phenomenon in prostate cancer: recent evidence on new drugs and next generation imaging.

Over the years, an increasing proportion of metastatic prostate cancer patients has been found to experience an initial bone flare phenomenon under both standard therapies (androgen deprivation therapy, chemotherapy, radiotherapy, abiraterone, enzalutamide) and novel agents (immunotherapy, bone-targeting radioisotopes). The underlying biological mechanisms of the flare phenomenon are still elusive and need further clarification, particularly in relation to different types of treatment and their treatment response assessment. Flare phenomenon is often underestimated and, in some cases, can negatively affect clinical outcome. In cases with suspected bone flare, the treatment should be continued for a minimum of 12 more weeks before further decisions about efficacy can be taken. Physicians and patients should be aware of this effect to avoid unwarranted anxiety and inadequate early discontinuation of treatment. This review aims at highlighting new evidence on flare phenomenon arising after the introduction of new drugs extending across the biochemical, radiographic and clinical spectrum of the disease.

Is It Time to Introduce PET/CT in Colon Cancer Guidelines?

International colon cancer guidelines suggest F-FDG PET/CT in a few circumstances: (1) at disease presentation in case of suspected or proven metastatic synchronous adenocarcinoma; (2) in the workup of recurrent colon cancer with metachronous metastases documented by CT, MRI, or biopsy and in case of serial CEA elevation with negative colonoscopy and negative CT; and (3) in case of contraindication to iodine- and gadolinium-based contrast agents. However, review of the literature has shown that PET/CT can also be used in other scenarios with significant levels of diagnostic advantage. This review aims to emphasize differences between guidelines and scientific literature for the use of PET/CT in colon cancer.

Is It Time to Introduce PET/CT in Rectal Cancer Guidelines?

At the moment, international guidelines for rectal cancer suggest to consider F-FDG PET/CT scan in a few conditions: (1) at disease presentation in case of suspected or proven metastatic synchronous adenocarcinoma with potentially curable M1 disease; (2) in the recurrence workup for serial carcinoembryonic antigen level elevation; (3) in the recurrence workup with metachronous metastases documented by CT, MRI, or biopsy; (4) in case of strong contraindication to IV contrast agent administration; and (5) to evaluate an equivocal finding on a contrast-enhanced CT or MRI. PET/CT is not indicated in the follow-up or surveillance of rectal cancer. On the other hand, an attentive evaluation of the literature shows that PET/CT may also be used in some circumstances with significant levels of diagnostic accuracy. This review article aims to emphasize differences between current international guidelines and scientific literature in the role of PET/CT in rectal cancer.

SUV95th as a Reliable Alternative to SUVmax for Determining Renal Uptake in [68Ga] PSMA PET/CT.

PURPOSE: Widely used in clinical practice, the maximum standardized uptake value (SUVmax) is a statistical index highly prone to physical and biological variations, which can lead to unpredictable errors. This study has a methodological aim: to identify a more robust SUV-based index representing the tracer accumulation. In particular, the new metric was tested to confirm the potential of mannitol to reduce renal uptake Ga-68 prostate-specific membrane antigen ([68Ga]PSMA). PROCEDURES: To this aim, our previously published work, proving the efficacy of mannitol, was considered as a background study. Renal SUVmax was calculated in nine patients undergoing [68Ga]PSMA positron emission tomography (PET)/X-ray computed tomography (CT) at baseline (b-PET/CT) and at follow-up after intravenous infusion of 500 ml of 10 % mannitol (m-PET/CT). SUV values of kidney volumes were extracted by a new 3D segmentation method. A new parameter, the median computed on the upper 10% of the SUV distribution (SUV95th), was introduced to better characterize the tracer accumulation. A comparison between SUVmax and SUV95th was also performed. Kruskal-Wallis test was used to assess the statistical significance of the differences in SUV95th between b-PET/CT and m-PET/CT. RESULTS: SUV95th not only confirmed the efficacy of mannitol as demonstrated in the previous study but improved the separability of b-PET/CT and m-PET/CT examinations, overturning SUVmax findings in two cases. The outcomes of the Kruskal-Wallis test computed for each kidney proved that differences between b-PET/CT and m-PET/CT SUV95th values were significant (p value < 0.001). CONCLUSIONS: Our findings indicate that SUV95th is a more robust index to assess high uptake level, representing a reliable alternative to SUVmax. Independently from the segmentation method, the superiority of SUV95th and its easy computation could make its clinical impact decisive. The results obtained with SUV95th, more representative of tracer uptake than those with SUVmax suggest, in our opinion, that mannitol infusion could be used to reduce the adsorbed dose to the kidneys during [68Ga]PSMA PET/CT and Lu-177 or Ac-225 therapy. Our future goal will be confirming this effect in a larger cohort of patients, also verifying the role of SUV95th in the evaluation of tumor response to therapy.

Targeted Alpha Therapy in mCRPC (Metastatic Castration-Resistant Prostate Cancer) Patients: Predictive Dosimetry and Toxicity Modeling of 225Ac-PSMA (Prostate-Specific Membrane Antigen).

Radioligand therapy is a type of internal radiotherapy combining a short-range radioisotope labeled to a carrier with a high affinity for a specific receptor expressed on tumor cells. Targeted alpha therapy (TAT) combines a high-linear energy transfer (LET) emitter (225Ac) with a prostate-specific membrane antigen (PSMA) carrier, specifically binding tumor cells in patients with metastatic castration-resistant prostate cancer. Although the antitumor activity of 225Ac-PSMA is well-documented, this treatment is nowadays only used as salvage therapy because the high incidence of xerostomia limits the therapeutic window. Thus, methods to reduce salivary toxicity and models able to describe xerostomia incidence are needed. We recently studied the efficacy of salivary gland protectors administered in combination with 177Lu-PSMA therapy. Starting from these data, we performed a predictive dosimetric evaluation of 225Ac-PSMA to assess the impact of salivary gland protectors in TAT. 225Ac-PSMA predictive dosimetry was performed in 13 patients treated with 177Lu-PSMA. Sequential whole-body planar images were acquired 0.5-1, 16-24, 36-48, and 120 h post-injection. 177Lu time-activity curves were corrected for 225Ac physical decay and assumed in equilibrium for all daughters. The OLINDA/EXM spherical model was used for dose estimation of the parotid and submandibular glands. The dose for each daughter was calculated and summed for the total dose estimation. The biologically effective dose formalism was extended to high-LET emitters. For the total biologically effective dose formalism extended to high-LET emitters, including the contribution of all daughter isotopes, the brachytherapy formalism for a mixture of radionuclides was implemented. Equivalent doses in 2 Gy/fraction (EQD2) were then calculated and compared with the normal tissue complication probability model derived from external beam radiotherapy for grade ≥2 xerostomia induction. Median predictive doses were 0.86 BdRBE5/MBq for parotid glands and 1.05 BdRBE5/MBq for submandibular glands, with a 53% reduction compared with previously published data. The results show that the radiobiological model implemented is conservative, as it overestimates the complication rate with respect to the clinical data. Our data shows the possibility of reducing salivary gland uptake in TAT with the coadministration of organ protectors, but these results should be confirmed for TAT with 225Ac-PSMA by carrying out prospective trials with defined toxicity endpoints and dosimetry procedures.