Quantification of biochemical PSA dynamics after radioligand therapy with [177Lu]Lu-PSMA-I&T using a population pharmacokinetic/pharmacodynamic model.

BACKGROUND: There is an unmet need for prediction of treatment outcome or patient selection for [177Lu]Lu-PSMA therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Quantification of the tumor exposure-response relationship is pivotal for further treatment optimization. Therefore, a population pharmacokinetic (PK) model was developed for [177Lu]Lu-PSMA-I&T using SPECT/CT data and, subsequently, related to prostate-specific antigen (PSA) dynamics after therapy in patients with mCRPC using a pharmacokinetic/pharmacodynamic (PKPD) modelling approach. METHODS: A population PK model was developed using quantitative SPECT/CT data (406 scans) of 76 patients who received multiple cycles [177Lu]Lu-PSMA-I&T (± 7.4 GBq with either two- or six-week interval). The PK model consisted of five compartments; central, salivary glands, kidneys, tumors and combined remaining tissues. Covariates (tumor volume, renal function and cycle number) were tested to explain inter-individual variability on uptake into organs and tumors. The final PK model was expanded with a PD compartment (sequential fitting approach) representing PSA dynamics during and after treatment. To explore the presence of a exposure-response relationship, individually estimated [177Lu]Lu-PSMA-I&T tumor concentrations were related to PSA changes over time. RESULTS: The population PK model adequately described observed data in all compartments (based on visual inspection of goodness-of-fit plots) with adequate precision of parameters estimates (< 36.1% relative standard error (RSE)). A significant declining uptake in tumors (k14) during later cycles was identified (uptake decreased to 73%, 50% and 44% in cycle 2, 3 and 4-7, respectively, compared to cycle 1). Tumor growth (defined by PSA increase) was described with an exponential growth rate (0.000408 h-1 (14.2% RSE)). Therapy-induced PSA decrease was related to estimated tumor concentrations (MBq/L) using both a direct and delayed drug effect. The final model adequately captured individual PSA concentrations after treatment (based on goodness-of-fit plots). Simulation based on the final PKPD model showed no evident differences in response for the two different dosing regimens currently used. CONCLUSIONS: Our population PK model accurately described observed [177Lu]Lu-PSMA-I&T uptake in salivary glands, kidneys and tumors and revealed a clear declining tumor uptake over treatment cycles. The PKPD model adequately captured individual PSA observations and identified population response rates for the two dosing regimens. Hence, a PKPD modelling approach can guide prediction of treatment response and thus identify patients in whom radioligand therapy is likely to fail.

Adaptive FDG-PET/CT guided dose escalation in head and neck squamous cell carcinoma: Late toxicity and oncologic outcomes (The ADMIRE study).

Purpose: To report on the late toxicity and local control (LC) of head and neck cancer patients treated with adaptive FDG-PET/CT response-guided radiotherapy (ADMIRE) with dose escalation (NCT03376386). Materials and methods: Between December 2017 and April 2019, 20 patients with stage II-IV squamous cell carcinoma of the larynx, hypopharynx or oropharynx were treated within the ADMIRE study where FDG-PET/CT response-guided (Week 2&4) dose escalation was applied (total dose 70-78 Gy). Cisplatin or cetuximab was added to radiotherapy in case of T3-4 and/or N2c disease. To compare the LC and late toxicity of the study population, we used an external control group (n = 67) consisting of all eligible patients for the study (but not participated). These patients were treated in our institution during the same period with the current standard of 70 Gy radiotherapy. To reduce the effect of confounding, logistic regression analyses was done using stabilized inverse probability of treatment weighting (SIPTW). Results: After median follow-up of 40 and 43 months for the ADMIRE and control groups, the 3-year LC-rates were 74% and 78%, respectively (adjusted HR after SIPTW 0.80, 95 %CI 0.25-2.52, p = 0.70). The incidences of any late G3 toxicity were 35% and 18%, respectively. The adjusted OR for any late G3 toxicity was 5.09 (95 %CI 1.64-15.8, p = 0.005), for any late G ≥ 2 toxicity was 3.67 (95 %CI 1.2-11.7, p = 0.02), for persistent laryngeal edema was 10.95 (95% CI 2.71-44.29, p = 0.001), for persistent mucosal ulcers was 4.67 (95% CI 1.23-17.7, p = 0.023), and for late G3 radionecrosis was 15.69 (95 %CI 2.43-101.39, p = 0.004). Conclusion: Given the comparable LC rates with increased late toxicity in the ADMIRE group, selection criteria for future adaptive dose escalation trials (preferably randomized) need to be refined to include only patients at higher risk of local failure and/or lower risk of severe late toxicity.

Treating Primary Node-Positive Prostate Cancer: A Scoping Review of Available Treatment Options.

There is currently no consensus on the optimal treatment for patients with a primary diagnosis of clinically and pathologically node-positive (cN1M0 and pN1M0) hormone-sensitive prostate cancer (PCa). The treatment paradigm has shifted as research has shown that these patients could benefit from intensified treatment and are potentially curable. This scoping review provides an overview of available treatments for men with primary-diagnosed cN1M0 and pN1M0 PCa. A search was conducted on Medline for studies published between 2002 and 2022 that reported on treatment and outcomes among patients with cN1M0 and pN1M0 PCa. In total, twenty-seven eligible articles were included in this analysis: six randomised controlled trials, one systematic review, and twenty retrospective/observational studies. For cN1M0 PCa patients, the best-established treatment option is a combination of androgen deprivation therapy (ADT) and external beam radiotherapy (EBRT) applied to both the prostate and lymph nodes. Based on most recent studies, treatment intensification can be beneficial, but more randomised studies are needed. For pN1M0 PCa patients, adjuvant or early salvage treatments based on risk stratification determined by factors such as Gleason score, tumour stage, number of positive lymph nodes, and surgical margins appear to be the best-established treatment options. These treatments include close monitoring and adjuvant treatment with ADT and/or EBRT.

Sentinel Node Procedure to Select Clinically Localized Prostate Cancer Patients with Occult Nodal Metastases for Whole Pelvis Radiotherapy.

Background: Accurate identification of men who harbor nodal metastases is necessary to select patients who most likely benefit from whole pelvis radiotherapy (WPRT). Limited sensitivity of diagnostic imaging approaches for the detection of nodal micrometastases has led to the exploration of the sentinel lymph node biopsy (SLNB). Objective: To evaluate whether SLNB can be used as a tool to select pathologically node-positive patients who likely benefit from WPRT. Design setting and participants: We included 528 clinically node-negative primary prostate cancer (PCa) patients with an estimated nodal risk of >5% treated between 2007 and 2018. Intervention: A total of 267 patients were directly treated with prostate-only radiotherapy (PORT; non-SLNB group), while 261 patients underwent SLNB to remove lymph nodes directly draining from the primary tumor prior to radiotherapy (SLNB group); pN0 patients were treated with PORT, while pN1 patients were offered WPRT. Outcome measurements and statistical analysis: Biochemical recurrence-free survival (BCRFS) and radiological recurrence-free survival (RRFS) were compared using propensity score weighted (PSW) Cox proportional hazard models. Results and limitations: The median follow-up was 71 mo. Occult nodal metastases were found in 97 (37%) SLNB patients (median metastasis size: 2 mm). Adjusted 7-yr BCRFS rates were 81% (95% confidence interval [CI] 77-86%) in the SLNB group and 49% (95% CI 43-56%) in the non-SLNB group. The corresponding adjusted 7-yr RRFS rates were 83% (95% CI 78-87%) and 52% (95% CI 46-59%), respectively. In the PSW multivariable Cox regression analysis, SLNB was associated with improved BCRFS (hazard ratio [HR] 0.38, 95% CI 0.25-0.59, p < 0.001) and RRFS (HR 0.44, 95% CI 0.28-0.69, p < 0.001). Limitations include the bias inherent to the study's retrospective nature. Conclusions: SLNB-based selection of pN1 PCa patients for WPRT was associated with significantly improved BCRFS and RRFS compared with (conventional) imaging-based PORT. Patient summary: Sentinel node biopsy can be used to select patients who will benefit from the addition of pelvis radiotherapy. This strategy results in a longer duration of prostate-specific antigen control and a lower risk of radiological recurrence.

Tolerability of concurrent external beam radiotherapy and [177Lu]Lu-PSMA-617 for node-positive prostate cancer in treatment naïve patients, phase I study (PROQURE-I trial).

BACKGROUND: Prostate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29-47%. [177Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of [177Lu]Lu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields. METHODS: The PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic [177Lu]Lu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding [177Lu]Lu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle [177Lu]Lu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of [177Lu]Lu-PSMA-617. DISCUSSION: This is the first prospective study to combine EBRT and ADT with [177Lu]Lu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of [177Lu]Lu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments. TRIAL REGISTRATION: ClinicalTrials, NCT05162573 . Registered 7 October 2021.

Current research topics in FAPI theranostics: a bibliometric analysis.

PURPOSE: The study aimed to provide a comprehensive bibliometric overview of the current scientific publications on fibroblast activation protein inhibitor (FAPI) positron emission tomography imaging and radionuclide therapy. METHODS: A PubMed search was performed to identify all MEDLINE-indexed publications on FAPI imaging and radionuclide therapy. The last update was performed on 31 May 2022. An online database of this literature was created, and hierarchical topic-related tags were subsequently assigned to all relevant studies. Frequency analysis was used to evaluate the distribution of the following characteristics: first author's country of origin, journal of publication, study design, imaging techniques and radiopharmaceutical used, histopathological correlation, the type of cancer, and benign disease/uptake types evaluated. RESULTS: A total of 294 relevant publications on original studies were identified, consisting of 209 (71%) case reports/series and 85 cohort studies (29%). The majority of studies focused on imaging topics, predominantly comparing uptake on FAPI-PET/CT with 2-[18F]FDG-PET/CT, anatomical imaging, and/or histopathology results. 68% of studies focused on malignancies, with gastro-intestinal cancer, hepato-pancreato-biliary cancer, mixed cancers/metastases, lung cancer, sarcoma, head and neck cancer, and breast cancer being the most frequently reported. 42% of studies focused on benign disease categories, with cardiovascular, musculoskeletal, HPB, head and neck, and IgG4-related disease as most common categories. 16/294 (5%) studies focused on radionuclide therapy, with preliminary reports of acceptable toxicity profiles, tumour activity retention, and suggestion of disease control. CONCLUSION: FAPI research is rapidly expanding from diagnostic studies in malignancies and benign diseases to the first reports of salvage radionuclide therapy. The research activity needs to shift now from low-level-of-evidence case reports and series to prospectively designed studies in homogenous patient groups to provide evidence on how and in which clinical situations FAPI theranostics can be of added value to clinical care. We have provided an overview of current research topics to build upon.

Dose response modelling of secretory cell loss in salivary glands using PSMA PET.

BACKGROUND AND PURPOSE: Xerostomia remains a common side effect of radiotherapy (RT) for patients with head and neck (H&N) cancer despite advancements in treatment planning and delivery. Secretory salivary gland cells express the prostate-specific membrane antigen (PSMA), and show significant uptake on PET scans using 68Ga/18F-PSMA-ligands. We aimed to objectively quantify the dose-response of salivary glands to RT using PSMA PET. METHODS AND MATERIALS: 28H&N cancer patients received RT with 70 Gy in 35 fractions over 7 weeks. PSMA PET/CT was acquired at baseline (BL), during treatment (DT) and at 1-&6-months post-treatment (PT1M/PT6M). Dose, BL- PT1M- and PT6M-SUV were extracted for every voxel inside each parotid (PG) and submandibular (SMG) gland. The PT1M/6M data was analysed using a generalised linear mixed effects model.Patient-reported xerostomia and DT-PSMA loss was also analysed. RESULTS: Dose had a relative effect on BL SUV. For a population average gland (BL-SUV of 10), every 1 Gy increment, decreased the PT1M/PT6M-SUV by 1.6 %/1.6 % for PGs and by 0.9 %/1.8 % for SMGs. TD50 of the population curves was 26.5/31.3 Gy for PGs, and 22.9/27.8 Gy for SMGs at PT1M /PT6M. PSMA loss correlated well with patient-reported xerostomia at DT/PT1M (Spearman's ρ = -0.64, -0.50). CONCLUSION: A strong relationship was demonstrated between radiation dose and loss of secretory cells in salivary glands derived using PSMA PET/CT. The population curve could potentially be used as a dose planning objective, by maximising the predicted post-treatment SUV. BL scans could be used to further tailor this to individual patients.

ADC Values of Cytologically Benign and Cytologically Malignant 18 F-FDG PET-Positive Lymph Nodes of Head and Neck Squamous Cell Carcinoma.

Nodal staging (N-staging) in head and neck squamous cell carcinoma (HNSCC) is essential for treatment planning and prognosis. 18F-fluordeoxyglucose positron emission tomography (FDG-PET) has high performance for N-staging, although the distinction between cytologically malignant and reactive PET-positive nodes, and consequently, the selection of nodes for ultrasound-guided fine needle aspiration cytology (USgFNAC), is challenging. Diffusion-weighted magnetic resonance imaging (DW-MRI) can help to detect nodal metastases. We aim to investigate the potential of the apparent diffusion coefficient (ADC) as a metric to distinguish between cytologically reactive and malignant PET-positive nodes in order to improve node selection criteria for USgFNAC. PET-CT, real-time image-fused USgFNAC and DW-MRI to calculate ADC were available for 78 patients offered for routine N-staging. For 167 FDG-positive nodes, differences in the ADC between cytologically benign and malignant PET-positive nodes were evaluated, and both were compared to the ADC values of PET-negative reference nodes. Analyses were also performed in subsets of nodes regarding HPV status. A mild negative correlation between SUVmax and ADC was found. No significant differences in ADC values were observed between cytologically malignant and benign PET-positive nodes overall. Within the subset of non-HPV-related nodes, ADCb0-200-1000 was significantly lower in cytologically malignant PET-positive nodes when compared to benign PET-positive nodes. ADCb0-1000 and ADCb0-200-1000 were significantly lower (p = 0.018, 0.016, resp.) in PET-negative reference nodes than in PET-positive nodes. ADC was significantly higher in PET-negative reference nodes than in PET-positive nodes. The non-HPV-related subgroup showed significantly (p = 0.03) lower ADC values in cytologically malignant than in cytologically benign PET-positive nodes, which should help inform the node selection procedure for puncture.

Effects of furosemide and tracer selection on urinary activity and peri-bladder artefacts in PSMA PET/CT: a single-centre retrospective study.

BACKGROUND: High urinary activity in urinary bladder and ureters may hamper interpretation of prostate cancer and regional nodal metastases in prostate-specific membrane antigen (PSMA) PET/CT. The goal of this study was to assess effects of furosemide and choice of tracer on urinary activity in the bladder and ureters, as well as on occurrence of peri-bladder artefacts in PET/CT. METHODS: Four cohorts with a total of 202 men staged with PSMA PET/CT for prostate cancer received either 68Ga-PSMA-11 as tracer, with (cohort G+) or without 10mg intravenous furosemide (G-) concurrent with tracer, or 18F-DCFPyL with (F+) or without furosemide (F-). SUVmax of bladder and ureters, presence, type, and severity of peri-bladder artefacts were compared between cohorts. The influence of furosemide and choice of tracer was determined while taking differences in biodistribution time into account. RESULTS: Median SUVmax bladder was 43,5; 14,8; 61,7 and 22,8 in cohorts G-, G+, F- and F+, respectively, resulting in significant overall (p < 0.001) and between cohort differences (p adjusted < 0.001 to 0.003) except between G- and F+. Median SUVmax ureter was 6.4; 4.5; 8.1 and 6.0 in cohorts G-, G+, F- and F+, respectively, resulting in significant overall (p < 0.001) and between cohort differences for G+ : F- and F- : F+ (p < 0.001, respectively, 0.019). Significant effects of furosemide and choice of tracer on SUVmax bladder (p < 0.001 resp. p = 0.001) and of furosemide on SUVmax ureter (p < 0.001) were found, whereas differences in biodistribution time had not impacted these results significantly. Peri-bladder artefacts were present in 42/202 (21%) patients and were significantly more frequent in the F- cohort, respectively, less frequent in the G+ cohort (p = 0.001 resp. p < 0.001). Peri-bladder artefacts had a direct positive correlation with SUVmax bladder (p = 0.033). CONCLUSIONS: Increased urinary activity and higher incidence of peri-bladder artefacts were found in 18F-DCFPyL compared to 68Ga-PSMA-11 PET/CT. Effective reduction of urinary activity may be reached through forced diuresis using 10mg intravenous furosemide, which is especially advantageous in 18F-DCFPyL PET/CT.

Characteristics of tumour stroma in regional lymph node metastases in colorectal cancer patients: a theoretical framework for future diagnostic imaging with FAPI PET/CT.

PURPOSE: The recently developed fibroblast activation protein inhibitor (FAPI) tracer for PET/CT, binding tumour-stromal cancer-associated fibroblasts, is a promising tool for detection of positive lymph nodes. This study provides an overview of features, including sizes and tumour-stromal content, of lymph nodes and their respective lymph node metastases (LNM) in colorectal cancer (CRC), since literature lacks on whether LNMs contain sufficient stroma to potentially allow FAPI-based tumour detection. METHODS: Haematoxylin and eosin-stained tissue slides from 73 stage III colon cancer patients were included. Diameters and areas of all lymph nodes and their LNMs were assessed, the amount of stroma by measuring the stromal compartment area, the conventional and total tumour-stroma ratios (TSR-c and TSR-t, respectively), as well as correlations between these parameters. Also, subgroup analysis using a minimal diameter cut off of 5.0 mm was performed. RESULTS: In total, 126 lymph nodes were analysed. Although positive correlations were observed between node and LNM for diameter and area (r = 0.852, p < 0.001 and r = 0.960, p < 0.001, respectively), and also between the LNM stromal compartment area and nodal diameter (r = 0.612, p < 0.001), nodal area (r = 0.747, p < 0.001) and LNM area (r = 0.746, p < 0.001), novel insight was that nearly all (98%) LNMs contained stroma, with median TSR-c scores of 35% (IQR 20-60%) and TSR-t of 20% (IQR 10-30%). Moreover, a total of 32 (25%) positive lymph nodes had a diameter of < 5.0 mm. CONCLUSION: In LNMs, stroma is abundantly present, independent of size, suggesting a role for FAPI PET/CT in improved lymph node detection in CRC.

[18F]FDG-PET accurately identifies pathological response early upon neoadjuvant immune checkpoint blockade in head and neck squamous cell carcinoma.

PURPOSE: To investigate the utility of [18F]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous cell carcinoma (HNSCC) before surgery. METHODS: In the IMCISION trial (NCT03003637), 32 patients with stage II‒IVb HNSCC were treated with neoadjuvant nivolumab with (n = 26) or without (n = 6) ipilimumab (weeks 1 and 3) before surgery (week 5). [18F]FDG-PET/CT scans were acquired at baseline and shortly before surgery in 21 patients. Images were analysed for SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG). Major and partial pathological responses (MPR and PPR, respectively) to immunotherapy were identified based on the residual viable tumour in the resected primary tumour specimen (≤ 10% and 11-50%, respectively). Pathological response in lymph node metastases was assessed separately. Response for the 2 [18F]FDG-PET-analysable patients who did not undergo surgery was determined clinically and per MR-RECIST v.1.1. A patient with a primary tumour MPR, PPR, or primary tumour MR-RECIST-based response upon immunotherapy was called a responder. RESULTS: Median ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG decreased in the 8 responders and were significantly lower compared to the 13 non-responders (P = 0.05, P = 0.002, P < 0.001, and P < 0.001). A ΔMTV or ΔTLG of at least - 12.5% detected a primary tumour response with 95% accuracy, compared to 86% for the EORTC criteria. None of the patients with a ΔTLG of - 12.5% or more at the primary tumour site developed a relapse (median FU 23.0 months since surgery). Lymph node metastases with a PPR or MPR (5 metastases in 3 patients) showed a significant decrease in SUVmax (median - 3.1, P = 0.04). However, a SUVmax increase (median + 2.1) was observed in 27 lymph nodes (in 11 patients), while only 13 lymph nodes (48%) contained metastases in the corresponding neck dissection specimen. CONCLUSIONS: Primary tumour response assessment using [18F]FDG-PET-based ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant ICB in HNSCC, outperforming the EORTC criteria, although pseudoprogression is seen in neck lymph nodes. [18F]FDG-PET could, upon validation, select HNSCC patients for response-driven treatment adaptation in future trials. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov/ , NCT03003637, December 28, 2016.

Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma.

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.

Diagnostic Performance of [18F]FDG PET in Staging Grade 1-2, Estrogen Receptor Positive Breast Cancer.

Positron emission tomography using [18F]fluorodeoxyglucose (FDG PET) potentially underperforms for staging of patients with grade 1-2 estrogen receptor positive (ER+) breast cancer. The aim of this study was to retrospectively investigate the diagnostic accuracy of FDG PET in this patient population. Suspect tumor lesions detected on conventional imaging and FDG PET were confirmed with pathology or follow up. PET-positive lesions were (semi)quantified with standardized uptake values (SUV) and these were correlated with various pathological features, including the histological subtype. Pre-operative imaging detected 155 pathologically verified lesions (in 74 patients). A total of 115/155 (74.2%) lesions identified on FDG PET were classified as true positive, i.e., malignant (in 67 patients) and 17/155 (10.8%) lesions as false positive, i.e., benign (in 9 patients); 7/155 (4.5%) as false negative (in 7 patients) and 16/155 (10.3%) as true negative (in 14 patients). FDG PET incorrectly staged 16/70 (22.9%) patients. The FDG uptake correlated with histological subtype, showing higher uptake in ductal carcinoma, compared to lobular carcinoma (p < 0.05). Conclusion: Within this study, FDG PET inadequately staged 22.9% of grade 1-2, ER + BC cases. Incorrect staging can lead to inappropriate treatment choices, potentially affecting survival and quality of life. Prospective studies investigating novel radiotracers are urgently needed.

Update to a randomized controlled trial of lutetium-177-PSMA in Oligo-metastatic hormone-sensitive prostate cancer: the BULLSEYE trial.

BACKGROUND: The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. CHANGES IN METHODS AND MATERIALS: Two important changes were made to the original protocol: (1) the study will now use 177Lu-PSMA-617 instead of 177Lu-PSMA-I&T and (2) responding patients with residual disease on 18F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177Lu-PSMA-617 will also receive an interim 18F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; "Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer" and is now partly supported by Advanced Accelerator Applications, a Novartis Company. CONCLUSIONS: We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177Lu-PSMA-I&T under the previous protocol will be replaced. TRIAL REGISTRATION: ClinicalTrials.gov NCT04443062 . First posted: June 23, 2020.

A decade of multi-modality PET and MR imaging in abdominal oncology.

OBJECTIVES: To investigate trends observed in a decade of published research on multimodality PET(/CT)+MR imaging in abdominal oncology, and to explore how these trends are reflected by the use of multimodality imaging performed at our institution. METHODS: First, we performed a literature search (2009-2018) including all papers published on the multimodality combination of PET(/CT) and MRI in abdominal oncology. Retrieved papers were categorized according to a structured labelling system, including study design and outcome, cancer and lesion type under investigation and PET-tracer type. Results were analysed using descriptive statistics and evolutions over time were plotted graphically. Second, we performed a descriptive analysis of the numbers of MRI, PET/CT and multimodality PET/CT+MRI combinations (performed within a ≤14 days interval) performed during a similar time span at our institution. RESULTS: Published research papers involving multimodality PET(/CT)+MRI combinations showed an impressive increase in numbers, both for retrospective combinations of PET/CT and MRI, as well as hybrid PET/MRI. Main areas of research included new PET-tracers, visual PET(/CT)+MRI assessment for staging, and (semi-)quantitative analysis of PET-parameters compared to or combined with MRI-parameters as predictive biomarkers. In line with literature, we also observed a vast increase in numbers of multimodality PET/CT+MRI imaging in our institutional data. CONCLUSIONS: The tremendous increase in published literature on multimodality imaging, reflected by our institutional data, shows the continuously growing interest in comprehensive multivariable imaging evaluations to guide oncological practice. ADVANCES IN KNOWLEDGE: The role of multimodality imaging in oncology is rapidly evolving. This paper summarizes the main applications and recent developments in multimodality imaging, with a specific focus on the combination of PET+MRI in abdominal oncology.

PSMA-11-PET/CT versus choline-PET/CT to guide stereotactic ablative radiotherapy for androgen deprivation therapy deferral in patients with oligometastatic prostate cancer.

BACKGROUND: In patients with oligometastatic recurrent prostate cancer, standard treatment is androgen deprivation therapy (ADT). However, ADT has many potential side effects that may result in impaired quality of life. Early identification to select patients suitable for stereotactic ablative radiotherapy (SABR) is of utmost importance to prevent or delay start of ADT and its side effects. Because Prostate-Specific Membrane Antigen-11-Positron Emission Tomography (PSMA-11-PET) has a higher sensitivity than choline-PET, we hypothesise that PSMA-11-PET based SABR results in longer response duration and subsequent longer delay in starting ADT than choline-PET. METHODS: Patients with oligometastatic (≤4 metastases) recurrent prostate cancer (with no local recurrence) based on PSMA-11-PET or choline-PET treated with SABR from January 2012 until December 2017 were included. Primary endpoint was ADT-free survival. Secondary endpoints were Prostate Specific Antigen (PSA) response after SABR and time to PSA rise after SABR. RESULTS: Fifty patients (n = 40 PSMA-11-PET and n = 10 choline-PET) with in total 72 lesions were included. Median follow-up was 24.3 months. PSMA-11-PET enabled eligibility of patients with lower PSA levels than choline-PET (median 1.8 versus 4.2 ng/mL, p = 0.03). The PSMA-11-PET group had a significant longer PSA response duration (median 34.0 months (95% confidence interval (CI), 16.0-52.0) versus 14.7 months (95% CI 4.7-24.7), p = 0.004) with a subsequent longer ADT-free survival (median 32.7 months (95% CI, 20.8-44.5) versus 14.9 months (95% CI, 5.7-24.1), p = 0.01). CONCLUSIONS: With PSMA-11-PET we are able to select patients with oligometastatic recurrent prostate cancer suitable for SABR in an earlier disease stage at lower PSA levels. PSMA-11-PET guided SABR resulted in a significant longer response duration and ADT-free survival compared with choline-PET and can therefore prevent or delay ADT related side effects.

68Ga-PSMA-11 PET, 18F-PSMA-1007 PET, and MRI for Gross Tumor Volume Delineation in Primary Prostate Cancer: Intermodality and Intertracer Variability.

PURPOSE: To assess the intermodality and intertracer variability of gallium-68 (68Ga)- or fluorine-18 (18F)-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) and biparametric magnetic resonance imaging (bpMRI)-based gross tumor volume (GTV) delineation for focal boosting in primary prostate cancer. METHODS: Nineteen prospectively enrolled patients with prostate cancer underwent a PSMA PET/MRI scan, divided into a 1:1 ratio between 68Ga-PSMA-11 and 18F-PSMA-1007, before radical prostatectomy (IWT140193). Four delineation teams performed manual contouring of the GTV based on bpMRI and PSMA PET imaging, separately. Index lesion coverage (overlap%) and interobserver variability were assessed. Furthermore, the distribution of the voxelwise normalized standardized uptake values (SUV%) was determined for the majority-voted (>50%) GTV (GTVmajority) and whole prostate gland to investigate intertracer variability. The median patientwise SUV% contrast ratio (SUV%-CR, calculated as median GTVmajority SUV% / median prostate gland without GTVmajority SUV%) was calculated according to the tracer used. RESULTS: A significant difference in overlap% favoring PSMA PET compared with bpMRI was found in the 18F subgroup (median, 63.0% vs 53.1%; P = .004) but was not present in the 68Ga subgroup (32.5% vs 50.6%; P = .100). Regarding interobserver variability, measured Sørensen-Dice coefficients (0.58 vs 0.72) and calculated mean distances to agreement (2.44 mm vs 1.22 mm) were statistically significantly lower and higher, respectively, for the 18F cohort compared with the 68Ga cohort. For the bpMRI-based delineations, the median Sørensen-Dice coefficient and mean distance to agreement were 0.63 and 1.76 mm, respectively. Median patientwise SUV%-CRs of 1.8 (interquartile range [IQR], 1.6-2.7) for 18F-PSMA and 3.3 (IQR, 2.7-5.9) for 68Ga-PSMA PET images were found. CONCLUSIONS: Both MRI and PSMA PET provided consistent intraprostatic GTV lesion detection. However, the PSMA tracer seems to have a major influence on the contour characteristics, owing to an apparent difference in SUV% distribution in the prostate gland.

The dynamics and prognostic value of FDG PET-metrics in weekly monitoring of (chemo)radiotherapy for NSCLC.

PURPOSE: To test if the relative change in FDG-PET SUVmax over the course of treatment was associated with disease progression and overall survival. Additionally, the prognostic values of other first-order PET-metric changes were investigated. METHODS: The study included 38 patients with stage II-III NSCLC, who underwent concurrent chemoradiotherapy. Patients received two pre-treatment FDG-PET scans and four during-treatment scans at weekly intervals. SUVmax was normalized to the start of treatment and analyzed using linear regression. Linear regression coefficients of other first order PET-metrics were grouped according to dissimilarity. Associations to patient outcome were analyzed using Cox hazard ratio. RESULTS: Twenty-eight patients satisfied the criteria for analysis. All PET-metrics demonstrated a strong linear correlation with time during treatment [median R-range: -0.87: -0.97]. No strong associations (p > 0.10) were found for the relative slope of SUVmax to patient outcomes. Other first-order metrics did correlate with outcome but the single imaging time-point maximizing the association of PET response with outcome varied per PET metric and outcome parameter. CONCLUSION: All investigated FDG PET metrics linearly decreased during treatment. Relative change in SUVmax was not associated to patient outcome while several other first order PET-metrics were related to patient outcome. A single optimal imaging time-point could not be identified.

The increasing potential of nuclear medicine imaging for the evaluation and reduction of normal tissue toxicity from radiation treatments.

Radiation therapy is an effective treatment modality for a variety of cancers. Despite several advances in delivery techniques, its main drawback remains the deposition of dose in normal tissues which can result in toxicity. Common practices of evaluating toxicity, using questionnaires and grading systems, provide little underlying information beyond subjective scores, and this can limit further optimization of treatment strategies. Nuclear medicine imaging techniques can be utilised to directly measure regional baseline function and function loss from internal/external radiation therapy within normal tissues in an in vivo setting with high spatial resolution. This can be correlated with dose delivered by radiotherapy techniques to establish objective dose-effect relationships, and can also be used in the treatment planning step to spare normal tissues more efficiently. Toxicity in radionuclide therapy typically occurs due to undesired off-target uptake in normal tissues. Molecular imaging using diagnostic analogues of therapeutic radionuclides can be used to test various interventional protective strategies that can potentially reduce this normal tissue uptake without compromising tumour uptake. We provide an overview of the existing literature on these applications of nuclear medicine imaging in diverse normal tissue types utilising various tracers, and discuss its future potential.

Evaluation of Early Response to Preoperative Accelerated Partial Breast Irradiation (PAPBI) by Histopathology, Magnetic Resonance Imaging, and 18F-fluorodexoyglucose Positron Emission Tomography/Computed Tomography (FDG PET/CT).

PURPOSE: This study aimed to find indicators for early response to radiation therapy in breast cancer. These would be of help in tailoring treatment for individual patients. METHODS AND MATERIALS: We analyzed 66 patients with low-risk breast cancer (≥60 years; cT1-2pN0) treated within the Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial. Patients received radiation therapy (RT; 10 x 4 Gray or 5 x 6 Gray), followed by a wide local excision after 6 weeks. Patients underwent magnetic resonance imaging (MRI) and 18F-fluorodexoyglucose (FDG) positron emission tomography/computed tomography (PET/CT) before RT and 5 weeks after RT, before surgery. We assessed the response to PAPBI using a histopathologic assessment and correlated this with responses on MRI and FDG PET/CT. We calculated the positive predictive values (PPVs) of MRI and PET/CT as the number of true positives (complete response on MRI/normalized at visual evaluation on PET/CT and pathologic complete response) divided by the number of patients with a complete response on MRI/normalized at visual evaluation on PET/CT. Similarly, the negative predictive values (NPVs) of MRI and PET/CT were calculated. RESULTS: The pathologic response was (nearly) complete in 15 (23%) of the 66 patients and partially complete in 28 (42%). The remaining 23 patients (35%) were nonresponders. The PPV of MRI (Response evaluation criteria in solid tumors [RECIST]) was 87.5% and the NPV was 85%. The PPV and NPV of PET/CT were 25% and 92%, respectively. CONCLUSIONS: The most accurate method to predict a response and residual disease after preoperative RT in low-risk breast cancer was MRI, using RECIST.