Therapeutic effects of in-vivo radiodynamic therapy (RDT) for lung cancer treatment: a combination of 15MV photons and 5-aminolevulinic acid (5-ALA).

Objective.Radiodynamic therapy (RDT) uses high-energy photon beams instead of visible/near-infrared light to treat deep-seated tumors that photodynamic therapy cannot achieve due to the low penetration depth of laser beams. The purpose of this study is to investigate the therapeutic effect of RDT with 15 MV photon beams combined with 5-aminolevulinic acid (5-ALA) using a mouse model.Approach.A subcutaneous C57BL/6 mouse model of KP1 small-cell lung cancer cell line was used. The tumors (N = 120) were randomized into four groups to observe individual and synergistic effects of 5-ALA and radiation treatment: control (untreated, N = 42), radiation treatment (RT) only (N = 20), 5-ALA only (N = 20), and RDT (N = 38). For the RT only and RDT groups, 4 Gy in a single fraction was delivered to the tumors using 15 MV photons. For the 5-ALA only and RDT groups, 5-ALA was injected at a dose of 100 mg kg-1by tail-vein 4 h prior to RT. The tumor response was assessed by monitoring tumor growth using 1.5 T MR, maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) using [18F]FDG PET/CT, and animal survival.Main results.RDT achieved a statistically significant delay in tumor growth by 52.1%, 48.1%, and 57.9% 7 days post-treatment compared to 5-ALA only, RT only, and control group (P < 0.001), respectively. There were no significant differences in tumor growth between 5-ALA only and RT only groups. An additional 38.5%-40.9% decrease in tumor growth was observed, showing a synergistic effect with RDT. Furthermore, RDT significantly decreased [18F]FDG uptakes in SUVmaxand TLG 7 days post-treatment by 47.4% and 66.5% (P < 0.001), respectively. RDT mice survived the longest of all treatment groups.Significance.RDT with 15 MV photons and 5-ALA resulted in greater tumor control compared to the control and other treatment groups. A significant synergistic effect was also observed with RDT. These preliminary results demonstrate an effective cancer treatment modality.

Kinetic analysis of dominant intraprostatic lesion of prostate cancer using quantitative dynamic [18F]DCFPyL-PET: comparison to [18F]fluorocholine-PET.

PURPOSE: Identification of the dominant intraprostatic lesion(s) (DILs) can facilitate diagnosis and treatment by targeting biologically significant intra-prostatic foci. A PSMA ligand, [18F]DCFPyL (2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid), is better than choline-based [18F]FCH (fluorocholine) in detecting and localizing DIL because of higher tumour contrast, particularly when imaging is delayed to 1 h post-injection. The goal of this study was to investigate whether the different imaging performance of [18F]FCH and [18F]DCFPyL can be explained by their kinetic behaviour in prostate cancer (PCa) and to evaluate whether DIL can be accurately detected and localized using a short duration dynamic positron emission tomography (PET). METHODS: 19 and 23 PCa patients were evaluated with dynamic [18F]DCFPyL and [18F]FCH PET, respectively. The dynamic imaging protocol with each tracer had a total imaging time of 22 min and consisted of multiple frames with acquisition times from 10 to 180 s. Tumour and benign tissue regions identified by sextant biopsy were compared using standardized uptake value (SUV) and tracer kinetic parameters from kinetic analysis of time-activity curves. RESULTS: For [18F]DCFPyL, logistic regression identified Ki and k4 as the optimal model to discriminate tumour from benign tissue (84.2% sensitivity and 94.7% specificity), while only SUV was predictive for [18F]FCH (82.6% sensitivity and 87.0% specificity). The higher k3 (binding) of [18F]FCH than [18F]DCFPyL explains why [18F]FCH SUV can differentiate tumour from benign tissue within minutes of injection. Superior [18F]DCFPyL tumour contrast was due to the higher k4/k3 (more rapid washout) in benign tissue compared to tumour tissue. CONCLUSIONS: DIL was detected with good sensitivity and specificity using 22-min dynamic [18F]DCFPyL PET and avoids the need for delayed post-injection imaging timepoints. The dissimilar in vivo kinetic behaviour of [18F]DCFPyL and [18F]FCH could explain their different SUV images. Clinical Trial Registration NCT04009174 (ClinicalTrials.gov).

Predicting pathological complete response (pCR) after stereotactic ablative radiation therapy (SABR) of lung cancer using quantitative dynamic [18F]FDG PET and CT perfusion: a prospective exploratory clinical study.

BACKGROUND: Stereotactic ablative radiation therapy (SABR) is effective in treating inoperable stage I non-small cell lung cancer (NSCLC), but imaging assessment of response after SABR is difficult. This prospective study aimed to develop a predictive model for true pathologic complete response (pCR) to SABR using imaging-based biomarkers from dynamic [18F]FDG-PET and CT Perfusion (CTP). METHODS: Twenty-six patients with early-stage NSCLC treated with SABR followed by surgical resection were included, as a pre-specified secondary analysis of a larger study. Dynamic [18F]FDG-PET and CTP were performed pre-SABR and 8-week post. Dynamic [18F]FDG-PET provided maximum and mean standardized uptake value (SUV) and kinetic parameters estimated using a previously developed flow-modified two-tissue compartment model while CTP measured blood flow, blood volume and vessel permeability surface product. Recursive partitioning analysis (RPA) was used to establish a predictive model with the measured PET and CTP imaging biomarkers for predicting pCR. The model was compared to current RECIST (Response Evaluation Criteria in Solid Tumours version 1.1) and PERCIST (PET Response Criteria in Solid Tumours version 1.0) criteria. RESULTS: RPA identified three response groups based on tumour blood volume before SABR (BVpre-SABR) and change in SUVmax (ΔSUVmax), the thresholds being BVpre-SABR = 9.3 mL/100 g and ΔSUVmax = - 48.9%. The highest true pCR rate of 92% was observed in the group with BVpre-SABR < 9.3 mL/100 g and ΔSUVmax < - 48.9% after SABR while the worst was observed in the group with BVpre-SABR ≥ 9.3 mL/100 g (0%). RPA model achieved excellent pCR prediction (Concordance: 0.92; P = 0.03). RECIST and PERCIST showed poor pCR prediction (Concordance: 0.54 and 0.58, respectively). CONCLUSIONS: In this study, we developed a predictive model based on dynamic [18F]FDG-PET and CT Perfusion imaging that was significantly better than RECIST and PERCIST criteria to predict pCR of NSCLC to SABR. The model used BVpre-SABR and ΔSUVmax which correlates to tumour microvessel density and cell proliferation, respectively and warrants validation with larger sample size studies. TRIAL REGISTRATION: MISSILE-NSCLC, NCT02136355 (ClinicalTrials.gov). Registered May 8, 2014, https://clinicaltrials.gov/ct2/show/NCT02136355.

Short-duration dynamic [18F]DCFPyL PET and CT perfusion imaging to localize dominant intraprostatic lesions in prostate cancer: validation against digital histopathology and comparison to [18F]DCFPyL PET/MR at 120 minutes.

PURPOSE: Localized prostate cancer (PCa) in patients is characterized by a dominant focus in the gland (dominant intraprostatic lesion, DIL). Accurate DIL identification may enable more accurate diagnosis and therapy through more precise targeting of biopsy, radiotherapy and focal ablative therapies. The goal of this study is to validate the performance of [18F]DCFPyL PET and CT perfusion (CTP) for detecting and localizing DIL against digital histopathological images. METHODS: Multi-modality image sets: in vivo T2-weighted (T2w)-MRI, 22-min dynamic [18F]DCFPyL PET/CT, CTP, and 2-h post-injection PET/MR were acquired in patients prior to radical prostatectomy. The explanted gland with implanted fiducial markers was imaged with T2w-MRI. All images were co-registered to the pathologist-annotated digital images of whole-mount mid-gland histology sections using fiducial markers and anatomical landmarks. Regions of interest encompassing DIL and non-DIL tissue were drawn on the digital histopathological images and superimposed on PET and CTP parametric maps. Logistic regression with backward elimination of parameters was used to select the most sensitive parameter set to distinguish DIL from non-DIL voxels. Leave-one-patient-out cross-validation was performed to determine diagnostic performance. RESULTS: [18F]DCFPyL PET and CTP parametric maps of 15 patients were analyzed. SUVLate and a model combining Ki and k4 of [18F]DCFPyL achieved the most accurate performance distinguishing DIL from non-DIL voxels. Both detection models achieved an AUC of 0.90 and an error rate of < 10%. Compared to digital histopathology, the detected DILs had a mean dice similarity coefficient of 0.8 for the Ki and k4 model and 0.7 for SUVLate. CONCLUSIONS: We have validated using co-registered digital histopathological images that parameters from kinetic analysis of 22-min dynamic [18F]DCFPyL PET can accurately localize DILs in PCa for targeting of biopsy, radiotherapy, and focal ablative therapies. Short-duration dynamic [18F]DCFPyL PET was not inferior to SUVLate in this diagnostic task. CLINICAL TRIAL REGISTRATION NUMBER: NCT04009174 (ClinicalTrials.gov).

Assessment of tumour response after stereotactic ablative radiation therapy for lung cancer: A prospective quantitative hybrid 18 F-fluorodeoxyglucose-positron emission tomography and CT perfusion study.

INTRODUCTION: Stereotactic ablative radiotherapy (SABR) is a guideline-recommended treatment for inoperable stage I non-small cell lung cancer (NSCLC), but imaging assessment of response after SABR is difficult. The goal of this study was to evaluate imaging-based biomarkers of tumour response using dynamic 18 F-FDG-PET and CT perfusion (CTP). METHODS: Thirty-one patients with early-stage NSCLC participated in this prospective correlative study. Each underwent dynamic 18 F-FDG-PET/CTP studies on a PET/CT scanner pre- and 8 weeks post-SABR. The dynamic 18 F-FDG-PET measured the tumour SUVmax , SUVmean and the following parameters: K1 , k2 , k3 , k4 and Ki , all using the Johnson-Wilson-Lee kinetic model. CTP quantitatively mapped BF, BV, MTT and PS in tumours and measured largest tumour diameter. Since free-breathing was allowed during CTP scanning, non-rigid image registration of CT images was applied to minimize misregistration before generating the CTP functional maps. Differences between pre- and post-SABR imaging-based parameters were compared. RESULTS: Tumour size changed only slightly after SABR (median 26 mm pre-SABR vs. 23 mm post-SABR; P = 0.01). However, dynamic 18 F-FDG-PET and CTP study showed substantial and significant changes in SUVmax , SUVmean , k3 , k4 and Ki . Significant decreases were evident in SUVmax (median 6.1 vs. 2.6; P < 0.001), SUVmean (median 2.5 vs. 1.5; P < 0.001), k3 (relative decrease of 52%; P = 0.002), Ki (relative decrease of 27%; P = 0.03), whereas there was an increase in k4 (+367%; P < 0.001). CONCLUSIONS: Hybrid 18 F-FDG-PET/CTP allowed the response of NSCLC to SABR to be assessed regarding metabolic and functional parameters. Future studies are needed, with correlation with long-term outcomes, to evaluate these findings as potential imaging biomarkers of response.