Comparison of quantitative whole body PET parameters on [68Ga]Ga-PSMA-11 PET/CT using ordered Subset Expectation Maximization (OSEM) vs. bayesian penalized likelihood (BPL) reconstruction algorithms in men with metastatic castration-resistant prostate cancer.

BACKGROUND: PSMA PET/CT is a predictive and prognostic biomarker for determining response to [177Lu]Lu-PSMA-617 in patients with metastatic castration resistant prostate cancer (mCRPC). Thresholds defined to date may not be generalizable to newer image reconstruction algorithms. Bayesian penalized likelihood (BPL) reconstruction algorithm is a novel reconstruction algorithm that may improve contrast whilst preventing introduction of image noise. The aim of this study is to compare the quantitative parameters obtained using BPL and the Ordered Subset Expectation Maximization (OSEM) reconstruction algorithms. METHODS: Fifty consecutive patients with mCRPC who underwent [68Ga]Ga-PSMA-11 PET/CT using OSEM reconstruction to assess suitability for [177Lu]Lu-PSMA-617 therapy were selected. BPL algorithm was then used retrospectively to reconstruct the same PET raw data. Quantitative and volumetric measurements such as tumour standardised uptake value (SUV)max, SUVmean and Molecular Tumour Volume (MTV-PSMA) were calculated on both reconstruction methods. Results were compared (Bland-Altman, Pearson correlation coefficient) including subgroups with low and high-volume disease burdens (MTV-PSMA cut-off 40 mL). RESULTS: The SUVmax and SUVmean were higher, and MTV-PSMA was lower in the BPL reconstructed images compared to the OSEM group, with a mean difference of 8.4 (17.5%), 0.7 (8.2%) and - 21.5 mL (-3.4%), respectively. There was a strong correlation between the calculated SUVmax, SUVmean, and MTV-PSMA values in the OSEM and BPL reconstructed images (Pearson r values of 0.98, 0.99, and 1.0, respectively). No patients were reclassified from low to high volume disease or vice versa when switching from OSEM to BPL reconstruction. CONCLUSIONS: [68Ga]Ga-PSMA-11 PET/CT quantitative and volumetric parameters produced by BPL and OSEM reconstruction methods are strongly correlated. Differences are proportional and small for SUVmean, which is used as a predictive biomarker. Our study suggests that both reconstruction methods are acceptable without clinical impact on quantitative or volumetric findings. For longitudinal comparison, committing to the same reconstruction method would be preferred to ensure consistency.

Dose-effect Relationship of Kidney Function After Stereotactic Ablative Body Radiotherapy for Primary Renal Cell Carcinoma: Trog 15.03 Fastrack Ii.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a novel option to treat primary renal cell carcinoma (RCC). However, a high radiation dose may be received by the treated kidney, which may affect its function post-treatment. This study investigates the dose-effect relationship of kidney SABR with posttreatment renal function. METHODS: This was a prespecified secondary endpoint of the multicenter FASTRACK II clinical trial (NCT02613819). Patients received either 26 Gy in a single fraction (SF) for tumors with a maximal diameter of 4 cm or less, or 42 Gy in three fractions (multi-fraction (MF)) for larger tumors. To determine renal function change, 99mTc-DMSA SPECT/CT scans were acquired, and the glomerular filtration rate (GFR) was estimated at baseline, 12-, and 24-months post-treatment. Imaging datasets were rigidly registered to the planning CT where kidneys were segmented to calculate dose-response curves. RESULTS: From 71 enrolled patients, data from 36 (51%) and 26 (37%) patients were included in this study based on availability of post-treatment data at 12- and 24-months, respectively. The ipsilateral kidney GFR decreased from baseline by 42% and 39% in the SF cohort, and by 45% and 62% in the MF cohort, at 12- and 24-months respectively (p-values < 0.03). The loss in renal function was 3.6±0.8% and 4.5±1.0% in the SF cohort, and 1.7±0.1% and 1.7±0.2% in the MF cohort, at 12- and 24-months respectively. The major loss in renal function occurred in high-dose regions, where dose-response curves converged to a plateau. CONCLUSIONS: For the first time in a multicenter study, the dose-effect relationship at 12- and 24-months post-SABR treatment for primary RCC was quantified. Kidney function reduces linearly with dose up to 100 Gy BED3.

Quantitative calibration of Tb-161 SPECT/CT in view of personalised dosimetry assessment studies.

BACKGROUND: Terbium-161 (161Tb)-based radionuclide therapy poses an alternative to current Lutetium-177 (177Lu) approaches with the additional benefit of secondary Auger and conversion electron emissions capable of delivering high doses of localised damage to micro-metastases including single cells. Quantitative single-photon emission computed tomography, paired with computed tomography (SPECT/CT), enables quantitative measurement from post-therapy imaging. In view of dosimetry extrapolations, a Tb-161 sensitivity SPECT/CT camera calibration was performed using a method previously validated for 177Lu. METHODS: Serial imaging of a NEMA/IEC body phantom with Tb-161 was performed on SPECT/CT with low-energy high-resolution collimators employing a photopeak of 75 keV with a 20% width. Quantitative stability and recovery coefficients were investigated over a sequence of 19 scans with buffered 161Tb solution at total phantom activity ranging from 70 to 4990 MBq. RESULTS: Sphere recovery coefficients were 0.60 ± 0.05, 0.52 ± 0.07, 0.45 ± 0.07, 0.39 ± 0.07, 0.28 ± 0.08, and 0.20 ± 0.08 for spheres 37, 28, 22, 17, 13, and 10mm, respectively, when considered across all activity and scan durations with dual-energy window scatter correction. Whole-field reconstructed sensitivity was calculated as 1.42E-5 counts per decay. Qualitatively, images exhibited no visual artefacts and were comparable to 177Lu SPECT/CT. CONCLUSIONS: Quantitative SPECT/CT of 161Tb is feasible over a range of activities enabling dosimetry analogous to 177Lu whilst also producing suitable imaging for clinical review. This has been incorporated into a prospective trial of 161Tb-PSMA for men with metastatic prostate cancer.

Administering [177Lu]Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localised Prostate Cancer (LuTectomy): A Single-centre, Single-arm, Phase 1/2 Study.

BACKGROUND: High-risk localised prostate cancer (HRCaP) has high rates of biochemical recurrence; [177Lu]Lu-PSMA-617 is effective in men with advanced prostate cancer. OBJECTIVE: To investigate the dosimetry, safety, and efficacy of upfront [177Lu]Lu-PSMA-617 in men with HRCaP prior to robotic radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: In this single-arm, phase I/II trial, we recruited men with HRCaP (any of prostate-specific antigen [PSA] >20 ng/ml, International Society of Urological Pathology (ISUP) grade group [GG] 3-5, and ≥cT2c), with high tumour uptake on [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography (PSMA PET/CT), and scheduled for RP. INTERVENTION: Cohort A (n = 10) received one cycle and cohort B (n = 10) received two cycles of [177Lu]Lu-PSMA-617 (5 GBq) followed by surgery 6 weeks later. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was tumour radiation absorbed dose. Adverse events (AEs; Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), surgical safety (Clavien-Dindo), imaging, and biochemical responses were evaluated (ClinicalTrials.gov: NCT04430192). RESULTS AND LIMITATIONS: Between May 29, 2020 and April 28, 2022, 20 patients were enrolled. The median PSA was 18 ng/ml (interquartile range [IQR] 11-35), Eighteen (90%) had GG ≥3, and six (30%) had N1 disease. The median (IQR) highest tumour radiation absorbed dose after cycle 1 for all lesions was 35.5 Gy (19.5-50.1), with 19.6 Gy (11.3-48.4) delivered to the prostate. Five patients received radiation to lymph nodes. Nine (45%) patients achieved >50% PSA decline. The most common AEs related to [177Lu]Lu-PSMA-617 were grade 1 fatigue in eight (40%), nausea in seven (35%), dry mouth in six (30%), and thrombocytopenia in four (20%) patients. No grade 3/4 toxicities or Clavien 3-5 complications occurred. Limitations include small a sample size. CONCLUSIONS: In men with HRCaP and high prostate-specific membrane antigen (PSMA) expression, [177Lu]Lu-PSMA-617 delivered high levels of targeted radiation doses with few toxicities and without compromising surgical safety. Further studies of [177Lu]Lu-PSMA-617 in this population are worthwhile to determine whether meaningful long-term oncological benefits can be demonstrated. PATIENT SUMMARY: In this study, we demonstrate that up to two cycles of [177Lu]Lu-PSMA-617 given prior to radical prostatectomy in patients with high-risk localised prostate cancer are safe and deliver targeted doses of radiation to tumour-affected tissues. It is tolerated well with minimal treatment-related adverse events, and surgery is safe with a low rate of complications. Activity measured through PSA reduction, repeat PSMA PET/CT, and histological response is promising.

Evaluation of manual and automated approaches for segmentation and extraction of quantitative indices from [18F]FDG PET-CT images.

Utilisation of whole organ volumes to extract anatomical and functional information from computed tomography (CT) and positron emission tomography (PET) images may provide key information for the treatment and follow-up of cancer patients. However, manual organ segmentation, is laborious and time-consuming. In this study, a CT-based deep learning method and a multi-atlas method were evaluated for segmenting the liver and spleen on CT images to extract quantitative tracer information from Fluorine-18 fluorodeoxyglucose ([18F]FDG) PET images of 50 patients with advanced Hodgkin lymphoma (HL). Manual segmentation was used as the reference method. The two automatic methods were also compared with a manually defined volume of interest (VOI) within the organ, a technique commonly performed in clinical settings. Both automatic methods provided accurate CT segmentations, with the deep learning method outperforming the multi-atlas with a DICE coefficient of 0.93 ± 0.03 (mean ± standard deviation) in liver and 0.87 ± 0.17 in spleen compared to 0.87 ± 0.05 (liver) and 0.78 ± 0.11 (spleen) for the multi-atlas. Similarly, a mean relative error of -3.2% for the liver and -3.4% for the spleen across patients was found for the mean standardized uptake value (SUVmean) using the deep learning regions while the corresponding errors for the multi-atlas method were -4.7% and -9.2%, respectively. For the maximum SUV (SUVmax), both methods resulted in higher than 20% overestimation due to the extension of organ boundaries to include neighbouring, high-uptake regions. The conservative VOI method which did not extend into neighbouring tissues, provided a more accurate SUVmaxestimate. In conclusion, the automatic, and particularly the deep learning method could be used to rapidly extract information of the SUVmeanwithin the liver and spleen. However, activity from neighbouring organs and lesions can lead to high biases in SUVmaxand current practices of manually defining a volume of interest in the organ should be considered instead.

Safety of Lutetium-177 prostate-specific membrane antigen-617 (PSMA-617) radioligand therapy in the setting of severe renal impairment: a case report and literature review.

Reported here is a case of rapidly progressive metastatic castration-resistant prostate cancer treated with [177Lu]Lu-PSMA-617 in the setting of severe renal impairment and impending ureteric obstruction. PSMA is expressed on renal tubular cells, raising the possibility of radiation-induced nephrotoxicity, and this level of renal impairment would typically exclude the patient from [177Lu]Lu-PSMA-617 therapy. Multidisciplinary input, individualized dosimetry, and patient-specific dose reduction were used to ensure the cumulative dose to the kidneys remained within acceptable limits. He was initially planned for treatment with six cycles of [177Lu]Lu-PSMA-617. However, he had an excellent response to therapy following four cycles of treatment and the last two cycles were omitted. He has been followed for 1-year posttherapy without evidence of disease recurrence. No acute or chronic nephrotoxicity was observed. This case report highlights the utility of [177Lu]Lu-PSMA-617 therapy in severe renal impairment and provides evidence of relative safety in patients who would otherwise not be considered candidates for therapy.

This report presents a case of a man with aggressive metastatic prostate cancer who received [¹⁷⁷Lu]Lu-PSMA-617 therapy, despite having severely reduced kidney function and worsening ureter obstruction. This treatment could have potential side effects on kidney function, but the medical team used a personalized approach to reduce patient risk. The man was initially planned to have six cycles of therapy, but his excellent response to treatment after four cycles meant the last two cycles were not given. The man has been followed for 1 year after treatment and has not experienced any worsening kidney function. This case shows the safe and effective use of [¹⁷⁷Lu]Lu-PSMA-617 therapy in a patient with severely reduced kidney function who would not normally qualify for this treatment.

Combined biology-guided radiotherapy and Lutetium PSMA theranostics treatment in metastatic castrate-resistant prostate cancer.

Background: Lutetium-177 [177Lu]-PSMA-617 is a targeted radioligand that binds to prostate-specific membrane antigen (PSMA) and delivers radiation to metastatic prostate cancer. The presence of PSMA-negative/FDG-positive metastases can preclude patients from being eligible for this treatment. Biology-guided radiotherapy (BgRT) is a treatment modality that utilises tumour PET emissions to guide external beam radiotherapy. The feasibility of combining BgRT and Lutetium-177 [177Lu]-PSMA-617 for patients with PSMA-negative/FDG-positive metastatic prostate cancer was explored. Materials and methods: All patients excluded from the LuPSMA clinical trial (ID: ANZCTR12615000912583) due to PSMA/FDG discordance were retrospectively reviewed. A hypothetical workflow where PSMA-negative/FDG-positive metastases would be treated with BgRT whilst PSMA-positive metastases would be treated with Lutetium-177 [177Lu]-PSMA-617 was considered. Gross tumour volume (GTV) of PSMA-negative/FDG-positive tumours were delineated on the CT component of the FDG PET/CT scan. Tumours were deemed suitable for BgRT if (1) normalised SUV (nSUV), defined as the ratio of maximum SUV (SUVmax) inside the GTV to mean SUV inside a 5 mm/10 mm/20 mm margin expansion of the GTV, was larger than a pre-specified nSUV threshold and (2) there was no PET avidity inside the margin expansion. Results: In 75 patients screened for Lutetium-177 [177Lu]-PSMA-617 treatment, 6 patients were excluded due to PSMA/FDG discordance and 89 PSMA-negative/FDG-positive targets were identified. GTV volumes ranged from 0.3 cm3 to 186 cm3 (median GTV volume = 4.3 cm3, IQR = 2.2 cm3 - 7.4 cm3). SUVmax inside GTVs ranged between 3 and 12 (median SUVmax = 4.8, IQR = 3.9 - 6.2). With nSUV ≥ 3, 67%/54%/39% of all GTVs were suitable for BgRT within 5 mm/10 mm/20 mm from the tumour. Bone and lung metastases were the best candidates for BgRT (40%/27% of all tumours suitable for BgRT with nSUV ≥ 3 within 5 mm from the GTV were bone/lung GTVs). Conclusions: Combined BgRT/Lutetium-177 [177Lu]-PSMA-617 therapy is feasible for patients with PSMA/FDG discordant metastases.

Feasibility of biology-guided radiotherapy for metastatic renal cell carcinoma driven by PSMA PET imaging.

Background: Biology-guided radiotherapy (BgRT) is a novel treatment where the detection of positron emission originating from a volume called the biological tracking zone (BTZ) initiates dose delivery. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is a novel imaging technique that may improve patient selection for metastasis-directed therapy in renal cell carcinoma (RCC). This study aims to determine the feasibility of BgRT treatment for RCC. Material and methods: All consecutive patients that underwent PSMA PET/CT scan for RCC staging at our institution between 2014 and 2020 were retrospectively considered for inclusion. GTVs were contoured on the CT component of the PET/CT scan. The tumor-to-background ratio was quantified from the normalized standardized uptake value (nSUV), defined as the ratio between SUVmax inside the GTV and SUVmean inside the margin expansion. Tumors were classified suitable for BgRT if (1) nSUV was greater or equal to an nSUV threshold and (2) if the BTZ was free of any PET-avid region other than the tumor. Results: Out of this cohort of 83 patients, 47 had metastatic RCC and were included in this study. In total, 136 tumors were delineated, 1 to 22 tumors per patient, mostly in lung (40%). Using a margin expansion of 5 mm/10 mm/20 mm and nSUV threshold = 3, 66%/63%/41% of tumors were suitable for BgRT treatment. Uptake originating from another tumor, the kidney, or the liver was typically inside the BTZ in tumors judged unsuitable for BgRT. Conclusions: More than 60% of tumors were found to be suitable for BgRT in this cohort of patients with RCC. However, the proximity of PET-avid organs such as the liver or the kidney may affect BgRT delivery.

Comparison of dual-energy CT with positron emission tomography for lung perfusion imaging in patients with non-small cell lung cancer.

Objective.Functional lung avoidance (FLA) radiotherapy treatment aims to spare lung regions identified as functional from imaging. Perfusion contributes to lung function and can be measured from the determination of pulmonary blood volume (PBV). An advantageous alternative to the current determination of PBV from positron emission tomography (PET) may be from dual energy CT (DECT), due to shorter examination time and widespread availability. This study aims to determine the correlation between PBV determined from DECT and PET in the context of FLA radiotherapy.Approach.DECT and PET acquisitions at baseline of patients enrolled in the HI-FIVE clinical trial (ID: NCT03569072) were reviewed. Determination of PBV from PET imaging (PBVPET), from DECT imaging generated from a commercial software (Syngo.via, Siemens Healthineers, Forchheim, Germany) with its lowest (PBVsyngoR=1) and highest (PBVsyngoR=10) smoothing level parameter value (R), and from a two-material decomposition (TMD) method (PBVTMDL) with variable median filter kernel size (L) were compared. Deformable image registration between DECT images and the CT component of the PET/CT was applied to PBV maps before resampling to the PET resolution. The Spearman correlation coefficient (rs) between PBV determinations was calculated voxel-wise in lung subvolumes.Main results.Of this cohort of 19 patients, 17 had a DECT acquisition at baseline. PBV maps determined from the commercial software and the TMD method were very strongly correlated [rs(PBVsyngoR=1,PBVTMDL=1) = 0.94 ± 0.01 andrs(PBVsyngoR=10,PBVTMDL=9) = 0.94 ± 0.02].PBVPETwas strongly correlated withPBVTMDL[rs(PBVPET,PBVTMDL=28) = 0.67 ± 0.11]. Perfusion patterns differed along the posterior-anterior direction [rs(PBVPET,PBVTMDL=28) = 0.77 ± 0.13/0.57 ± 0.16 in the anterior/posterior region].Significance. A strong correlation between DECT and PET determination of PBV was observed. Streak and smoothing effects in DECT and gravitational artefacts and misregistration in PET reduced the correlation posteriorly.

Fast and Low-GPU-memory abdomen CT organ segmentation: The FLARE challenge.

Automatic segmentation of abdominal organs in CT scans plays an important role in clinical practice. However, most existing benchmarks and datasets only focus on segmentation accuracy, while the model efficiency and its accuracy on the testing cases from different medical centers have not been evaluated. To comprehensively benchmark abdominal organ segmentation methods, we organized the first Fast and Low GPU memory Abdominal oRgan sEgmentation (FLARE) challenge, where the segmentation methods were encouraged to achieve high accuracy on the testing cases from different medical centers, fast inference speed, and low GPU memory consumption, simultaneously. The winning method surpassed the existing state-of-the-art method, achieving a 19× faster inference speed and reducing the GPU memory consumption by 60% with comparable accuracy. We provide a summary of the top methods, make their code and Docker containers publicly available, and give practical suggestions on building accurate and efficient abdominal organ segmentation models. The FLARE challenge remains open for future submissions through a live platform for benchmarking further methodology developments at https://flare.grand-challenge.org/.

Feasibility of biology-guided radiotherapy using PSMA-PET to boost to dominant intraprostatic tumour.

Background: Biology-guided radiotherapy (BgRT) delivers dose to tumours triggered from positron emission tomography (PET) detection. Prostate specific membrane antigen (PSMA) PET uptake is abundant in the dominant intraprostatic lesion (DIL). This study investigates the feasibility of BgRT to PSMA-avid subvolume in the prostate region. Methods: Patients enrolled in the prospective randomized trial ProPSMA at our institution were included (ID: ANZCTR12617000005358). Gross tumour volumes (GTVs) were delineated on the PET component of a PET/CT scan from a standardized uptake value (SUV) threshold technique. Suitability for BgRT requires a strong signal-to-background ratio with a surrounding tissue free of significant PSMA uptake. The signal-to-background ratio was quantified from the calculation of the normalized SUV (nSUV), defined as the ratio between SUVmax within the GTV and SUVmean inside a 3D margin expansion of the GTV. The PSMA distribution surrounding the tumour was quantified as a function of the distance from the GTV. Results: In this cohort of 84 patients, 83 primary tumours were included. Prostate volume ranged from 19 cm3 to 148 cm3 (median = 52 cm3; IQR = 39 cm3 - 63 cm3). SUVmax inside the prostate was between 2 and 125 (median = 19; IQR = 11 - 30). More than 50% of GTVs generated with threshold between 25%SUVmax (median volume = 10.0 cm3; IQR = 4.5 cm3 - 20.0 cm3) and 50%SUVmax (median volume = 1.9 cm3; IQR = 1.1 cm3 - 3.8 cm3) were suitable for BgRT by using nSUV ≥ 3 and a margin expansion of 5 mm. Conclusions: It is feasible to identify GTVs suitable for BgRT in the prostate. These GTVs are characterized by a strong signal-to-background ratio and a surrounding tissue free of PSMA uptake.

Utility of Biology-Guided Radiotherapy to De Novo Metastases Diagnosed During Staging of High-Risk Biopsy-Proven Prostate Cancer.

Background: Biology-guided radiotherapy (BgRT) uses real-time functional imaging to guide radiation therapy treatment. Positron emission tomography (PET) tracers targeting prostate-specific membrane antigen (PSMA) are superior for prostate cancer detection than conventional imaging. This study aims at describing nodal and distant metastasis distribution from prostate cancer and at determining the proportion of metastatic lesions suitable for BgRT. Methods: A single-institution patient subset from the ProPSMA trial (ID ACTRN12617000005358) was analysed. Gross tumour volumes (GTV) were delineated on the CT component of a PSMA PET/CT scan. To determine the suitability of BgRT tracking zones, the normalized SUV (nSUV) was calculated as the ratio of SUVmax inside the GTV to the SUVmean of adjacent three-dimensional shells of thickness 5 mm/10 mm/20 mm as a measure of signal to background contrast. Targets were suitable for BgRT if (1) nSUV was larger than an nSUV threshold and (2) non-tumour tissue inside adjacent shell was free of PET-avid uptake. Results: Of this cohort of 84 patients, 24 had at least one pelvic node or metastatic site disease, 1 to 13 lesions per patient, with a total of 98 lesions (60 pelvic nodes/38 extra-pelvic nodal diseases and haematogenous metastases). Target volumes ranged from 0.08 to 9.6 cm3 while SUVmax ranged from 2.1 to 55.0. nSUV ranged from 1.9 to 15.7/2.4 to 25.7/2.5 to 34.5 for the 5 mm/10 mm/20 mm shell expansion. Furthermore, 74%/68%/34% of the lesions had nSUV ≥ 3 and were free of PSMA PET uptake inside the GTV outer shell margin expansion of 5 mm/10 mm/20 mm. Adjacent avid organs were another lesion, bladder, bowel, ureter, prostate, and liver. Conclusions: The majority of PSMA PET/CT-defined radiotherapy targets would be suitable for BgRT by using a 10-mm tracking zone in prostate cancer. A subset of lesions had adjacent non-tumour uptake, mainly due to the proximity of ureter or bladder, and may require exclusion from emission tracking during BgRT.

Dose assessment for daily cone-beam CT in lung radiotherapy patients and its combination with treatment planning.

With the increased use of X-ray imaging for patient alignment in external beam radiation therapy, particularly with cone-beam computed tomography (CBCT), the additional dose received by patients has become of greater consideration. In this study, we analysed the radiation dose from CBCT for clinical lung radiotherapy and assessed its relative contribution when combined with radiation treatment planning for a variety of lung radiotherapy techniques. The Monte Carlo simulation program ImpactMC was used to calculate the 3D dose delivered by a Varian TrueBeam linear accelerator to patients undergoing thorax CBCT imaging. The concomitant dose was calculated by simulating the daily CBCT irradiation of ten lung cancer patients. Each case was planned with a total dose of 50-60 Gy to the target lesion in 25-30 fractions using the 3DCRT or IMRT plan and retrospectively planned using VMAT. For each clinical case, the calculated CBCT dose was summed with the planned dose, and the dose to lungs, heart, and spinal cord were analysed according to conventional dose conformity metrics. Our results indicate greater variations in dose to the heart, lungs, and spinal cord based on planning technique, (3DCRT, IMRT, VMAT) than from the inclusion of daily cone-beam imaging doses over 25-30 fractions. The average doses from CBCT imaging per fraction to the lungs, heart and spinal cord were 0.52 ± 0.10, 0.49 ± 0.15 and 0.39 ± 0.08 cGy, respectively. Lung dose variations were related to the patient's size and body composition. Over a treatment course, this may result in an additional mean absorbed dose of 0.15-0.2 Gy. For lung V5, the imaging dose resulted in an average increase of ~ 0.6% of the total volume receiving 5 Gy. The increase in V20 was more dependent on the planning technique, with 3DCRT increasing by 0.11 ± 0.09% with imaging and IMRT and VMAT increasing by 0.17 ± 0.05% and 0.2 ± 0.06%, respectively. In this study, we assessed the concomitant dose for daily CBCT lung cancer patients undergoing radiotherapy. The additional radiation dose to the normal lungs from daily CBCT was found to range from 0.15 to 0.2 Gy when the patient was treated with 25-30 fractions. Consideration of potential variation in relative biological effectiveness between kilovoltage imaging and megavoltage treatment dose was outside the scope of this study. Regardless of this, our results show that the assessment of imaging dose can be incorporated into the treatment planning process and the relative effect on overall dose distribution was small compared to the difference among planning techniques.

Radiation Dosimetry in 177Lu-PSMA-617 Therapy.

Radionuclide therapy using the small molecule PSMA bound to the beta-emitting radionuclide, Lutetium-177 (177Lu-PSMA) has demonstrated efficacy and survival benefit castrate resistant metastatic disease and represents a novel new line of therapy. Whilst dosimetry was critical for early development, it was not incorporated into either the TheraP or VISION randomized studies, highlighting the difficulty of adopting dosimetry in routine clinical practice. Accumulated clinical experience has also shown that the common (and generally low grade) toxicities such as nausea, xerostomia, and cytopenias are not readily predicted on the basis of dosimetry estimates. The majority of dosimetry and clinical literature deals with the radiopharmaceutical 177Lu-PSMA-617 which displays relatively consistent patterns of retention among normal tissues and high specificity for metastatic prostate cancer phenotypes. Population dosimetry incorporating estimates to the kidneys, salivary glands, and bone marrow have been widely reported the typical range of doses is becoming well established. There is growing interest on tumor dosimetry in 177Lu-PSMA-617 therapy as an overall modest side-effect profile from primary organ retention has been observed. A focus away from normal organ dosimetry to whole body tumor dosimetry may enable early prediction of treatment failure. Given the safety of 177Lu-PSMA there is also potential to escalate administered radioactivity to further improve outcomes. Importantly, the variability of uptake between individuals, both to tumor and normal organs, has also been highlighted which provides some rationale for the utility of personalized radiation analysis to optimize treatment based on potential toxicity thresholds or tumor control. Methods to perform dosimetry using serial post treatment imaging may incorporate planar, 3D SPECT, or hybrid datasets. Reliable measurements may be obtained through either method, however, continued developments in computational analysis are better suited to fully 3D imaging; particularly in conjunction with volumetric CT to assist with alignment and contouring. Dose analysis over sequential treatment cycles is vital to understand the radiobiology of these treatments which is unique compared to external beam therapy due to dose rate, fractionation scheme, and potential for intratumoral nonuniformity.

Cascaded deep learning-based auto-segmentation for head and neck cancer patients: Organs at risk on T2-weighted magnetic resonance imaging.

PURPOSE: To investigate multiple deep learning methods for automated segmentation (auto-segmentation) of the parotid glands, submandibular glands, and level II and level III lymph nodes on magnetic resonance imaging (MRI). Outlining radiosensitive organs on images used to assist radiation therapy (radiotherapy) of patients with head and neck cancer (HNC) is a time-consuming task, in which variability between observers may directly impact on patient treatment outcomes. Auto-segmentation on computed tomography imaging has been shown to result in significant time reductions and more consistent outlines of the organs at risk. METHODS: Three convolutional neural network (CNN)-based auto-segmentation architectures were developed using manual segmentations and T2-weighted MRI images provided from the American Association of Physicists in Medicine (AAPM) radiotherapy MRI auto-contouring (RT-MAC) challenge dataset (n = 31). Auto-segmentation performance was evaluated with segmentation similarity and surface distance metrics on the RT-MAC dataset with institutional manual segmentations (n = 10). The generalizability of the auto-segmentation methods was assessed on an institutional MRI dataset (n = 10). RESULTS: Auto-segmentation performance on the RT-MAC images with institutional segmentations was higher than previously reported MRI methods for the parotid glands (Dice: 0.860 ± 0.067, mean surface distance [MSD]: 1.33 ± 0.40 mm) and the first report of MRI performance for submandibular glands (Dice: 0.830 ± 0.032, MSD: 1.16 ± 0.47 mm). We demonstrate that high-resolution auto-segmentations with improved geometric accuracy can be generated for the parotid and submandibular glands by cascading a localizer CNN and a cropped high-resolution CNN. Improved MSDs were observed between automatic and manual segmentations of the submandibular glands when a low-resolution auto-segmentation was used as prior knowledge in the second-stage CNN. Reduced auto-segmentation performance was observed on our institutional MRI dataset when trained on external RT-MAC images; only the parotid gland auto-segmentations were considered clinically feasible for manual correction (Dice: 0.775 ± 0.105, MSD: 1.20 ± 0.60 mm). CONCLUSIONS: This work demonstrates that CNNs are a suitable method to auto-segment the parotid and submandibular glands on MRI images of patients with HNC, and that cascaded CNNs can generate high-resolution segmentations with improved geometric accuracy. Deep learning methods may be suitable for auto-segmentation of the parotid glands on T2-weighted MRI images from different scanners, but further work is required to improve the performance and generalizability of these methods for auto-segmentation of the submandibular glands and lymph nodes.

CT slice alignment to whole-body reference geometry by convolutional neural network.

Volumetric medical imaging lacks a standardised coordinate geometry which links image frame-of-reference to specific anatomical regions. This results in an inability to locate anatomy in medical images without visual assessment and precludes a variety of image analysis tasks which could benefit from a standardised, machine-readable coordinate system. In this work, a proposed geometric system that scales based on patient size is described and applied to a variety of cases in computed tomography imaging. Subsequently, a convolutional neural network is trained to associate axial slice CT image appearance with the standardised coordinate value along the patient superior-inferior axis. The trained neural network showed an accuracy of ± 12 mm in the ability to predict per-slice reference location and was relatively stable across all annotated regions ranging from brain to thighs. A version of the trained model along with scripts to perform network training in other applications are made available. Finally, a selection of potential use applications are illustrated including organ localisation, image registration initialisation, and scan length determination for auditing diagnostic reference levels.

A Deep Learning Model to Automate Skeletal Muscle Area Measurement on Computed Tomography Images.

BACKGROUND: Muscle wasting (Sarcopenia) is associated with poor outcomes in cancer patients. Early identification of sarcopenia can facilitate nutritional and exercise intervention. Cross-sectional skeletal muscle (SM) area at the third lumbar vertebra (L3) slice of a computed tomography (CT) image is increasingly used to assess body composition and calculate SM index (SMI), a validated surrogate marker for sarcopenia in cancer. Manual segmentation of SM requires multiple steps, which limits use in routine clinical practice. This project aims to develop an automatic method to segment L3 muscle in CT scans. METHODS: Attenuation correction CTs from full body PET-CT scans from patients enrolled in two prospective trials were used. The training set consisted of 66 non-small cell lung cancer (NSCLC) patients who underwent curative intent radiotherapy. An additional 42 NSCLC patients prescribed curative intent chemo-radiotherapy from a second trial were used for testing. Each patient had multiple CT scans taken at different time points prior to and post- treatment (147 CTs in the training and validation set and 116 CTs in the independent testing set). Skeletal muscle at L3 vertebra was manually segmented by two observers, according to the Alberta protocol to serve as ground truth labels. This included 40 images segmented by both observers to measure inter-observer variation. An ensemble of 2.5D fully convolutional neural networks (U-Nets) was used to perform the segmentation. The final layer of U-Net produced the binary classification of the pixels into muscle and non-muscle area. The model performance was calculated using Dice score and absolute percentage error (APE) in skeletal muscle area between manual and automated contours. RESULTS: We trained five 2.5D U-Nets using 5-fold cross validation and used them to predict the contours in the testing set. The model achieved a mean Dice score of 0.92 and an APE of 3.1% on the independent testing set. This was similar to inter-observer variation of 0.96 and 2.9% for mean Dice and APE respectively. We further quantified the performance of sarcopenia classification using computer generated skeletal muscle area. To meet a clinical diagnosis of sarcopenia based on Alberta protocol the model achieved a sensitivity of 84% and a specificity of 95%. CONCLUSIONS: This work demonstrates an automated method for accurate and reproducible segmentation of skeletal muscle area at L3. This is an efficient tool for large scale or routine computation of skeletal muscle area in cancer patients which may have applications on low quality CTs acquired as part of PET/CT studies for staging and surveillance of patients with cancer.

Automated assessment of functional lung imaging with 68Ga-ventilation/perfusion PET/CT using iterative histogram analysis.

PURPOSE: Functional lung mapping from Ga68-ventilation/perfusion (V/Q) PET/CT, which has been shown to correlate with pulmonary function tests (PFTs), may be beneficial in a number of clinical applications where sparing regions of high lung function is of interest. Regions of clumping in the proximal airways in patients with airways disease can result in areas of focal intense activity and artefact in ventilation imaging. These artefacts may even shine through to subsequent perfusion images and create a challenge for quantitative analysis of PET imaging. We aimed to develop an automated algorithm that interprets the uptake histogram of PET images to calculate a peak uptake value more representative of the global lung volume. METHODS: Sixty-six patients recruited from a prospective clinical trial underwent both V/Q PET/CT imaging and PFT analysis before treatment. PET images were normalised using an iterative histogram analysis technique to account for tracer hotspots prior to the threshold-based delineation of varying values. Pearson's correlation between fractional lung function and PFT score was calculated for ventilation, perfusion, and matched imaging volumes at varying threshold values. RESULTS: For all functional imaging thresholds, only FEV1/FVC PFT yielded reasonable correlations to image-based functional volume. For ventilation, a range of 10-30% of adapted peak uptake value provided a reasonable threshold to define a volume that correlated with FEV1/FVC (r = 0.54-0.61). For perfusion imaging, a similar correlation was observed (r = 0.51-0.56) in the range of 20-60% adapted peak threshold. Matched volumes were closely linked to ventilation with a threshold range of 15-35% yielding a similar correlation (r = 0.55-0.58). CONCLUSIONS: Histogram normalisation may be implemented to determine the presence of tracer clumping hotspots in Ga-68 V/Q PET imaging allowing for automated delineation of functional lung and standardisation of functional volume reporting.

Clinical Trial Protocol for LuTectomy: A Single-arm Study of the Dosimetry, Safety, and Potential Benefit of 177Lu-PSMA-617 Prior to Prostatectomy.

LuTectomy is an open-label phase 1/2 nonrandomised clinical trial evaluating the dosimetry, efficacy, and toxicity of the lutetium-177-radiolabelled small molecule PSMA-617 in men with high-risk localised/locoregional advanced prostate cancer with high prostate-specific membrane antigen expression who are undergoing radical prostatectomy and pelvic lymph node dissection.

Single-arm prospective interventional study assessing feasibility of using gallium-68 ventilation and perfusion PET/CT to avoid functional lung in patients with stage III non-small cell lung cancer.

BACKGROUND: In the curative-intent treatment of locally advanced lung cancer, significant morbidity and mortality can result from thoracic radiation therapy. Symptomatic radiation pneumonitis occurs in one in three patients and can lead to radiation-induced fibrosis. Local failure occurs in one in three patients due to the lungs being a dose-limiting organ, conventionally restricting tumour doses to around 60 Gy. Functional lung imaging using positron emission tomography (PET)/CT provides a geographic map of regional lung function and preclinical studies suggest this enables personalised lung radiotherapy. This map of lung function can be integrated into Volumetric Modulated Arc Therapy (VMAT) radiotherapy planning systems, enabling conformal avoidance of highly functioning regions of lung, thereby facilitating increased doses to tumour while reducing normal tissue doses. METHODS AND ANALYSIS: This prospective interventional study will investigate the use of ventilation and perfusion PET/CT to identify highly functioning lung volumes and avoidance of these using VMAT planning. This single-arm trial will be conducted across two large public teaching hospitals in Australia. Twenty patients with stage III non-small cell lung cancer will be recruited. All patients enrolled will receive dose-escalated (69 Gy) functional avoidance radiation therapy. The primary endpoint is feasibility with this achieved if ≥15 out of 20 patients meet pre-defined feasibility criteria. Patients will be followed for 12 months post-treatment with serial imaging, biomarkers, toxicity assessment and quality of life assessment. DISCUSSION: Using advanced techniques such as VMAT functionally adapted radiation therapy may enable safe moderate dose escalation with an aim of improving local control and concurrently decreasing treatment related toxicity. If this technique is proven feasible, it will inform the design of a prospective randomised trial to assess the clinical benefits of functional lung avoidance radiation therapy. ETHICS AND DISSEMINATION: This study was approved by the Peter MacCallum Human Research Ethics Committee. All participants will provide written informed consent. Results will be disseminated via publications. TRIALS REGISTRATION NUMBER: NCT03569072; Pre-results.