SPECT image segmentation for estimation of tumour volume and activity concentration in 177Lu-DOTATATE radionuclide therapy

Background: Dosimetry in radionuclide therapy has the potential to allow for a treatment tailored to the individual patient. One therapeutic radiopharmaceutical where patient-specific dosimetry is feasible is 177Lu-DOTATATE, used for the treatment of neuroendocrine tumours. The emission of gamma photons by 177Lu allows for imaging with SPECT (single photon emission computed tomography). One important step for dosimetry using this imaging technique is the SPECT image segmentation, which needs to be robust and accurate for the estimated quantities to be reliable. This work investigates different methods for automatic tumour delineation in 177Lu-DOTATATE SPECT images. Three segmentation methods are considered: a fixed 42% threshold (FT), the Otsu method (OM) and a method based on Fourier surfaces (FS). Effects of including resolution compensation in the iterative SPECT image reconstruction are also studied. Evaluation is performed based on Monte Carlo-simulated SPECT images from 24 h and 336 h post injection (p.i.), for determination of the volume, activity concentration and dice similarity coefficient. In addition, patient data are used to investigate the correspondence of tumour volumes when delineated in SPECT or morphological CT or MR images. Patient data are also used to examine the sensitivity to the operator-dependent initialization. Results: For simulated images from 24 h p.i. reconstructed without resolution compensation, a volume and activity-concentration root-mean-square error below 15% is typically obtained for tumours above approximately 10 cm3 when using OM or FS, while FT performs considerably worse. When including resolution compensation, the tumour volume becomes underestimated and the activity concentration overestimated. The FS method appears to be robust to noise, as seen for the 336 h images. The differences between the tumour volumes estimated from the SPECT images and the volumes estimated from morphological images are generally larger than the discrepancies seen for the simulated data sets. Conclusions: Segmentation results are encouraging for future dosimetry of tumours with volumes above approximately 10 cm3. Using resolution compensation in the reconstruction may have a negative effect on volume estimation

Phase II study of everolimus and temozolomide as first-line treatment in metastatic high-grade gastroenteropancreatic neuroendocrine neoplasms.

BACKGROUND The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients. METHODS Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed. RESULTS For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment. CONCLUSION Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (NTC02248012)

Mutation Spectrum in Liquid Versus Solid Biopsies From Patients With Advanced Gastroenteropancreatic Neuroendocrine Carcinoma.

PURPOSE Gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC) are rare and have a poor prognosis. Most GEP-NEC are diagnosed with metastatic disease, with only minor biopsies available for molecular diagnostics. We assessed the applicability of liquid biopsies for molecular profiling of GEP-NEC. MATERIALS AND METHODS We performed massive parallel sequencing of 76 cancer-related genes in circulating tumor DNA from 50 patients with advanced GEP-NEC and compared findings to previous analyses of solid tumor biopsies from the same patients. Plasma samples were collected before therapy, and the median time span between blood and tissue sampling was 25 days. RESULTS We detected 178 somatic mutations in the liquid biopsies, 127 (71%) were also detected in the solid biopsies, whereas 51 (29%) were unique to the liquid biopsies. In the same 76 genes, we previously detected 199 somatic mutations (single nucleotide variants) in solid biopsies, of which 127 (64%) were also now detected in liquid biopsies. In exploratory subgroup assessments, concordance was higher in patients with liver metastases (P = 1.5 × 10-5) and increasing with level of liver involvement (P = 1.2 × 10-4). The concordance was similar between GEP-NEC with different primary sites, except being lower in esophageal cases (P = .001). Concordance was not associated with tumor mutation burden. Tumor tissue mutations also detected in liquid biopsies was lower for MSI (40%) versus MSS tumors (70%; P = 7.8 × 10-4). We identified potentially targetable mutations in plasma of 26 (52%) of patients with GEP-NEC; nine patients (18%) had potentially targetable mutation detected only in liquid biopsies. CONCLUSION Liquid biopsy analyses may be an applicable alternative to solid biopsies in GEP-NEC. Liquid biopsies may add additional mutations compared with tumor biopsies alone and could be useful for biomarker assessment in clinical trials for these patients

Germline pathogenic variants in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms.

High-grade gastroenteropancreatic (HG-GEP) NEN are highly aggressive cancers. The molecular etiology of these tumors remains unclear and the prevalence of pathogenic germline variants in patients with HG-GEP-NEN is unknown. We assessed sequencing data of 360 cancer genes in normal tissue, from 240 patients with HG GEP-NEN; 198 patients with NEC and 42 with NET G3. Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in 3 patients and a recurrent MUTYH variant in 2 patients, indicating that these genes may be important underlying risk factors for HG-GEP-NEN, when mutated. Further, germline variants were found in canonical tumor suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in-silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0-17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP-NEC. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG GEP-NEN with germline pathogenic variants is relatively high, but still <10%, meaning that that germline mutations cannot be the major underlying cause of HG GEP-NEN

The Role of RANK-Ligand Inhibition in Cancer: The Story of Denosumab

The bone is a very common site of metastasis in patients with advanced cancer. Skeletal metastases are most common in breast and prostate cancer, but virtually any advanced cancer may disseminate to the bone. On the basis of recent advances in the understanding of bone remodeling processes, denosumab, a fully human monoclonal antibody against RANK-L, has been developed. Phase III clinical trials have demonstrated that denosumab is well tolerated and effective in the treatment of bone loss and prevention of skeletal-related events in patients with bone metastases

Tailoring Radionuclide Therapy of Neuroendocrine Tumors - Bridging the Gaps

Background and Aims: Radionuclide therapy is systemic, targeted radiotherapy. As such, we can apply the basic principles of radiobiology used in everyday practice in radiation oncology, as a means of tailoring the treatment to each patient and optimizing the balance between efficacy and toxicity. The most common type of radionuclide therapy used for the treatment of neuroendocrine tumors, is 177Lu-DOTATATE. It has proven to be safe and effective, even without any tailoring. The aim of the work presented in this thesis is to systematically explore how we can further improve results for patients by tailoring the treatment. Methods and Results: The thesis is based on two clinical trials – Iluminet and Gapetto – which were both designed to address different aspects of the overall aim. The Iluminet trial is a phase II trial in which patients, instead of receiving the standard four cycles of 7.4 GBq of 177Lu-DOTATATE, are treated to the maximum number of cycles within the predefined limits for radiation dose to the kidneys. Safety and efficacy data are collected during treatment and follow-up. The Gapetto trial was a prospective observational study looking at the effect of somatostatin analog treatment on the uptake of 68Ga-DOTATATE in PET/CT. Papers I and II are based on the first 51 patients included in the Iluminet trial. Paper I presents data from an interim analysis of renal function, and also describes the effects that tailoring has on treatment planning. The mean number of treatment cycles the patients received was 5, but there were large interindividual variations. No serious renal toxicity was detected during the 24-month median follow-up. Paper II describes the consequences of simplifying the dosimetric protocol in order to make dosimetry more feasible in clinical practice. The results show that basing dosimetry on just one SPECT-image taken att 96h is as accurate as doing full hybrid dosimetry, which is the reference in the trial protocol. Paper III describes the pituitary function in 68 evaluable patients during long-term follow-up in the Iluminet trial. A significant decrease in IGF1 was detected, which could be secondary to the radiation received by the pituitary gland during treatment with 177Lu-DOTATATE, but other possible explanations are also discussed. Paper IV is based on the Gapetto trial. The SUV values in 68Ga-DOTATATE PET/CT were compared before and after initiating treatment with long-acting somatostatin analogs. The effect of the time from the last injection to the PET/CT was also analyzed. Results showed that the use of somatostatin analogs decreased the SUV in normal tissues, but not in tumor. The time since last injection did not affect the SUV-values. Conclusions: Tailoring radionuclide treatment based on individual dosimetry is feasible and safe, and leads to considerable interindividual variations in the number of treament cycles received. No signs of serious renal or pituitary toxicity have been detected. Dosimetry can be substantially simplified without compromising accuracy. Treatment with long-acting somatostatin analogs improves the tumor-to-normal ratio in 68Ga-DOTATATE PET/CT, and possibly also in the therapeutic setting, i.e. when using 177Lu-DOTATATE to treat neuroendocrine tumors

Health-Related Quality of Life After Surgery for Small Intestinal Neuroendocrine Tumours

Background: Overall survival for patients with small intestinal neuroendocrine tumours (siNETs) is long, even with metastatic disease, making quality of life issues relevant. The impact of surgery on quality of life is not known. We investigated determinants of health-related quality of life in patients who had undergone surgery for a siNET. Methods: Patients operated for a siNET between 1998 and 2016 at Skåne University Hospital (Lund, Sweden), who were alive in February 2017, were sent two questionnaires constructed by the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30, EORTC QLQ-GINET21). Global quality of life, physical function, disease-related worries, diarrhoea and endocrine symptoms were evaluated with linear and logistic regression in relation to patient-, tumour- and treatment-related factors. Statistical analysis was performed using STATA 11®. Results: One hundred patients (84%) completed the questionnaires. Women had worse global quality of life (p = 0.019), more disease-related worries (p < 0.001) and endocrine symptoms (p = 0.017) than men. Older age was associated with more disease-related worries (p = 0.007), but fewer endocrine symptoms (p = 0.034). Non-symptomatic tumour versus symptomatic tumour (p = 0.002), and treatment with somatostatin analogues versus no treatment (p = 0.040) were associated with less diarrhoea. Small versus large bowel resection was associated with better global quality of life (p = 0.036) and physical function (p = 0.035). Conclusions: Male gender, younger age, treatment with somatostatin analogues, non-symptomatic tumour, and small intestinal surgery rather than large bowel surgery were associated with better quality of life

Characterisation of a hand-held CZT-based gamma camera for 177Lu imaging

Background: Currently, hand-held gamma cameras are being developed for 99mTc imaging, mainly for sentinel lymph node detection. These cameras offer advantages, such as mobility and ease of access, and may be useful also for other applications such as biokinetic studies in animals or for imaging of small, superficial structures in patients. In this work, the suitability of a CZT-based hand-held camera for 177Lu imaging is investigated. The energy response of CZT-based detectors combined with the multiple photon emissions of 177Lu poses new challenges compared to 99mTc imaging, and a thorough camera characterisation is thus warranted. Methods: Three collimators (LEHR, LEHS, and MEGP) and three energy windows (55 keV, 113 keV, and 208 keV) are investigated. Characterised camera properties include the system spatial resolution, energy resolution, sensitivity, image uniformity, septal penetration, and temperature dependence. Characterisations are made starting from NEMA guidelines when applicable, with adjustments made when required. The applicability of the camera is demonstrated by imaging of a superficially located tumour in a patient undergoing [177 Lu]Lu-DOTA-TATE therapy. Results: Overall, the results are encouraging. Compared to a conventional gamma camera, the hand-held camera generally has a higher sensitivity for a given collimator. For source-collimator distances below 3 cm, the spatial resolution FWHM is within 6 mm for the LEHR and MEGP collimators. Before uniformity correction, the central field-of-view integral uniformity shows best results for the 113-keV window, with values obtained between 11 and 14%. The corresponding values after uniformity correction are within 3%. Effects of septal penetration are observed but are manageable with a proper combination of collimator and energy window setting. Septal penetration and collimator scatter not only affect the 208-keV window but also contribute with counts in lower windows due to energy-tailing effects. The patient study revealed non-uniform uptake patterns in a region that appeared uniform in a conventional gamma camera image. Conclusions: The results show that the hand-held camera can be used for 177Lu imaging. A 113-keV energy window combined with LEHR or MEGP collimators provides the best image system characteristics

AI-based quantification of whole-body tumour burden on somatostatin receptor PET/CT

Abstract Background Segmenting the whole-body somatostatin receptor-expressing tumour volume (SRETVwb) on positron emission tomography/computed tomography (PET/CT) images is highly time-consuming but has shown value as an independent prognostic factor for survival. An automatic method to measure SRETVwb could improve disease status assessment and provide a tool for prognostication. This study aimed to develop an artificial intelligence (AI)-based method to detect and quantify SRETVwb and total lesion somatostatin receptor expression (TLSREwb) from [68Ga]Ga-DOTA-TOC/TATE PET/CT images. Methods A UNet3D convolutional neural network (CNN) was used to train an AI model with [68Ga]Ga-DOTA-TOC/TATE PET/CT images, where all tumours were manually segmented with a semi-automatic method. The training set consisted of 148 patients, of which 108 had PET-positive tumours. The test group consisted of 30 patients, of which 25 had PET-positive tumours. Two physicians segmented tumours in the test group for comparison with the AI model. Results There were good correlations between the segmented SRETVwb and TLSREwb by the AI model and the physicians, with Spearman rank correlation coefficients of r = 0.78 and r = 0.73, respectively, for SRETVwb and r = 0.83 and r = 0.81, respectively, for TLSREwb. The sensitivity on a lesion detection level was 80% and 79%, and the positive predictive value was 83% and 84% when comparing the AI model with the two physicians. Conclusion It was possible to develop an AI model to segment SRETVwb and TLSREwb with high performance. A fully automated method makes quantification of tumour burden achievable and has the potential to be more widely used when assessing PET/CT images

Dosimetric quantities of neuroendocrine tumors over treatment cycles with 177Lu-DOTA-TATE

Tumor dosimetry was performed for 177Lu-DOTA-TATE with the aims of better understanding i) the range and variation of the tumor absorbed doses (ADs), ii) how different dosimetric quantities evolve over the treatment cycles, and iii) whether this evolution differs depending on the tumor grade. Such information is important for radiobiological interpretation and may inform the design of alternative administration schemes. Methods: Data come from 41 patients with neuroendocrine tumors (NETs) of grade 1 (n = 23) or 2 (n = 18), that had received between 2 and 9 treatment cycles. Dosimetry was performed for 182 individual lesions, giving in total 880 individual AD assessments across all cycles. Hybrid planar-SPECT/CT imaging was used, including quantitative SPECT reconstruction, voxel-based absorbed-dose-rate calculation, semi-automatic image segmentation, and partial-volume correction. Linear mixed-effect models were used to analyze changes over cycles in tumor ADs, absorbed-dose rates and activity concentrations at day-1, effective half-times, and tumor volumes. Tumors smaller than 8 ml were excluded from analyses. Results: Tumor ADs ranged between 2 and 77 Gy per cycle. On average the AD decreased over the cycles, with significantly different rates (P < 0.05) for grade 1 and 2 NETs of 6% and 14% per cycle, respectively. The absorbed-dose rates and activity concentrations at day-1 decreased by similar amounts. The effective half-times were less variable but shorter for grade 2 than grade 1 (P < 0.001). For grade 2 NETS the tumor volumes decreased, with a similar tendency in grade 1. Conclusion: The tumor AD, absorbed-dose rate and activity uptake decrease, in parallel with tumor volumes, between 177Lu-DOTA-TATE treatment cycles, particularly for grade 2 NETs. The effective half-times vary less but are lower for grade 2 than grade 1 NETs. These results may indicate the development of radiation-induced fibrosis and could have implications for the design of future treatment and dosimetry protocols