Optimizing the Schedule of PARP Inhibitors in Combination with 177Lu-DOTATATE: A Dosimetry Rationale.

177Lu-DOTATATE for neuroendocrine tumours is considered a low-toxicity treatment and may therefore be combined with other pharmaceuticals to potentiate its efficacy. One approach is to add a poly-[ADP-ribose]-polymerase (PARP) inhibitor to decrease the ability of tumour cells to repair 177Lu-induced DNA damage. To decrease the risk of side effects, the sequencing should be optimized according to the tumour-to-normal tissue enhanced dose ratio (TNED). The aim of this study was to investigate how to enhance 177Lu-DOTATATE by optimal timing of the addition of a PARP inhibitor. Biokinetic modelling was performed based on the absorbed dose to the bone marrow, kidneys and tumour; determined from SPECT/CT and planar images from 17 patients treated with 177Lu-DOTATATE. To investigate the theoretical enhanced biological effect of a PARP inhibitor during 177Lu-DOTATATE treatment, the concept of relative biological effectiveness (RBE) was used, and PARP inhibitor administration was simulated over different time intervals. The absorbed dose rate for the tumour tissue demonstrated an initial increase phase until 12 h after infusion followed by a slow decrease. In contrast, the bone marrow showed a rapid initial dose rate decrease. Twenty-eight days after infusion of 177Lu-DOTATATE, the full absorbed dose to the bone marrow and kidney was reached. Using an RBE value of 2 for both the tumour and normal tissues, the TNED was increased compared to 177Lu-DOTATATE alone. According to the modelling, the PARP inhibitor should be introduced approximately 24 h after the start of 177Lu-DOTATATE treatment and be continued for up to four weeks to optimize the TNED. Based on these results, a phase I trial assessing the combination of olaparib and 177Lu-DOTATATE in somatostatin receptor-positive tumours was launched in 2020 (NCT04375267).

Bone Marrow Absorbed Doses and Correlations with Hematologic Response During 177Lu-DOTATATE Treatments Are Influenced by Image-Based Dosimetry Method and Presence of Skeletal Metastases.

This study aimed to compare different image-based methods for bone marrow dosimetry and study the dose-response relationship during treatment with 177Lu-DOTATATE in patients with and without skeletal metastases. Methods: This study included 46 patients with advanced neuroendocrine tumors treated with at least 2 fractions of 177Lu-DOTATATE at Sahlgrenska University Hospital. High- and low-uptake compartments were automatically outlined in planar images collected at 2, 24, 48, and 168 h after injection. The bone marrow absorbed doses were calculated from the cross doses of the high- and low-uptake compartments and the self-dose, using the time-activity concentration curve for the low-uptake compartment. This time-activity concentration curve was adjusted using a fixed constant of 1.8 for the planar dosimetry method and using the activity concentrations in vertebral bodies in SPECT images at 24 h after injection of 177Lu-DOTATATE in 4 hybrid methods: L4-SPECT used the activity concentration in the L4 vertebra, whereas V-SPECT, L-SPECT, and T-SPECT used the median activity concentration in all visible vertebrae, lumbar vertebrae, and thoracic vertebrae, respectively. Results: Using the planar method, L4-SPECT, V-SPECT, L-SPECT, and T-SPECT, the estimated median bone marrow absorbed doses were 0.19, 0.36, 0.40, 0.39, and 0.46 Gy/7.4 GBq, respectively, with respective ranges of 0.12-0.33, 0.15-1.44, 0.19-1.71, 0.21-1.60, and 0.18-2.12 Gy/7.4 GBq. For all methods, the bone marrow absorbed dose significantly correlated with decreased platelet counts. This correlation increased after treatment fraction 2: the Spearman correlation (rs) were -0.49 for the planar method, -0.61 for L4-SPECT, -0.63 for V-SPECT, -0.63 for L-SPECT, and -0.57 for T-SPECT. A separate analysis revealed an increased correlation for patients without skeletal metastases using the planar method (rs = -0.67). In contrast, hybrid methods had poor correlations for patients without metastases and stronger correlations for patients with skeletal metastases (rs = -0.61 to -0.74). The mean bone marrow absorbed doses were 3%-69% higher for patients with skeletal metastases than for patients without. Conclusion: The estimated bone marrow absorbed doses by image-based techniques and the correlation with platelets are influenced by the choice of measured vertebrae and the presence of skeletal metastases.

Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in 177Lu-DOTATATE Treatments.

BACKGROUND: In 177Lu-DOTATATE treatments, bone marrow (BM) is one of the most important organs at risk. The authors previously developed an image-based two-compartment method for BM dosimetry, showing a significant correlation between absorbed dose to BM and hematological toxicity in 177Lu-DOTATATE treatments. In the present study, they aimed to further evaluate this BM dosimetry method by finding optimal settings for dividing the whole body into two compartments; in terms of minimizing the coefficient of variation (CV) for the individual absorbed doses and studying its correlation to the BM response. The authors have also added specific absorbed fractions for male and female. Finally, they compare this two-compartment method with whole-body dosimetry. METHODS: This study included 46 patients with advanced neuroendocrine tumors treated with 177Lu-DOTATATE on two to five occasions at Sahlgrenska University Hospital. Planar gamma camera images were collected at four time points postinjection, and a segmentation tool using a normalized number of uptake foci (nNUF) to divide the whole body into high- and low-uptake compartments was used. The authors characterized the two-compartment model and compared it with whole-body dosimetry. RESULTS AND CONCLUSION: The dosimetry method was robust, with an optimal nNUF value of 0.1-0.2. Using an nNUF value of 0.15, the absorbed BM dose was estimated as 0.20 Gy/7.4 GBq, and the CV as 8.4%. Compared to whole-body dosimetry, stronger correlation was found between absorbed dose to BM and hematological response using the two-compartment method. The two-compartment method has potential as a valuable image-based alternative to blood-based BM dosimetry.

Temporal Deformity Objectively Measured Before and After Surgery for Metopic Synostosis: Retrusion Rather than Hollowing.

The temporal contour deformity typical of metopic synostosis is often referred to as temporal hollowing, but has not been quantitatively defined. This deformity is present before surgery and remains to a varying extent at long-term follow-up. The present study aimed to objectively evaluate the degree of this contour deformity in metopic synostosis before and after surgical correction.All children surgically treated for metopic synostosis at Sahlgrenska University Hospital between 2002 and 2014 (n = 120) with appropriate computed tomography scans (n = 160) performed preoperatively and/or at follow-up at 3 years of age were included. Depending on age, 1 of 2 surgical techniques was used. Children presenting before the age of 6 months were treated with frontal remodeling in combination with a spring (S group), whereas children older than 6 months were treated with a bone transplant (BT group). The bony temporal deformity was measured with a semiautomatic MATLAB program and patients were compared to sex- and age-matched controls.The deformity was significantly reduced in both groups (P < 0.001). In the S group, it was reduced from a mean ±â€Šstandard deviation of 3.6 ±â€Š1.9% to 1.0 ±â€Š1.2% and in the BT group, it was reduced from 3.3% ±â€Š1.4% to 1.1% ±â€Š0.8%.The contour deformity in metopic synostosis is present both before and after surgery and should therefore be termed temporal retrusion (TR). This assessment method enables objective comparison of TR before and after surgical correction and is a potential tool to evaluate TR in metopic synostosis.

A novel planar image-based method for bone marrow dosimetry in (177)Lu-DOTATATE treatment correlates with haematological toxicity.

BACKGROUND: (177)Lu-DOTATATE is a valuable treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. Though well tolerated in general, bone marrow toxicity can, besides renal exposure, become dose limiting and affect the ability to sustain future therapies. The aim of this study was to develop a novel planar image-based method for bone marrow dosimetry and evaluate its correlation with haematological toxicity during (177)Lu-DOTATATE treatment. In this study, 46 patients with advanced neuroendocrine tumours were treated with 7.2 GBq (3.5-8.3 GBq) of (177)Lu-DOTATATE on two to five occasions. Planar gamma camera images were acquired at 2, 24, 48 and 168 h post-injection. Whole-body regions of interest were created in the images, and a threshold-based segmentation algorithm was applied to separate the uptake of (177)Lu-DOTATATE into high and low uptake compartments. The conjugate view method was used to quantify the activity, the accumulated activity was calculated and the absorbed dose to the bone marrow was estimated according to the MIRD scheme. Patients were monitored for haematological toxicity based on haemoglobin (Hb), white blood cell (WBC) and platelet (PLT) counts every other week during the treatment period. RESULTS: The mean absorbed dose to the bone marrow was estimated to 0.20 Gy (0.11-0.37 Gy) per 7.4 GBq of (177)Lu-DOTATATE, and the mean dose per fraction correlated with a decrease in Hb (p = 0.01), WBC (p < 0.01) and PLT (p < 0.01) counts. The total mean absorbed dose to the bone marrow was 0.64 Gy (0.30-1.5 Gy) per 24 GBq (8.2-37 GBq) of (177)Lu-DOTATATE and also correlated with a decrease in Hb (p < 0.01), WBC (p = 0.01) and PLT (p < 0.01) counts. CONCLUSIONS: The planar image-based method developed in this study resulted in similar absorbed doses to the bone marrow as reported in earlier studies with blood-based bone marrow dosimetry. The results correlated with haematological toxicity, making it a promising method for estimating bone marrow doses in (177)Lu-DOTATATE treatment without the need for blood and urine sampling.

Radiation exposure of the spleen during (177)Lu-DOTATATE treatment and its correlation with haematological toxicity and spleen volume.

BACKGROUND: Somatostatin analogue-based radionuclide therapy with (177)Lu-DOTATATE is an important treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. In addition to the kidneys, the bone marrow is a major dose-limiting organ. The correlation between developed haematological toxicity and absorbed dose to the bone marrow is poor, which indicates that other factors affect haematological response. The spleen has an important role in the haematopoetic system, including being a reservoir for blood cells. It is also the organ that receives the highest mean absorbed dose during (177)Lu-DOTATATE treatment. The aim of this study was to analyse mean absorbed dose to the spleen and its correlation with haematological toxicity, and to explore changes in splenic volume. The study included 41 patients treated with 7.2 GBq (3.5-8.3 GBq) of (177)Lu-DOTATATE on two to five occasions. Following each fraction, planar whole-body scans were acquired at 2, 24, 48, and 168 h, and a SPECT/CT at 24 h post-injection. Mean absorbed spleen dose was calculated utilising planar images for time-activity data and SPECT to adjust activity amounts. Splenic volume information was collected from diagnostic CT scans at baseline and follow-up. RESULTS: Median and total absorbed spleen doses were estimated to 4.5 and 15 Gy, respectively. Total absorbed spleen dose correlated with decrease in Hb (p = 0.02), but not WBC (p = 0.31) or PLT (p = 0.65) counts. For patients without bone metastases, mean absorbed spleen dose correlated with decrease in PLT (p = 0.04) but not Hb (p = 0.16) or WBC (p = 0.42) counts. The spleen volume was reduced to 75 % (p < 0.001) of original values (200 vs. 260 ml) at a mean follow-up of 36 months. CONCLUSIONS: Haematological toxicity according to Hb counts was moderately but significantly correlated with total absorbed spleen dose. This supports the possibility that radiation exposure of the spleen affects overall haematological response during (177)Lu-DOTATATE treatment.

A new quantitative image-based method for evaluation of bony temporal hollowing in metopic synostosis.

OBJECTIVE: Premature craniosynostosis is a congenital disorder causing a skull deformity. For both functional and cosmetic reasons, the deformity is surgically treated with a cranioplasty before the age of 1 year. Temporal hollowing is a common and undesirable remaining deformity after cranioplasty for metopic synostosis. The most common method to determine the degree of temporal hollowing is subjective judgement of the temporal region. The aim of the present project was to develop a quantitative semi-automatic computer tool for objective measurement of bony temporal hollowing. METHODS: Using MATLAB, a tool was developed to segment computed tomography images, defining the outermost contour. The images were dorsally limited to the widest point of the head. In each case, a sex- and age-matched control was identified and the contours compared. The bony temporal hollowing of the cases was calculated. RESULTS: The intra-user coefficient of variation (CV) was 5.0% (95% CI = 4.2%-6.2%) and the inter-user CV was 3.0% (95% CI = 2.1%-8.6%). For clinical testing purposes, the tool was used in 14 patients, seven of whom had been operated on with a spring-assisted cranioplasty and seven with a cranioplasty using a bone graft. CONCLUSIONS: In summary, this study presents a new tool for objective measurement of the surgical result after cranioplasty for metopic synostosis.