Short-course PET based simultaneous integrated boost for locally advanced cervical cancer

Background Patients with large, locally advanced cervical cancers (LACC) are challenging to treat. The purpose of this work is to use 18F-FDG PET as planning basis for a short-course simultaneous integrated boost (SIB) in external beam radiotherapy of LACC in order to increase tumour shrinkage and likelihood of local control. Methods Ten previously treated patients with LACC were included, all with pre-treatment FDG PET/CT images available. The FDG avid tumour volume, MTV50, was dose escalated in silico by intensity modulated radiotherapy from the standard 1.8 Gy to 2.8 Gy per fraction for the 10 first fractions; a short-course SIB. For the 18 remaining external fractions, standard pelvic treatment followed to total PTV and MTV50 doses of 50.4 Gy and 60.4 Gy, respectively. Photon and proton treatment were considered using volumetric modulated arc treatment (VMAT) and intensity-modulated proton therapy (IMPT), respectively. All treatment plans were generated using the Eclipse Treatment Planning System (TPS). The impact of tumour shrinkage on doses to organs at risk (OARs) was simulated in the TPS for the SIB plans. Results Dose escalation could be implemented using both VMAT and IMPT, with a D98 ≥ 95 % for MTV50 being achieved in all cases. The sum of the 10 fraction short-course SIB and subsequent 18 standard fractions was compared to the standard non-SIB approach by dose volume histogram (DVH) analysis. Only marginal increase of dose to OARs was found for both modalities and a small further increase estimated from tumour shrinkage. Most DVH parameters showed a mean difference below 2 %. IMPT had, compared to VMAT, reduced OAR doses in the low to intermediate dose range, but showed no additional advantage in dose escalation. Conclusions Planning of dose escalation based on a FDG avid boost volume was here demonstrated feasible. The concept may allow time for enhanced tumour shrinkage before brachytherapy. Thus, this strategy may prove clinically valuable, in particular for patients with large tumours

Myelosuppression in patients treated with 177Lutetium-lilotomab satetraxetan can be predicted with absorbed dose to the red marrow as the only variable

Background The aim of this study was to investigate dosimetry data and clinical variables to predict hematological toxicity in non-Hodgkin lymphoma (NHL) patients treated with [177Lutetium]Lu-lilotomab satetraxetan. Material and methods A total of 17 patients treated with [177Lu]Lu-lilotomab satetraxetan in a first-in-human phase 1/2a study were included. Absorbed dose to the red marrow was explored using SPECT/CT-imaging of the lumbar vertebrae L2–L4 over multiple time points. Percentage reduction of thrombocytes and neutrophils at nadir compared to baseline (PBN) and time to nadir (TTN) were chosen as indicators of myelosuppression and included as dependent variables. Two models were applied in the analysis, a multivariate linear model and a sigmoidal description of toxicity as a function of absorbed dose. A total of 10 independent patient variables were investigated in the multivariate analysis. Results Absorbed dose to the red marrow ranged from 1 to 4 Gy. Absorbed dose to the red marrow was found to be the only significant variable for PBN for both thrombocytes and neutrophils. The sigmoid function gave similar results in terms of accuracy when compared to the linear model. Conclusion Myelosuppression in the form of thrombocytopenia and neutropenia in patients treated with [177Lu]Lu-lilotomab satetraxetan can be predicted from the SPECT/CT-derived absorbed dose estimate to the red marrow

Assessment of pulmonary 18 F-FDG-PET uptake and cytokine profiles in non-small cell lung cancer patients treated with radiotherapy and erlotinib

Purpose: To investigate effects of radiotherapy (RT) and erlotinib on pulmonary glucose uptake using 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography (PET) during and after treatment of non-small cell lung cancer (NSCLC) and to identify associations between serum cytokine levels and lung glucose uptake. Material and methods: Twenty-seven patients with advanced NSCLC, receiving RT alone or concomitant RT and erlotinib therapy, were examined by 18F-FDG PET before, during, and after treatment. A total of 57 18F-FDG PET scans were analyzed. Pulmonary 18F-FDG uptake and radiotherapy dose mapping were used to acquire dose-response curves for each patient, where subsequent linear regression gave a glucose uptake level in the un-irradiated parts of the lungs (SUV0) and a response slope (ΔSUV). Serum cytokine levels at corresponding time points were assessed using a multiplex bioassay. Correlations between the most robust cytokines and lung 18F-FDG dose response parameters were further investigated. Results: From the dose response analysis, SUV0 at post-therapy was significantly higher (P < 0.001) than at mid- and pre-therapy (45% and 58%, respectively) for the group receiving RT + erlotinib. Also, SUV0 at post-therapy was higher for patients receiving RT + erlotinib compared to RT alone (42%; P < 0.001). No differences in ΔSUV were seen with treatments or time. SUV0 was positively associated (r = 0.47, P = 0.01) with serum levels of the chemokine C–C motif ligand 21 (CCL21) for patients receiving RT + erlotinib. Conclusions: Concomitant RT and erlotinib causes an elevation in pulmonary 18F-FDG uptake post treatment compared to RT alone. Pulmonary glucose uptake is associated with an upregulation of a chemokine (CCL21) involved in inflammatory reactions

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

Purpose 177Lu-lilotomab satetraxetan targets the CD37 antigen and has been investigated in a first-in-human phase 1/2a study for relapsed non-Hodgkin lymphoma (NHL). Tumor dosimetry and response evaluation can be challenging after radioimmunotherapy (RIT). Changes in FDG PET/CT parameters after RIT and correlations with tumor-absorbed doses has not been examined previously in patients with lymphoma. Treatment-induced changes were measured at FDG PET/CT and ceCT to evaluate response at the lesion level after treatment, and correlations with tumor-absorbed doses were investigated. Methods Forty-five tumors in 16 patients, with different pre-treatment and pre-dosing regimens, were included. Dosimetry was performed based on multiple SPECT/CT images. FDG PET/CT was performed at baseline and at 3 and 6 months. SUVmax, MTV, TLG, and changes in these parameters were calculated for each tumor. Lesion response was evaluated at 3 and 6 months (PET3months and PET6months) based on Deauville criteria. Anatomical changes based on ceCT at baseline and at 6 and 12 months were investigated by the sum of perpendiculars (SPD). Results Tumor-absorbed doses ranged from 35 to 859 cGy. Intra- and interpatient variations were observed. Mean decreases in PET parameters from baseline to 3 months were ΔSUVmax-3months 61%, ΔMTV3months 80%, and ΔTLG3months 77%. There was no overall correlation between tumor-absorbed dose and change in FDG PET or ceCT parameters at the lesion level or significant difference in tumor-absorbed doses between metabolic responders and non-responders after treatment. Conclusion Our analysis does not show any correlation between tumor-absorbed doses and changes in FDG PET or ceCT parameters for the included lesions. The combination regimen, including cold antibodies, may be one of the factors precluding such a correlation. Increased intra-patient response with increased tumor-absorbed doses was observed for most patients, implying individual variations in radiation sensitivity or biology

Pre-dosing with lilotomab prior to therapy with 177Lu-lilotomab satetraxetan significantly increases the ratio of tumor to red marrow absorbed dose in non-Hodgkin lymphoma patients

Purpose: 177Lu-lilotomab satetraxetan is a novel anti-CD37 antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma (NHL). Four arms with different combinations of pre-dosing and pre-treatment have been investigated in a first-in-human phase 1/2a study for relapsed CD37+ indolent NHL. The aim of this work was to determine the tumor and normal tissue absorbed doses for all four arms, and investigate possible variations in the ratios of tumor to organs-at-risk absorbed doses. Methods: Two of the phase 1 arms included cold lilotomab pre-dosing (arm 1 and 4; 40 mg fixed and 100 mg/m2 BSA dosage, respectively) and two did not (arms 2 and 3). All patients were pre-treated with different regimens of rituximab. The patients received either 10, 15, or 20 MBq 177Lu-lilotomab satetraxetan per kg body weight. Nineteen patients were included for dosimetry, and a total of 47 lesions were included. The absorbed doses were calculated from multiple SPECT/CT-images and normalized by administered activity for each patient. Two-sided Student’s t tests were used for all statistical analyses. Results: Organs with distinct uptake of 177Lu-lilotomab satetraxetan, in addition to tumors, were red marrow (RM), liver, spleen, and kidneys. The mean RM absorbed doses were 0.94, 1.55, 1.44, and 0.89 mGy/MBq for arms 1–4, respectively. For the patients not pre-dosed with lilotomab (arms 2 and 3 combined) the mean RM absorbed dose was 1.48 mGy/MBq, which was significantly higher than for both arm 1 (p = 0.04) and arm 4 (p = 0.02). Of the other organs, the highest uptake was found in the spleen, and there was a significantly lower spleen absorbed dose for arm-4 patients than for the patient group without lilotomab pre-dosing (1.13 vs. 3.20 mGy/MBq; p < 0.01). Mean tumor absorbed doses were 2.15, 2.31, 1.33, and 2.67 mGy/MBq for arms 1–4, respectively. After averaging the tumor absorbed dose for each patient, the patient mean tumor absorbed dose to RM absorbed dose ratios were obtained, given mean values of 1.07 for the patient group not pre-dosed with lilotomab, of 2.16 for arm 1, and of 4.62 for arm 4. The ratios were significantly higher in both arms 1 and 4 compared to the group without pre-dosing (p = 0.05 and p = 0.02). No statistically significant difference between arms 1 and 4 was found. Conclusions: RM is the primary dose-limiting organ for 177Lu-lilotomab satetraxetan treatment, and pre-dosing with lilotomab has a mitigating effect on RM absorbed dose. Increasing the amount of lilotomab from 40 mg to 100 mg/m2 was found to slightly decrease the RM absorbed dose and increase the ratio of tumor to RM absorbed dose. Still, both pre-dosing amounts resulted in significantly higher tumor to RM absorbed dose ratios. The findings encourage continued use of pre-dosing with lilotomab

Biodistribution and dosimetry results from a phase 1 trial of therapy with the antibody-Radionuclide conjugate 177Lu-Lilotomab satetraxetan

177Lu-lilotomab satetraxetan is a novel antibody radionuclide conjugate (ARC) currently in a phase 1/2a first-in-human dosage escalation trial for patients with relapsed CD37+ indolent non Hodgkin lymphoma (NHL). The aim of this study was to investigate biodistribution and absorbed doses to organs at risk. Methods: A total of seven patients treated with 177Lu-lilotomab satetraxetan were included for dosimetry. Patients were grouped based on two different pre-dosing regimens (with and without pre-dosing with 40 mg lilotomab) and were treated with different levels of activity per body weight (10, 15 and 20 MBq/kg). All patients were pre-treated with rituximab. Serial planar and SPECT/CT-images were used to determine time activity curves and patient specific masses for organs with 177Lu-lilotomab satetraxetan uptake. Doses were calculated with OLINDA/EXM. Results: Organs with distinct uptake of 177Lu-lilotomab satetraxetan, in addition to red bone marrow and tumors, were liver, spleen and kidneys. Largest uptake was found in the spleen, where doses ranged from 1.54 to 3.60 mGy/MBq. The liver received 0.70 to 1.15 mGy/MBq. The kidneys received the lowest dose of the source organs investigated; 0.16 to 0.79 mGy/MBq. No statistical significant differences in soft tissue absorbed doses for the two pre-dosing regimens were found. Whole body (WB) dose ranged from 0.08 to 0.17 mGy/MBq. Conclusion: The biodistribution study for patients treated with 177Lu-lilotomab satetraxetan revealed highest physiological uptake in liver and spleen, besides red marrow. For all dosage levels investigated, doses were found modest when compared to commonly assumed tolerance limits

A new method to assess pulmonary changes using (18)F-fluoro-2-deoxyglucose positron emission tomography for lung cancer patients following radiotherapy

BACKGROUND: (18)F-fluoro-2-deoxyglucose positron emission tomography ((18)F-FDG-PET) may be used for assessing radiation induced alterations in the lung. However, there is a need to further develop methodologies to improve quantification. Using computed tomography (CT), a local structure method has been shown to be superior to conventional CT-based analysis. Here, we investigate whether the local structure method based on (18)F-FDG-PET improves radiotherapy (RT) dose-response quantification for lung cancer patients. MATERIAL AND METHODS: Sixteen patients with lung cancer undergoing fractionated RT were examined by (18)F-FDG-PET/CT at three sessions (pre, mid, post) and the lung was delineated in the planning CT images. The RT dose matrix was co-registered with the PET images. For each PET image series, mean (μ) and standard deviation (σ) maps were calculated based on cubes in the lung (3 × 3 × 3 voxels), where the spread in pre-therapy μ and σ was characterized by a covariance ellipse in a sub-volume of 3 × 3 × 3 cubes. Mahalanobis distance was used to measure the distance of individual cube values to the origin of the ellipse and to further form local structure 'S' maps. The structural difference maps (ΔS) and mean difference maps (Δμ) were calculated by subtracting pre-therapy maps from maps at mid- and post-therapy. Corresponding maps based on CT images were also generated. RESULTS: ΔS identified new areas of interest in the lung compared to conventional Δμ maps. ΔS for PET and CT gave a significantly elevated lung signal compared to a control group during and post-RT (p < .05). Dose-response analyses by linear regression showed that ΔS between pre- and post-therapy for (18)F-FDG-PET was the only parameter significantly associated with local lung dose (p = .04). CONCLUSIONS: The new method using local structures on (18)F-FDG-PET provides a clearer uptake dose-response compared to conventional analysis and CT-based approaches and may be valuable in future studies addressing lung toxicity

Biodistribution and dosimetry results from a phase 1 trial of therapy with the antibody-Radionuclide conjugate 177Lu-Lilotomab satetraxetan

177Lu-lilotomab satetraxetan is a novel antibody–radionuclide conjugate currently in a phase 1/2a first-in-humans dose escalation trial for patients with relapsed CD37-positive indolent non-Hodgkin lymphoma. The aim of this study was to investigate biodistribution and absorbed doses to organs at risk. Methods: In total, 7 patients treated with 177Lu-lilotomab satetraxetan were included for dosimetry. Patients were grouped on the basis of 2 different predosing regimens (with and without predosing with 40 mg of lilotomab) and were treated with different levels of activity per body weight (10, 15, and 20 MBq/kg). All patients were pretreated with rituximab. Serial planar and SPECT/CT images were used to determine time–activity curves and patient-specific masses for organs with 177Lu-lilotomab satetraxetan uptake. Doses were calculated with OLINDA/EXM. Results: The organs (other than red bone marrow and tumors) with distinct uptake of 177Lu-lilotomab satetraxetan were the liver, spleen, and kidneys. The highest uptake was found in the spleen, with doses ranging from 1.54 to 3.60 mGy/MBq. The liver received 0.70–1.15 mGy/MBq. The kidneys received the lowest dose of the source organs investigated, 0.16–0.79 mGy/MBq. No statistically significant differences in soft-tissue absorbed doses were found between the two predosing regimens. The whole-body dose ranged from 0.08 to 0.17 mGy/MBq. Conclusion: The biodistribution study for patients treated with 177Lu-lilotomab satetraxetan revealed the highest physiologic uptake to be in the liver and spleen (besides the red marrow). For all treatment levels investigated, the absorbed doses were found to be modest when compared with commonly assumed tolerance limits