Actual Tumor Volume Research Articles

Recommendation for Clinical T Staging in Patients with Non-Small Cell Lung Cancer: Volumetric Measurement: A Retrospective Study from Turkey.

Currently, clinical T staging in non-small cell lung cancer (NSCLC) is based on the largest radiological diameter observed on computed tomography (CT). Under this system, tumors with varying shapes-such as spherical, amorphous, or spiculated tumors- can be assigned the same T stage even with different volumes. We aimed to propose a 3-dimensional (3D) volumetric staging system for NSCLC as an alternative to diameter-based T staging and to conduct comparative survival analyses between these methods. We retrospectively analyzed data from patients who underwent surgery for pT1-4N0M0 primary NSCLC between January 2018 and May 2022. Digital Imaging and Communications in Medicine data from patient CT scans were uploaded to 3D Slicer software for volumetric tumor measurement. Using the paired samples t-test or the Wilcoxon test, we compared the expected tumor volumes, calculated by tumor diameter, with the actual volumes measured by 3D Slicer. Receiver operating characteristic analysis was employed to determine the cut-off value for tumor volume. Kaplan-Meier analysis was utilized to assess overall survival, while the log-rank method was applied to compare survival differences between groups. The significance of changes in T stage was evaluated using the marginal homogeneity test. The study included 136 patients. Significant differences were observed between expected and actual tumor volumes (p=0.01), and associated changes in T stage were also significant (p=0.04). The survival analysis performed using tumor volume (p=0.009) yielded superior results compared to that based on diameter (p=0.04) in paients with early tumor stage. T-factor staging based on tumor volume could represent an alternative staging method for NSCLC.

RECIST 1.1 Target Lesion Categorical Response in Metastatic Renal Cell Carcinoma: A Comparison of Conventional versus Volumetric Assessment.

Purpose To investigate Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) approximations of target lesion tumor burden by comparing categorical treatment response according to conventional RECIST versus actual tumor volume measurements of RECIST target lesions. Materials and Methods This is a retrospective cohort study of individuals with metastatic renal cell carcinoma enrolled in a clinical trial (from 2003 to 2017) and includes individuals who underwent baseline and at least one follow-up chest, abdominal, and pelvic CT study and with at least one target lesion. Target lesion volume was assessed by (a) Vmodel, a spherical model of conventional RECIST 1.1, which was extrapolated from RECIST diameter, and (b) Vactual, manually contoured volume. Volumetric responses were determined by the sum of target lesion volumes (Vmodel-sum TL and Vactual-sum TL, respectively). Categorical volumetric thresholds were extrapolated from RECIST. McNemar tests were used to compare categorical volume responses. Results Target lesions were assessed at baseline (638 participants), week 9 (593 participants), and week 17 (508 participants). Vmodel-sum TL classified more participants as having progressive disease (PD), compared with Vactual-sum TL at week 9 (52 vs 31 participants) and week 17 (57 vs 39 participants), with significant overall response discordance (P < .001). At week 9, 25 (48%) of 52 participants labeled with PD by Vmodel-sum TL were classified as having stable disease by Vactual-sum TL. Conclusion A model of RECIST 1.1 based on a single diameter measurement more frequently classified PD compared with response assessment by actual measured tumor volume. Keywords: Urinary, Kidney, Metastases, Oncology, Tumor Response, Volume Analysis, Outcomes Analysis ClinicalTrials.gov registration no. NCT01865747 © RSNA, 2023 Supplemental material is available for this article.

Measurement of mouse head and neck tumors by automated analysis of CBCT images

Animal experiments are often used to determine effects of drugs and other biological conditions on cancer progression, but poor accuracy and reproducibility of established tumor measurement methods make results unreliable. In orthotopic mouse models of head and neck cancer, tumor volumes approximated from caliper measurements are conventionally used to compare groups, but geometrical challenges make the procedure imprecise. To address this, we developed software to better measure these tumors by automated analysis of cone-beam computed tomography (CBCT) scans. This allows for analyses of tumor shape and growth dynamics that would otherwise be too inaccurate to provide biological insight. Monitoring tumor growth by calipers and imaging in parallel, we find that caliper measurements of small tumors are weakly correlated with actual tumor volume and highly susceptible to experimenter bias. The method presented provides a unique window to sources of error in a foundational aspect of preclinical head and neck cancer research and a valuable tool to mitigate them.

Abstract P5-13-34: A multi-modal biomarker of immunotherapy response

Abstract Background Immunotherapy (IO) is expected to become a part of standard neoadjuvant therapy for early-stage, triple-negative breast cancer. However, only a minority of patients benefit from the addition of IO to standard neoadjuvant chemotherapy (NACT). Biomarkers of IO response in the metastatic setting, such as PD-L1 expression, fail to predict benefit from IO in the early-stage setting. Given the financial cost of IO and the potential for irreversible, immune-related toxicities, predictive biomarkers are desperately needed. SimBioSys TumorScope (TS), a commercially available biophysical model, has been previously validated as a highly accurate predictor of response to standard NAT regimens. TS has the potential to identify patients treated with IO who would have responded well to standard NACT, and those who truly benefited from IO, enabling biomarker discovery. Methods We identified 17 pts who received pembrolizumab in combination with standard NACT. From these cases, dynamic contrast-enhanced MRIs were assessed from multiple timepoints throughout treatment. Using a proprietary convolutional neural net, the tumor region from each MRI was segmented to assess volume over time. We compared actual tumor volumes to predicted response to standard NACT (without pembrolizumab) generated with the TS platform. By contrasting the tumor volume across the simulation and the longitudinal MRI timepoints, a metric of response directly attributable to pembrolizumab (“IO benefit”) was generated. Clinical, radiological, metabolic, tumor morphology, and microvasculature features were extracted from TS simulations, and after quality control and removal of redundant metrics, used in linear models as predictors of IO benefit. Results Nine clinical, seven metabolic, 16 microvasculature, ten tumor morphology, and 77 radiological features were used as individual predictors of IO benefit in linear models. Eight out of 17 cases had positive IO benefit values. In all, 12 out of the 119 metrics of interest nominally significant predictors of IO benefit (p&amp;lt;0.05). Top relationships of interest included: tumor convex hull surface area to volume ratio (b=-51.4, p=0.010), maximum 2D diameter column (a metric of longest tumor dimension) (b=1.8, p=0.011), and percentage of tumor cells with low oxygen concentration at simulation outset (hypoxic fraction) (b=1.0, p=0.034). In further analyses, we observed nominally significant relationships between IO benefit and hypoxic fraction measures taken across simulation timepoints. Significant relationships were salient in hypoxic fraction measures taken at early simulation timepoints, including weeks three (p=0.017), two (p=0.024), and five (p=0.038). Importantly, between IO benefit/hypoxic fraction relationships, we observed concordant positive directions of effect (i.e., higher hypoxic cancer fraction, higher IO benefit). Conclusion IO is likely to soon gain regulatory approval for early-stage TNBC, but biomarkers to predict benefit are lacking. PD-L1 expression has previously been correlated with hypoxic tumor environments and high density of tumor infiltrating lymphocytes. Even within a limited dataset, TS provided a biologically explainable marker to identify patients who may benefit from IO. Work is underway to further validate these findings in a larger dataset, and to validate hypoxic tumor fraction as a predictor of IO response. Citation Format: JR Pfeiffer, Joseph R. Peterson, Frederick Howard, Tyler M. Earnest, Tushar Pandey, Gong He, Rita Nanda. A multi-modal biomarker of immunotherapy response [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-34.

Implementing CT tumor volume and CT pleural thickness into future staging systems for malignant pleural mesothelioma

ObjectivesTumor thickness and tumor volume measured by computed tomography (CT) were suggested as valuable prognosticator for patients’ survival diagnosed with malignant pleural mesothelioma (MPM). The purpose was to assess the accuracy of CT scan based preoperatively measured tumor volume and thickness compared to actual tumor weight of resected MPM specimen and pathologically assessed tumor thickness, as well as an analysis of their impact on overall survival (OS).MethodsBetween 09/2013–08/2018, 74 patients were treated with induction chemotherapy followed by (extended) pleurectomy/decortication ((E)PD). In 53 patients, correlations were made between CT-measured volume and -tumor thickness (cTV and cTT) and actual tumor weight (pTW) based on the available values. Further cTV and pT/IMIG stage were correlated using Pearson correlation. Overall survival (OS) was calculated with Kaplan Meier analysis and tested with log rank test. For correlation with OS Kaplan-Meier curves were made and log rank test was performed for all measurements dichotomized at the median.ResultsMedian pathological tumor volume (pTV) and pTW were 530 ml [130 ml – 1000 ml] and 485 mg [95 g – 982 g] respectively. Median (IQR) cTV was 77.2 ml (35.0–238.0), median cTT was 9.0 mm (6.2–13.7). Significant association was found between cTV and pTV (R = 0.47, p < 0.001) and between cTT and IMIG stage (p = 0,001) at univariate analysis. Multivariate regression analysis revealed, that only cTV correlates with pTV. Median follow-up time was 36.3 months with 30 patients dead at the time of the analysis. Median OS was 23.7 months. 1-year and 3-year survival were 90 and 26% respectively and only the cTV remained statistically associated with OS.ConclusionPreoperatively assessed CT tumor volume and actual tumor volume showed a significant correlation. CT tumor volume may predict pathological tumor volume as a reflection of tumor burden, which supports the integration of CT tumor volume into future staging systems.

In-vivo lung biomechanical modeling for effective tumor motion tracking in external beam radiation therapy

Lung cancer is the most common cause of cancer-related death in both men and women. Radiation therapy is widely used for lung cancer treatment; however, respiratory motion presents challenges that can compromise the accuracy and/or effectiveness of radiation treatment. Respiratory motion compensation using biomechanical modeling is a common approach used to address this challenge. This study focuses on the development and validation of a lung biomechanical model that can accurately estimate the motion and deformation of lung tumor. Towards this goal, treatment planning 4D-CT images of lung cancer patients were processed to develop patient-specific finite element (FE) models of the lung to predict the patients' tumor motion/deformation. The tumor motion/deformation was modeled for a full respiration cycle, as captured by the 4D-CT scans. Parameters driving the lung and tumor deformation model were found through an inverse problem formulation. The CT datasets pertaining to the inhalation phases of respiration were used for validating the model's accuracy. The volumetric Dice similarity coefficient between the actual and simulated gross tumor volumes (GTVs) of the patients calculated across respiration phases was found to range between 0.80 ± 0.03 and 0.92 ± 0.01. The average error in estimating tumor's center of mass calculated across respiration phases ranged between 0.50 ± 0.10 (mm) and 1.04 ± 0.57 (mm), indicating a reasonably good accuracy of the proposed model. The proposed model demonstrates favorable accuracy for estimating the lung tumor motion/deformation, and therefore can potentially be used in radiation therapy applications for respiratory motion compensation.

The shape of breast cancer.

Little is known about the three-dimensional shape of breast cancer. Implicit to approaches that localize the center of the tumor for breast-conserving surgery (BCS) of non-palpable cancers is the assumption that breast cancers are spherical about a central point, which may not be accurate. Pre-operative supine breast MRI images were obtained of 83 breast cancer patients undergoing partial mastectomy using supine MRI-guided resection techniques. Three-dimensional (3D) tumor models were derived after radiologists outlined tumor edges on successive MRI slices. Ideal resection volumes were determined by adding 1cm in every dimension to the actual tumor volume. Geometrically defined parameters were used to define tumor shapes and associations between clinical variables and shapes were examined. Seventy-five patients had invasive cancer. Breast cancers were categorized into four tumor shapes: 34% of tumors were discoidal, 29% segmental, 19% spherical, and 18% irregular. If hypothetical spherical excisions were performed, non-spherical cases would excise 143% more tissue than the ideal resection volume. When the 3D shape of each tumor was provided to the surgeon during MR-guided BCS, the percentage of tissue overexcised in non-spherical cases was significantly less (143% vs. 66%, p < 0.001). Information obtained from a supine MRI can be used to generate 3D tumor models and rapidly classify breast tumor shapes. The vast majority of invasive cancers and DCIS are not spherical. Knowledge of tumor shape may allow surgeons to excise breast cancer more precisely.

Understanding the Uptake of Nanomedicines at Different Stages of Brain Cancer Using a Modular Nanocarrier Platform and Precision Bispecific Antibodies.

Increasing accumulation and retention of nanomedicines within tumor tissue is a significant challenge, particularly in the case of brain tumors where access to the tumor through the vasculature is restricted by the blood–brain barrier (BBB). This makes the application of nanomedicines in neuro-oncology often considered unfeasible, with efficacy limited to regions of significant disease progression and compromised BBB. However, little is understood about how the evolving tumor–brain physiology during disease progression affects the permeability and retention of designer nanomedicines. We report here the development of a modular nanomedicine platform that, when used in conjunction with a unique model of how tumorigenesis affects BBB integrity, allows investigation of how nanomaterial properties affect uptake and retention in brain tissue. By combining different in vivo longitudinal imaging techniques (including positron emission tomography and magnetic resonance imaging), we have evaluated the retention of nanomedicines with predefined physicochemical properties (size and surface functionality) and established a relationship between structure and tissue accumulation as a function of a new parameter that measures BBB leakiness; this offers significant advancements in our ability to relate tumor accumulation of nanomedicines to more physiologically relevant parameters. Our data show that accumulation of nanomedicines in brain tumor tissue is better correlated with the leakiness of the BBB than actual tumor volume. This was evaluated by establishing brain tumors using a spontaneous and endogenously derived glioblastoma model providing a unique opportunity to assess these parameters individually and compare the results across multiple mice. We also quantitatively demonstrate that smaller nanomedicines (20 nm) can indeed cross the BBB and accumulate in tumors at earlier stages of the disease than larger analogues, therefore opening the possibility of developing patient-specific nanoparticle treatment interventions in earlier stages of the disease. Importantly, these results provide a more predictive approach for designing efficacious personalized nanomedicines based on a particular patient’s condition.

Three-Phase Automatic Brain Tumor Diagnosis System Using Patches Based Updated Run Length Region Growing Technique.

Manually finding and segmenting brain tumor is a tedious process in MR brain images due to the unpredictable appearance of tissues with a different pattern, contour, mass, and positions. The proposed work has three phases automatic tumor diagnosis system for tumorous slice detection, segmentation, and visualization from MRI human head volumes. The proposed method has an automatic classification followed by segmentation and is called as patch-based updated run length region growing technique (PR2G). In the first phase, classification is done through training and testing process using SVM classifier with 8 × 8 patches. Three optimal features are chosen using infinite feature selection (IFS) method. The purpose of the first phase is to automatically cluster the input MRI image into a normal or tumorous slice and localize the tumor. The second phase aims to segment the tumor in abnormal tumorous slices identified by the first phase using run length region growing technique. Finally, the third phase contains a post metric evaluation like 3D tumor volume construction and estimation from actual and segmented tumor volume using Carelieri's estimator. Classification accuracy is measured using sensitivity, specificity, accuracy, and error rates also calculated using false alarm (FA) and missed alarm (MA). Segmentation accuracy is calculated using Dice similarity, positive predictive value (PPV), sensitivity, and accuracy. Datasets used for this experiment are collected from whole brain atlas (WBA) and BraTS repositories. Experimental results show that the PR2G achieves 97% of classification accuracy and 80% of Dice segmentation accuracy.

Abstract 2148: Image-guided catheter-based ultrasound thermal ablation of intramuscular and retroperitoneal sarcomas in the transgenic Oncopig cancer model

Abstract Soft-tissue sarcomas (STS) are aggressive, often lethal mesenchymal tumors that represent roughly 1% of adult cancers. The 5-year survival rate of STS has remained unchanged for decades at 50%, highlighting the need for more effective therapies. We are developing protocols and assessing the treatment efficacy of 3D spatially-registered real-time image-guided needle/catheter based ultrasound (CBUS) ablative thermal therapy in STS induced in the transgenic Oncopig cancer model (OCM). The transgenic Oncopig carries a Cre recombinase inducible transgene encoding KRASG12D and TP53R167H; both mutations commonly in human cancers. Cre recombinase induces expression of the transgenes and transformation of cells in culture and rapid and reproducible development of leiomyosarcomas when introduced into the muscle of oncopigs. The flexibility of the model allowed induction of sarcomas in two clinically relevant intramuscular (IM) sites in both the hind limb and retroperitoneal (RP) regions, to closely simulate human disease. We have previously shown that these Oncopig tumors present the same transcriptional hallmarks as human STS including altered TP53 signaling, Wnt signaling activation and evidence of epigenetic reprogramming. Initial acute studies revealed that the tumors could be successfully grown in the muscle reaching mean tumor volume of 19.76cm3 (RP, n= 8) and 25.12cm3 (IM, n=14) cm3 within two weeks following AdCre (5.0x108 to 1.0x109 PFU) injections. Tumors were then treated utilizing ultrasound image guidance combined with 3D EM tracking to place the applicator in the target region. Sectored tubular transducers were introduced through a small skin incision and used to precisely deliver thermal energy to the treatment region. Tumors were treated for 6-9 minutes at 7 watts acoustic power (10.2W/cm2). Thermocouples were inserted into the tumors monitored temperature throughout the treatment. Post-treatment analysis revealed that the mean induced lesion volume exceeded the actual tumor volume for both IM (43.41 cm3) and RP (22.87 cm3) tumors with mean peak temperatures reaching 64.56 ° C (IM) and 58.75 ° C (RP). The mean peak thermal dose (thermal equivalent minutes at 43 ° C - TEM43) accumulated for IM tumors was 3.70E+08, and 1.46E+06 for RP tumors. Histopathology analysis verified that treatment areas reached past tumor margins using single applicator configuration. This study clearly demonstrates that the Oncopig is a suitable model in size and clinically relevant tumor type for evaluation of ultrasound ablation instrumentation. In addition, these STS treatment protocols can reliably and accurately target and treat tumor volumes plus surrounding margins. Future work will include monitoring of treatment lesions for up to 3 months post ablation. Funded by NIH 5R21CA195433 Citation Format: Laurie A. Rund, Goutam Ghoshal, Emery Williams, Paul Neubauer, Lance Frith, R Tamas Heffter, Patrick Roady, Lawrence B. Schook, E Clif Burdette. Image-guided catheter-based ultrasound thermal ablation of intramuscular and retroperitoneal sarcomas in the transgenic Oncopig cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2148.

Effect of Wilms tumor histology on response to neoadjuvant chemotherapy

PurposeTo evaluate the association between Wilms tumor histology at diagnosis and the change in Wilms' tumor volume during preoperative chemotherapy. MethodsWe included all the 52 patients operated for Wilms tumor at 1988–2015, who had both pathology samples and either CT or MRI-images before and after preoperative chemotherapy, available for reevaluation. ResultsThe median tumor volume was 586 ml (IQR 323–903) at diagnosis. The median change in tumor volume was −68% (IQR −85 to −40, p < 0.001) and the proportion of tumor necrosis 85% (IQR 24–97), after preoperative chemotherapy. There was a correlation between blastemal cell content in prechemotherapy cutting needle biopsy (CNB) sample and the reduction in tumor volume (Rho = −0.452, p = 0.002). High stromal and epithelial cell contents in CNB samples were associated with the lesser change in tumor volume (Rho = 0.279, p =0.053 and Rho = 0.300, p = 0.038 respectively). Reduction of tumor volume and the proportion of tumor necrosis after chemotherapy were associated (Rho = −0.502, p < 0.001). The actual viable tumor volume decreased in median by 97% (IQR 65–100), and the decrease could be seen in all cellular components. In three patients, the tumor volume increased more than 10% during the preoperative chemotherapy. Two of them had anaplastic tumor in the nephrectomy specimen. ConclusionWilms tumor total and viable tumor volumes were reduced by 68% and 97% with preoperative chemotherapy, respectively. High proportion of blastemal cells in CNB was associated with greatest decrease in Wilms tumor volume. Increase in tumor volume during preoperative chemotherapy may indicate anaplastic tumor and prolonging of preoperative therapy should be avoided. Type of studyRetrospective review. Level of evidenceLevel III.

Expanding the limits of endoscopic intraorbital tumor resection using 3-dimensional reconstruction

IntroductionEndoscopic orbital surgery is a nascent field and new tools are required to assist with surgical planning and to ascertain the limits of the tumor resectability. ObjectiveWe purpose to utilize three-dimensional radiographic reconstruction to define the theoretical lateral limit of endoscopic resectability of primary orbital tumors and to apply these boundary conditions to surgical cases. MethodsA three-dimensional orbital model was rendered in 4 representative patients presenting with primary orbital tumors using OsiriX open source imaging software. A 2-Dimensional plane was propagated between the contralateral nare and a line tangential to the long axis of the optic nerve reflecting the trajectory of a trans-septal approach. Any tumor volume falling medial to the optic nerve and/or within the space inferior to this plane of resectability was considered theoretically resectable regardless of how far it extended lateral to the optic nerve as nerve retraction would be unnecessary. Actual tumor volumes were then superimposed over this plan and correlated with surgical outcomes. ResultsAmong the 4 lesions analyzed, two were fully medial to the optic nerve, one extended lateral to the optic nerve but remained inferior to the plane of resectability, and one extended both lateral to the optic nerve and superior to the plane of resectability. As predicted by the three-dimensional modeling, a complete resection was achieved in all lesions except one that transgressed the plane of resectability. No new diplopia or vision loss was observed in any patient. ConclusionThree-dimensional reconstruction enhances preoperative planning for endoscopic orbital surgery. Tumors that extend lateral to the optic nerve may still be candidates for a purely endoscopic resection as long as they do not extend above the plane of resectability described herein.

Serum alpha-fetoprotein level per total tumor volume as a predictor of recurrence of hepatocellular carcinoma after resection

BackgroundAlpha-fetoprotein has been used as a predictor of recurrence for hepatocellular carcinoma and disease-free survival post-resection. Studies in East Asia have shown that serum alpha-fetoprotein per total tumor volume ratio is a better prognostic indicator than alpha-fetoprotein alone. Similar studies in the United States evaluating serum alpha-fetoprotein to total tumor volume ratio have not been conducted. Its relevance is incompletely understood. MethodsConsecutive patients undergoing resection for hepatocellular carcinoma at a single tertiary center between 2000 and 2013 were identified for inclusion in this retrospective cohort study. Patient demographics, associated liver disease, Child-Pugh and Model for End-Stage Liver Disease scores, preoperative imaging, surgical pathology, alpha-fetoprotein at diagnosis, last alpha-fetoprotein before surgery, and peak alpha-fetoprotein levels were recorded. Actual tumor volume by imaging volumetrics was used when available (n = 70). For the remaining cases, total tumor volume was calculated using the sum of the volumes of all the tumors ((4/3)πr3) where “r” is the mean radius of each lesion. Peak serum alpha-fetoprotein was used to calculate the alpha-fetoprotein to total tumor volume ratio. ResultsA total of 124 patients resected for hepatocellular carcinoma between 2000 and 2013 were identified. Overall 1-, 3-, and 5-year survival post resection was 76%, 53%, and 35%, respectively. On multivariate analysis, peak alpha-fetoprotein to total tumor volume ratio > 20 (P < .001, HR = 3.72, 95% CI [1.82–7.58]) and lymphovascular space invasion (P = .002, HR = 3.30, 95% CI [1.57–6.94]) were found to affect hepatocellular carcinoma recurrence-free survival. ConclusionA variety of prognostic values predict the recurrence of hepatocellular carcinoma postresection. Peak preoperative alpha-fetoprotein to total tumor volume > 20 and lymphovascular space invasion has been shown to predict recurrence of hepatocellular carcinoma. Our study confirms findings from East Asian studies. But larger series are needed to establish this correlation in patients with hepatocellular carcinoma not treated by resection.

Primary tumor volume measurements in Ewing sarcoma: MRI inter- and intraobserver variability and comparison with FDG-PET

Background: Primary tumor volume is as an important and independent prognostic factor in Ewing sarcoma. However, the observer variability of magnetic resonance imaging (MRI)-based primary tumor volume measurements in newly diagnosed Ewing sarcoma has never been investigated. Furthermore, it is unclear how MRI-based volume measurements compare to 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)-based volume measurements. This study aimed to determine the observer variability of simplified MRI-based primary tumor volume measurements in newly diagnosed treatment-naive Ewing sarcoma and to compare them to the actual primary tumor volume at MRI and the FDG-PET-based metabolically active tumor volume (MATV).Material and methods: Twenty-nine newly diagnosed Ewing sarcoma patients with pretreatment MRI (of whom 11 also underwent FDG-PET) were included. Both exact and dichotomized (according to the proposed threshold of 200 mL) primary tumor volume measurements were analyzed.Results: Mean inter- and intraobserver differences of MRI-based simplified tumor volume ± limits of agreement varied between 15–42 ± 155–204 mL and between 9–16 ± 64–250 mL, respectively. Inter- and intraobserver agreements of dichotomized MRI-based simplified tumor volume measurements was very good (κ = 0.827–1.000). Mean difference between simplified and actual tumor volumes at MRI ± limits of agreement was 60 ± 381 mL. Agreement between dichotomized simplified and actual tumor volumes at MRI was very good (κ = 0.839). Mean difference between MRI-based simplified tumor volume and MATV ± limits of agreement was 181 ± 549 mL and almost significantly different (p = .0581). Agreement between dichotomized MRI-based simplified tumor volume and MATV was moderate (κ = 0.560).Conclusions: Exact MRI-based simplified primary tumor volume measurements in Ewing sarcoma suffer from considerable observer variability, but observer agreement of dichotomized measurements (≤200 mL vs. >200 mL) is very good and generally matches MRI-based actual volume measurements. MRI-based primary tumor volume measurements poorly-moderately agree with and tend to be higher than the MATV.

OA22.07 Correlation of CT Scan Based Tumor Volume Measurement to Actual Resected Tumor Volume - A New T-Factor?

Tumor volume has been reported to be a valuable prognosticator for malignant pleural mesothelioma (MPM) survival. We wanted to assess the precision of CT scan based preoperatively measured tumor volume when correlated to the actual resected tumor weight and tumor volume after pleurectomy/decortication. From 10/2012 – 06/2016 the tumor weight of surgery specimens was measured in 32 patients undergoing macroscopic complete resection by (extended) pleurectomy/decortication ((e)P/D). The median tumor weight of all patients was (n=32) 443g (95-783g). In all patients tumor volume was measured in the CT or PET-CT scans performed before surgery as described previously (Frauenfelder 2011). Tumor volume of the resected specimen was additionally measured in 21 patients. Relations between tumor weight, tumor volume at surgery, CT-volume, cT stage and pT stage were analyzed using Spearman rank correlation. Median time between CT scan and surgery was 18 days (range 1-48). The analysis revealed a moderate correlation between CT tumor volume and weight (p=0.001, correlation coefficient 0.58, CT volume and tumor volume at surgery showed strong correlation (p=0.001, correlation coefficient 0.65). No significant correlation was observed between cT stage and tumor weight (p=0.1, correlation coefficient 0.31), but a moderate correlation between cT stage and CT volume (p=0.001, correlation coefficient 0.58) as well as specimen volume (p=0.008, correlation coefficient 0.58). There was a moderate correlation of tumor weight with pT stage (p=0.02, correlation coefficient 0.42), but no correlation of CT volume (p=0.1, correlation coefficient 0.31) as well as specimen volume with the pT stage (p=0.2, correlation coefficient 0.32). The correlation between preoperatively assessed CT tumor volume and volume of the resected specimen showed a strong correlation. To assess the prognostic role of CT measured tumor volume a correlation to prognosis has to be performed before implementation as a new T-factor.

Perfusion and Volume Response of Canine Brain Tumors to Stereotactic Radiosurgery and Radiotherapy.

BackgroundStereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) are highly conformal, high‐dose radiation treatment techniques used to treat people and dogs with brain tumors.ObjectivesTo evaluate the response to SRS‐ and SRT‐treated tumors using volume and perfusion variables and to measure the survival times of affected dogs.AnimalsProspective study of 34 dogs with evidence of brain tumors undergoing stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT).MethodsComputed tomography and MRI imaging were used to calculate tumor volume and perfusion at baseline, and at 3 months and 6 months after treatment. Survival analysis was performed to evaluate treatment efficacy.ResultsMean tumor volume significantly declined from baseline to the first recheck by −0.826 cm3 (95% CI: −1.165, −0.487) (P < .001); this reduction was maintained at the second recheck. Blood flow and blood volume declined significantly in the tumor after treatment. Median survival was 324 days (95% CI: 292.8, 419.4), and 4 dogs survived longer than 650 days. Neither actual tumor volume (hazard ratio = 1.21, P = .19) nor the change in tumor volume from the baseline (hazard ratio = 1.38, P = .12) significantly affected the hazard of death because of the tumor.Conclusions and Clinical ImportanceStereotactic radiosurgery and SRT are effective treatments for reducing tumor volume, blood flow, and blood volume. Treated dogs surviving for more than 1 year are more likely to die from other causes than of their primary brain tumor. SRS and SRT should be considered for noninvasive treatment of intracranial brain tumors.

Gradient-Based Algorithm for Determining Tumor Volumes in Small Animals Using Planar Fluorescence Imaging Platform.

Planar fluorescence imaging is widely used in biological research because of its simplicity, use of nonionizing radiation, and high-throughput data acquisition. In cancer research, where small animal models are used to study the in vivo effects of cancer therapeutics, the output of interest is often the tumor volume. Unfortunately, inaccuracies in determining tumor volume from surface-weighted projection fluorescence images undermine the data, and alternative physical or conventional tomographic approaches are prone to error or are tedious for most laboratories. Here, we report a method that uses a priori knowledge of a tumor xenograft model, a tumor-targeting near infrared probe, and a custom-developed image analysis planar view tumor volume algorithm (PV-TVA) to estimate tumor volume from planar fluorescence images. Our algorithm processes images obtained using near infrared light for improving imaging depth in tissue in comparison with light in the visible spectrum. We benchmarked our results against the actual tumor volume obtained from a standard water volume displacement method. Compared with a caliper-based method that has an average deviation from an actual volume of 18% (204.34 ± 115.35 mm3), our PV-TVA average deviation from the actual volume was 9% (97.24 ± 70.45 mm3; P < .001). Using a normalization-based analysis, we found that bioluminescence imaging and PV-TVA average deviations from actual volume were 36% and 10%, respectively. The improved accuracy of tumor volume assessment from planar fluorescence images, rapid data analysis, and the ease of archiving images for subsequent retrieval and analysis potentially lend our PV-TVA method to diverse cancer imaging applications.

Abstract B43: ANG1005, a novel brain-penetrant drug conjugate, in CNS metastases from breast cancer: FLT-PET imaging as a predictor of response

Abstract Background: The novel drug conjugate ANG1005 consists of 3 molecules of paclitaxel covalently linked to Angiopep-2. After binding to the low-density lipoprotein receptor-related protein, ANG1005 crosses the blood brain barrier (BBB) by endocytosis. A multi-center Phase II study, with the primary endpoint of intracranial response in patients with breast cancer brain metastases is in progress. At the NCI, a biomarker substudy is evaluating 18F-FLT (3'-Fluoro-3' deoxythymidine)-PET for response assessment. Methods: Patients with measurable brain metastases from breast cancer received ANG1005 at a dose of 550mg/m2 IV once every 21 days. Before and after cycle 1, all patients on study underwent imaging with 18F-FLT, a thymidine analog and novel imaging agent; retention of 18F-FLT correlating with DNA synthesis. In order to detect brain metastases and assess response to treatment, we compared FLT PET images with MRI-gadolinium contrast scans, obtaining both dynamic and static images. We determined the percentage (%) change after treatment with ANG1005; a decrease in ≥20% was considered significant. Results: Ten patients were enrolled on study. A total of 32 target and 20 non target CNS lesions in 10 patients were imaged and analyzed by MRI and FLT-PET. At 30 minutes, SUVmax ranged from 0.8 to 6.3 at baseline (mean 2.64), and the SUV80%, (mean of top 20% SUV units) ranged from 0.7 to 5.12. The median% change from baseline to post one cycle of ANG1005 was -19.9% for SUVmax (range +85.4 to -67.7, and was median -20.2% for SUV80% (range 95.7 to -69%). Two patients had confirmed partial responses lasting 6 and 18 cycles, respectively. Six patients had stable disease and received a median of 6 cycles. Tumor reductions, as determined by MRI per CNS RECIST version 1.1 ranged from -5% to -60% in lesion size, compared to baseline. Both FLT-PET parameters correlated with the% change in MRI measurements in the target lesions (R2 = 0.64, P = 0.0002). Conclusion: The development of CNS-directed therapies designed to cross the BBB, such as the paclitaxel conjugate ANG1005, is a research priority. As contrast-enhanced MRI detection of brain metastases is representative of gadolinium leakage through the BBB, as opposed to actual tumor volume, better approaches are needed to evaluate drug efficacy. Pilot evaluations of FLT-PET imaging in this setting suggest that it is a promising tool that may serve as a complementary assessment method for breast cancer brain metastases going forward. Citation Format: Ciara C. O'Sullivan, Maria Lindenberg, Christine Bryla, Nicole Davarpanah, Cody Peer, Nicholas Patronas, Laleh Amiri-Kordestani, Sanjeeve Balasubramaniam, Tito Fojo, William D. Figg, Peter Choyke. ANG1005, a novel brain-penetrant drug conjugate, in CNS metastases from breast cancer: FLT-PET imaging as a predictor of response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B43.

Intrahepatic Activity Distribution in Radioembolization with Yttrium-90–Labeled Resin Microspheres Using the Body Surface Area Method—A Less than Perfect Model

PurposeTo retrospectively assess the influence of the parameters of the body surface area (BSA) method in hepatic radioembolization using yttrium-90–labeled microspheres on the determination of the prescribed activity. Materials and MethodsData from 283 consecutive patients treated with radioembolization (BSA method) were included. For interindividual comparisons, activity concentrations (ACs; MBq/mL) were calculated for each liver. The impact of the BSA method parameters was assessed by analysis of variance and pairwise t test with Bonferroni-Holm correction. ResultsPrescribed activity was 1.01–2.71 GBq, with BSA, liver volume (LV), tumor burden, and the liver-lung shunt reduction factor (LLS RF) being significant contributing factors to the AC (all P < .0001, analysis of variance). BSA and LV correlated only moderately (ρ = 0.46, P < .0001). Compared with base activity defined by the BSA (median = 1.67 GBq; range, 1.20–2.32 GBq), the activity contribution of tumor burden was small (median = 150 MBq; range, 3–800 MBq). Resulting activities were reduced according to LLS RF by 20% in 12.4% and by 40% in 3.5% of patients. AC was significantly (up to 56%) lower in association with larger LV than in small LV (LV < 1,500 mL vs ≥ 2,500 mL, P < .0001). ConclusionsIn the BSA model, BSA and LV showed only a moderate correlation, resulting in a significantly lower AC in patients with larger livers. Tumor burden percentage contributed little to the prescribed activity because the BSA model did not account for actual LVs and tumor volumes. These inaccuracies may potentially result in underdosage in patients with larger livers, especially if further LLS RF needs to be applied.

P2.01 - ANG-1005 in Patients with Brain Metastases from Breast Cancer: Correlative Imaging with 18F-FLT-PET/CT

ABSTRACT Background: ANG1005 (formerly GRN1005) is a novel drug conjugate consisting of 3 paclitaxel molecules covalently linked to Angiopep-2 designed to cross the blood brain barrier via endocytosis after binding the low-density lipoprotein (LDL) receptor-related protein (LRP). In development for taxane-sensitive brain metastases, a multi-center, single-arm study with the primary endpoint of intra-cranial overall response rate in patients with brain metastases from breast cancer is ongoing. Since MRI detection of brain metastases utilizes gadolinium leakage rather than actual tumor volume, new assessment methods are needed. A pilot study at the NCI enrolled patients to evaluate the utility of 18F-FLT (3'-fluoro-3' deoxythymidine)-PET. Methods: Patients with measurable brain metastases from breast cancer were eligible. ANG1005 was administered IV at 550 mg/m2 q 21 days. MRI imaging with gadolinium was used to determine clinical response, and compared to 18F-FLT PET/CT imaging performed before and after cycle 1. FLT incorporation reflects DNA synthesis. Dynamic scans were obtained over 30 min and a static whole body PET image at 1 hour. The % change in standard uptake value (SUV) before and after ANG1005 was determined, considering a significant change > 20%. Results: Eighteen metastatic brain lesions in eight patients were analyzed with FLT PET. The maximum (SUVmax) ranged from 0.8 to 4.0 at baseline, mean 1.8. Tumor to normal (T:N) ratios ranged from 2.9 to 22.3, mean 7.7. Twelve of the 18 lesions showed a >20% decrease post-therapy. The average % change in SUVmax was -24.8% (11 to -66.8%), and T:N ratios -7.7%. The FLT-PET response was frequently discordant with the MRI result. Two patients had confirmed partial responses with durations of response of 6 and 13 cycles. One patient had an unconfirmed PR, with progression after 6 cycles. Two patients had stable disease, receiving 6 and 8 cycles. Conclusion: Therapy for CNS metastases from breast cancer is an important unmet need, as is assessment of therapeutic outcome. ANG1005 is a paclitaxel conjugate with demonstrated activity designed to cross the blood-brain barrier. Pilot evaluations of FLT-PET imaging of brain metastases suggest it is a promising tool for detection and measurement of CNS disease.