Tumor Volume Response Research Articles

CTNI-16. MONOGERM, A NOVEL PROOF-OF-PRINCIPLE BAYESIAN PHASE II TRIAL DESIGN OF CARBOPLATIN OR VINBLASTINE MONOTHERAPY INDUCTION PRIOR TO RADIOTHERAPY FOR INTRACRANIAL GERMINOMA

Abstract BACKGROUND Current European standard-of-care for localised intracranial germinoma is multi-agent chemotherapy (carboPEI: carboplatin/etoposide/ifosfamide) followed by definitive radiotherapy, with excellent survival. MonoGerm is a de-escalation, non-inferiority trial aiming to reduce toxicity. Twelve-week carboplatin (PMID:8039122) AUC10 or vinblastine (PMIDs:32642701/34520101) induction will be evaluated to test if as effective as carboPEI from SIOP-CNS-GCT-II. A novel trial design was required to answer this question pragmatically/safely. METHODS Clinical trials in rare diseases recruit slowly, allowing continuous monitoring of efficacy outcomes. Efficacy-transition-pathways (ETP) are innovative visual tools to aid determination of trial design parameters, and an extension of the dose-transition-pathways concept introduced for dose-finding trials (PMID:28733440). RESULTS MonoGerm includes two monotherapies, with each single arm recruiting six cohorts of three patients, with interim assessment after each recruited cohort and final analysis at 18 patients (total n=36). Insufficient tumour volume response (<30%) at 6-week safety MRI results in 12-weeks carboPEI. Primary outcome is radiological complete response (CR) by 12-weeks of induction monotherapy. A beta-binomial conjugate analysis will generate posterior probability distributions, combining observed trial data as realisations from a binomial distribution with a minimally informative Beta (1,1) prior. Decision criteria to allow early stopping at interim analyses and go/no-go decisions at final analysis are based on probabilities from these posterior distributions. ETP visually maps out parameters used to assert decisions after each interim assessment as a pyramid decision tree. For each recruited cohort and every CR outcome, estimates of the true CR rate and probabilities with associated decisions are mapped out. ETP allows clear communication between statisticians, clinicians, and patient-public-involvement (PPI) teams, facilitating informed decisions in an efficient/realistic trial design. CONCLUSION MonoGerm, a novel Bayesian de-escalation trial, funded by Little Princess Trust (https://www.littleprincesses.org.uk/), uses ETP and continuous monitoring with built-in stopping rules to ensure patient safety in this treatment de-escalation trial.

Metabolic Tumor Volume Response after Bridging Therapy Determines Chimeric Antigen Receptor T-Cell Outcomes in Large B-Cell Lymphoma.

Greater disease burden is a well-established predictor of poorer outcomes following chimeric antigen receptor T-cell (CAR T) therapy. Although bridging therapy (BT) is widely used between leukapheresis and CAR T infusion, limited data have evaluated the impact of BT on CAR T outcomes. In this study, we hypothesized that the quantitative dynamics of radiomic cytoreduction during bridging are prognostic. Patients with large B-cell lymphoma treated with CD19-CAR T from 2016 to 2022 were included in the study. Metabolic tumor volume (MTV) was determined for all patients on pre-leukapheresis PET and on post-BT/pre-infusion PET in those who received BT. Patients were stratified into "High" and "Low" disease burden using an MTV cutpoint of 65.4cc established by maximally selected log-rank statistic for progression-free survival (PFS). Of 191 patients treated with CAR T, 144 (75%) received BT. In the BT cohort, 56% had a reduction in MTV post-BT. On multivariate analysis, the MTV trajectory across the bridging period remained significantly associated with PFS (P < 0.001); however, notably, patients with improved MTV (High->Low) had equivalent PFS compared with those with initially and persistently low MTV (Low->Low; HR for High->Low MTV: 2.74; 95% confidence interval, 0.82-9.18). There was a reduction in any grade immune effector cell-associated neurotoxicity syndrome in the High->Low MTV cohort as compared with the High->High MTV cohort (13% vs. 41%; P = 0.05). This is the first study to use radiomics to quantify disease burden pre- and post-BT in a large real-world large B-cell lymphoma cohort. We demonstrate that effective BT can enable initially high-disease burden patients to achieve post-CAR T outcomes comparable with low-disease burden patients.

GCT-03. MONOGERM, A NOVEL PROOF-OF-PRINCIPLE BAYESIAN PHASE II TRIAL DESIGN OF CARBOPLATIN OR VINBLASTINE MONOTHERAPY INDUCTION PRIOR TO RADIOTHERAPY FOR INTRACRANIAL GERMINOMA

Abstract BACKGROUND Current European standard-of-care for localised intracranial germinoma is multi-agent chemotherapy (carboPEI: carboplatin/etoposide/ifosfamide) followed by definitive radiotherapy, with excellent survival. MonoGerm is a de-escalation, non-inferiority trial aiming to reduce toxicity. Twelve-week carboplatin (PMID:8039122) AUC10 or vinblastine (PMIDs:32642701/34520101) induction will be evaluated to test if as effective as carboPEI from SIOP-CNS-GCT-II. A novel trial design was required to answer this question pragmatically/safely. METHODS Clinical trials in rare diseases recruit slowly, allowing continuous monitoring of efficacy outcomes. Efficacy-transition-pathways (ETP) are innovative visual tools to aid determination of trial design parameters, and an extension of the dose-transition-pathways concept introduced for dose-finding trials (PMID:28733440). RESULTS MonoGerm includes two monotherapies, with each single arm recruiting six cohorts of three patients, with interim assessment after each recruited cohort and final analysis at 18 patients (total n=36). Insufficient tumour volume response (&amp;lt;30%) at 6-week safety MRI results in 12-weeks carboPEI. Primary outcome is radiological complete response (CR) by 12-weeks of induction monotherapy. A beta-binomial conjugate analysis will generate posterior probability distributions, combining observed trial data as realisations from a binomial distribution with a minimally informative Beta (1,1) prior. Decision criteria to allow early stopping at interim analyses and go/no-go decisions at final analysis are based on probabilities from these posterior distributions. ETP visually maps out parameters used to assert decisions after each interim assessment as a pyramid decision tree. For each recruited cohort and every CR outcome, estimates of the true CR rate and probabilities with associated decisions are mapped out. ETP allows clear communication between statisticians, clinicians, and patient-public-involvement (PPI) teams, facilitating informed decisions in an efficient/realistic trial design. CONCLUSION MonoGerm, a novel Bayesian de-escalation trial, funded by Little Princess Trust (https://www.littleprincesses.org.uk/), uses ETP and continuous monitoring with built-in stopping rules to ensure patient safety in this treatment de-escalation trial.

Baseline and on Treatment Biodistribution Variability of 18 F-FLT Uptake in Patients With Advanced Melanoma: Brief Communication.

This prospective study evaluates the biodistribution of 18 F-FLT PET in patients with advanced melanoma before and after treatment with BRAF/MEK inhibitors. Eighteen BRAF-positive unresectable stage IIIc or IV melanoma patients referred for 18 F-FLT PET/CT before (BL) and during (D14) BRAF/MEK inhibition were included. 18 F-FLT accumulation in the liver, bone marrow, blood, and muscle was quantified. Baseline interpatient 18 F-FLT uptake had a coefficient-of-variation between 17.5% and 21.5%. During treatment, liver uptake increased (SUV meanBL = 4.86 ± 0.98, SUV meanD14 = 6.31 ± 1.36, P < 0.001) and bone marrow uptake decreased (SUV meanBL = 7.67 ± 1.65, SUV meanD14 = 6.78 ± 1.19, P < 0.025). Both changes were unrelated to baseline metabolic tumor volume or tumor response. To assess 18 F-FLT PET, both liver and bone marrow uptake may be used as normal tissue references at baseline, but 18 F-FLT biodistribution significantly changes in longitudinal response studies when treated with BRAF/MEK inhibitors.

A reduction in tumor volume exceeding 65% predicts a good histological response to neoadjuvant chemotherapy in patients with Ewing sarcoma.

No consensus exists for tumor volume response criteria in patients with Ewing sarcoma. This study aimed to identify an optimal cutoff for predicting a good histological response by analyzing tumor volume changes and tumor necrosis after neoadjuvant chemotherapy. We performed a retrospective analysis of 184 Ewing sarcoma patients, analyzing tumor volume changes before and after neoadjuvant chemotherapy. Patients were divided into two groups based on histological response: good (tumor necrosis ≥ 95%) and poor (tumor necrosis < 95%) responders. The receiver operating characteristic (ROC) area under the curve (AUC) method was used to determine the optimal thresholds for predicting the histological response. Additionally, the prognostic value of this cutoff for relapse-free survival was assessed. Out of 184 patients, 83 (45%) had tumor necrosis ≥ 95%, while 101 (55%) had tumor necrosis < 95%. ROC analysis identified the optimal cutoff for a good histological response as over 65% tumor volume reduction (AUC = 0.69; p < 0.001). Patients with volume reduction of ≥ 65% had a higher likelihood of a good histological response than those with lesser reductions (p = 0.004; odds ratio = 2.61). Multivariable analysis indicated a correlation between poor histological response and reduced relapse-free survival (hazard ratio = 2.17; p = 0.01), while tumor volume reduction itself did not impact survival. We reported that a tumor volume reduction of ≥ 65% was able to predict a good histological response in Ewing sarcoma patients. We recommend preoperative tumor volume assessment to identify patients at greater risk for poor histological response who could benefit from more intensive chemotherapy protocols or additional radiotherapy.

Correlation of primary tumor volume and histopathologic response following neoadjuvant treatment of esophageal adenocarcinoma

IntroductionIn esophageal cancer, histopathologic response following neoadjuvant therapy and transthoracic esophagectomy is a strong predictor of long-term survival. At the present, it is not known whether the initial tumor volume quantified by computed tomography (CT) correlates with the degree of pathologic regression. MethodsIn a retrospective analysis of a consecutive patient cohort with esophageal adenocarcinoma, tumor volume in CT prior to chemoradiotherapy or chemotherapy alone was quantified using manual segmentation. Primary tumor volume was correlated to the histomorphological regression based on vital residual tumor cells (VRTC) (Cologne regression scale, CRS: grade I, >50% VRTC; grade II, 10–50% VRTC; grade III, <10% VRTC and grade IV, complete response without VRTC). ResultsA total of 287 patients, 165 with neoadjuvant chemoradiotherapy according to the CROSS protocol and 122 with chemotherapy according to the FLOT regimen, were included. The initial tumor volume for patients following CROSS and FLOT therapy was measured (CROSS: median 24.8 ml, IQR 13.1–41.1 ml, FLOT: 23.4 ml, IQR 10.6–37.3 ml). All patients underwent an Ivor-Lewis esophagectomy. 180 patients (62.7 %) were classified as minor (CRS I/II) and 107 patients (37.3 %) as major or complete responder (CRS III/IV). The median tumor volume was calculated as 24.2 ml (IQR 11.9–40.3 ml). Ordered logistic regression revealed no significant dependence of CRS from tumor volume (OR = 0.99, p-value = 0.99) irrespective of the type of multimodal treatment. ConclusionThe initial tumor volume on diagnostic CT does not aid to differentiate between potential histopathological responders and non-responders to neoadjuvant therapy in esophageal cancer patients. The results emphasize the need to establish other biological markers of prediction.

Contribution of neoadjuvant chemotherapy and radiation therapy (intensity-modulated radiation therapy with concurrent chemotherapy versus stereotactic body radiation therapy alone) on tumor volume regression in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma: A single institution experience.

707 Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a minority of patients (pts) eligible for curative resection. Pts with borderline resectable or locally advanced (BR/LA) PDAC frequently receive neoadjuvant chemotherapy (NAC) +/- radiation therapy (RT) to improve resectability. Here, we report the individual contribution of NAC and RT (either intensity modulated RT + concurrent chemotherapy (IMRT+CC) or stereotactic body RT (SBRT) alone) on tumor regression by measuring tumor volumes. Methods: We performed a single institution retrospective review of PDAC pts who underwent resection between 2011-2021 and were part of a tumor biobank registry. Tumor measurements were performed at baseline, post-NAC, and post-RT by five independent, blinded abdominal radiologists. Analyses were performed using paired t-tests, two-proportion z-tests, log-rank tests, and Mann-Whitney U test. Results: We identified 49 BR/LA pts who received NAC followed by RT who had complete pre- and post-treatment imaging. Fifteen pts received IMRT+CC and 28 received SBRT. The effect of NAC on tumor volumes (-29.2% vs -26.3%, p=0.66; mean percent change) and maximum diameter (-9.2% vs -12.0%, p=0.58) was similar within the IMRT+CC and SBRT groups. Both IMRT+CC (-7.12 cm3, p=0.003) and SBRT (-2.70 cm3, p=0.001) resulted in significant tumor regressions. IMRT+CC achieved a significantly greater overall mean percent change in tumor volume (-53.4% vs -28.8%, p=0.024) and maximum diameter (-30.4% vs -16.2%, p=0.020) compared to SBRT. Pts receiving IMRT+CC or SBRT had similar tumor volumes (10.88 vs 11.74 cm3, p=0.87, respectively) and maximum diameter (3.45 vs 3.17 cm, p=0.48) prior to RT. IMRT+CC resulted in improved tumor volume response (&gt;30% regression; 80.0% vs 46.4%; p=0.033) but not an improved response rate by RECIST criteria (46.7% vs 21.4%; p=0.085). Mean resected tumor volumes (by pathological review) for those receiving IMRT+CC (n=9) and SBRT (n=23) were 4.34 vs 13.1 cm3 (p=0.049). The R0 (86.7% vs 85.7%, p=0.93) and N0 (73.3% vs 53.6%, p=0.21) resection rates between the two groups were similar. Compared to SBRT, IMRT+CC resulted in an improved recurrence free survival (RFS; 2.36 vs 1.31 years; p=0.026), but did not meet statistical significance for an overall survival benefit (mOS; 2.85 vs 2.03 years, p=0.19). Conclusions: We found that IMRT+CC yielded superior radiographic volumetric regression and improved RFS but did not significantly impact mOS. Correspondingly, resected tumors from patients treated with IMRT+CC were smaller than those obtained from patients treated with SBRT. The role of IMRT+CC and SBRT in PDAC remains to be clearly defined.

Radio-Immune Response Model for Radiotherapy Plans with Heterogeneous Dose Distribution

In order to model the immune response in tumor of the patients under radiotherapy for cancer. Characteristics of the numerical model and preliminary application are presented. Immune response was modelled by 4 set of ordinary difference equations (ODE) as a function of biomedical variables including the amount of tumor antigen naturally released by tumor, the activation of cytotoxic T-lymphocytes (CTL) by radiation, immune suppression by tumor volume and the use of immunotherapy drugs. The effect of heterogeneous radiation dose distribution is also considered by hyperbolic tangent function to account for the immunogenic response of tissue under highly heterogeneous dose distribution intentionally modulated in spatially fractionated radiotherapy. Boundary behaviors of the model were investigated for tumors with different biomedical characteristics and under different treatment conditions. The developed model was applied to the tumor volume change in a mouse with 67NR tumors after radiation of 10 Gy to full or half volume of tumor and a clinical patient treated for sarcoma three times over 4 years. Tumor growth is exponential at early phase, slow down over time with increasing immune response and eventually reaches an equilibrium condition (known as terminal tumor volume) for tumors with little to no immune suppression capability (ISC) even in the lack of radiation treatment. Breaking-through the equilibrium for tumor to grow exponentially happens when ISC is larger than the bifurcation threshold, analytically calculated from the proposed model. Tumor with ISC close to the bifurcation threshold can show complex growth behavior depending on the treatment condition and it should be carefully considered for the optimal treatment. Tumor volume change over 30 days period on mouse was modeled well with this model. Full dose irradiation reduced the tumor volume faster in the first 10 days but half volume irradiation reduced the tumor volume faster at later stage due to the improved immune response which cannot be modelled with traditional linear quadratic model. Tumor volume on a patient retreated three times over 4 years was also accurately estimated. The proposed immune response model is capable to estimate tumor volume response under full or partial volume irradiation considering the complex immune characteristics of the tissue.

Enhancing Immune-Mediated Radiotherapy Efficacy in Murine Models of Head and Neck Cancer through Peroxisome Proliferator-Activated Receptor Modulation

The tumor microenvironment (TME) in HPV-unrelated head and neck cancer (HNC) is considered to be immunologically "cold," and immunometabolic adaptations to radiotherapy (RT) can exacerbate these conditions and lead to radioresistance. Peroxisome proliferator-activated receptor-α (PPARα) agonism may improve the immune response to RT by reducing glucose scarcity through upregulation of fatty acid utilization in cancer cells. Our clinical trial data shows that high serum oleic acid (OA), a PPAR ligand, correlates with response to radioimmunotherapy. Orthotopic buccal tumor implantations of MOC2 and LY2 HNC cell lines were performed in C57BL/6 and BALB/c mice, respectively. Mice were placed on a high OA diet (38% kcal from OA) 3 weeks prior to tumor implantation. Control diet consisted of 1% kcal from OA. In vitro RT was performed to characterize the metabolic effects on the cancer cell lines. For in vivo studies, tumors were irradiated upon reaching 100 mm^3 with three 8 Gy fractions, given every 4-5 days. The PPARα agonist fenofibrate (FF, 100mg/kg/day) was given via oral gavage or intraperitoneal injection starting 5 days after RT. Tumor volume and overall survival were measured as objective outcomes, and flow cytometry was used to characterize the immune landscape of the tumor, blood, and lymph nodes. Mass spectrometry was employed for bulk proteomics and metabolomics on serum samples, and stable isotope labeling was performed on CD8 T cells from treated mice ex vivo. Extracellular flux analyses were performed on tumor cells and CD8 T cells to determine metabolic phenotypic changes. In vitro cytotoxicity was met for MOC2 and LY2 cancer cells in 100 uM FF and OA in comparison to solvent (p<0.01). Extracellular flux analyses show that RT upregulates the glycolytic phenotype of MOC2 and LY2 cancer cells; and that FF and/or OA decrease the glycolytic capacity of the cancer cells. Ex vivo extracellular flux analyses showed increased glycolytic capacity of CD8 T cells in mice treated with FF in comparison to RT alone. RT in combination with FF significantly improved tumor volume response in comparison to RT alone (mean 99.4 vs 182.7 mm^3, p = 0.001) and was comparable to combination radioimmunotherapy (with anti-PDL1 therapy; mean 99.4 vs. 132.3 mm^3). Unexpectedly, OA negated this improvement in efficacy in both MOC2 and LY2 tumor models; mice on the high OA diet had significantly higher average body weight (p<0.01). Significant changes in adaptive immune response were observed within the TME with the addition of FF. This was mirrored by changes in serum metabolomics. PPARα agonism improved the efficacy of RT in murine HNC models and could be considered in future translational clinical trial design.

Computer-aided diagnosis of skeletal metastases in multi-parametric whole-body MRI

The confident detection of metastatic bone disease is essential to improve patients' comfort and increase life expectancy. Multi-parametric magnetic resonance imaging (MRI) has been successfully used for monitoring of metastatic bone disease, allowing for comprehensive and holistic evaluation of the total tumour volume and treatment response assessment. The major challenges of radiological reading of whole-body MRI come from the amount of data to be reviewed and the scattered distribution of metastases, often of complex shapes. This makes bone lesion detection and quantification demanding for a radiologist and prone to error. Additionally, whole-body MRI are often corrupted with multiple spatial and intensity distortions, which further degrade the performance of image reading and image processing algorithms. In this work we propose a fully automated computer-aided diagnosis system for the detection and segmentation of metastatic bone disease using whole-body multi-parametric MRI. The system consists of an extensive image preprocessing pipeline aiming at enhancing the image quality, followed by a deep learning framework for detection and segmentation of metastatic bone disease. The system outperformed state-of-the-art methodologies, achieving a detection sensitivity of 63% with a mean of 6.44 false positives per image, and an average lesion Dice coefficient of 0.53. A provided ablation study performed to investigate the relative importance of image preprocessing shows that introduction of region of interest mask and spatial registration have a significant impact on detection and segmentation performance in whole-body MRI. The proposed computer-aided diagnosis system allows for automatic quantification of disease infiltration and could provide a valuable tool during radiological examination of whole-body MRI.

A prospective study to assess for the prognostic value of tumour volume reduction rate in head and neck cancer, during definitive chemo-radiation in a tertiary care hospital.

Tumour volume (TV) is an important factor influencing Radiation therapy(RT) outcome of patients. Logically, total dose and its fractionation should be tailored to the initial number of tumor cells which strongly correlated with tumor volume (TV) rather than to the tumor diameter or stage T. Aims and objectives: To assess tumour volume reduction rate weekly in patients with biopsy proven head and neck cancers treated with definitive chemo-radiation ant to correlate with histology haemoglobin and BMI . Methods and Materials: All oral cavity, oropharyngeal, hypopharyngeal, nasopharyngeal, and laryngeal cancer patients meeting inclusion criteria were included after obtaining informed written consent. All patients received definitive chemoradiation with weekly CT scanning of head and neck for the assessment of tumour and nodal volume response to chemoradiation. Tumour volume was contoured every week on CT scanning images. Tumour volume response rate (TVRR) was calculated. Results: Fourty patients were recruited. Most tumours were MDSCC accounting for 55%. Phase 1 TVRR was marginal which steeply increase 3rd week onwards during chemoradiation. In the phase 2, TVRR increased markedly. The mean TVRR on week 7 for WDSCC, MDSCC and PDSCC were 14.38 ± 7.01%, 15.01 ± 7.95% and 19.82 ± 10.44% respectively. The maximum TVRR was observed on the 7 th week of treatment which is the last week of treatment period. Patients with PDSCC had higher TVRR . Conclusion: Our study demonstrated TVVR increased markedly third week onwards and it was found to be maximum at 7th week .

Effect of Radiotherapy Dose on Outcome in Nonmetastatic Ewing Sarcoma

Radiation therapy (RT) is an integral part of Ewing sarcoma (EwS) therapy. The Ewing 2008 protocol recommended RT doses ranging from 45 to 54 Gy. However, some patients received other doses of RT. We analyzed the effect of different RT doses on event-free survival (EFS) and overall survival (OS) in patients with EwS. The Ewing 2008 database included 528 RT-admitted patients with nonmetastatic EwS. Recommended multimodal therapy consisted of multiagent chemotherapy and local treatment consisting of surgery (S&RT group) and/or RT (RT group). EFS and OS were analyzed with uni- and multivariable Cox regression models including known prognostic factors such as age, sex, tumor volume, surgical margins, and histologic response. S&RT was performed in 332 patients (62.9%), and 145 patients (27.5%) received definitive RT. Standard dose ≤ 53 Gy (d1) was admitted in 57.8%, high dose of 54 to 58 Gy (d2) in 35.5%, and very high dose ≥ 59 Gy (d3) in 6.6% of patients. In the RT group, RT dose was d1 in 11.7%, d2 in 44.1%, and d3 in 44.1% of patients. Three-year EFS in the S&RT group was 76.6% for d1, 73.7% for d2, and 68.2% for d3 (P=.42) and in the RT group 52.9%, 62.5%, and 70.3% (P=.63), respectively. Multivariable Cox regression revealed age ≥ 15 years (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.63-4.38) and nonradical margins (HR, 1.76; 95% CI, 1.05-2.93) for the S&RT group (sex, P=.96; histologic response, P=.07; tumor volume, P=.50; dose, P=.10) and large tumor volume (HR, 2.20; 95% CI, 1.21-4.0) for the RT group as independent factors (dose, P=.15; age, P=.08; sex, P=.40). In the combined local therapy modality group, treatment with higher RT dose had an effect on EFS, whereas higher dose of radiation when treated with definitive RT was associated with an increased OS. Indications for selection biases for dosage were found. Upcoming trials will assess the value of different RT doses in a randomized manner to control for potential selection bias.

Ultrasound stiffness and perfusion markers correlate with tumor volume responses to immunotherapy

Immunotherapy has revolutionized the treatment of dozens of cancers and became a standard of care for some tumor types. However, the majority of patients do not benefit from current immunotherapeutics and many develop severe toxicities. Therefore, the identification of biomarkers to classify patients as likely responders or non-responders to immunotherapy is a timely task. Here, we test ultrasound imaging markers of tumor stiffness and perfusion. Ultrasound imaging is non-invasive and clinically available and can be used both for stiffness and perfusion evaluation. In this study, we employed syngeneic orthotopic models of two breast cancers, a fibrosarcoma and a melanoma, to demonstrate that ultrasound-derived measures of tumor stiffness and perfusion (i.e., blood volume) correlate with the efficacy of immune checkpoint inhibition (ICI) in terms of changes in primary tumor volume. To modulate tumor stiffness and perfusion and thus, get a range of therapeutic outcomes, we employed the mechanotherapeutic tranilast. Mechanotherapeutics combined with ICI are advancing through clinical trials, but biomarkers of response have not been tested until now. We found the existence of linear correlations between tumor stiffness and perfusion imaging biomarkers as well as strong linear correlations between the stiffness and perfusion markers with ICI efficacy on primary tumor growth rates. Our findings set the basis for ultrasound biomarkers predictive of ICI therapy in combination with mechanotherapeutics. Statement of significanceHypothesis: Monitoring Tumor Microenvironment (TME) mechanical abnormalities can predict the efficacy of immune checkpoint inhibition and provide biomarkers predictive of response. Tumor stiffening and solid stress elevation are hallmarks of tumor patho-physiology in desmoplastic tumors. They induce hypo-perfusion and hypoxia by compressing tumor vessels, posing major barriers to immunotherapy. Mechanotherapeutics is a new class of drugs that target the TME to reduce stiffness and improve perfusion and oxygenation. In this study, we show that measures of stiffness and perfusion derived from ultrasound shear wave elastography and contrast enhanced ultrasound can provide biomarkers of tumor response.

Application of four-dimensional cone beam computed tomography in lung cancer radiotherapy

ObjectiveThis study explored the application of four-dimensional cone beam computed tomography (4D CBCT) in lung cancer patients, seeking to improve the accuracy of radiotherapy and to establish a uniform protocol for the application of 4D CBCT in radiotherapy for lung cancer.Methods4D CBCT was applied to evaluate tumor volume response (TVR), motion, and center coordinates during radiotherapy in 67 eligible individuals with lung cancer diagnoses. The differences between 4D CBCT and 3D CBCT in different registration methods were compared.ResultsTVR was observed during treatment in 41% of patients (28/67), with a mean volume reduction of 41.7% and a median time to TVR of 19 days. Tumor motion was obvious in 16 patients, with a mean value of 0.52 cm (0.22 to 1.34 cm), and in 3 of 6 tumors close to the diaphragm (0.28 to 0.66 cm). Gray value registration based on mean density projection could still achieve close results to the 4D gray value registration. However, when the registration was based on bone alone, partial off-targeting occurred in the treatment in 41.8% of cases. The off-target rate was 19.0% when the tumor motion was ≤ 0.5 cm and 52.2% when the motion was > 0.5 cm.ConclusionTumor volume and motion of intrapulmonary lesions in individuals diagnosed with lung cancer varied significantly in the third week of radiotherapy. 4D CBCT may be more advantageous for isolated lesions without reference to relative anatomical structures or those near the diaphragm. Grayscale registration based on mean density projection is feasible.

An Experimental Study: Treatment of Subcutaneous C6 Glioma in Rats Using Acoustic Droplet Vaporization.

The objective of this study was to investigate the treatment effects of acoustic droplet vaporization (ADV) on tumors. Experiments were conducted on subcutaneous C6 glioma implanted in 37 rats. Twenty-five rats were divided into five groups treated by ultrasound (US) + dodecafluoropentane (DDFP), US + microbubble (MB), US, DDFP, or saline, respectively. ADV was performed using DDFP droplets (2-5μm) triggered by non-focused pulsed ultrasound. Macroscopic and histological changes of the tumor were compared with investigation of the tumor ablation effect of ADV. Tumor temperature was measured before and immediately after treatment to explore temperature changes. Furthermore, another 12 rats with bilateral tumors were divided into two groups. Six animals received ADV treatment on unilateral tumor, while another six received saline injection on unilateral tumor. The tumor blood perfusion, tumor volume and related immune response were measured. The tumors treated by ADV were partially damaged without significant temperature rise. For the animals with bilateral tumors, the tumor blood perfusion around the damaged area on the side receiving ADV still existed. Additionally, the bilateral tumors of animals treated with ADV were smaller than those of animals treated with saline, along with stronger immune response and more tumor cell apoptosis in tumors on both sides. The study demonstrated that ADV treatment could damage subcutaneous glioma in rats by mechanical effect and enhance systemic immune response to furtherly inhibit the tumor growth.

Abstract P4-01-06: LP-184, an acylfulvene class small molecule therapeutic, is synthetically lethal in HR deficient and PARP inhibitor resistant triple negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer accounting for approximately 15% to 20% of all newly diagnosed breast cancer cases. TNBCs are defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2).Due to its special molecular phenotype, it is not sensitive to endocrine therapy or targeted therapy. Therefore, chemotherapy such as anthracyclines or taxanes is the main systemic treatment, but the efficacy of conventional postoperative adjuvant chemoradiotherapy is poor. ~35% of TNBC tumors show abnormalities in the HR pathway, making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) and DNA-damaging agents. Although more than 40% BRCA1/2-deficient patients fail to respond to PARPi and a substantial proportion of patients acquire PARPi resistance over time. TNBCs heterogeneous nature, poor prognosis and limited treatment options presents the urgent need of development of novel agents targeting tumor specific alterations. Lantern Pharma is advancing LP-184, an acylfulvene-derived prodrug that is specifically activated in tumors that overexpress the oxidoreductase enzyme Prostaglandin Reductase 1 (PTGR1), for the treatment of solid tumor indications including TNBC. LP-184 has multiple mechanisms of action (MOA). While It is synthetically lethal in tumors harboring DNA damage repair defects including Homologous Recombination (HR) deficiencies, it can also interrupt transcription. LP-184 efficacy was tested in a panel of breast cancer cell lines and patient derived TNBC xenografts models, both sensitive as well as resistant to PARP inhibitors and anthracyclines. LP-184 demonstrated nanomolar potency in six NCI-60 breast cancer cell lines (median IC50 = 327 nM). Subcutaneous patient-derived TNBC xenograft mouse models were used to determine tumor volume responses to LP-184 treatment in vivo. Xenograft tumors were derived from 10 treatment-naive HR deficient (HRD score &amp;gt; 50) primary TNBC patients with known BRCA1/2 loss of heterozygosity (LOH), 7 of which subsequently progressed on PARP inhibitor Olaparib. LP-184 (4mg/kg i.v., (q2d x 5 then 7 days off)x2) led to complete and durable regression in all 10 TNBC HRD-PDX models tested as compared to control (p &amp;lt; 0.0001). A tumor growth inhibition range of 107-141% was achieved across all the 10 models. For LP-184, T/C at the control group end day was 0% in 10/10 models, whereas across the same models for Olaparib, T/C was 0% in 2/10 models and ranged from 15 - 90% in 8/10 models. Terminal body weight change was only a transient weight loss &amp;lt; 4% with LP-184 treatment across all models. LP-184 exhibited superior potency than olaparib in TNBC PDX models that carry HRD mutations including PARP resistant models and was well tolerated in mice. As acylfulvene-induced damage is primarily repaired by transcription-coupled nucleotide-excision repair (TC-NER) and HR pathways, response to LP-184 is influenced by tumor DNA damage repair pathway status. Recent data highlight an important role of super enhancer driven core transcription regulatory circuits in the pathogenesis of TNBCs. Our results support the superior efficacy of LP-184 in TNBCs, likely linked to the multiple MOAs, and establish LP-184 as a promising new agent for future clinical testing in TNBC patients. We finally propose that LP-184 may be broadly efficacious in solid tumors with HR and/or TC-NER pathway defects, such as pancreatic, prostate, ovarian and bladder cancers. Citation Format: Aditya Kulkarni, Neha Biyani, Laura Brullé-Soumaré, Stefano Cairo, Panna Sharma, Kishor Bhatia. LP-184, an acylfulvene class small molecule therapeutic, is synthetically lethal in HR deficient and PARP inhibitor resistant triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-06.

Intravoxel Incoherent Motion MRI and PET in Locally Advanced Cervical Carcinoma Undergoing Concurrent Chemoradiation Therapy

<h3>Purpose/Objective(s)</h3> Dynamic contrast enhanced (DCE) CT or MRI and FDG PET have been used to evaluate the impact of tumor perfusion and metabolism on the course and effectiveness of concurrent chemoradiation therapy (CCRT) for cervical cancer. Combining perfusion and metabolic measures allows better identification of radioresistant sub-volumes: however, use of contrast and additional dose are barriers to frequent dual perfusion-metabolic imaging. Here, we investigated a contrast-free, non-ionizing alternative to DCE: intravoxel incoherent motion (IVIM) MRI which provides both perfusion and diffusion measurements. Our objective was to evaluate changes of PET and IVIM parameters in cervical cancer patients before and during CCRT and to correlate these parameters and their changes with tumor volume response during CCRT. <h3>Materials/Methods</h3> Pre- and on-treatment IVIM scans were performed on 15 cervical cancer patients undergoing definitive chemoradiation (median [range] age: 66 [29 to 85]; FIGO: 1 IB1, 1 IIA, 3 IIB, 1 IIIB, 1 IIIC, 5 IIIC1, 2 IIIC2, 1 IVA; hist: 11 squamous cell carcinoma, 3 endocervical adenocarcinoma, 1 large cell neuroendocrine carcinoma), of whom 14 also underwent pre-treatment PET scans. The on-treatment MRI occurred generally during the last week or shortly after completing EBRT. Diffusion weighted images (DWIs) were acquired at 3T scanners using a free-breathing single shot spin echo planar imaging (EPI) sequence. IVIM MRI maps were generated by Bayesian fitting of a two-compartment IVIM model to the DWIs. Three-dimensional co-registered maps of PET standardized uptake value (SUV) and IVIM diffusion coefficient (D), perfusion fraction (f), and pseudo-diffusion coefficient (D*) were generated. Summary statistics (mean +/- standard deviation) for these and other imaging parameters were calculated pre- and on-treatment. Univariate analysis was performed to determine relationships between relative change in gross tumor volume (ΔGTV) and pre-treatment imaging measurements. <h3>Results</h3> In tumors, pre- versus on-treatment values significantly changed for the following parameters: ΔGTV (66.8 +/- 43.2 vs. 32.0+/-23.0 ml, p<.001) and D (0.00109 +/- 0.00023 vs. 0.00120 +/- 0.00026 mm²/s, p=.02). The perfusion fraction f increased and D* decreased, but not significantly (f: 0.127 +/- 0.022 vs. 0.154 +/- 0.057 %, p=.07, D*: 0.0137 +/- 0.0035 vs. 0.0133 +/- 0.0039 mm²/s, p=.6). Pre-treatment SUV_max (r=.76, p=.002) and SUV_mean (r=.70, p=.007) were positively related with ΔGTV, while pre-treatment f, D*, and D were negatively but not significantly related with ΔGTV (r=-.44, p=.1; D*: r=-.14, p=.6; D: r=-.12, p=.7). <h3>Conclusion</h3> Both perfusion fraction and diffusion coefficient IVIM increased in locally advanced cervical carcinoma patients undergoing CCRT – reflecting changes in the tumor microenvironment during treatment. These weak relationships observed here suggest a potential complementary role and motivating the combined use of these modalities for tumor characterization.

Vestibular schwannoma associated with neurofibromatosis type 2: Clinical course following stereotactic radiosurgery.

ObjectiveA lack of understanding of the clinical course of neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS) often complicates the decision-making in terms of optimal timing and mode of treatment. We investigated the outcomes of stereotactic radiosurgery (SRS) in this population.MethodsWe retrospectively analyzed NF2 patients treated with Gamma-Knife SRS for VS in our tertiary referral center. A total of 41 treated lesions from 33 patients were collected with a follow-up period of 69.1 (45.0-104.8) months. We reviewed the treatment history, hearing function, and other treatment-related morbidities in individual cases. We also analyzed pre- and post-treatment tumor volumes via imaging studies. Longitudinal volumetric analyses were conducted for the tumor volume response of the 41 treated lesions following SRS. The growth pattern of 22 unirradiated lesions during an observation period of 83.4 (61.1-120.4) months was separately evaluated.ResultsMost treated lesions showed effective tumor control up to 85% at 60 months after SRS, whereas unirradiated lesions progressed with a relative volume increase of 14.0% (7.8-27.0) per year during the observation period. Twelve (29%) cases showed pseudoprogression with significant volume expansion in the early follow-up period, which practically reduced the rate of tumor control to 57% at 24 months. Among the patients with serviceable hearing, two (20%) cases lost the hearing function on the treated side during the early follow-up period within 24 months.ConclusionsProgressive NF2-associated VS can be adequately controlled by SRS but the short-term effects of this treatment are not highly advantageous in terms of preserving hearing function. SRS treatment candidates should therefore be carefully selected.

Predictive role of diffusion-weighted MRI in the assessment of response to total neoadjuvant therapy in locally advanced rectal cancer.

To investigate the predictive role of diffusion-weighted magnetic resonance imaging (DW-MRI) in the assessment of response to total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC). In this single-center retrospective study, patients with LARC who underwent staging MRI and TNT were enrolled. MRI-based staging, tumor volume, and DWI-ADC values were analyzed. Patients were classified as complete responders (pCR) and non-complete responders (non-pCR), according to post-surgical outcome. Pre-treatment ADC values were compared to pathological outcome, post-treatment downstaging, and reduction of tumor volume. The diagnostic accuracy of DWI-ADC in differentiating between pCR and non-pCR groups was calculated with receiver operating characteristic (ROC) analysis. A total of 36 patients were evaluated (pCR, n = 20; non-pCR, n = 16). Pre-treatment ADC values were significantly different between the two groups (p = 0.034), while no association was found between pre-TNT tumor volume and pathological response. ADC values showed significant correlations with loco-regional downstaging after therapy (r = -0.537, p = 0.022), and with the reduction of tumor volume (r = -0.480, p = 0.044). ADC values were able to differentiate pCR from non-pCR patients with a sensitivity of 75% and specificity of 70%. ADC values on pre-treatment MRI were strongly associated with the outcome in patients with LARC, both in terms of pathological response and in loco-regional downstaging after TNT, suggesting the use of DW-MRI as a potential predictive tool of response to therapy. • ADC values of pre-TNT MRI examinations of patients with LARC were significantly associated with a pathological complete response (pCR) and with post-treatment regression of TNM staging. • An ADC value of 1.042 ×10-3 mm2/s was found to be the optimal cutoff value for discriminating between pCR and non-pCR patients, with a sensitivity of 75% and specificity of 70%. • DW-MRI proved to have a potential predictive role in the assessment of response to therapy in patients with LARC, throughout the analysis of ADC map values.

Ranking the most influential predictors of CT-based radiomics feature values in metastatic lung adenocarcinoma

PurposeTo investigate which acquisition, post-processing, tumor, and patient characteristics contribute the most to the value of radiomics features (RFs) in lung adenocarcinoma in order to better understand and order the potential sources of bias in radiomics studies in a multivariate setting. MethodsThis single-center retrospective study included all consecutive patients with newly-diagnosed lung adenocarcinoma treated between December 2016 and September 2018 who had pre-treatment contrast-enhanced CT-scan showing ≥ 2 target lesions per response evaluation criteria in solid tumors (RECIST) v1.1. All measurable lesions were manually segmented; 49 RFs were extracted using LIFEx v7.0.0. Afterwards, we reverted the usual radiomics approach (i.e., predicting a clinical outcome base on multiple RFs). To do so, for each RF, random forests and linear regression algorithms were trained using cross-validation to predict the RF value depending on the following variables: patient, mutational status, phase of CT-scan acquisition, discretization (binsize), lesion location, lesion volume, and best response obtained during the first line of treatment (partial response per RECIST vs other). The most important contributors to the value of reproducible RFs (intra-class correlation coefficient > 0.80) according to the best random forests model (selected via R-squared) were ranked. Results101 patients (median age: 62.3) were included, with a median of 5 target lesions per patient (range: 2–10) providing 466 segmented lesions. Twenty-nine RFs were reproducible. The most important predictors of the reproducible RFs values were, in order: tumor volume, binsize, tumor location, CT-scan phase, KRAS mutation, and treatment response (average importance: 61.7%, 57.4%, 8.1%, 3.3%, 3%, and 2.7%, respectively). The treatment response and KRAS and EGFR/ROS1/ALK mutational status remained independently correlated with the RF value for 64.3%, 32.1%, and 50% reproducible RFs, respectively. ConclusionTumor volume, location, acquisition and post-processing parameters should systematically be incorporated in radiomics-based modeling; however, most reproducible RFs do have significant relationships with mutational status and treatment response.