Tumor Volume Response Research Articles

Cerebrospinal Fluid Access Devices in Pediatric Diffuse Midline Glioma Patients: Literature Review and Evaluation of Institutional Practices

Abstract INTRODUCTION Diffuse midline gliomas (DMG) are the number one cause of cancer death in children. H3K27M mutations occur in 80% of DMG, with distinct tumor biology and poorer response to treatment. H3K27M is detectable in cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA), depending on CSF tumor proximity, and correlates with tumor volume and treatment response. Ventricular access devices (VAD) for serial CSF sampling (liquid biopsy) could therefore play a significant role in DMG management. Here, we set to characterize VAD placement practices in pediatric DMG. METHODS A retrospective review of patients <21 yr treated for DMG at our institution was performed (1984-2019). A MEDLINE search was conducted to identify reports of VAD placement in DMG. Full-text English reports of patients = 21 yr with VAD outcomes were analyzed. RESULTS A total of 106 DMG patients at our institution were identified. In total 49% had brainstem disease (n = 52). A total of 46.23% (n = 49) had VADs: 32.65% transient (ETV n = 5, EVD n = 11), 67.35% permanent (reservoir n = 7, shunt n = 26). A total of 17 had ETV at biopsy, 7 with concurrent reservoir placement. Of 10 ETV patients without initial reservoir, 5 ultimately underwent permanent VAD placement (reservoir n = 1, shunt n = 4). A total of 9 patients received EVDs at tumor surgery, 8 required EVD for acute hydrocephalus (HCP), with 6 converted to shunts. A total of 15 shunts were placed at tumor diagnosis: 4 required revision (27%). A total of 14 articles describing 240 DMG patients cited HCP in 22%-100%, with VAD placement in 22%-63%, and shunt-induced extraneural metastases in 7. Ventricular chemotherapy via indwelling reservoirs (481 patients) was associated with 29 infectious and 50 noninfectious complications. Standardized reservoir access procedures decreased infection rates. CONCLUSION VAD placement is clinically indicated in a significant proportion of pediatric DMG patients, with low morbidity. Ventricular CSF is superior to lumbar for ctDNA sequencing and quantification. VAD placement should therefore be considered to facilitate liquid biopsy in DMG.

The Relationship between Primary Gross Tumor Volume and Tumor Response of Locally Advanced Rectal Cancer: pGTV as a More Accurate Tumor Size Indicator

Purpose: To identify the clinical predictive factors of tumor response and to evaluate the significance of primary gross tumor volume (pGTV), obtained from radiotherapy planning, in predicting tumor response. Materials and Methods: We retrospectively analyzed data of consecutive locally advanced rectal cancer (LARC) patients who were treated with neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery at our institution between March 2009 and December 2017. We identify independent predictors of tumor response to nCRT by statistical analysis. Disease-free survival (DFS) starting from the time of surgery was calculated by the Kaplan–Meier method, and log-rank tests were performed to compare DFS between patients with superior and inferior tumor response. Results: Overall, 185 LARC patients received nCRT, of whom 89 (48.11%) achieved superior tumor response. Diminutive pGTV (p = 0.038) and distance from the anal verge (DAV) (p = 0.006) were independent predictive factors of superior tumor response. Meanwhile, pGTV can be regarded as an independent predictor of pathologic complete response (pCR) (p = 0.036). The log-rank test revealed that DFS was longer in the diminutive pGTV group than in the giant pGTV group (p = 0.001). Conclusions: pGTV, as a measure of tumor size, is not only an important prognostic indicator but also an independent predictive factor of tumor response, even pCR.

Evaluation of the multi-kinase inhibitor regorafenib in the Pediatric Preclinical Testing Consortium osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma in vivo models.

10038 Background: Regorafenib is a multi-kinase inhibitor, developed by adding a fluorine atom to the phenyl ring of sorafenib. Regorafenib inhibits multiple kinases including BRAF, FGFR1, KIT, PDGFRB, RAF, RET, and VEGFR1-3, many at a higher potency than sorafenib. Prior studies within the Pediatric Preclinical Testing Consortium (PPTC) demonstrated sorafenib exhibited intermediate activity for tumor growth inhibition in more than 50% of the sarcoma models tested at a dose of 60mg/kg by oral gavage daily (5 days/wk for 6 consecutive weeks). The in vivo effects of regorafenib were studied in the PPTC osteosarcoma (OS), rhabdomyosarcoma (Rh) and Ewing (EW) sarcoma xenograft models. Methods: The in vivo anticancer effects of regorafenib were assessed in a panel of 6 osteosarcoma models (OS2, OS9, OS31, OS33, OS36, OS60), two rhabdomyosarcoma models (Rh30, Rh41), and one Ewing sarcoma model (EW5). Regorafenib was administered by oral gavage at a dose of 30 mg/kg/day given daily for 21 consecutive days. Time to event and tumor volume responses were defined and analyzed utilizing standard PPTC statistical methods. Results: Regorafenib induced significant improvements in event-free survival (EFS) compared to control in 100% (9/9) of sarcoma models tested. Most models showed pronounced slowing of tumor growth compared to control during the 21 days of regorafenib treatment, with tumor growth generally approximating control rates soon after completion of regorafenib treatment. Three out of 8 sarcoma models demonstrated EFS T/C values > 2 (1/6 OS, 2/2 Rh, 0/1 EW). Minimum relative tumor volumes ranged from 0.74 to 1.60, with no models meeting criteria for objective response. Conclusions: Regorafenib induced modest inhibition of tumor growth in the PPTC sarcoma models evaluated. The overall pattern of response to the multi-kinase inhibitor regorafenib against the PPTC sarcoma models appears similar to that of the kinase inhibitor sorafenib, with pronounced slowing of tumor growth in some models that is limited to the period of agent administration being the primary treatment effect.

F18 Fluciclovine PET/CT in Assessing Tumor Volume and Radiation Therapy Response in Patients With Glioblastoma Undergoing Surgery

F18 Fluciclovine PET/CT in Assessing Tumor Volume and Radiation Therapy Response in Patients With Glioblastoma Undergoing Surgery

Incidence and Time of Onset of Osseous Pseudoprogression in Patients With Metastatic Spine Disease From Renal Cell or Prostate Carcinoma After Treatment With Stereotactic Body Radiation Therapy.

Tumor osseous pseudoprogression (PP), defined as an imaging-based transient increase in tumor size following treatment, was recently described in patients with spinal metastases following stereotactic body radiation therapy. Distinguishing PP from true tumor progression is critical. To describe the incidence, time of onset, and time range of PP following stereotactic body radiation therapy in patients treated for spinal metastases from either prostate cancer (PC) or renal cell carcinoma (RCC), and associated predictive factors. A retrospective study was conducted on our institution's cancer database from 2009 to 2015. Selection was based on single level, no prior radiation or surgery, ≥2 follow-up spine magnetic resonance imaging (MRI), and metastases arising from either PC or RCC. Gross tumor volume was contoured on pre- and up to 5 posttreatment MRIs. Patients were sorted into groups depending on gross tumor volume response: PP, non-PP, or progressive disease. Clinical and dosimetric variables were compared using either Fisher's exact test or Kruskal-Wallis analyses. Forty-three spinal segments from 31 patients were analyzed. RCC and PC patients showed similar incidence of PP (∼37%). Whether the primary was lytic or sclerotic was a significant predictive factor with more PP in the lytic group (P = .0208). There was a trend of earlier PP onset in RCC (within 6-18 mo) as compared to PC; however, PC segments showed more time-confined presentation of PP (9-12 mo). There was a higher incidence of PP in lytic compared to sclerotic primary tumor type. PP in spinal metastatic sites may have variable presentations depending on the primary cancer.

The relation of radiological tumor volume response to histological response and outcome in patients with localized Ewing Sarcoma.

BackgroundMagnetic resonance imaging (MRI) is the modality of choice for local staging and response evaluation of Ewing sarcoma (EwS). Aim of this study was to determine the relevance of tumor volume response (TVR) in relation to histological response (HisRes) and survival, in order to evaluate if early modification of chemotherapy might be indicated in patients with inadequate TVR.MethodsThree dimensional (3D)‐tumor volume data at diagnosis, during early induction phase (1‐3 courses of chemotherapy; n = 195) and/or late induction phase (4‐6 courses; n = 175) from 241 localized patients were retrospectively analyzed. A distinction was made between adequate response (reduction ≥67%) and inadequate response (reduction <67% or progression). Correlations between TVR, HisRes, event free survival (EFS), and overall survival (OS) were analyzed using chi‐square tests, log‐rank tests, and the Cox‐regression model.ResultsEarly adequate TVR, noted in 41% of patients, did not correlate with EFS (P = 0.92) or OS (P = 0.38). During late induction phase 62% of patients showed an adequate TVR. EFS for patients with late adequate TVR was better (78%) than for those with inadequate late TVR (61%) (P = 0.01); OS was 80% and 69% (P = 0.26), respectively. No correlation was found between TVR and HisRes. Multivariate analysis showed that poor HisRes, pelvic location and late inadequate TVR were associated with poor outcome.ConclusionsEarly inadequate TVR does not predict adverse outcome; therefore, changing the treatment to second line chemotherapy is not indicated in case of inadequate early TVR. Late adequate TVR and good HisRes correlate with better EFS; patients with late inadequate TVR might benefit from augmented therapy.

Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis.

Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC. Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9. The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response. Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.

Magnetic Resonance-based Response Assessment and Dose Adaptation in Human Papilloma Virus Positive Tumors of the Oropharynx treated with Radiotherapy (MR-ADAPTOR): An R-IDEAL stage 2a-2b/Bayesian phase II trial

BackgroundCurrent standard radiotherapy for oropharynx cancer (OPC) is associated with high rates of severe toxicities, shown to adversely impact patients’ quality of life. Given excellent outcomes of human papilloma virus (HPV)-associated OPC and long-term survival of these typically young patients, treatment de-intensification aimed at improving survivorship while maintaining excellent disease control is now a central concern. The recent implementation of magnetic resonance image – guided radiotherapy (MRgRT) systems allows for individual tumor response assessment during treatment and offers possibility of personalized dose-reduction. In this 2-stage Bayesian phase II study, we propose to examine weekly radiotherapy dose-adaptation based on magnetic resonance imaging (MRI) evaluated tumor response. Individual patient’s plan will be designed to optimize dose reduction to organs at risk and minimize locoregional failure probability based on serial MRI during RT. Our primary aim is to assess the non-inferiority of MRgRT dose adaptation for patients with low risk HPV-associated OPC compared to historical control, as measured by Bayesian posterior probability of locoregional control (LRC). MethodsPatients with T1-2 N0-2b (as per AJCC 7th Edition) HPV-positive OPC, with lymph node <3 cm and <10 pack-year smoking history planned for curative radiotherapy alone to a dose of 70 Gy in 33 fractions will be eligible. All patients will undergo pre-treatment MRI and at least weekly intra-treatment MRI. Patients undergoing MRgRT will have weekly adaptation of high dose planning target volume based on gross tumor volume response. The stage 1 of this study will enroll 15 patients to MRgRT dose adaptation. If LRC at 6 months with MRgRT dose adaptation is found sufficiently safe as per the Bayesian model, stage 2 of the protocol will expand enrollment to an additional 60 patients, randomized to either MRgRT or standard IMRT. DiscussionMultiple methods for safe treatment de-escalation in patients with HPV-positive OPC are currently being studied. By leveraging the ability of advanced MRI techniques to visualize tumor and soft tissues through the course of treatment, this protocol proposes a workflow for safe personalized radiation dose-reduction in good responders with radiosensitive tumors, while ensuring tumoricidal dose to more radioresistant tumors. MRgRT dose adaptation could translate in reduced long term radiation toxicities and improved survivorship while maintaining excellent LRC outcomes in favorable OPC. Trial registrationClinicalTrials.gov ID: NCT03224000; Registration date: 07/21/2017.

Tumor Shrinkage During Chemoradiation in Locally Advanced Cervical Cancer Patients: Prognostic Significance, and Impact for Image-Guided Adaptive Brachytherapy

To study the prognostic value of gross tumor volume (GTV) shrinkage and its dosimetric implication in a large cohort of patients with cervical cancer receiving definitive chemoradiotherapy plus image guided adaptive brachytherapy. Clinical records of consecutive patients treated in our institution between February 2004 and November 2015 by concurrent chemoradiotherapy (45Gy in 25 fractions±lymph node boosts) followed by a magnetic resonance imaging-guided adaptive pulse-dose rate brachytherapy were included. The prognostic value of GTV and its evolution after chemoradiotherapy were examined first on initial staging magnetic resonance imaging and then at time of brachytherapy. All measures and measurement cutoffs were selected using time-dependent area under the curve for 3-year progression-free survival (PFS). GTV evolution between diagnosis and the time of brachytherapy was assessed in 247 patients. After chemoradiotherapy, complete response was observed in 75 patients (28%). Optimal cutoffs were GTV=55cm3 at diagnosis, GTV=7.5cm3 at brachytherapy, and GTV reduction ≥90%. All patients with volume above or reduction below these cutoffs had significant reduced overall survival, PFS, local control, and distant metastasis control (P<.001). Patients with anemia at diagnosis had a lower tumor volume response rate (P<.001). In multivariate analysis, incorporating the International Federation of Gynecology and Obstetrics stage, N+ stage, anemia, and dosimetric parameters for image guided adaptive brachytherapy, GTV optimal volume reduction after chemoradiotherapy was independently associated with improved overall survival, PFS, local control, and distant metastasis control (P<.001). These results could provide a rationale for dose de-escalation studies in brachytherapy for patients displaying optimal GTV volumetric reduction after chemoradiotherapy and may reinforce the need for dose escalation in poorly responding patients.

18F]FDG and [18F]FLT PET for the evaluation of response to neo-adjuvant chemotherapy in a model of triple negative breast cancer.

RationalePathological response to neo-adjuvant chemotherapy (NAC) represents a commonly used predictor of survival in triple negative breast cancer (TNBC) and the need to identify markers that predict response to NAC is constantly increasing. Aim of this study was to evaluate the potential usefulness of PET imaging with [18F]FDG and [18F]FLT for the discrimination of TNBC responders to Paclitaxel (PTX) therapy compared to the response assessed by an adapted Response Evaluation Criteria In Solid Tumors (RECIST) criteria based on tumor volume (Tumor Volume Response).MethodsNu/nu mice bearing TNBC lesions of different size were evaluated with [18F]FDG and [18F]FLT PET before and after PTX treatment. SUVmax, Metabolic Tumor Volume (MTV) and Total Lesion Glycolysis (TLG) and Proliferation (TLP) were assessed using a graph-based random walk algorithm.ResultsWe found that in our TNBC model the variation of [18F]FDG and [18F]FLT SUVmax similarly defined tumor response to therapy and that SUVmax variation represented the most accurate parameter. Response evaluation using Tumor Volume Response (TVR) showed that the effectiveness of NAC with PTX was completely independent from lesions size at baseline.ConclusionsOur study provided interesting results in terms of sensitivity and specificity of PET in TNBC, revealing the similar performances of [18F]FDG and [18F]FLT in the identification of responders to Paclitaxel.

Intratumoral Spatial Heterogeneity at Perfusion MR Imaging Predicts Recurrence-free Survival in Locally Advanced Breast Cancer Treated with Neoadjuvant Chemotherapy.

Purpose To characterize intratumoral spatial heterogeneity at perfusion magnetic resonance (MR) imaging and investigate intratumoral heterogeneity as a predictor of recurrence-free survival (RFS) in breast cancer. Materials and Methods In this retrospective study, a discovery cohort (n = 60) and a multicenter validation cohort (n = 186) were analyzed. Each tumor was divided into multiple spatially segregated, phenotypically consistent subregions on the basis of perfusion MR imaging parameters. The authors first defined a multiregional spatial interaction (MSI) matrix and then, based on this matrix, calculated 22 image features. A network strategy was used to integrate all image features and classify patients into different risk groups. The prognostic value of imaging-based stratification was evaluated in relation to clinical-pathologic factors with multivariable Cox regression. Results Three intratumoral subregions with high, intermediate, and low MR perfusion were identified and showed high consistency between the two cohorts. Patients in both cohorts were stratified according to network analysis of multiregional image features regarding RFS (log-rank test, P = .002 for both). Aggressive tumors were associated with a larger volume of the poorly perfused subregion as well as interaction between poorly and moderately perfused subregions and surrounding parenchyma. At multivariable analysis, the proposed MSI-based marker was independently associated with RFS (hazard ratio: 3.42; 95% confidence interval: 1.55, 7.57; P = .002) adjusting for age, estrogen receptor (ER) status, progesterone receptor status, human epidermal growth factor receptor type 2 (HER2) status, tumor volume, and pathologic complete response (pCR). Furthermore, imaging helped stratify patients for RFS within the ER-positive and HER2-positive subgroups (log-rank test, P = .007 and .004) and among patients without pCR after neoadjuvant chemotherapy (log-rank test, P = .003). Conclusion Breast cancer consists of multiple spatially distinct subregions. Imaging heterogeneity is an independent prognostic factor beyond traditional risk predictors.

Abstract A103: ATM inhibitor AZD0156 in combination with irinotecan: the use of mathematical modeling to predict efficacious doses and schedules from preclinical data

Abstract AZD0156 is a first- and only-in-class, potent, and selective ATM inhibitor. It is being investigated in clinical ascending dose studies in combination with olaparib or irinotecan. Preclinical data on the AZD0156 irinotecan combination have been used to determine which doses and schedules should be investigated to maximize efficacy. The effects of AZD0156 and irinotecan in combination on the distribution of cell cycle phases have been investigated in vitro by flow cytometry. Cell population growth and DNA damage response biomarkers such as pATM foci, gH2AX foci, and micronuclei were described in detail using high-throughput immunofluorescence imaging. In vivo, preclinical xenograft studies have been carried out to examine the effects on pharmacodynamics and tumor growth from different doses and schedules of both agents. These in vitro and in vivo data have been integrated into a mechanistic mathematical model that supports the combination hypothesis, and allows prediction of pharmacodynamic and tumor volume responses under different doses and schedules. In particular, the effects of clinical doses and schedules can be predicted by taking into account differences between mouse and human pharmacokinetics for the co-agents. It can be challenging to identify the optimum schedule during clinical ascending dose studies, especially in combination cases with multiple variables, such as the doses of each agent, time gaps between doses, and times without dosing between cycles. Preclinical information, together with mathematical modeling, can be used to guide the prioritization of clinical experiments. Citation Format: Elaine Cadogan. ATM inhibitor AZD0156 in combination with irinotecan: the use of mathematical modeling to predict efficacious doses and schedules from preclinical data [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A103.

Effectiveness of induction chemotherapy consisting of docetaxel, cisplatin, and S-1 (DCS) followed by esophagectomy for cT4 esophageal cancer

Introduction: The prognosis of cT4 esophageal cancer is dismal unless the tumor is completely removed by esophagectomy after induction treatment successfully reducing the tumor volume. However, esophagectomy for cT4 esophageal cancer after induction treatment is associated with high morbidity and mortality rates and recommended induction treatment remains unclear. The aim of the study is to evaluate the feasibility and efficacy of 3-course chemotherapy consisting of docetaxel, cisplatin, and S-1 (DCS) followed by esophagectomy in comparison with 2-course chemotherapy consisting of 5-FU, doxorubicin, and nedaplatin (FAN) for cT4 esophageal cancer in a prospective cohort study. Methods: Since 2002, we have performed a prospective cohort study of induction treatment in patients with cT4 esophageal cancer. FAN chemotherapy, 40-66 Gy chemoradiotherapy, and DCS chemotherapy was performed in patients with cT4 esophageal cancer during the period of 2002-2006, 2006-2013, and 2013-2016, respectively. The short- and long-term results of DCS group (n = 18) were compared with FAN group (n = 17). In DCS group’s patients, cStage III and IV diseases were found in 1 and 17 respectively, whereas the respective number was 3 and 14 in the FAN group’s patients. Results: The completion rate of the planned therapy was 89% and 65% in the DCS and FAN group, respectively (p = 0.121). The response rate for primary tumor (83%) of DCS group was significantly higher than that (35%) of FAN group (p = 0.006). However, the occurrence rate of the toxicity grade 3 or higher was not significantly different between two groups: 61% and 47% in the DCS and FAN group, respectively (p = 0.505). There were no treatment-related deaths during the chemotherapy in two groups. The esophagectomy rate was 67% of DCS group and 59% of FAN group, respectively (p = 0.733). R0 resection rate was 61% of DCS group and 47% of FAN group, respectively (p = 0.505). There were not significantly different between two groups but DCS group showed high Esophagectomy and R0 resection rates in comparison with FAN group. The surgery-related morbidity rate was 75% and 50% in DCS and FAN groups, respectively (p = 0.378). There were not significantly different between the 2 groups. The surgery-related mortality was occurred in two patients of FAN group, but there were not in DCS group. The 5-years overall survival rates for all patients, the 45% of DCS group was significantly better than 12% of FAN group (p = 0.029). Conclusion: The induction DCS therapy is safe and feasible, and has strong power to reduce tumor volume (response rate: 83%) even in cases of T4 esophageal tumor. Esophagectomy and R0 resection rates after the DCS therapy were better than those after the FAN therapy. Furthermore, the 5-years overall survival rates for all patients in DCS group significantly better than that in FAN group. Therefore, the DCS therapy may be promising as the induction treatment for cT4 esophageal cancer.

(S009) In Silico Trial of MR-Guided Mid-Treatment Adaptive Planning for Hypofractionated Stereotactic Radiotherapy in Centrally Located Thoracic Tumors

Hypofractionated (>5fx) stereotactic radiotherapy (HSRT) may allow for biologically equivalent dose to tumor with a lower risk of organ at risk (OAR) toxicity in centrally located thoracic tumors (CTT). Adaptive planning may further improve OAR sparing while maintaining planning target volume (PTV) coverage. We evaluate potential dosimetric advantages of mid-treatment adaptive re-planning during HSRT for CTT using magnetic resonance image-guided radiotherapy (MR-IGRT). Thirteen patients with CTT received HSRT using MR-IGRT. Clinically delivered regimens were 60Gy/12fractions (n=8) or 62.5Gy/10fractions (n=3), with low-field-MR (0.35T) volumetric setup imaging acquired at each fraction. Daily GTV/OAR were retrospectively re-defined on fx1, 6, and 10 MR-image sets, and tumor volume response was recorded. Simulated initial plans (PI) were created with prescribed dose of 60Gy/12fx based on fx1 MRI. Fx6 and fx10 adaptive plans (PA) were created based on fx6 and fx10 anatomy-of-the-day. All PI/PA were created using an isotoxicity approach with goal 95%PTV coverage, subject to hard OAR constraints, to represent clinically ideal OAR sparing. PI/PA were then compared for projected OAR sparing/PTV coverage. All patients demonstrated on-treatment MRI-defined GTV reduction (median 52.1%; range 30.5-70.8%). At fx6, median reduction was 34.8%. All PI met initial hard OAR constraints. PI application to fx6 and fx10 anatomy resulted in 8 OAR violations (5/13 patients) and 12 OAR violations (6/13 patients), respectively. All violations observed in fx6 were persistent in fx10; average magnitude of OAR violation was higher in fx10 than fx6. Adaptive planning reversed 100% of OAR violations. In 55%(6/11) of fractions where OAR violation resulted from PI application to fx6/fx10 anatomy, PTV coverage was increased concomitantly with violation reversal. Midpoint adaptive planning based on tumor response may be dosimetrically advantageous for sparing of surrounding critical structures in HSRT for central thorax malignancies.

Role of Diffusion-weighted Magnetic Resonance Imaging in Cervical Cancer for Prediction and Monitoring of Chemo-radiotherapy Response

Objectives: To investigate the possibility of DWI as an imaging bio marker and evaluate its role in prediction and monitoring of chemoradiotherapy response in cervical carcinoma. Methods: 30 carcinoma cervix patients undergoing radiation for Carcinoma Cervix were examined with routine pelvic MRI and DWI before chemoradiation, following EBRT and on completion of brachytherapy. Based on the response on conventional MRI patients were categorized into complete, good and partial response groups. Analysis of variance (ANOVA) and Student t test (two tailed, independent) were used to compare the ADC, size and volume parameters between response groups and therapeutic times. Pearson's correlation test was calculated between ADC parameters and tumor size and volume response. Results: Cervical cancer demonstrated serial increase in tumor ADC values with corresponding decrease in tumor diameters and volumes during the therapy (all p values <0.001). significant and moderate positive linear correlation was found between the tumor ADC values and final size and volume responses at pre-treatment, post EBRT and post-treatment. Tumors with high diffusion values responded better to therapy than with low diffusion values. Patients with greater post EBRT tumor ADC changes and greater size and volume responses responded better to therapy. The pretreatment tumor ADC values, post EBRT ADC changes were found to be correlating well with the final outcome. However ADC mapping was less useful in predicting the extension and staging of carcinoma. Conclusion: DWI and its quantitative parameter, ADC has a potential role in the prediction, assessment and monitoring of cervical cancer treatment response to chemo radiation therapy.

Pretreatment tumor volume as a prognostic factor in metastatic colorectal cancer treated with selective internal radiation to the liver using yttrium-90 resin microspheres.

Yttrium-90 (90Y)-resin microspheres can prolong intrahepatic disease control and improve overall survival (OS) in patients with metastatic colorectal cancer (CRC). Prognostic factors for improved outcomes in patients undergoing selective internal radiation therapy (SIRT) have been studied, but the relationship between pre-SIRT liver tumor volume and outcomes has not well described. We retrospectively reviewed the records of patients with metastatic CRC who were treated at our institution with 90Y-resin microspheres. Each patient underwent either MR or CT imaging of the liver with intravenous (IV) contrast before and within ~2-3 months after SIRT. Imaging data were transferred into our treatment planning system. Each metastatic liver lesion was contoured, and the volume of each lesion was summed to determine the total liver tumor volume at a given time point. We evaluated whether pretreatment liver tumor volume was related to OS. We also evaluated the relationship between pre-SIRT tumor volume and radiographic treatment response by either unidimensional Response Evaluation Criteria in Solid Tumors (RECIST) or three-dimensional volumetric criteria. We included 60 patients with a median age of 59 years (range, 38-97 years); 60% of patients received sequential lobar treatment. The median number of chemotherapy cycles received prior to SIRT was 2. Median follow-up from first SIRT was 8.9 months. Pre- and post-SIRT tumor volumes were primarily calculated on CT (87%). The median pre-SIRT tumor volume was 77 cc (range, 4.5-2,170.4 cc). The median intervals between the first SIRT and the first, second, and third follow-up scans were 2.2, 4.4, and 7.7 months, respectively. No patient experienced a radiographic complete response. Pretreatment volume was a significant predictor for estimating the odds of a patient having stable disease or partial response using volumetric response criteria at first (P=0.016), second (P=0.023), and third (P=0.015) follow-ups. For each unit increase in log volume, a patient's odds of having a stable or partial response were 0.57, 0.63, and 0.61 times as likely at first, second, and third follow-up, respectively. OS was not significantly associated with pretreatment tumor volume. Patients with metastatic CRC with larger overall pretreatment liver tumor volumes, regardless of number of individual liver lesions, are less likely to have radiographic evidence of stable disease or partial response following SIRT using volumetric response criteria. However, pretreatment volume was not significantly associated with OS, and thus SIRT should be considered for patients with larger pretreatment volumetric tumor burden.

Molecular Targeting of Cytotoxic Radiosensitizing Chemotherapies

Resistance to radiotherapy is a significant barrier to improving outcomes of patients diagnosed with locally advanced cancers. The clinical utility of more potent radiosensitizers is curtailed by dose limiting toxicity. To provide a solution to these issues, we are developing antibody drug conjugates (ADC) to selectively deliver potent radiosensitizers to tumors based on cell surface receptor expression. We are testing the hypothesis that the therapeutic window of cetuximab, trastuzumab, and pertuzumab can be widened, by re-purposing their therapeutic task. Instead of being utilized as inhibitors of ErbB signaling for which resistance emerges from bypass signaling, we propose they be used as receptor targeted delivery vehicles for potent radiosensitizers. We synthesized theranostic ADC by conjugating ErbB antibodies to the potent anti-tubulin drug monomethyl auristatin E to create cetuximab-MMAE (C-MMAE), trastuzumab-MMAE (T-MMAE) and pertuzumab-MMAE (P-MMAE). Each ADC was labeled with Cy5 to allow for non-invasive monitoring in cell culture and murine models. Experiments were done in EGFR+ and HER2+ tumor cell lines of various histologies. Binding, functionality and toxicity of each ADC was measured by flow cytometry, confocal microscopy, cell cycle analysis and alamar blue assay. Radiosensitization was tested by neutral comet assays and clonogenic survival. For in vivo studies, tumor xenografts were grown subcutaneously in nude mice to > 100 mm3. ADC (0.25 nmoles) was given intravenously followed by focal IR (3 Gy x 3). Fluorescent imaging for Cy5 labeled ADC allowed for evaluation of tumor targeting and therapeutic efficacy was determined by tumor volume response. Statistical analysis was performed by ANOVA. In cell culture, the specificity/functionality of C-MMAE, T-MMAE, and P-MMAE was first tested. C-MMAE specifically bound to EGFR+ tumor cell lines (CAL-27, SCC-61, and A-549) and resulted in MMAE mediated G2/M arrest at 0.5-5 nM. In contrast, T-MMAE and P-MMAE bound selectively to HER2+ cells lines (OE-19, CALU-3, and BT-474). Importantly, while free MMAE decreased survival of all cell lines indiscriminately, ErbB antibody conjugation restricted MMAE toxicity and radiosensitization to EGFR+ cells or HER2+ cells in the 0.5 – 5 nM range, P < 0.05. At 20 nM, antibody alone was not tumoricidal and did radiosensitize EGFR+ or HER2+ tumor cells. In vivo, Cy5 imaging demonstrated C-MMAE localized to EGFR+ tumor xenografts (CAL27, SCC-61) while T-MMAE selectively accumulated in HER2+ OE19 tumor xenografts. Therapeutically, C-MMAE or T-MMAE and fractionated IR produced significant tumor growth delay when compared to IR and antibody alone, P < 0.01. Our studies demonstrate a potent ADC radiosensitization approach that is biomarker-driven and histology agnostic. We propose an alternative paradigm for ErbB radiosensitization, using tumor cell surface receptors as beacons for drug delivery, instead of as targets for signal inhibition.

Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy.

The validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response to sorafenib monotherapy in any cancer published until April 20, 2012. We estimated effect sizes from experiments assessing changes in tumor volume and conducted subgroup analyses based on prespecified experimental design elements associated with internal, construct, and external validity. The meta-analysis included 97 experiments involving 1,761 animals. We excluded 94 experiments due to inadequate reporting of data. Design elements aimed at reducing internal validity threats were implemented only sporadically, with 66% reporting animal attrition and none reporting blinded outcome assessment or concealed allocation. Anticancer activity against various malignancies was typically tested in only a small number of model systems. Effect sizes were significantly smaller when sorafenib was tested against either a different active agent or combination arm. Trim and fill suggested a 37% overestimation of effect sizes across all malignancies due to publication bias. We detected a moderate dose-response in one clinically approved indication, hepatocellular carcinoma, but not in another approved malignancy, renal cell carcinoma, or when data were pooled across all malignancies tested. In support of other reports, we found that few preclinical cancer studies addressed important internal, construct, and external validity threats, limiting their clinical generalizability. Our findings reinforce the need to improve guidelines for the design and reporting of preclinical cancer studies. Cancer Res; 76(16); 4627-36. ©2016 AACR.

Abstract 1470: Cancer treatment by near infrared photoimmunotherapy targeting intratumoral regulatory T cells

Abstract Introduction and Purpose: CD4+CD25+Foxp3+ regulatory T cells (Tregs) are known to suppress immune responses against cancers. Treg-mediated immunosuppression is a key mechanism for tumor immune-evasion, which could lead cancer immunotherapies to failures. Systemic depletion of Tregs have been tried by using antibodies against them; however, intravenously delivering these antibodies might not sufficiently deplete Tregs in the tumor microenvironment or could substantially deplete effector cells, in case anti-CD25 antibody was used. In addition, development of auto-immune responses could cause potential side effects. To overcome these problems, we exploited near infrared photoimmunotherapy (NIR-PIT) at the tumor to quickly deplete only intratumoral Tregs, aiming to induce anti-tumor immune activation. Experimental Design: F(ab’)2 fragments of an anti-mouse CD25 antibody, PC61.3, were generated and conjugated with a phthalocyanine dye, IRDye-700DX (αnti-CD25-F(ab’)2-IR700). Using the anti-CD25-F(ab’)2-IR700, in vitro NIR-PIT effect was examined against CD25-expressing mouse T lymphocytes, HT-2 clone A5E cells. In vivo CD25-target-NIR-PIT of the tumor was performed after an intravenous injection of the conjugate to mice bearing subcutaneous, luciferase transfected, LL/2 (Lewis lung carcinoma, LL/2-luc) or MC38 (mouse colon cancer, MC38-luc) cancers. Tumor volume, bioluminescence signals (BLI), and Immune responses following a local CD25-target-NIR-PIT were examined. Results: In vitro NIR-PIT-induced cytotoxicity was light dose dependent. CD25-target-NIR-PIT at the tumor quickly and selectively depleted Tregs in the cancers, yet, Tregs in any other organs were not affected. The local CD25-target-NIR-PIT induced a rapid activation and cytotoxic action of CD8 T cells and NK cells within LL/2-luc or MC38-luc tumors. This led to significant reductions of tumor volume (p &amp;lt; 0.0001) and BLI (p &amp;lt; 0.05) in both LL/2-luc and MC38-luc models and prolonged the survival of the mice (p &amp;lt; 0.0001) compared to the non-treated controls. Intriguingly, this local CD25-target-NIR-PIT induced a transient systemic cytokine storm and antitumor-effects on distant non-irradiated specific tumors. Effects of local CD25-target-NIR-PIT were significantly (p &amp;lt; 0.0001) inhibited by a CD8-, NK-, or INFγ−depletion, suggesting the anti-tumor roles of CD8 T cells and NK cells. Conclusions: Quick depletion of intratumoral Tregs by a local CD25-target-NIR-PIT rapidly induced CD8 T- and NK-cell activation, thereby restoring local anti-tumor immunity. Consequently, activated immunity led to regression of not only NIR-PIT-treated tumors but also non-NIR light exposed tumors in separate parts of the body. These observations suggest that using local CD25-target-NIR-PIT may be a promising new strategy for cancer immunotherapy. Citation Format: Kazuhide Sato, Noriko Sato, Biying Xu, Yuko Nakamura, Tadanobu Nagaya, Peter L. Choyke, Hisataka Kobayashi. Cancer treatment by near infrared photoimmunotherapy targeting intratumoral regulatory T cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1470.

Metabolic history impacts mammary tumor epithelial hierarchy and early drug response in mice.

The emerging links between breast cancer and metabolic dysfunctions brought forth by the obesity pandemic predict a disproportionate early disease onset in successive generations. Moreover, sensitivity to chemotherapeutic agents may be influenced by the patient's metabolic status that affects the disease outcome. Maternal metabolic stress as a determinant of drug response in progeny is not well defined. Here, we evaluated mammary tumor response to doxorubicin in female mouse mammary tumor virus-Wnt1 transgenic offspring exposed to a metabolically compromised environment imposed by maternal high-fat diet. Control progeny were from dams consuming diets with regular fat content. Maternal high-fat diet exposure increased tumor incidence and reduced tumor latency but did not affect tumor volume response to doxorubicin, compared with control diet exposure. However, doxorubicin-treated tumors from high-fat-diet-exposed offspring demonstrated higher proliferation status (Ki-67), mammary stem cell-associated gene expression (Notch1, Aldh1) and basal stem cell-like (CD29(hi)CD24(+)) epithelial subpopulation frequencies, than tumors from control diet progeny. Notably, all epithelial subpopulations (CD29(hi)CD24(+), CD29(lo)CD24(+), CD29(hi)CD24(+)Thy1(+)) in tumors from high-fat-diet-exposed offspring were refractory to doxorubicin. Further, sera from high-fat-diet-exposed offspring promoted sphere formation of mouse mammary tumor epithelial cells and of human MCF7 cells. Untargeted metabolomics analyses identified higher levels of kynurenine and 2-hydroxyglutarate in plasma of high-fat diet than control diet offspring. Kynurenine/doxorubicin co-treatment of MCF7 cells enhanced the ability to form mammosphere and decreased apoptosis, relative to doxorubicin-only-treated cells. Maternal metabolic dysfunctions during pregnancy and lactation may be targeted to reduce breast cancer risk and improve early drug response in progeny, and may inform clinical management of disease.