Improve Chemotherapy Delivery Research Articles

Modulation of blood-tumor barrier transcriptional programs improves intra-tumoral drug delivery and potentiates chemotherapy in GBM.

Glioblastoma (GBM) is the most common malignant primary brain tumor. GBM has an extremely poor prognosis and new treatments are badly needed. Efficient drug delivery to GBM is a major obstacle as the blood-brain barrier (BBB) prevents passage of the majority of cancer drugs into the brain. It is also recognized that the blood-brain tumor barrier (BTB) in the growing tumor represents a challenge. The BTB is heterogeneous and poorly characterized, but similar to the BBB it can prevent therapeutics from reaching effective intra-tumoral doses, dramatically hindering their potential. Here, we identified a 12-gene signature associated with the BTB, with functions related to vasculature development, morphogenesis and cell migration. We identified CDH5 as a core molecule in this set and confirmed its over-expression in GBM vasculature using spatial transcriptomics of GBM patient specimens. We found that the indirubin-derivative, 6-bromoindirubin acetoxime (BIA), could downregulate CDH5 and other BTB signature genes, causing endothelial barrier disruption in endothelial monolayers and BBB 3D spheroids in vitro. Treatment of tumor-bearing mice with BIA enabled increased intra-tumoral accumulation of the BBB non-penetrant chemotherapeutic drug cisplatin and potentiated cisplatin-mediated DNA damage by targeting DNA repair pathways. Finally, using an injectable BIA nanoparticle formulation, PPRX-1701, we significantly improved the efficacy of cisplatin in patient-derived GBM xenograms and prolonged their survival. Overall, our work reveals potential targets at the BTB for improved chemotherapy delivery and the bifunctional properties of BIA as a BTB modulator and potentiator of chemotherapy, supporting its further development.

Neo-train: study protocol and feasibility results for a two-arm randomized controlled trial investigating the effect of supervised exercise during neoadjuvant chemotherapy on tumour response in patients with breast cancer

BackgroundPrehabilitation with exercise interventions during neoadjuvant chemotherapy (NACT) is effective in reducing physical and psychosocial chemotherapy-related adverse events in patients with cancer. In preclinical studies, data also support a growth inhibitory effect of aerobic exercise on the tumour microenvironment with possible improved chemotherapy delivery but evidence in human patients is limited. The aim of the study here described is to investigate if supervised exercise with high-intensity aerobic and resistance training during NACT can improve tumour reduction in patients with breast cancer.MethodsThis parallel two-armed randomized controlled trial is planned to include 120 women aged ≥ 18 years with newly diagnosed breast cancer starting standard NACT at a university hospital in Denmark (a total of 90 participants needed according to the power calculation and allowing 25% (n = 30) dropout). The participants will be randomized to usual care or supervised exercise consisting of high-intensity interval training on a stationary exercise bike and machine-based progressive resistance training offered three times a week for 24 weeks during NACT, and screening-based advice to seek counselling in case of moderate-severe psychological distress (Neo-Train program). The primary outcome is tumour size change (maximum diameter of the largest lesion in millimetre) measured by magnetic resonance imaging prior to surgery. Secondary outcomes include clinical/pathological, physical and patient-reported measures such as relative dose intensity of NACT, hospital admissions, body composition, physical fitness, muscle strength, health-related quality of life, general anxiety, depression, and biological measures such as intratumoural vascularity, tumour infiltrating lymphocytes, circulating tumour DNA and blood chemistry. Outcomes will be measured at baseline (one week before to 1–2 weeks after starting NACT), during NACT (approximately week 7, 13 and 19), pre-surgery (approximately week 21–29), at surgery (approximately week 21–30) and 3 months post-surgery (approximately 33–42 weeks from baseline).DiscussionThis study will provide novel and important data on the potential benefits of supervised aerobic and resistance exercise concomitant to NACT on tumour response and the tumour microenvironment in patients with breast cancer, with potential importance for survival and risk of recurrence. If effective, our study may help increase focus of exercise as an active part of the neoadjuvant treatment strategy.Trial registrationThe trial was registered at ClinicalTrials.gov (NCT04623554) on November 10, 2020.

Active bone marrow-sparing to reduce the incidence of grade 3+ acute hematologic toxicity in patients with locally advanced cervical cancer who receive chemoradiotherapy: A single-center prospective randomized controlled trial.

5524 Background: Acute haematologic toxicity is the most common side effect of chemoradiotherapy in patients with locally advanced cervical cancer .We aim to test the efficacy of single-photon emission computed tomography-defined active bone marrow-sparing volumetric-modulated arc therapy in reducing grade 3+ acute hematologic toxicity (HT) in locally advanced cervical cancer patients treated with chemoradiotherapy. Methods: This was a prospective, single-center, open label, randomized clinical trial that enrolled locally advanced cervical cancer patients. Participants were randomized to the 99mTc sulfur colloid SPECT-defined ABMS VMAT (ABMS group) or control group, who received weekly cisplatin concurrently with volumetric-modulated arc therapy followed by high-dose-rate intracavitary brachytherapy. The ABMS group additionally received SPECT-defined ABM dose constraints. The primary endpoint was the incidence of grade 3+ acute hematologic toxicity.Secondary objectives included acute gastrointestinal toxicity, planning Target Volume (PTV) coverage, dosimetric parameters of organs at risk (OARs), progression-free survival (PFS), overall survival (OS). Results: A total of 192 FIGO stage IB-IIIB patients were randomized treated (96 each in the ABMS control groups). The median follow-up was 24.0 months. The incidence of grade 3+ acute hematologic toxicity in the ABMS group was significantly lower than that in the control group (32.3% vs 53.1%, p<0.01). The number of patients completing five cycles of cisplatin was 88.5% in the ABMS group and 75% in the control group, and the difference was significant (p=0.02). There were no significant differences in the mean dose to 95%, 97% and 99%of the PTV between the ABMS group (45.1 Gy, 44.6 Gy, and 43.3 Gy, respectively) and the control group (45.4 Gy, 44.8 Gy, and 43.6 Gy). There were no differences in dosimetric parameters of OARs ,acute gastrointestinal toxicity, 2-year PFS or 2-year OS between the two groups. Patients in the control group had nonsignificantly worse 2-year distant metastasis than patients in the ABMS group (17.8% vs. 11.1%, p=0.19). Conclusions: ABMS VMAT significantly reduced grade 3+ acute HT and improved chemotherapy delivery compared with the control treatment. We found weak evidence of the effect of ABMS VMAT on distant metastasis. Clinical trial information: ChiCTR-IOR-16010214 .

Pre-treatment levels of inflammatory markers and chemotherapy completion rates in patients with early-stage breast cancer.

Chemotherapy efficacy is largely dependent on treatment adherence, defined by the relative dose intensity (RDI). Identification of new modifiable risk factors associated with low RDI might improve chemotherapy delivery. Here, we evaluated the association between low RDI and pre-chemotherapy factors, including patient- and treatment-related characteristics and markers of inflammation. This exploratory analysis assessed data from 267 patients with early-stage breast cancer scheduled to undergo (neo-)adjuvant chemotherapy included in the Physical training and Cancer (Phys-Can) trial. The association between low RDI, defined as < 85%, patient-related (age, body mass index, co-morbid condition, body surface area) and treatment-related factors (cancer stage, receptor status, chemotherapy duration, chemotherapy dose, granulocyte colony-stimulating factor) was investigated. Analyses further included the association between RDI and pre-chemotherapy levels of interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP) and Tumor Necrosis Factor-alpha (TNF-α) in 172 patients with available blood samples. An RDI of < 85% occurred in 31 patients (12%). Univariable analysis revealed a significant association with a chemotherapy duration above 20weeks (p < 0.001), chemotherapy dose (p = 0.006), pre-chemotherapy IL-8 (OR 1.61; 95% CI (1.01; 2.58); p = 0.040) and TNF-α (OR 2.2 (1.17; 4.53); p = 0.019). In multivariable analyses, inflammatory cytokines were significant association with low RDI for IL-8 (OR: 1.65 [0.99; 2.69]; p = 0.044) and TNF-α (OR 2.95 [1.41; 7.19]; p = 0.007). This exploratory analysis highlights the association of pre-chemotherapy IL-8 and TNF-α with low RDI of chemotherapy for breast cancer. IL-8 and TNF-α may therefore potentially help to identify patients at risk for experiencing dose reductions. Clinical trial number NCT02473003 (registration: June 16, 2015).

SPECT-defined, active bone marrow–sparing, volumetric-modulated arc therapy reduces the incidence of acute hematologic toxicity in patients with locally advanced cervical cancer who receive chemoradiotherapy.

5527 Background: Acute haematologic toxicity is the most common side effect of chemoradiotherapy in patients with locally advanced cervical cancer.We are aim to test the efficacy of defined active bone marrow sparing volumetric-modulated arc therapy reduces grade 3 or higher (grade 3+) acute haematologic toxicity for patients with locally advanced cervical cancer treated with chemoradiotherapy. Methods: This was a prospective, single-center, open label, randomized clinical trial that enrolled locally advanced cervical cancer.Patients were randomized to 99mTc sulfur colloid SPECT-defined active bone marrow sparing volumetric-modulated arc therapy group (ABMS group) or control group.The control group received weekly cisplatin concurrently with volumetric-modulated arc therapy(VMAT),followed by high-dose-rate intracavitary brachytherapy. The active bone marrow sparing volumetric-modulated arc therapy group additionally received 99mTc sulfur colloid SPECT-defined active bone marrow dose constrain. The primary endpoint was the incidence of grade 3 or higher (grade 3+) acute haematologic toxicity. Secondary objectives included acute gastrointestinal toxicity, planning Target Volume (PTV) coverage and dosimetric parameters of organs at risk(OARs). Results: A total of 148 patients with Federation of Gynaecology and Obstetrics(FIGO) stage IB-IIIB fromJanuary 2017 to April 2019 were randomized，and 146 were treated(74 in ABMS group and 74 in control group). The median follow-up was 20.0 months.The incidence of grade 3 or higher (grade 3+) acute haematologic toxicity in the ABMS group was 29.7%,significantly lower than the 48.6% incidence in the control group(p = 0.03).The incidence of grade 3+ neutropenia (ABMS group：20.3%,control group:36.5%;p = 0.04), Grade 3+ leukopenia (ABMS group：25.7%,control group:44.6%;p = 0.02) and Grade 3+ lymphopenia (ABMS group：4.1%,control group:14.9%;p = 0.04) were significantly differences between the two group.The were no differences in Grade 3+ anemia (ABMS group：1.4%,control group:5.5%;p = 0.37) and Grade 3+ acute gastrointestinal toxicity(ABMS group：1.4%,control group:1.4%;p = 1.00) between the two group.The number of patients completing five cycles of cisplatin in the ABMS group was 88.5%,,significantly higher than the 75% in the control group(p = 0.02).There were no differences in PTV coverage and dosimetric parameters of OARs between the two group. Conclusions: SPECT-defined active bone marrow sparing VMAT signifificantly reduced grade 3+ acute haematologic toxicity,and improved chemotherapy delivery compared with control group. Clinical trial information: ChiCTR-IOR-16010214.

Letter to the Editor on: "The Effects of Physical Exercise on Tumor Vasculature: Systematic Review and Meta-Analysis."

Dear Editor,We read with interest the recent article "The Effects of Physical Exercise on Tumor Vasculature: Systematic Review and Meta-analysis" 1 and after careful appraisal and consideration we feel that some aspects of the data and analysis warrant further review. The study reported some promising results, namely that both chronic and acute exercise appear to improve intratumoral vascularisation in animal models. This is an important finding given increased vascularisation through tumor modulation may have the potential to improve chemotherapy delivery and efficacy 2. However, after conducting further investigations, we query several details in the data extraction and analysis decision-making that we believe impact the conclusions of this article.

Neoadjuvant Therapy Is Associated with Improved Chemotherapy Delivery and Overall Survival Compared to Upfront Resection in Pancreatic Cancer without Increasing Perioperative Complications.

Simple SummaryThe role of neoadjuvant therapy in pancreatic cancer is poorly defined. Our results show improved overall survival in patients who received neoadjuvant therapy, driven by improved chemotherapy delivery, with no apparent increase in early or late perioperative complications.The role of neoadjuvant chemoradiotherapy and/or chemotherapy (neoCHT) in patients with pancreatic ductal adenocarcinoma (PDAC) is poorly defined. We hypothesized that patients who underwent neoadjuvant therapy (NAT) would have improved systemic therapy delivery, as well as comparable perioperative complications, compared to patients undergoing upfront resection. This is an IRB-approved retrospective study of potentially resectable PDAC patients treated within an academic quaternary referral center between 2011 and 2018. Data were abstracted from the electronic medical record using an institutional cancer registry and the National Surgical Quality Improvement Program. Three hundred and fourteen patients were eligible for analysis and eighty-one patients received NAT. The median overall survival (OS) was significantly improved in patients who received NAT (28.6 vs. 20.1 months, p = 0.014). Patients receiving neoCHT had an overall increased mean duration of systemic therapy (p < 0.001), and the median OS improved with each month of chemotherapy delivered (HR = 0.81 per month CHT, 95% CI (0.76–0.86), p < 0.001). NAT was not associated with increases in early severe post-operative complications (p = 0.47), late leaks (p = 0.23), or 30–90 day readmissions (p = 0.084). Our results show improved OS in patients who received NAT, driven largely by improved chemotherapy delivery, without an apparent increase in early or late perioperative complications compared to patients undergoing upfront resection.

Cerebral microcirculation in glioblastoma: A major determinant of diagnosis, resection, and drug delivery.

Glioblastoma (GBM) is the most common primary brain tumor with a dismal prognosis. Current standard of treatment is safe maximal tumor resection followed by chemotherapy and radiation. Altered cerebral microcirculation and elevated blood-tumor barrier (BTB) permeability in tumor periphery due to glioma-induced vascular dysregulation allow T1 contrast-enhanced visualization of resectable tumor boundaries. Newer tracers that label the tumor and its vasculature are being increasingly used for intraoperative delineation of glioma boundaries for even more precise resection. Fluorescent 5-aminolevulinic acid (5-ALA) and indocyanine green (ICG) are examples of such intraoperative tracers. Recently, magnetic resonance imaging (MRI)-based MR thermometry is being employed for laser interstitial thermal therapy (LITT) for glioma debulking. However, aggressive, fatal recurrence always occurs. Postsurgical chemotherapy is hampered by the inability of most drugs to cross the blood-brain barrier (BBB). Understanding postsurgical changes in brain microcirculation and permeability is crucial to improve chemotherapy delivery. It is important to understand whether any microcirculatory indices can differentiate between true recurrence and radiation necrosis. LITT leads to peri-ablation BBB opening that persists for several weeks. Whether it can be a conduit for chemotherapy delivery is yet to be explored. This review will address the role of cerebral microcirculation in such emerging ideas in GBM diagnosis and therapy.

Rapid stromal remodeling by short-term VEGFR2 inhibition increases chemotherapy delivery in esophagogastric adenocarcinoma.

Anti‐angiogenic agents combined with chemotherapy is an important strategy for the treatment of solid tumors. However, survival benefit is limited, urging the improvement of combination therapies. We aimed to clarify the effects of vascular endothelial growth factor receptor 2 (VEGFR2) targeting on hemodynamic function and penetration of drugs in esophagogastric adenocarcinoma (EAC). Patient‐derived xenograft (PDX) models of EAC were subjected to long‐term and short‐term treatment with anti‐VEGFR2 therapy followed by chemotherapy injection or multi‐agent dynamic contrast‐enhanced (DCE‐) MRI and vascular casting. Long‐term anti‐VEGFR2‐treated tumors showed a relatively lower flow and vessel density resulting in reduced chemotherapy uptake. On the contrary, short‐term VEGFR2 targeting resulted in relatively higher flow, rapid vasodilation, and improved chemotherapy delivery. Assessment of the extracellular matrix (ECM) revealed that short‐term anti‐angiogenic treatment drastically remodels the tumor stroma by inducing nitric oxide synthesis and hyaluronan degradation, thereby dilating the vasculature and improving intratumoral chemotherapy delivery. These previously unrecognized beneficial effects could not be maintained by long‐term VEGFR2 inhibition. As the identified mechanisms are targetable, they offer direct options to enhance the treatment efficacy of anti‐angiogenic therapy combined with chemotherapy in EAC patients.

SCIDOT-02. A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN (ONIVYDE) USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS: RESULTS THUS FAR

Abstract BACKGROUND Chemotherapy for high grade gliomas (HGG) is limited by the blood-brain-barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal-irinotecan (Onivyde) showed to be a superior delivery route for anti-tumor activity in animal models. An advance of this trial is the development and use of real time CED, which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents, monitoring delivery into the brain and affording for corrective action. METHODS This is a 3 + 3 single dose escalation trial with 2 cohorts: 20mg/ml and 40mg/ml. Onivyde and GAD were co-infused via the same catheters in a one-time delivery. The total dose was personalized based on the patient’s tumor volume, and ranged from 20–680 mg of Onivyde, given via up to 4 catheters. Tumor diameters were allowed to be 1 – 4 cm, with injection volumes ranging from 2 – 17 mL of infusate. RESULTS 13 patients have been treated on this protocol, all in under 5 hours. There were 9 GBs, 1 gliosarcoma, 2 AAs, and 1 oligoastrocytoma. Utilizing imaging software, we correlated pre-infusion modeling of the drug distribution with post-infusion imaging. A number of technical challenges were overcome by real time monitoring; the total volume of distribution (Vd), and the Vd to volume infused (Vi) ratio for each infusion was ~2. Of all patients, the only notable AE was encephalopathy, which was resolved. CONCLUSIONS Image-guided distribution allows for safe real-time placement and adjustment of CED cannula of Onivyde into patient’s brains. Such methods allow for maximum tumor coverage and warrant further studies with repeat dosing.

Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma.

Recent studies in mouse models of cancer have shown that exercise improves tumor vascular function, thereby improving chemotherapy delivery and efficacy. However, the mechanisms underlying this improvement remain unclear and the effect of exercise on Ewing sarcoma (ES), a pediatric bone and soft tissue cancer, is unknown. The effect of exercise on tumor vascular hyperpermeability, which inversely correlates with drug delivery to the tumor, has also not been evaluated. We hypothesized that exercise improves chemotherapy efficacy by enhancing its delivery through improving tumor vascular permeability. We treated ES-bearing mice with doxorubicin with or without moderate treadmill exercise. Exercise did not significantly alter ES tumor vessel morphology. However, compared to control mice, tumors of exercised mice had significantly reduced hyperpermeability, significantly decreased hypoxia, and higher doxorubicin penetration. Compared to doxorubicin alone, doxorubicin plus exercise inhibited tumor growth more efficiently. We evaluated endothelial cell sphingosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) as potential mediators of the improved vascular permeability and increased function afforded by exercise. Relative to tumors from control mice, vessels in tumors from exercised mice had increased S1PR1 and decreased S1PR2 expression. Our results support a model in which exercise remodels ES vasculature to reduce vessel hyperpermeability, potentially via modulation of S1PR1 and S1PR2, thereby improving doxorubicin delivery and inhibiting tumor growth more than doxorubicin alone does. Our data suggest moderate aerobic exercise should be tested in clinical trials as a potentially useful adjuvant to standard chemotherapy for patients with ES.

ACTR-67. A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN (ONIVYDE) USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS: RESULTS THUS FAR

BACKGROUND Chemotherapy for high grade gliomas (HGG) is limited by the blood-brain-barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal-irinotecan (Onivyde) showed to be a superior delivery route for anti-tumor activity in animal models. An advance of this trial is the development and use of real time CED, which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents, monitoring delivery into the brain and affording for corrective action.

Study protocol for a controlled trial of an eHealth system utilising patient reported outcome measures for personalised treatment and care: PROMPT-Care 2.0

BackgroundRoutine assessment and clinical utilisation of patient-reported outcome (PRO) measures can lead to improved patient outcomes. The PROMPT-Care eHealth system facilitates PRO data capture from cancer patients, data linkage and retrieval to support clinical decisions, patient self-management, and shared care. Pilot testing demonstrated acceptability and feasibility of PROMPT-Care Version 1.0. This study aims to implement PROMPT-Care Version 2.0 and determine its efficacy in reducing emergency department (ED) presentations, and improving chemotherapy delivery and health service referrals, compared to usual care.MethodsGroups eligible to participate in the intervention arm of this controlled trial are patients receiving cancer care (including follow-up). PROMPT-Care patients will complete monthly assessments (distress, symptoms, unmet needs) until voluntary withdrawal or death. In Version 1.0, the care team accessed patients’ clinical feedback reports in ‘real time’ to guide their care, and patients received links to support their self-management, tailored to their PRO responses. Version 2.0 was extended to include: i) an additional alert system notifying the care team of ongoing unresolved clinical issues, ii) patient self-management resources, and iii) an auto-populated Treatment Summary and Survivorship Care Plan (SCP). The control population will be patients extracted from hospital databases of the general cancer patient population who were seen at the participating cancer therapy centres during the study period, with a ratio of 1:4 of intervention to control patients.A minimum sample size of 1760 (352 intervention and 1408 control) patients will detect a 14% reduction in the number of ED presentations (primary outcome) in the PROMPT-Care group compared with the control group. Intervention patients will provide feedback on system usability and value of the self-management materials; oncology staff will provide feedback on usefulness of PROMPT-Care reports, response to clinical alerts, impact on routine care, and usefulness of the SCPs; and GPs will provide feedback on the usefulness of the SCPs and attitudes towards shared-care models of survivorship care planning.DiscussionThis study will inform the PROMPT-Care system’s impact on healthcare utilisation and utility as an alternative model for ongoing supportive care.Trial registrationAustralian New Zealand Clinical Trials Registry (ACTRN12616000615482) on 12th May 2016 (www.anzctr.org.au).

Abstract 5281: An exercise intervention for pancreas cancer patients increases tumor vascularity

Abstract We and others have demonstrated in mice that moderate aerobic exercise remodels tumor vasculature and improves chemotherapy delivery. The sparse, dysfunctional vasculature in pancreatic ductal adenocarcinoma (PDAC) is one major barrier to delivering chemotherapy to the tumor. Improved vascular function and chemotherapy delivery could substantially improve patient survival over the current 7% rate. We first evaluated whether exercise might improve survival for patients with PDAC using a patient-derived xenograft (PDX) mouse model and moderate treadmill running. Treatment of PDX-bearing mice with gemcitabine or gemcitabine plus exercise caused tumor regression. However, gemcitabine was more effective when combined with exercise and excitingly, regrowth of tumors after treatment cessation was significantly delayed in mice treated with exercise combined with gemcitabine compared to gemcitabine alone. Our animal data suggests that exercise may be beneficial for patients with pancreatic cancer. However, it is unclear whether a sufficient level of exercise can be performed by patients with advanced cancers to achieve improved vascular function as predicted by animal studies. Recently, we completed a pilot study delivering a home-based aerobic and strength training exercise program (EP) to patients with potentially operable pancreas cancer. Fifty-eight patients (48% female, median age 66) completed the EP concurrent with chemotherapy or chemoradiation over a mean duration of 15 weeks prior to pancreatectomy. Participants completed a mean of 145.8 minutes of weekly moderate to vigorous physical activity. Surgical tumor specimens were obtained from 28 patients who participated in the EP, and were evaluated for the total number of vessels, vessel density, average number of open lumens, and number of elongated vessels. We found that tumors of patients who participated in the EP had significantly increased vessel density and a significantly increased number of elongated vessels compared to tumors from control patient, similar to our observations in mice. This is the first demonstration that an EP is feasible during the chemotherapy/ chemoradiation phases for pancreatic cancer patients, and importantly, that moderate exercise changes human tumor vascular biology. There was also a trend toward increased immune cell infiltration in tumors from patients who exercised. Cell death in tumors is being evaluated. This data suggests that exercise is a low-cost, low risk way to remodel human tumor vasculature and therefore may be an adjuvant to chemotherapy. Remodeled vasculature may increase chemotherapy delivery to the tumor, improving survival, as predicted in animal models. Further studies evaluating the impact of exercise on patient outcome as well as angiogenic biomarkers are underway. Citation Format: Claudia Alvarez Florez, Nathan Parker, Matthew Katz, An Ngo-Huang, Carol Ferreira Cardoso, Huamin Wang, Maria Petzel, David Fogelman, Keri Schadler. An exercise intervention for pancreas cancer patients increases tumor vascularity [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 5281.

Phase III randomized trial of image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT) for locoregionally advanced cervical cancer: The INTERTECC-3 trial.

TPS5600 Background: Cervical cancer is a leading cause of cancer death in women worldwide. Image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT) has shown potential to reduce acute toxicity of chemoradiotherapy and improve chemotherapy delivery in phase I and II trials (Mell LK, Sirák I, Wei L, et al. Bone Marrow-sparing IMRT With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2). Int J Radiat Oncol Biol Phys 2017;97:536-545. Mell LK, Saenz CC, Yashar CM, et al. Phase I Trial of Bone Marrow Sparing IMRT With Concurrent Cisplatin and Gemcitabine in Stage IB-IVA Cervical Cancer (abstr.) Int J Radiat Oncol Biol Phys 2016; 96: S14.). Methods: INTERTECC-3 is a randomized phase III trial designed to test the effect of IG-BMS-IMRT on progression-free survival (PFS) for women with unresected FIGO stage IB-IVA cervical carcinoma (clinicaltrials.gov #NCT01554397). It presently involves centers in the U.S., Czech Republic, U.K., India, Japan, and China. Women are randomized 3:2 to either (A) IG-BMS-IMRT or (B) standard chemoradiation, with 6 cycles of concurrent cisplatin (40 mg/m2) weekly in both arms. Secondary objectives are to compare overall survival, treatment-related toxicity, disease recurrence, quality of life, chemotherapy delivery, and radiation quality assurance. Planning objectives require maintaining pelvic marrow and active marrow mean doses &lt; 27 Gy and &lt; 28.5 Gy respectively. Correlative studies involve longitudinal collection of magnetic resonance restriction spectrum imaging and 18F-fluorothydimine positron emission tomography scans to assess imaging biomarkers of treatment response in select patients. 415 women will be enrolled to determine if IG-BMS-IMRT improves the median PFS from 3.2 to 5.0 years with 80% power and alpha = 0.05. INTERTECC-3 opened in the U.S. and Czech Republic in 2016. To date, 17 patients have been randomized. The trial will be activated at additional international sites in late 2017 and 2018. We are seeking to recruit sites who wish to collaborate. Clinical trial information: NCT01554397.

Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy.

Targeted therapies aimed at tumor vasculature are utilized in combination with chemotherapy to improve drug delivery and efficacy after tumor vascular normalization. Tumor vessels are highly disorganized with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel and normalize tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Recently, moderate aerobic exercise has been shown to induce vascular normalization in mouse models. Here, we provide a mechanistic explanation for the tumor vascular normalization induced by exercise. Shear stress, the mechanical stimuli exerted on endothelial cells by blood flow, modulates vascular integrity. Increasing vascular shear stress through aerobic exercise can alter and remodel blood vessels in normal tissues. Our data in mouse models indicate that activation of calcineurin-NFAT-TSP1 signaling in endothelial cells plays a critical role in exercise-induced shear stress mediated tumor vessel remodeling. We show that moderate aerobic exercise with chemotherapy caused a significantly greater decrease in tumor growth than chemotherapy alone through improved chemotherapy delivery after tumor vascular normalization. Our work suggests that the vascular normalizing effects of aerobic exercise can be an effective chemotherapy adjuvant.

A phase I study of convection-enhanced delivery of nanoliposomal irinotecan using real-time imaging in patients with recurrent high grade glioma.

TPS2081 Background: Cytotoxic drug delivery to high grade glioma (HGG) is limited by the blood brain barrier (BBB). Convection-enhanced delivery (CED) improves chemotherapy delivery by utilizing fl...

AT-25 * A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

BACKGROUND: Chemotherapy for high grade glioma (HGG) is limited by the blood brain barrier. Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal irinotecan (MM-398) has been optimized in animal models and shows superior anti-tumor activity. An advance in the use of CED is the development of real time CED (RCD), which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents and thus monitor delivery into the brain and to take corrective action. METHODS: With support from an R21 we're conducting a phase I study of CED of liposomal-irinotecan using real-time imaging in patients with recurrent HGG. This is a 3 + 3 dose escalation trial; dose levels are 20 mg, 40 mg, 60 mg, and 80 mg liposomal-irinotecan, given via up to 3 catheters surgically placed in an intra-tumoral location. Concentration of gadoteridol will be 2 mM for all groups; both agents will be co-infused via the same catheters. Subjects in the two lowest dose groups will have tumor volumes of 1-4 cm3, the third dose group will be 2-5 cm3 and the highest dose group 2-6 cm3. Maximum total volume infused will be 1.0 ml for two lowest dose groups, 1.5 ml for the third dose group, and 2.0 ml for the highest dose group. RESULTS: Interim safety, efficacy, and imaging response results will be presented. Utilizing imaging software, we'll present the correlation of pre-infusion modeling of the drug distribution with post-infusion imaging and determination of the total volume of distribution (Vd) and the Vd to volume infused (Vi) ratio for each infusion. CONCLUSIONS: Image-guided distribution allows for real-time placement and adjustment of cannula for real time CED of MM-398 into the brains of patients with recurrent HGG.

Tumor Vessel Normalization by Chloroquine Independent of Autophagy

Chloroquine (CQ) has been evaluated as an autophagy blocker for cancer treatment, but it is unknown if it acts solely by inhibiting cancer cell autophagy. We report that CQ reduced tumor growth but improved the tumor milieu. By normalizing tumor vessel structure and function and increasing perfusion, CQ reduced hypoxia, cancer cell invasion, and metastasis, while improving chemotherapy delivery and response. Inhibiting autophagy in cancer cells or endothelial cells (ECs) failed to induce such effects. CQ's vessel normalization activity relied mainly on alterations of endosomal Notch1 trafficking and signaling in ECs and was abrogated by Notch1 deletion in ECs invivo. Thus, autophagy-independent vessel normalization by CQ restrains tumor invasion and metastasis while improving chemotherapy, supporting the use of CQ for anticancer treatment.

A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA

BACKGROUND: Chemotherapy for high grade glioma (HGG) is limited by poor activity of available agents and compromised delivery across the blood brain barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection established as a result of a pressure gradient, obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal irinotecan (MM-398) has been optimized in rat, dog, and primate models. A recent study in mice with intracranial glioblastoma xenografts compared routes of delivery for liposomal irinotecan by CED or IV and showed superior anti-tumor activity of CED. A major clinical advance in the use of CED over recent trials is the development of real time CED (RCD), which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents and thus monitor delivery into the brain and to take corrective action for technical complexities. METHODS: With support from an R21 we will conduct the first in human phase I study of CED of liposomal-irinotecan using real-time imaging with gadolinium in patients with recurrent HGG. This is a single center, prospective, 3 + 3 dose escalating, single-arm, phase I trial with a four-level dose escalation, expecting to enroll at least 3 patients in each level and expanding the highest level to 12 patients total. Dose levels are 20 mg, 40 mg, 60 mg, and 80 mg liposomal-irinotecan, given via up to 3 catheters surgically placed in an intra-tumoral (IT) location. Concentration of gadoteridol will be 2 mM for all dose groups; both agents will be combined and co-infused via the same catheters. Subjects in the two lowest dose groups will have tumor volumes of 1-4 cm3, the third dose group will be 2-5 cm3 and the highest dose group will have tumor volume 2-6 cm3. Maximum total volume infused will be 1.0 ml for two lowest dose groups, 1.5 ml for the third dose group, and 2.0 ml for the highest dose group. RESULTS: Interim safety, efficacy, and imaging response results will be presented. Utilizing imaging software, we'll present the correlation of pre-infusion modeling of the drug distribution with post-infusion imaging and determination of the total volume of distribution (Vd) and the Vd to volume infused (Vi) ratio for each infusion. CONCLUSIONS: Image-guided distribution allows for real-time placement and adjustment of cannula for real time CED of MM-398 into the brains of patients with recurrent HGG. SECONDARY CATEGORY: Imaging.