Oncological Regimens Research Articles

Harmonizing cancer care delivery for AYAs with osteosarcoma: Comparison of pediatric and medical oncology approaches in a single center.

10039 Background: Osteosarcoma (OS) has a peak incidence amongst adolescents and young adults (AYA). Nuances in chemotherapeutic regimens are largely influenced by the training of pediatric or medical oncologists. MAP is the standard chemotherapy regimen used by pediatric oncologists. Chemotherapy regimens used by medical oncologists vary; our center uses preoperative doxorubicin/cisplatin (AP) followed by either doxorubicin/ifosfamide (AI) or a combination of HD methotrexate and HD ifosfamide. We undertook this analysis to characterize the treatment response, toxicity, and survival outcomes for AYAs with OS treated with pediatric vs medical oncology regimens as an initial step towards harmonizing our institutional approach to the treatment of AYA patients with bone sarcomas. Methods: We retrospectively reviewed the records of AYAs with OS receiving primary treatment at our center. Clinicopathologic characteristics and outcomes for patients treated with MAP vs. AP+ were compared. Progression-free survival (PFS) was defined as the time from either MAP/AP+ initiation or surgery to the time of first recurrence or death. Overall survival was defined as the time from MAP/AP+ initiation or surgery to death. The distributions of PFS and overall survival were estimated by the Kaplan-Meier method. Log-rank test was performed to test the difference in survival between groups. Regression analyses of survival data based on the Cox proportional hazard (PH) model were conducted on the time to event outcomes. Results: Between 2016-2022, 209 OS patients were seen at our center for initial diagnosis and treatment recommendations including 124 AYAs (59%). Amongst AYAs, 41 patients (median age 22y, range 14-38y) initiated and received the majority of their chemotherapy at our center and were included in analysis. Of the 41 AYAs, 17 were treated on MAP; 24 were treated using AP+. Ten patients < 20 years received MAP; one patient >30 years received MAP. The median time from initiation of therapy to surgery for those receiving MAP was 87.5 days vs 95.5 days for AP (p = 0.0052). Percent tumor necrosis varied widely with both regimens (range 0-99%) and was not statistically different (p = 0.11). There was no statistically significant difference in PFS between AYAs treated with MAP as compared to AP+ (Three-year PFS rates 80% vs 66%, p = 0.40). Evaluation of treatment related toxicity and late effects is ongoing. Conclusions: We had insufficient data to compare survival outcomes in this limited retrospective series. This limited retrospective study did not show a statistically significant difference in PFS for AYA patients with OS treated with a standard pediatric vs. adult type regimen containing at least 3-drug chemotherapy. Further study is needed to refine treatment for this patient population. These data support prospective efforts to harmonize AYA treatment paradigms in osteosarcoma.

Modelling chemotherapy-induced cardiotoxicity with live myocardial slices: from bedside to bench and back again

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Netherlands Heart Institute & Dutch Heart Foundation (Dekker Senior Clinical Scientist 2019) Introduction Cancer therapy related cardiac dysfunction (CTRCD) is a common side-effect of many oncological regimens. The prevention, diagnosis and treatment of CTRCD requires a well-orchestrated management by a multidisciplinary team composed by oncologists, cardiologists, radiologists, but less often translational scientists. Purpose In this work, we investigated the translational potential of live myocardial slices derived from a patient presenting with acute biventricular failure, with no history of cardiovascular disease, who had previously received neo-adjuvant chemotherapy containing doxorubicin (240 mg/m2) and trastuzumab, for the treatment of a breast carcinoma. In contrast to anthracycline cardiotoxicity, which is often permanent, cardiac dysfunction caused by trastuzumab is commonly reversible after cessation of treatment. Herein, we provide a novel side-by-side comparison of myocardial function ex vivo and clinical outcomes in the patient. Methods After several days on extracorporeal life support and inotropic therapy, the patient’s cardiac function did not improve. The patient was ultimately implanted with a left- and right-ventricular assist device (LVAD and RVAD, respectively). Live myocardial slices were produced from the apical biopsy obtained during LVAD implantation and cultured in a biomimetic system under physiological mechanical and electrical conditions. Slices were subsequently exposed to doxorubicin, trastuzumab or vehicle (0.1% DMSO) for a continued period of 7 days. Contractile force was recorded continuously, and a custom-made stimulation protocol applied every 24h. To evaluate responsiveness to inotropes, slices were incubated with milrinone before culture termination. Calcium transients and action potentials were determined optically using calcium and voltage-sensitive dyes. Results Continued exposure to either doxorubicin or trastuzumab limited the recovery of contractility in myocardial slices. In contrast, vehicle controls showed a robust recovery and development of stronger contractile forces. Doxorubicin-treated slices were less responsive to stimulation, displayed increased stimulation threshold and were less able to follow pacing at higher frequencies. Optical mapping revealed that exposure to doxorubicin led to the development of abnormal calcium handling. In parallel to the ex vivo findings, RVAD/LVAD-mediated cardiac unloading and the absence of any chemotherapy drug, resulted in a significant recovery of right-ventricular function, enabling RVAD removal within 2 weeks. Conclusions The complex nature of chemotherapy-induced cardiotoxicity imposes numerous challenges in clinical decision-making. In this unique case, patient care could be paralleled by concomitant state-of-the-art ex vivo tissue culture. We observed that myocardial tissue slices could partially recapitulate clinical observations, highlightings the promising synergy between translational science and personalized patient care.

A novel pan-PI3K inhibitor KTC1101 synergizes with anti-PD-1 therapy by targeting tumor suppression and immune activation

BackgroundPhosphoinositide 3-kinases (PI3Ks) are critical regulators of diverse cellular functions and have emerged as promising targets in cancer therapy. Despite significant progress, existing PI3K inhibitors encounter various challenges such as suboptimal bioavailability, potential off-target effects, restricted therapeutic indices, and cancer-acquired resistance. Hence, novel inhibitors that overcome some of these challenges are needed. Here, we describe the characterization of KTC1101, a novel pan-PI3K inhibitor that simultaneously targets tumor cell proliferation and the tumor microenvironment. Our studies demonstrate that KTC1101 significantly increases the anti-PD-1 efficacy in multiple pre-clinical mouse models.MethodsKTC1101 was synthesized and characterized employing chemical synthesis, molecular modeling, Nuclear Magnetic Resonance (NMR), and mass spectrometry. Its target specificity was confirmed through the kinase assay, JFCR39 COMPARE analysis, and RNA-Seq analysis. Metabolic stability was verified via liver microsome and plasma assays, pharmacokinetics determined by LC–MS/MS, and safety profile established through acute toxicity assays to determine the LD50. The antiproliferative effects of KTC1101 were evaluated in a panel of cancer cell lines and further validated in diverse BALB/c nude mouse xenograft, NSG mouse xenograft and syngeneic mouse models. The KTC1101 treatment effect on the immune response was assessed through comprehensive RNA-Seq, flow cytometry, and immunohistochemistry, with molecular pathways investigated via Western blot, ELISA, and qRT-PCR.ResultsKTC1101 demonstrated strong inhibition of cancer cell growth in vitro and significantly impeded tumor progression in vivo. It effectively modulated the Tumor Microenvironment (TME), characterized by increased infiltration of CD8+ T cells and innate immune cells. An intermittent dosing regimen of KTC1101 enhanced these effects. Notably, KTC1101 synergized with anti-PD-1 therapy, significantly boosting antitumor immunity and extending survival in preclinical models.ConclusionKTC1101's dual mechanism of action—directly inhibiting tumor cell growth and dynamically enhancing the immune response— represents a significant advancement in cancer treatment strategies. These findings support incorporating KTC1101 into future oncologic regimens to improve the efficacy of immunotherapy combinations.

HTA230 Comparative Evaluation of the Performance of Two Value Attribution Frameworks When Applied to Combination Regimens in Oncology

HTA230 Comparative Evaluation of the Performance of Two Value Attribution Frameworks When Applied to Combination Regimens in Oncology

Measuring the impact of monoclonal antibody therapies.

Monoclonal antibody (Mab) treatments have significantly improved the quality and quantity of life, but they are some of the most expensive treatments, resulting in a degree of hesitancy to introduce new Mab agents. A system for estimating the effect of Mab drugs, in general, would optimally inform health strategy and fully realize how a single scientific discovery can deliver health benefits. We evaluated such a method with several well-established Mab regimens. We selected five different Mab regimens in oncology and rheumatology in England. We carried out two systematic literature reviews and meta-analyses to assess health outcomes (Health Assessment Questionnaire-Disability Index for rheumatoid arthritis; overall mortality for melanoma) from real-world data and compared them to the outcomes from randomized control trials (RCTs). We applied economic modeling to estimate the net monetary benefits for health outcomes for the estimated patient population size for each Mab regimen. Meta-analyses of 27 eligible real-world data (RWD) sets and 26 randomized controlled trial (RCT) sets found close agreement between the observed and expected health outcomes. A Markov model showed the net positive monetary benefit in three Mab regimens and the negative benefit in two regimens. However, because of limited access to NHS data, the economic model made several assumptions about the number of treated patients and the cost of treatment to the NHS, the accuracy of which may affect the estimation of the net monetary benefit. RCT results reliably inform the real-world experience of Mab treatments. Calculation of the net monetary benefit by the algorithm described provides a valuable overall measure of the health impact, subject to the accuracy of data inputs. This study provides a compelling case for building a comprehensive, systematized, and accessible database and related analytics, on all Mab treatments within health services.

Annual cost and implementation of remote oncology pharmacist order review within a network of community oncology practices.

30 Background: The US Oncology Network’s ClinReview program employs a team of centralized clinical pharmacists providing remote services to community oncology practices. Literature demonstrating the clinical impact of the oncology pharmacist has been well established. However, comprehensive data supporting the financial value compensating these clinical services continues to prove challenging. The aim of this study is to evaluate the annual cost-avoidance realized by the ClinReview program through clinical and quality interventions. Methods: A team of 6 oncology clinical pharmacists electronically reviewed chemotherapy orders within 9 community oncology practices. The pharmacist identified opportunities to optimize oncology regimens by performing clinical treatment plan reviews, identifying orders requiring dose modifications, symptom management recommendations, clinical consultations, regimen entry, or drug interaction reviews. Recommendations were discussed with the treating provider or modified if permitted by approved practice policies. A retrospective, observational study was performed utilizing clinical intervention data entered by ClinReview pharmacists from October 2022 through March 2023. Interventions were allocated to specific cost-avoidance values based on previously validated studies and extrapolated to an annualized value. Results: During the 6-month study period, a total of 10,195 interventions were documented and categorized as treatment plan management (2,434, 24%), medication regimen/dosing change (6,365, 62%), symptom management (1,145, 11%), drug information consultation (103, 1%), regimen entry, (69, 1%), and drug interaction management (90, 1%). Based on previously validated cost-savings estimates, annualized cost avoidance realized from the ClinReview program was $2,247,818. Taking into account the cost of pharmacist time, the 6-month intervention data demonstrated an annualized net cost-avoidance of $1,896,164. Conclusions: The integration of the ClinReview program into community oncology practices delivers significant quality, safety, and financial benefits, with approximately $1.9 million in annual net cost-savings benefit. [Table: see text]

Immunosurveillance in clinical cancer management.

The progression of cancer involves a critical step in which malignant cells escape from control by the immune system. Antineoplastic agents are particularly efficient when they succeed in restoring such control (immunosurveillance) or at least establish an equilibrium state that slows down disease progression. This is true not only for immunotherapies, such as immune checkpoint inhibitors (ICIs), but also for conventional chemotherapy, targeted anticancer agents, and radiation therapy. Thus, therapeutics that stress and kill cancer cells while provoking a tumor-targeting immune response, referred to as immunogenic cell death, are particularly useful in combination with ICIs. Modern oncology regimens are increasingly using such combinations, which are referred to as chemoimmunotherapy, as well as combinations of multiple ICIs. However, the latter are generally associated with severe side effects compared with single-agent ICIs. Of note, the success of these combinatorial strategies against locally advanced or metastatic cancers is now spurring successful attempts to move them past the postoperative (adjuvant) setting to the preoperative (neoadjuvant) setting, even for patients with operable cancers. Here, the authors critically discuss the importance of immunosurveillance in modern clinical cancer management.

HTA43 Do Complexities of Combination Oncology Submissions Impact Reimbursement Outcomes: An Evaluation of Multi-Therapy Oncology Regimens in Canada

The increasing number of oncology combination regimens has highlighted the complexity of multiple manufacturer evaluations. This study aims to assess the dynamics of combination oncology regimen reviews with the Canadian Agency for Drugs and Technologies in Health (CADTH) and the subsequent pricing negotiations through the pan-Canadian Pharmaceutical Alliance (pCPA).

Improving evaluations and management of the appropriate application of modern anticancer drug therapy

Introduction. Evaluation and further improvement of the use of resources of the oncological service (including drug therapy) can lead to a subsequent qualitative gain in the availability of new types of effective antitumor technologies for a larger number of patients with severe oncological pathology. The experience of the Netherlands in managing the cancer care is useful for the local regional health services. Purpose of the study. Study of approaches to economically and clinically feasible use of anticancer therapy in real hospital practice. Material and methods. The scientific study was performed on the base of the search results in the databases of the Dutch digital educational platform, in the PubMed/Medline database and the Google search engine. The queries used the words: doelmatigheid, kanker, doelgerichte therapie, rationality, cancer, targeted therapy, etc. We analyzed the results published in 2021-2022. Results. There hаve bеen studied methods for increasing the expediency of clinical application of therapeutic regimens in oncology including a) rationalization of chemotherapy regimens; b) ensuring the mobility of patients receiving chemotherapy: chemotherapy on the principle of “connect and go” technology, self-administration of anticancer drugs; c) lean use of immunotherapy: drug therapy shelf life extension, vial count rounding and immunotherapy hybrid dosing; justified reduction in the duration of the course of immunotherapy. Limitations. In general, initiatives being put forward to improve the appropriateness of anticancer therapy should be previously tested in pilot projects. Conclusions. If positive opinions are received from expert institutions and regulatory authorities based on the results of pilot projects, innovative schemes for the appropriate use of drugs can be included in the list of services and programs reimbursed by the health insurer on an ongoing basis.

Using Clinical Measurements to Predict Breast Skin Necrosis: A Quantitative Analysis.

Breast skin necrosis can lead to poor healing, reoperation, and unaesthetic reconstructive outcomes after mastectomy. Furthermore, the prolonged recovery can delay adjuvant oncologic regimens. This study aims to explore the role of breast surface area as a risk factor for mastectomy skin flap necrosis and to identify predictive clinical measurements. The authors retrospectively identified patients who underwent immediate breast reconstruction (N = 926 breasts) by 2 surgeons at a single institution between 2011 and 2021. Preoperative breast measurements such as nipple-notch (NN) distance, nipple-inframammary fold (NF) distance, chest width (CW), breast circumference (BC), and breast height (BH) were used to estimate breast surface area. Univariate analysis and receiver operating characteristic curves were used to determine predictive measurements and optimal cutoff values. When approximated using either a cone without base or a half ellipsoid, larger surface area was a significant risk factor for mastectomy skin flap necrosis (P = 0.027 and P = 0.022, respectively). Larger NN, NF, CW, BC, and BH measurements were significant predictors of necrosis (P < 0.05). Surface area (cone without base) greater than 212 cm2, surface area (half ellipsoid) greater than 308 cm2, NN distance greater than 27 cm, NF greater than 8.5 cm, CW greater than 15 cm, BC greater than 29 cm, and BH greater than 10.5 cm are all values shown to increase the incidence of necrosis. Larger breast surface area is an independent risk factor for breast skin necrosis. Preoperative breast measurements can be a useful adjunct for predicting necrosis in postmastectomy patients.

MSR33 Application and Feasibility of Indirect Treatment Comparison of Switch Maintenance and Non-Maintenance Oncology Regimens to Inform HTA Decision-Making

MSR33 Application and Feasibility of Indirect Treatment Comparison of Switch Maintenance and Non-Maintenance Oncology Regimens to Inform HTA Decision-Making

Abstract 11659: Comparing Rates of Acute Myocardial Infarction Between Cancer Therapies in Patients With Non-Small Cell Lung Cancer

Introduction: The prevalence of cardiovascular disease (CVD) has increased in patients with cancer, contributing significantly to mortality among cancer survivors. Cardiotoxicity of anti-cancer drugs may play a role in the development of CVD among cancer survivors, including incidence of acute myocardial infarction (AMI). We analyzed AMI rates in patients with non-small cell lung cancer (NSCLC) treated with one of four cancer regimens. Methods: We used national data from the Veterans Affairs (VA) Corporate Data Warehouse and VA Cancer Registry. We identified 9,619 veterans diagnosed with NSCLC during 2015-2019 who initiated one of four oncological therapies: chemotherapy, immune checkpoint inhibitors (ICI) with chemotherapy, ICI monotherapy, or tyrosine kinase inhibitors monotherapy (TKI). Patients were categorized according to the first therapy received. We identified subsequent hospitalizations for AMI within two years of initiating the oncological treatment. We estimated AMI rates per 100 patient-years and risk adjusted relative hazard ratio (HR) of AMI by treatment type using Cox Regression Model to adjust for age, AMI history, comorbidities, malignancy stage, and histology. Results: Among 9,618 veterans identified, 5,510 (57.3%) initiated treatment with chemotherapy, 2,820 (29.3%) ICI with chemotherapy, 829 (8.6%) with ICI monotherapy, and 459 (4.8%) with TKI. Over a follow-up period of 2 years, 158 (1.6%) patients experienced an AMI and 5,917 (61.5%) died. The incidence of AMI per 100 patient-years (95% CI) was as follows; chemotherapy 0.86 (0.70-1.06), ICI with chemotherapy 0.77 (0.58-1.03), ICI monotherapy 0.91 (0.52-1.60), and TKI 0.43 (0.16-1.15). When compared to chemotherapy alone, adjusted HR (95% CI) for ICI with chemotherapy, ICI monotherapy, and TKI were 1.09 (0.91-1.31), 1.02 (0.75-1.38), and 1.50 (0.94-2.37), respectively. When compared to TKI or ICI with chemotherapy, the ICI monotherapy cohort did not have a statistically significant adjusted HR for AMI risk. Conclusion: Among Veterans with NSCLC, the incidence of AMI was low and there was no difference in risk between the initial oncological regimens. The high competing risk of mortality in our cohort may also have contributed to the lack of between-group differences.

Costs by Site of Service for Commercially-Insured Patients with Metastatic Pancreatic Cancer Receiving Guideline-Recommended Chemotherapy: Comparing Community Oncology and Hospital Outpatient Settings.

PurposeCompare total cost of care (TCOC) for commercially-insured patients with metastatic pancreatic cancer receiving FDA-approved/NCCN Category 1 preferred regimens in community oncology or hospital outpatient settings.Patients and MethodsWe used the 2016–2019 MarketScan® and Milliman Consolidated Health Cost Guidelines Sources Database (CHSD) administrative claims data to compare utilization of healthcare services and expenditures for commercially-insured patients receiving chemotherapy in community oncology or hospital outpatient settings. We identified patients with metastatic pancreatic cancer using ICD-10 diagnosis codes in 2016–2019 MarketScan® and Milliman Consolidated Health Cost Guidelines Sources Database files. Patients were assigned to cohorts based on where they received the plurality of chemotherapy services: community oncology or hospital outpatient settings. Total cost of care (TCOC) and healthcare resource utilization metrics were calculated per line of therapy (LOT) for patients receiving similar chemotherapy regimens in each cohort, and differences between cohorts were evaluated using t-testing and chi-squared statistical methods.ResultsAlthough cohorts had similar demographics, chemotherapy regimen use, and length of therapy, the mean TCOC among all patients receiving chemotherapy in hospital outpatient settings was 41% higher compared to community oncology settings. Median TCOC was 35% higher in hospital outpatient settings than in community oncology settings. Mean admissions and readmissions per beneficiary were 7% and 16% higher, respectively, for thse treated in hospital outpatient versus community oncology settings. We observed no differences in the use of emergency department or hospice care between the cohorts.ConclusionOur study indicates that patients receiving chemotherapy at community oncology centers are associated with better or equivalent outcomes and lower costs than patients receiving the same regimen in a hospital outpatient setting.

Why We Need a New Outcomes-Based Value Attribution Framework for Combination Regimens in Oncology

BackgroundNovel oncology treatment strategies increasingly use medicines with distinct but complementary mechanisms of action in combination or in close sequence. Payers, when confronted with higher total cost of providing combination regimens involving multiple therapies and usually longer treatment durations, are reluctant to reimburse them, particularly when they perceive the expected incremental benefits from adding a new medicine (the add-on) to a currently reimbursed medicine (the backbone) not to represent value for money to the health system. Nevertheless, depending on how value is attributed to the add-on versus the backbone, a clinically effective medicine used as part of a regimen that increases treatment duration might be found “not cost-effective at zero price.” This phenomenon, signaling a policy problem not a pricing issue, first needs to be better understood before a generalizable and transparent solution can be presented. ObjectiveThis article sets out when this policy challenge arises and describes general principles that any proposed solution to the value attribution problem must satisfy. MethodsWe develop a simplified conceptual framework and use this to address 2 topics. The first is to understand the origin of problems posed by the current approach for attributing value in incremental cost-effectiveness analyses of combination regimens. The second is to discuss 2 new approaches in the literature designed to address the challenge. FindingsWe find that neither meets our criteria, meaning that further work is needed to resolve the issue. Finally, we briefly discuss the implications of relaxing the simplifying assumptions in our conceptual framework.

HTA40 Challenges in Evaluating and Paying for Combination Therapies in Oncology - a Canadian Perspective

Cancer is characterized by a breakdown of multiple biological pathways. This has led to the development of therapies to target various individual pathways alone or in combination. Currently, there are several combination therapy (CT) regimens in oncology with clinical benefits beyond monotherapy. Yet, combining multiple on-patent treatments poses varied challenges wherein manufacturers are unable to demonstrate through existing health technology assessment (HTA) processes that the value of using such CTs is commensurate with observed clinical benefits, and payers are challenged to accommodate the cost of expensive CTs.

Quantitative proteomic profiling of esophageal adenocarcinoma tumors to assess prevalence of approved targets and elucidate novel biomarkers.

343 Background: Esophageal adenocarcinoma (EAC) continues to have extremely poor prognosis despite advances in surgical and oncological regimens. Targeted and immune therapy hold promise to improve outcomes in solid tumors including EAC. At present HER-2 and anti-PD-L1 therapies are approved by the FDA for EAC. Additionally, off-label use of EGFR directed therapy has been reported. The aim of this study is to measure expression of 80+ oncoproteins in EAC using multiplexed mass spectrometry to elucidate expression of currently approved-drug targets and explore promising new targets for drug development. Methods: After Institutional Review Board approval (Mayo Clinic and KUMC), EAC patients whose tumors were resected via esophagectomy before chemotherapy and/or radiation were identified. Normal esophageal mucosa samples with no history of EAC were also retrieved for analysis. Tissue sections were microdissected to exclude stroma from adenocarcinoma cells. Isolated EAC cells were solubilized for mass spectrometry-based quantitation of more than 80 clinically relevant tumor markers. Results: 55 EAC tissues were analyzed. HER2, PD-L1 and EGFR were overexpressed only in 16.3%, 0%, and 0% of patients, respectively. New oncoproteins #2 and #6 were noted to have high (7,634.0 and 27,222.6 attomoles/ug) and consistent (98.1% and 94.5%) overexpression in EAC samples. Expression of HER2, oncoproteins #2 and #6 were significantly higher in EAC compared to normal esophageal mucosa. There was no statistical difference in the expression of PD-L1 and EGFR between EAC and normal samples. Conclusions: Mass spectrometry revealed a very low prevalence of target oncoproteins in EAC for currently used drugs. Our study potentially reveals alternate markers which are near universally present at high levels and should be further explored for targeted treatment.[Table: see text]

S2906 Medical Management of Variceal Bleeding Associated With Portal Hypertension Secondary to Significant Metastatic Burden in the Liver: Strategies for Reducing Rebleeding Events

Introduction: Portal hypertension (pHTN) is a cirrhosis complication that can uncommonly develop in patients with high liver metastatic tumor burden, especially those undergoing oxaliplatin chemotherapy. Symptomatic pHTN, such as gastrointestinal variceal bleeding, can complicate oncological management. Transjugular intrahepatic portosystemic shunt (TIPS) may not be a safe option, but medical therapy strategies are lacking. Case Description/Methods: A 70-year-old male with a history of colorectal carcinoma metastatic to the liver, status-post ileocolectomy and end-ileostomy with mucus fistula, and treated with oxaliplatin-bevacizumab based therapy, presented twice in one week to the emergency department with acute anemia and bleeding from his mucus fistula and then his ostomy. Abdominal CT at presentation was notable for progressed metastatic tumor burden in the liver and splenomegaly, raising concern for developing pHTN. Vascular abdominal ultrasound showed umbilical vein recanalization. EGD revealed small esophageal varices and moderate portal hypertensive gastropathy, but ileoscopy did not show a bleeding source. Venography studies showed peri-fistular and stomal varices, which were successfully treated with transcutaneous sclerotherapy, and subsequent direct portal pressure of 16mmHg. Given high rebleeding risk, the patient required long-term therapies for pHTN management. His malignancy burden and hypercoagulable risk precluded him from TIPS. Medical management was recommended, patient started on carvedilol 12.5 mg twice daily and atorvastatin was increased to 80mg daily; he was discharged without further bleeding to date. Discussion: This case illustrates a difficult case of pHTN that can be can be associated with both metastatic liver burden but also fibrosis associated with oxaliplatin therapy. Bevacizumab is an additional cause for increased bleeding risk and poor wound healing. Oncologic regimens may also need to be altered given the new pHTN occurrence. While data support the use of beta blockers and statins in pHTN and variceal bleeding management, much of this evidence comes from cirrhosis literature. Further investigation into pharmacologic management of portal hypertension in patients with significant metastatic burden in the liver. Interestingly, the downregulation of VEGF synthesis by high-dose statins may assist with anti-angiogenesis effect of bevacizumab and may be of interest for future clinical research.Figure 1.: Figure 1a - CT imaging showing metastatic burden to the liver; figure 1b -- venography showing peristomal varices.Table 1.: Pertinent lab values at various points of disease course from diagnosis of metastatic cancer onward.

The Novel Nucleoside Analogue ProTide NUC-7738 Overcomes Cancer Resistance Mechanisms In Vitro and in a First-In-Human Phase I Clinical Trial.

Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a preactivated nucleoside released. 3'-Deoxyadenosine (3'-dA) is a naturally occurring adenosine analogue with established anticancer activity in vitro but limited bioavailability due to its rapid in vivo deamination by the circulating enzyme adenosine deaminase, poor uptake into cells, and reliance on adenosine kinase for its activation. In order to overcome these limitations, 3'-dA was chemically modified to create the novel ProTide NUC-7738. We describe the synthesis of NUC-7738. We determine the IC50 of NUC-7738 using pharmacokinetics (PK) and conduct genome-wide analyses to identify its mechanism of action using different cancer model systems. We validate these findings in patients with cancer. We show that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3'-dA and that its activation is dependent on ProTide cleavage by the enzyme histidine triad nucleotide-binding protein 1. PK and tumor samples obtained from the ongoing first-in-human phase I clinical trial of NUC-7738 further validate our in vitro findings and show NUC-7738 is an effective proapoptotic agent in cancer cells with effects on the NF-κB pathway. Our study provides proof that NUC-7738 overcomes cellular resistance mechanisms and supports its further clinical evaluation as a novel cancer treatment within the growing pantheon of anticancer ProTides.

Pilot study of a European oncology regimen reference library and matching algorithm

ObjectivesAs yet, there is no European data standard for naming and describing oncology regimens. To enable real-world cancer treatment data comparisons, the Oncology Data Network created a unified reference database...

Transitioning ifosfamide based chemotherapy to the outpatient setting: A model of implementation of transitioning chemotherapy outpatient in a safety net hospital.

1540 Background: Ifosfamide displays clinical activity against germ cell tumors as well as soft-tissue and bone sarcomas. It is used in different oncology regimens and commonly administered inpatient due to patient monitoring and side effect management. Transitioning certain chemotherapy regimens to the outpatient setting provides a novel approach to treating patients while maximizing patient satisfaction and decreasing total patient care costs1. There is limited data and protocol development to transition ifosfamide regimens to the ambulatory setting. This study’s purpose is to characterize a pharmacy managed ambulatory oncology workflow for transitioning ifosfamide based-regimens to the outpatient setting. Methods: A retrospective cohort chart review was conducted at a single center and included patients 18 years and older receiving at least one cycle of ifosfamide therapy between September 1, 2013 and July 31, 2019. The primary outcome was to evaluate the side effect profile and cost of treatment of ifosfamide. The secondary endpoint included number of hospitalizations. The adverse event grading system was defined using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. The highest grade observed for adverse effects was documented for every cycle of each patient. The cost was evaluated by labs ordered, drug used, length of stay in the hospital for chemotherapy or adverse reactions. Results: Ifosfamide therapy of 86 patients (57 OP, 29 IP) was reviewed. The predominant OP regimens were adriamycin-ifosfamide-mesna (AIM) with 43.9% and ifosfamide-etoposide (IE) with 29.8%. Grade 4 anemia, thrombocytopenia, and neutropenia were most frequent in IP vs OP therapies (22.9% IP vs 4.3% OP, 21.6% IP vs 9.2% OP, and 22.8% IP vs 19.6% OP respectively). Neutropenic fever (NF) occurred in 20 OP patients which were predominantly treated with AIM or IE, and led to average hospital stay of 6 days. Neurotoxicity, treated with methylene blue (MB), occurred in 4 OP patients. OP therapy saved a total of 783 hospital days, leading to a cost savings of $2,103,921. Conclusions: Transitioning to outpatient therapy is feasible for academic and community infusion centers. Administration of chemotherapy in the outpatient setting has shown to be safe, well-tolerated, and associated with decreased total cost of care, thereby lowering costs under the oncology care model when compared with inpatient chemotherapy costs.