Uptake Of Chemotherapy Research Articles

Interventions to reduce racial/ethnic disparities across the breast cancer care continuum.

160 Background: In the United States, racial/ethnic disparities in adoption of breast cancer evidence-based practices (EBPs) persist along the cancer care continuum. This scoping review applied an implementation science lens to describe the current evidence base for interventions to reduce disparities, synthesizing evidence on effective interventions while highlighting gaps in the literature. Methods: A formalized search strategy identified USA-based interventional studies aiming to improve adoption of an EBP along the breast cancer care continuum among racially/ethnically minoritized patients. Relevant articles from 1/2010 - 8/2022 (Medline, Embase, Cochrane, and Scopus) were included. For each article, two reviewers screened and extracted data, with a third resolving discrepancies. The PRISMA-ScR checklist and JBO Manual for Evidence Synthesis framework were followed. Results: Our search strategy yielded 45,215 articles. After applying inclusion/exclusion criteria, 59 articles were retained, targeting screening (85%, 50 of 59), treatment (12%, 7 of 59), and survivorship (5%, 3 of 59) (2 targeted multiple areas). No articles targeted end-of-life care. Of these, 49% (29 of 59) were randomized controlled trials (RCTs). Among 24 screening RCTs, the most common interventions—and fraction with statistically significant improved screening uptake—were patient navigation (100%, 11 of 11) and patient education (80%, 4 of 5). Among 4 treatment RCTs, 3 targeted adjuvant chemotherapy uptake. Of these, 1 had significant improvements and used patient navigation. The 2 studies without significant improvements used a patient tracking tool/alert system or patient education. Among 2 survivorship RCTs, one used email interventions, resulting in significantly improved physical activity and dietary health. A second used a nurse-facilitated internet support group, resulting in significantly improved physical/psychological symptoms. Early to mid-stage implementation outcomes (acceptability, adoption, appropriateness, feasibility, or fidelity) were commonly measured (81%, 48 of 59). No study measured later stage implementation outcomes (sustainability or costs). Conclusions: In multiple studies, patient navigation and education improved breast cancer screening among racially/ethnically minoritized populations. In one study, patient navigation improved completion of adjuvant treatment. Despite these studies, patient navigation is not reimbursed for cancer screening, and adoption has not been widespread. Future studies should focus on evaluating and improving later stage implementation outcomes (sustainability and costs). Based on these results, insurance reimbursement mechanisms for screening-related navigation may be warranted. Future breast cancer care delivery disparities research should also be expanded to include treatment, survivorship, and end-of-life care.

Real-world uptake and effectiveness of triplet versus doublet chemotherapy with bevacizumab in patients with metastatic colorectal cancer in the United States

Real-world uptake and effectiveness of triplet versus doublet chemotherapy with bevacizumab in patients with metastatic colorectal cancer in the United States

Phase II trial of biologically optimized schedule of gemcitabine and nab-paclitaxel in metastatic pancreatic cancer.

e16325 Background: Metastatic pancreatic adenocarcinoma (PDAC) has a poor prognosis and limited therapeutic options. In addition to efforts to develop novel agents, there is a need to optimize and maximize the benefit of currently approved drugs such as gemcitabine (G) + nab-paclitaxel (NP). NP is albumin–bound, hence albumin uptake is critical for its effect. Caveolae are small membrane invaginations essential for transendothelial albumin uptake. Cav-1 is the principal structural component of caveolae. We have shown that tumor cell-specific Cav-1 expression directly correlates with albumin and albumin-bound chemotherapy uptake and subsequent apoptotic response in tumor cells. In vitro studies showed that exposure of PDAC cells to G resulted in up-regulation of Cav-1 peaking 48 hours after G exposure. This Cav-1 up-regulation correlated with increased temporal albumin cellular uptake. In addition, we noted that exposure of PDAC cells to G resulted in a time–specific re-entry of cells into the G2/M phase (NP cytotoxicity phase) between 48-60 hours after G treatment. Collectively this data suggest that infusing NP 48 hours after G infusion would be optimal for both increased uptake as well as increased susceptibility to apoptosis of tumor cells. We have shown this effect on multiple cell lines and mouse models. Methods: This is a phase II trial (NCT04115163) where patients (pts) receive G + NP every 2 weeks with modification of the schedule to deliver NP 48 hours (2 days) after G infusions. The primary endpoint is ORR, with a null hypothesis of 20% vs a target of 35%. Employing a 2-stage minimax design minimax and assuming 80% power and a 0.05 significance level, a total of 53 pts are required. In the first stage, if at least 7/31 pts respond to therapy, an additional 22 pts will be added for a total of 53 pts. The study will be terminated early if ≤ 6 pts respond in the first stage. Observation of response in at least 16/53 pts would be required to warrant further investigation of this infusion schedule. Secondary endpoints include safety of the regimen schedule, relative dose intensity, disease control rate, PFS, and OS. The trial opened to enrolment in June 2020. Results: Interim analysis was conducted after 43 pts had been enrolled. 29 pts were found to be evaluable for the primary endpoint of response. Objective response was seen in 11 out of 29 (37.9%) evaluable pts thus meeting statistical criteria to continue enrolment on stage 2 of the study. The regimen was well tolerated with no new safety signals. Toxicities are summarized in table. Conclusions: Biologically optimized G + NP was well tolerated with interim analysis revealing response rate of 37.9%. Enrolment is ongoing with plans for correlative analysis related to Cav-1. Clinical trial information: NCT04115163 . [Table: see text]

Preoperative Strategies for Locally Advanced Colon Cancer.

Neoadjuvant chemotherapy is safe for patients with locally advanced colon cancer (LACC). The FOxTROT trial demonstrated a reduction in residual and recurrent cancer at 2 years with neoadjuvant chemotherapy for patients with cT3-4 LACC. Preoperative chemotherapy should be avoided, if possible, for patients with dMMR LACC, as over 50% of dMMR cancers have no pathologic response. Early universal testing of MMR status is critical to selecting the appropriate neoadjuvant therapy. Concerns about CT staging of LACC have limited uptake of neoadjuvant chemotherapy, as approximately 25% of patients with cT3-T4 cancer on CT have low-risk stage II disease. Development of CT criteria for malignant nodes should reduce the risk of over-staging. A multidisciplinary approach is needed to identify patients for neoadjuvant therapy. Neoadjuvant immunotherapy is safe and results in dramatic pathologic responses in patients with dMMR LACC. Longer follow-up is needed to determine if the exceptionally high pathologic response rates observed will translate into long-term remission. Remarkably, neoadjuvant immunotherapy has been found to cause major pathologic responses in a subset of patients with pMMR LACC, indicating the potential to cure more patients with this common cancer. Patients with cT4 LACC, whether stage II or III, have a substantial risk of recurrence despite adjuvant fluoropyrimidine plus oxaliplatin chemotherapy. We recommend neoadjuvant systemic therapy for all patients with cT4b LACC (dMMR and pMMR). Features of T4b disease are routinely reported by radiology. We use three cycles of FOLFOX chemotherapy for patients with cT4b pMMR LACC, due to the high rate of compliance and improvement in residual and recurrent disease. Patients with cT4b dMMR LACC should receive neoadjuvant immunotherapy, if there are no contraindications. Clinical trials of neoadjuvant therapy for LACC are of great interest and should provide training for radiologists to identify eligible patients. Results are anticipated from multiple ongoing trials of neoadjuvant chemotherapy, immunotherapy, and targeted therapy for pMMR LACC and immunotherapy for dMMR LACC.

Uptake and Outcomes of Neoadjuvant Chemotherapy Among US Patients With Less Common Epithelial Ovarian Carcinomas

ImportanceRandomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied.ObjectiveTo investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer.Design, Setting, and ParticipantsA retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy.ExposuresExposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group).Main Outcomes and MeasuresTemporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score.ResultsA total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P < .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score–weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype–specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas.Conclusions and RelevanceDespite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.

Ultrasound and Microbubbles Increase the Uptake of Platinum in Murine Orthotopic Pancreatic Tumors.

Currently available cytotoxic treatments have limited effect on pancreatic ductal adenocarcinoma (PDAC) because desmoplastic stroma limits drug delivery. Efforts have been made to overcome these barriers by drug targeting the tumor microenvironment. Results so far are promising, but without clinical impact. Our aim was to investigate whether ultrasound and microbubbles could improve the uptake and therapeutic response of conventional chemotherapy. Orthotopic pancreatic tumors growing in mice were treated with commercially available FOLFIRINOX (fluorouracil, irinotecan, oxaliplatin and calcium folinate) and SonoVue microbubbles combined with focused ultrasound. Tumor uptake of platinum (Pt) was measured by inductively coupled plasma mass spectroscopy (ICP-MS), and tumor volumes were measured by ultrasound imaging. Uptake of Pt, the active ingredient of oxaliplatin, was significantly increased after ultrasound treatment of orthotopic PDAC tumors. Multiple injections with FOLFIRONOX increased the amount of Pt in tumors. However, the enhanced accumulation did not improve therapeutic response. Increased uptake of Pt confirms that ultrasound and microbubbles have potential in clinical practice with existing drugs. The lack of therapeutic response, despite increased uptake in tumor tissue, emphasizes the importance of studying how to overcome stromal barriers.

Are physical performance and frailty assessments useful in targeting and improving access to adjuvant therapy in patients undergoing resection for pancreatic cancer?

BackgroundMany patients fail to receive adjuvant chemotherapy following pancreatic cancer surgery. This study implemented a multimodal, multidisciplinary approach to improving recovery after pancreatoduodenectomy (the ‘Fast Recovery’ programme) and measured its impact on adjuvant chemotherapy uptake and nutritional decline. The predictive accuracies of a bundle of frailty and physical performance assessments, with respect to the recipient of adjuvant chemotherapy, were also evaluated.ResultsThe N = 44 patients treated after the introduction of the ‘Fast Recovery’ programme were not found to have a significantly higher adjuvant chemotherapy uptake than the N = 409 treated before the pathway change (80.5 vs. 74.3%, p = 0.452), but did have a significantly lower average weight loss at six weeks post-operatively (mean: 4.3 vs. 6.9 kg, p = 0.013). Of the pre-operative frailty and physical performance assessments tested, the 6-min walk test was found to be the strongest predictor of the receipt of adjuvant chemotherapy (area under the ROC curve: 0.91, p = 0.001); all patients achieving distances ≥ 360 m went on to receive adjuvant chemotherapy, compared to 33% of those walking < 360 m.ConclusionsThe multimodal ‘Fast Recovery’ programme was not found to significantly improve access to adjuvant chemotherapy, but did appear to have benefits in reducing nutritional decline. Pre-operative assessments were found to be useful in identifying patients at risk of non-receipt of adjuvant therapies, with markers of physical performance appearing to be the best predictors. As such, these markers could be useful in targeting pre- and post-habilitation measures, such as physiotherapy and improved dietetic support.

Factors determining preventive chemotherapy uptake against soil-transmitted helminthiasis among school-age children in Ghana.

By 2020, the World Health Organization and the Ghana Neglected Tropical Diseases programme intended to treat 75% and 100% of school-age children, respectively, during preventative chemotherapy (PCT), to control soil-transmitted helminths. The performance of PCT was assessed, and the factors associated with albendazole uptake in 2019 were determined. This study comprised secondary data (2019 PCT) and a community-based cross-sectional study conducted among 352 children aged from 7 to 14years and enrolled with their caregivers. Logistic regression was used to determine the factors hindering or favouring the PCT uptake. According to surveillance data (2019 PCT), Krachi East Municipal reported coverage of 83% in schools and 40.9% for all children between 5 and 14years. The cross-sectional data showed that the median child age was 11years (IQR: 9-12). There was no gap in the estimates for coverage and uptake, which were both 90.9% (95%CI: 87.4-93.5%). Christians made up the majority of the caregivers (87.5%), and 48.0% had completed secondary or higher education. After controlling for potential confounders, caregiver religion (aOR = 0.07 95%CI: 0.01-0.36) and the perception of a child's PCT risk (aOR = 0.33 95%CI: 0.13-0.84) were the significant barriers of PCT uptake, whereas the child's age (aOR = 1.49 95%CI: 1.19-1.88) and the perception of a child's PCT's benefit (aOR = 10.26 95%CI: 2.57-40.95) were the significant facilitators among children 7-14years old. Although the performance of PCT was high, the national treatment target was not attained. Intensive and focused health education is therefore needed to improve positive perceptions towards PCT for school-age children.

A novel theatre-based behaviour change approach for influencing community uptake of schistosomiasis control measures

BackgroundAppropriate behaviour change with regard to safe water contact practices will facilitate the elimination of schistosomiasis as a public health concern. Various approaches to effecting this change have been trialled in the field but with limited sustainable outcomes. Our case study assessed the effectiveness of a novel theatre-based behaviour change technique (BCT), in combination with cohort awareness raising and capacity training intervention workshops.MethodologyOur study was carried out in four rural communities in the Mwanza region of Tanzania and in the semi-urban town of Kemise, Ethiopia. We adapted the Risk, Attitude, Norms, Ability and Self-regulation (RANAS) framework and four phases using a mixed methods approach. Participatory project phase engagement and qualitative formative data were used to guide the design of an acceptable, holistic intervention. Initial baseline (BL) data were collected using quantitative questionnaire surveys with 804 participants in Tanzania and 617 in Ethiopia, followed by the theatre-based BCT and capacity training intervention workshops. A post-intervention (PI) survey was carried out after 6 months, with a participant return rate of 65% in Tanzania and 60% in Ethiopia.ResultsThe intervention achieved a significant improvement in the knowledge of schistosomiasis transmission being associated with poorly managed sanitation and risky water contact. Participants in Tanzania increased their uptake of preventive chemotherapy (males: BL, 56%; PI, 73%, females: BL, 43%; PI, 50%). There was a significant increase in the selection of sanitation (Tanzania: BL, 13%; PI, 21%, Ethiopia: BL, 63%; PI, 90%), safe water and avoiding/minimising contact with infested waters as prevention methods in Tanzania and Ethiopia. Some of the participants in Tanzania followed on from the study by building their own latrines.ConclusionsThis study showed that substantial positive behaviour changes in schistosomiasis control can be achieved using theatre-based BCT intervention and disease awareness training. With the appropriate sensitisation, education and stakeholder engagement approaches, community members were more open to minimising risk-associated contact with contaminated water sources and were mobilised to implement preventive measures.Graphical

Abstract 376: Sonoporated size selected microbubblesand liposomal doxorubicinadditively induce apoptosis in neuroblastoma xenografts

Abstract Background: Neuroblastoma (NB) is the second most common malignancy diagnosed in infants, accounting for 15% of pediatric tumor deaths. Half of children with NB receive an intensive regimen including high-dose chemotherapy with 50% survival, resulting in acute and long term toxicities. One of the challenges of chemotherapy is irregular tumor vasculature. Thus, increasing targeted drug delivery without increasing drug dosage can result in enhanced drug efficacy and improved patient outcomes. We have shown that sonoporation (focused ultrasound-guided gas-filled microbubbles) increases high dose liposomal doxorubicin (L-DOX) uptake in NB xenografts by increasing tumor perfusion. However, these studies used polydisperse microbubbles (PMB), which were developed for imaging purposes. We hypothesized that MB size restriction would control their response to ultrasound pressure, yielding a higher L-DOX payload despite using using lower L-DOX dosages. Methods: Nude mice received 1x10^6 NGP cells (NB cells) intrarenally. When tumors reached 1 gram, NB xenografts received an intravenous polydisperse (PMB) or 4-5uM (SIMB) microbubble infusion with or without 1mg/kg liposomal doxorubicin (L-DOX) under focused ultrasound. Tumors were measured over 7 days with calipers, others sacrificed 24 hours after treatment for histology and immunohistochemistry. We assessed endomucin and isolectin-B4 (endothelium), Zona occludens-1 (ZO-1) (tight junction), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL, apoptosis). Results: Tumors receiving low dose L-DOX alone or PMB sonoporation with L-DOX were not different from untreated controls after 7 days. SIMB alone resulted in a slower tumor growth than control tumors (20 vs 100% p&amp;lt;0.05); L-DOX coupled with SIMB resulted in further tumor growth restriction 7 days after treatment (0 vs 100% p&amp;lt;0.05). SIMB increased tumor apoptosis (TUNEL staining) in the absence of L-DOX compared to controls (7 vs 58% of area p=0.003) as well as in the presence of L-DOX (7 vs 78% of area p&amp;lt;0.001). PMBs did not change TUNEL levels regardless of L-DOX. Tumor vascular lumens (widest axis within the endothelial marker endomucin) confirmed PMB duplicates lumen diameter compared to controls (p&amp;lt;0.05), and revealed SIMB triplicates lumen diameter (p&amp;lt;0.01) regardless of L-DOX. SIMB resulted in loss of tight junction protein ZO-1 both in vasculature and tumor cells and widespread L-DOX uptake. Together, our data shows SIMB sonoporation increases tumor blood volume and vascular permeability leading to higher chemotherapy uptake and apoptosis. Conclusions: Together, our data shows SIMB sonoporation enables chemotherapy uptake in poorly perfused NB xenografts by increasing perfusion and permeability, potentiating apoptotic effects. SIMB sonoporation could reduce acute and long term toxicities. Citation Format: Sonia L. Hernandez, Rachael Sundland, Donia Ballan, Aditi Bellary, Jessica J. Kandel, Jameel Feshitan, Shashank Sirsi. Sonoporated size selected microbubblesand liposomal doxorubicinadditively induce apoptosis in neuroblastoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 376.

Population-level uptake of neoadjuvant chemotherapy for stage IVB endometrial cancer

ObjectiveTo examine population-level trends, characteristics, and outcomes of patients with stage IVB endometrial cancer who received neoadjuvant chemotherapy (NACT) prior to surgery. MethodsThe National Cancer Institute's Surveillance, Epidemiology, and End Results Program was retrospectively queried by examining 5505 patients with stage IVB endometrial cancer from 2010 to 2018. Exposure allocation was per treatment: primary surgery followed by chemotherapy (n = 3052, 55.4%), NACT followed by surgery (n = 930, 16.9%), and chemotherapy alone (n = 1523, 27.7%). Main outcomes measured were (i) the trend of utilization of NACT and patient characteristics related to NACT assessed with multinomial regression analysis and (ii) overall survival (OS) assessed with multivariable Cox proportional hazards regression model. ResultsThe number of patients receiving NACT prior to surgery increased from 11.6% to 21.7% whereas those undergoing primary surgery followed by chemotherapy decreased from 62.7% to 48.3% (P < 0.001). Increasing utilization of NACT remained independent in multivariable analysis (adjusted-odds ratio per one-year increments 1.11, 95% confidence interval [CI] 1.08–1.15). Increasing utilization of NACT was observed in several sub-cohorts including patients aged <65 years, ≥65 years, White, non-White, endometrioid, non-endometrioid, and cases with non-distant organ metastasis (P < 0.05). In a multivariable analysis, NACT followed by surgery and primary surgery followed by chemotherapy had comparable OS (median 25 versus 26 months, adjusted-hazard ratio [HR] 1.03, 95%CI 0.93–1.15). When examined for metastatic extent, NACT followed by surgery was associated with decreased OS compared to primary surgery followed by chemotherapy in the non-distant organ metastasis group (adjusted-HR 1.20, 95%CI 1.05–1.36) whereas it was associated with improved OS in the distant organ metastasis group (adjusted-HR 0.79, 95%CI 0.66–0.95). ConclusionThe treatment of stage IVB endometrial cancer is shifting from primary surgery to NACT in the United States.

Diffuse plate-like sheets of desquamation

Diffuse plate-like sheets of desquamation

P-P20 ‘Fast Recovery’ A multidisciplinary approach to improving recovery after pancreatic resection and ultimately increasing uptake of adjuvant chemotherapy

Abstract Background Pancreatic cancer surgery has a multi-system impact on a potentially vulnerable population. Current rates of adjuvant chemotherapy uptake are low. Our group developed a multidisciplinary bundle of care with the aim of improving recovery after surgery. The primary aim was to improve uptake of adjuvant chemotherapy and the secondary aim was to prevent nutritional decline. Methods This prospective, observational, cohort study evaluated the effect of the ‘Fast Recovery’ programme. This programme, developed with input from dieticians, physiotherapists, surgeons, and geriatricians and comprising pre- and post-operative frailty assessments, nutritional support and physiotherapy was implemented for all within our unit undergoing pancreatic resection for cancer. (See Fig. 1) Results Over 1 year, patients enrolled in the Fast Recovery programme (N = 44) were compared to those treated prior to the pathway change (N = 409). The Fast Recovery programme was not associated with a significant increase of adjuvant chemotherapy uptake (80.5 vs. 74.3%, p = 0.452), but did lead to a significantly lower average weight loss (4.3 vs. 6.9kg, p = 0.013). Patients that did not receive adjuvant chemotherapy performed significantly worse on a pre-operative six minute walk test (mean distance: 277 vs. 454 metres, p = 0.001). Conclusions Feasibility of a multimodal package to improve patient care following pancreatic resection has been shown by this pilot study. No significant improvement in the chemotherapy uptake was observed, however, this was potentially a result of the study being underpowered. Pre-operative physical assessments were found to be predictive of adjuvant chemotherapy uptake and could potentially be used to identify those in need of additional support. Further work is needed to evaluate the routine use of such a programme.

Treatment and outcomes of unresectable and metastatic pancreatic cancer treated in public and private Australian hospitals.

Prior studies have reported for several cancer types that treatment in the private sector is associated with improved survival outcomes. Data for patients with locally advanced unresectable and metastatic pancreatic ductal adenocarcinoma (PDAC) have not previously been reported. Analysis of patients from January 2016 to June 2020 registered to a multicentre prospective cancer database. Baseline demographic and clinicopathologic characteristics were compared. The Kaplan-Meier method was used to compare overall survival (OS). Multivariate Cox and logistic regression analyses were used to determine predictors of mortality and first-line chemotherapy treatment, respectively. Of 822 patients, 22.5% received private care. Private patients were older (median 71.5 vs. 68.9 years, p≤.05), had better performance status (ECOG 0 to 1: 82.2vs. 73.5%, p=.05) and more likely to reside in an area with high socioeconomic advantage (67.0vs. 19.6%, p≤.01). Private patients were more likely to receive first-line chemotherapy (69.7vs. 54.2%, p≤.01) with logistic regression demonstrating private care (OR: 1.87, 95% CI: 1.20 to 2.97) as an independent predictor of receiving chemotherapy. Private patients had prolonged survival (median OS: 9.2vs. 6.9 months, HR 1.2, p=.05). Receiving first-line chemotherapy was an independent predictor of mortality, but private care was not. Care in the private system is associated with improved OS, with higher uptake of first-line chemotherapy appearing to be the main contributor. Given the discrepancy, further studies are needed to determine what factors are driving this difference.

Longitudinal Preclinical Imaging Characterizes Extracellular Drug Accumulation After Radiation Therapy in the Healthy and Leukemic Bone Marrow Vascular Microenvironment

Recent initial findings suggest that radiation therapy improves blood perfusion and cellular chemotherapy uptake in mice with leukemia. However, the ability of radiation therapy to influence drug accumulation in the extracellular bone marrow tissue is unknown, due in part to a lack of methodology. This study developed longitudinal quantitative multiphoton microscopy (L-QMPM) to characterize the bone marrow vasculature (BMV) and drug accumulation in the extracellular bone marrow tissue before and after radiation therapy in mice bearing leukemia. We developed a longitudinal window implant for L-QMPM imaging of the calvarium BMV before, 2 days after, and 5 days after total body irradiation (TBI). Live time-lapsed images of a fluorescent drug surrogate were used to obtain measurements, including tissue wash-in slope (WIStissue) to measure extracellular drug accumulation. We performed L-QMPM imaging on healthy C57BL/6 (WT) mice, as well as mice bearing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Implants had no effects on calvarium dose, and parameters for wild-type untreated mice were stable during imaging. We observed decreased vessel diameter, vessel blood flow, and WIStissue with the onset of AML and ALL. Two to 10 Gy TBI increased WIStissue and vessel diameter 2 days after radiation therapy in all 3 groups of mice and increased single-vessel blood flow in mice bearing ALL and AML. Increased WIStissue was observed 5 days after 10 Gy TBI or 4 Gy split-dose TBI (2 treatments of 2 Gy spaced 3 days apart). L-QMPM provides stable functional assessments of the BMV. Nonmyeloablative and myeloablative TBI increases extracellular drug accumulation in the leukemic bone marrow 2 to 5 days posttreatment, likely through improved blood perfusion and drug exchange from the BMV to the extravascular tissue. Our data show that neo-adjuvant TBI at doses from 2 Gy to 10 Gy conditions the BMV to improve drug transport to the bone marrow.

Cholecystokinin Receptor Antagonist Improves Efficacy of Chemotherapy in Murine Models of Pancreatic Cancer by Altering the Tumor Microenvironment.

Simple SummaryOur research team has identified the cholecystokinin-B receptor (or CCK-BR) as a novel target for treatment of pancreatic cancer. CCK-BRs are over-expressed in pancreatic cancer and activation stimulates growth in cell culture and in animal models. CCK-BRs are also expressed on pancreatic stellate cells—or the fibroblasts that are responsible for the dense fibrosis in the tumor microenvironment that impedes the penetration of chemotherapy. We show strong evidence that treatment with a CCK receptor antagonist, proglumide, decreases fibrosis in the pancreatic tumor microenvironment and increases the influx of T-cells rendering chemotherapy-resistant cancer, sensitive to gemcitabine. Mice treated with the combination therapy had fewer metastases and greater survival. Tumors from these mice had higher gemcitabine levels and novel differentially expressed genes by RNA-Seq. Proglumide is an older drug that was developed many years ago for peptic ulcer disease but is no longer in use. Repurposing this older drug may improve survival from this recalcitrant malignancy.Pancreatic cancer is resistant to chemotherapy in part due to the dense desmoplastic fibrosis surrounding the tumor, the immunosuppressive cells in the tumor microenvironment (TME), and the early rate of metastases. In this study, we examined the effects of a CCK receptor antagonist, proglumide, alone and in combination with gemcitabine in murine models of pancreatic cancer. Tumor growth rate, metastases, and survival were assessed in mice bearing syngeneic murine or human pancreatic tumors treated with PBS (control), gemcitabine, proglumide, or the combination of gemcitabine and proglumide. Excised tumors were evaluated histologically for fibrosis, immune cells, molecular markers, and uptake of chemotherapy by mass spectroscopy. Peripheral blood was analyzed with a microRNAs biomarker panel associated with fibrosis and oncogenesis. Differentially expressed genes between tumors of mice treated with gemcitabine monotherapy and combination therapy were compared by RNAseq. When given in combination the two compounds exhibited inhibitory effects by decreasing tumor growth rate by 70%, metastases, and prolonging survival. Proglumide monotherapy altered the TME by decreasing fibrosis, increasing intratumoral CD8+ T-cells, and decreasing arginase-positive cells, thus rendering the tumor sensitive to chemotherapy. Proglumide altered the expression of genes involved in fibrosis, epithelial–mesenchymal transition, and invasion. CCK-receptor antagonism with proglumide renders pancreatic cancer susceptible to chemotherapy.

Abstract 2617: Factors associated with utilization of post-mastectomy adjuvant therapies in privately insured female patients with early-stage invasive breast cancer

Abstract Background: In a commercially insured cohort of female patients with early-stage invasive breast cancer we examined geographic and clinical factors associated with variation in uptake of post-mastectomy adjuvant endocrine therapy (AET), cytotoxic chemotherapy (ACT) and biologic therapy (ABT). Methods: Retrospective observational study of the IBM® MarketScan® claims data from 01/01/2012-03/31/2018. Eligibility criteria included: 1) diagnosis of non-metastatic invasive breast cancer in female patients 18 years old or older, 2) mastectomy within 6 months of initial diagnosis. Patients with breast carcinoma in situ only and those who received neoadjuvant therapies were excluded. Multivariate logistic regression was used to identify factors associated with receipt of adjuvant therapy, including: 1) age, insurance plan type, and select chronic comorbid conditions, 2) sociodemographic, community-level (ZIP3) measures obtained from the 2019 Area Health Resource Files, and 3) time effects. Analyses were conducted at the patient level with standard errors clustered by ZIP3. Results: Of the 16,680 patients identified, 5,341 (32%) received AET only, 2,290 (14%) received ACT only and 729 (4%) received ABT. 7,911 (47%) did not have any claims for adjuvant therapy. 3% received adjuvant combinations, mostly post-radiation treatment (2%). We observed the following statistically significant associations (p&amp;lt;.001 to p&amp;lt;.05) between selected variables and adjuvant therapy use:- Increasing age and higher likelihood of AET (1.2-1.8) but decreased likelihood of ACT (.8-.03) and ABT (.98-.24).- Primary health policy holders were 13% more likely to receive ACT compared to a spouse or other dependent.- Patients residing in the Midwest and higher likelihood of receiving AET (OR=1.15), ACT (OR=1.14), and ABT (OR=1.44) compared to those in the Northeast whereas those in the West and South had higher likelihood of receiving ACT (OR=1.31; OR=1.21), and ABT (OR=1.66; OR=1.36).- Patients residing in areas with increased Black resident density (ZIP3 level) and lower likelihood of receiving AET (OR=.58), ACT (OR=.61), and ABT (OR=.45).- Percentage population with a 4-year college degree and decreased likelihood of ACT (OR=.33).- Genetic testing and increased likelihood of AET (OR=1.92), ACT (OR=2.72), and ABT (OR=1.91).- Breast carcinoma in situ diagnosis preceding invasive disease diagnosis and decreased likelihood of receiving AET (OR=.56), ACT (OR=.2) and ABT (OR=.65). Conclusions: In a large cohort of commercially insured patients with early-stage invasive breast cancer, uptake of post-mastectomy adjuvant therapies varied and was influenced by several non-clinical factors. Results of real-world evidence cancer studies may support treatment-decision making, guide adoption of value-based care models and reduce treatment disparities. Citation Format: Yull Arriaga, Joseph Tkacz, M Christopher Roebuck, Judy George, Van Willis, Irene Dankwa-mullan. Factors associated with utilization of post-mastectomy adjuvant therapies in privately insured female patients with early-stage invasive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2617.

Abstract 279: Transient opening of the blood brain barrier by Tumor Treating Fields (TTFields)

Abstract Introduction Alternating electric fields of intermediate frequency and low intensity, known as Tumor Treating Fields (TTFields), are an effective and clinically approved approach for treatment of glioblastoma (GBM). The optimal frequency for treatment of glioma cells based on the cytotoxic response is at 200 kHz. Combination of TTFields with chemotherapy appears to be synergistic with further increase in overall survival of patients with GBM, beyond that with chemotherapy alone. The blood brain barrier (BBB) limits delivery of a majority of drugs to the brain thus limiting treatment options for GBM patients. Recent in vitro studies suggest that TTFields applied at 100 kHz can disturb the BBB. In this study, we investigated the potential use of TTFields to transiently disturb the BBB in animal models. Methods BBB permeation was tested in healthy rats subsequently to 100 kHz TTFields or sham (heat) application to the rat head. BBB permeability was analyzed by several staining agents: (1) Evans Blue (EB) that was quantified at 610 nm in brain homogenates; (2) 4 kDa TRITC-dextran (TD) that was quantified based on fluorescence intensity in brain cryosections; and (3) the MRI contrast agent Gd-DTPA. Accumulation and clearance of Gd-DTPA were tracked by serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). In addition, brain sections were stained for claudin-5, occludin, PECAM-1 and immunoglobulin G (IgG). BBB permeation induced by TTFields was further evaluated in rats orthotopically bearing F98 glioma cells and treated with TTFields at 100 kHz in combination with the chemotherapeutic drug paclitaxel (PTX) for a duration of 72 h. Tumor cell proliferation was assessed by Ki67 staining and the tumor volume was measured by T2 weighted MRI. Results BBB permeation of EB and TD staining agents was observed in the brains of healthy rats after TTFields application. Moreover, brain cryosections displayed delocalization of claudin-5 and occludin, but not of PECAM-1. Accumulation of IgG in the brain parenchyma was also noted. Confirming these observations, DCE-MRI post-TTFields treatment showed accumulation of Gd in the brain. Return to normal BBB integrity was detected 96 h after TTFields treatment cessation, indicating the effect was transient and reversible. In GBM-induced rats, the combination of PTX (a drug which normally does not cross the BBB) with TTFields significantly decreased tumor cell proliferation and tumor volume compared to animals treated with TTFields alone, sham alone, or sham combined with PTX. Conclusions Administration of 100 kHz TTFields to the brain of rats led to transient alterations in BBB integrity and permeability, allowing increased uptake of combination chemotherapy. These data indicate that TTFields treatment may be a feasible, novel clinical strategy for transient opening of the BBB to allow for enhanced and more effective delivery of permeable and non-permeable anticancer drugs to the brain. Citation Format: Catherine Tempel Brami, Ellaine Salvador, Almuth F. Kessler, Malgorzata Burek, Tali Voloshin, Moshe Giladi, Ralf-Ingo Ernestus, Mario Löhr, Carola Förster, Carsten Hagemann. Transient opening of the blood brain barrier by Tumor Treating Fields (TTFields) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 279.

Video-assisted thoracoscopic versus open lobectomy in patients with early-stage lung cancer: One-year results from a randomized controlled trial (VIOLET).

8504 Background: Video assisted thoracoscopic surgery (VATS) is a popular access for lung cancer resection. However, there is limited information from RCTs from in-hospital to one-year clinical efficacy, safety and oncologic outcomes of a minimal access approach. Methods: VIOLET is a parallel group multi-center RCT conducted in 9 centers in the United Kingdom that recruited participants with known or suspected (cT1-3, N0-1 and M0) lung cancer (ISRCTN13472721). Trial protocol: https://bmjopen.bmj.com/content/9/10/e029507.info. Results: From July 2015 to February 2019, 503 participants were randomized to VATS (n=247) or open (n=256) lobectomy. Patients allocated to VATS had less pain with a mean difference (MD) in visual analogue score of -0.54 (95%CI -0.99 to -0.10) despite less analgesic consumption (mean ratio 0.90, 95%CI 0.80 to 1.01). After discharge pain was consistent on multiple sub-scales including overall pain (MD -7.19, -10.59 to -3.80), chest pain (MD -4.66, -7.96 to -1.36) and an 18% relative risk (RR) reduction in incision pain (RR 0.82; 0.72 to 0.94) up to one-year. Better functional recovery continued in VATS arm after discharge with better physical function (primary outcome) with MD of 4.65 (1.69 to 7.61; P=0.002) at 5 weeks and overall improvement in global health status with a MD of 4.21 (1.62 to 6.79; P=0.001). In hospital, VATS arm had fewer complications (RR 0.74, 0.66 to 0.84; P&lt;0.001) with no difference in serious adverse events (RR 0.98, 0.59 to 1.63; P=0.948). Median hospital stay was one day shorter in the VATS arm (4 vs 5 days) corresponding to hazard ratio (HR) for discharge of 1.34, 95%CI 1.09 to 1.65; P=0.006). After discharge VATS arm had 19% less serious adverse events (RR 0.81, 0.66 to 1.00; p=0.053) and lower readmission rates (29.0% vs. 35.9% respectively) to one-year. Of those with lymph node disease, 50.9% in the VATS and 45.9% in open arms received adjuvant treatment. There was no difference in the time to uptake of adjuvant chemotherapy (HR 1.12, 0.62 to 2.02; p=0.716). Recurrence with clinical follow up and CT at one-year was similar with 7.7% versus 8.1% in the VATS and open groups respectively. Progression-free survival (HR 0.74, 0.43 to 1.27; p=0.27) and overall survival HR 0.67, 0.32 to 1.40; p=0.282) was not significantly different. Conclusions: VATS lobectomy for lung cancer is associated with less pain, fewer in-hospital complications and shorter hospital stay, achieved without any compromise to early oncologic outcomes nor serious adverse events. Superior functional recovery continues in the post-operative period with improved physical function, lower re-admission rates and no difference in disease-free and overall survival up to one-year. Clinical trial information: ISRCTN13472721.

Biologically optimized schedule of gemcitabine and nab-paclitaxel regimen in metastatic pancreatic adenocarcinoma.

TPS4168 Background: Metastatic pancreatic adenocarcinoma has a poor prognosis, and improvements in therapy have been challenging. Alongside efforts in developing novel agents, there is a need to optimize and maximize the benefit of currently approved drugs. Gemcitabine + nab-paclitaxel is a frequently used regimen for pancreatic adenocarcinoma. Nab-paclitaxel is albumin–bound chemotherapy; hence the role of albumin uptake is critical for its effect. Caveolae are small membrane invaginations essential for transendothelial albumin uptake. Cav-1 is the principal structural component of caveolae. Williams and colleagues have published a series of preclinical studies demonstrating that tumor cell-specific Cav-1 expression directly correlates with albumin and albumin-bound chemotherapy uptake and subsequent apoptotic response in tumor cells. In vitro studies showed that exposure of pancreatic cancer cells to Gemcitabine resulted in up-regulation of Cav-1 peaking 48 hours after gemcitabine exposure. This Cav-1 up-regulation correlated with increased temporal albumin cellular uptake. In addition, Williams and colleagues noted that exposure of pancreatic cancer cell lines to Gemcitabine resulted in a time–specific re-entry of cells into the G2/M phase (nab-paclitaxel cytotoxicity phase) between 48-60 hours after gemcitabine treatment. Collectively this data suggest that infusing nab-paclitaxel after 48 hours of gemcitabine infusion would be optimal for both increased uptake as well as increased susceptible tumor cells. We had previously shown this effect on multiple cell lines as well as mouse models. Methods: This is a phase II trial; patients will receive a standard of care chemotherapy regimen consisting of FDA-approved Gemcitabine + nab-paclitaxel with modification of the schedule to deliver nab-paclitaxel 48 hours (2 days) after gemcitabine infusions. The primary endpoint is ORR, with a null hypothesis of 20% vs. a target of 35%. Employing a 2-stage design (minimax) and assuming 80% power and a 0.05 significance level, a total of 53 patients will be required. In the first stage, if at least 7/31 patients respond to therapy, an additional 22 patients will be added for a total of 53 patients. The study will be terminated early if ≤ six patients respond in the first stage. Observation of response in at least 16/53 patients would be required to warrant further investigation of this infusion schedule of combination therapy. The secondary endpoints include the safety of the regimen schedule, Relative dose intensity, disease control rate, PFS, and OS. The trial opened to enrollment in June 2020 and is accepting patients. Clinical trial information: NCT04115163.