Benkhadra, Raed

Abstract Background: Recent advancements in novel therapeutics have resulted in improved survival over the last decade for patients with metastatic breast cancer, but there remain subsets of patients who experience disproportionately poor outcomes. Patients with visceral crisis (VC), defined by the 5th ESO ESMO as the presence of visceral metastasis with severe organ compromise and/or rapid progression, are often excluded from clinical trials of novel therapeutics. This is despite patients with VC having poorer clinical outcomes and a lack of guidelines consensus on best therapeutic practices. Thus, we sought to better characterize this patient cohort via a meta-analysis to elucidate clinical characteristics and treatment options. Methods: We searched MEDLINE, Embase, Cochrane, Scopus and other sources, from each database's inception to March 2023. The search strategy was designed and conducted by an experienced librarian with input from the study's principal investigator. Controlled vocabulary supplemented with keywords was used to search for patients with breast cancer in visceral crisis. Outcomes of interest included mortality and progression at different time points. Meta-analysis was conducted using the random-effects model. Results: The studies matching our initial inquiry was 154. After evaluation for patient number, and VC related outcomes, 16 studies (12 abstract only) met initial criteria. After data extraction, 12 studies were excluded due to insufficient outcomes delineated by VC. The treatment period was 01/2008 until 01/2022. The mean age at diagnosis of VC was 53.9 with a total of 6404 patients, 6259 were hormone positive, 41 Her2 positive and 87 triple negative. The type of VC included 212 liver dysfunction, 84 respiratory dysfunction, 40 with bone marrow dysfunction, 4 with SVC syndrome, and 43 with meningeal disease (VC type is not reported in every study). The treatments were varied and included multiple platinum doublets, CDK4/6 with endocrine therapy, platinum with bevacizumab, endocrine monotherapy and Her-2 targeted agents. Unfortunately, the number of patients per treatment group or VC type is not enough for targeted outcome analysis. The proportion of patients who progressed at 1, 6, 12 and 18 months were 0.17, 0.64, 0.95 and 0.91 respectively (2 studies Yang et al and Funasaka et al). Mortality assessed as proportion who expired at 1, 6, 12 and 18 months at 0.07, 0.44, 0.64 and 0.77 respectively (3 studies Yang et al, Funasaka et al and Franzoi et al) and at 24 months 0.89 in 4 studies (Yang et al, Funasaka et al, Dawood et al and Franzoi et al) (Table 1). Conclusions In this systematic review, we clearly demonstrate a lack of clinical trial data available to demonstrate specific outcomes based on chemotherapy, visceral crisis type or targeted treatment. The prognosis, however, is consistently poor with mortality at 64 percent by 12 months. Thus, further studies are needed to guide best treatment strategies that address both the poor clinical outcomes and therapeutic toxicities for patients with VC. Clinical trial groups and regulatory bodies overseeing new drug development for breast cancer should consider specific arms for patients with VC, instead of targeted exclusion from trials, as this strategy has proven effective in expansion of therapeutics for other challenging breast cancer subtypes. Table 1 Table 1: Proportion of progression and mortality. Progression studies include Yang et al 2022, Funasaka et al 2021. Mortality studies at 1, 6 and 12 months Yang et al 2022, Funasaka et al 2021 and Franzoi et al 2021. Mortality studies at 24 months Yang et al 2022, Funasaka et al 2021, Franzoi et al 2021, Dawood et al 2021. Citation Format: Michael Auster, Raed Benkhadra, Sophia Lee, Tamarah Aldawoodi, Larry Prokop, Tarek Nayfeh, Paromita Datta, Kate Lathrop. Meta-Analysis of Clinical Characteristics and Outcomes in Breast Cancer Patients with Visceral Crisis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-03.

Background: The global obesity epidemic has been well characterized over decades of research, linking increased body mass index (BMI) ≥ 25 to multiple medical conditions including increased cancer risk, morbidity, and mortality. The International Agency for Research on Cancer (IARC) group found a positive correlation between obesity to 13 cancers and multiple studies suggest leukemia should be added to this list. The causation behind this risk in leukemia however is not well understood and the prognostic factors have not been well characterized. Acute Myeloid Leukemia (AML) specifically defines risk based on cytogenetics between favorable, intermediate and unfavorable which significantly affects treatment decisions. The link between obesity and cytogenic risk factors in AML have not previously been thoroughly evaluated. To address this knowledge gap, we conducted a comprehensive meta-analysis aiming to evaluate the cytogenetic risk with obesity and prognostic significance in patients with AML. Methods: A systematic search was conducted across major databases until June 2023, using tailored search structures, subject headings, and keywords developed in collaboration with a medical research librarian. Two investigators independently screened the studies for inclusion. The inclusion criteria encompassed retrospective and prospective clinical studies that reported on the association between established cytogenetic classifications and standardized measures of excessive weight (BMI 25-30) and obesity (BMI ≥ 30). Meta-analysis was conducted using restricted maximum likelihood random-effects model. Results: From an initial pool of 1673 identified studies, eleven studies met the inclusion criteria, encompassing a total of 5887 patients. Among these patients, 1363 met the criteria for obesity (BMI ≥ 30) and 2176 met the criteria for excessive weight (BMI 25-30). The median patient's age was 54 (ranging from 15 to 89). The included studies originated from diverse geographic regions, including the USA, Japan, and France. Baseline patient characteristics are summarized in Table 1. Compared to overweight patients, our meta-analysis revealed a significant association between obesity and higher odds of unfavorable/intermediate cytogenetic risk (odds ratio [OR] 1.27, 95% CI [1.04; 1.54]), as seen in Figure 1. However, no meaningful statistical inference could be made regarding the association between obesity and specific gene mutations (such as FLT3, NPM1, CEBPa, TET2, IDH1, IDH2, RUNX1, and KRAS) due to the limited number of studies and small number of patients involved. Conclusion: Our meta-analysis demonstrates a significant association between obesity and unfavorable/ intermediate cytogenetic risk in patients with AML. Although the precise biological mechanisms remain elusive, several potential explanations have been proposed. These include the impact of obesity leading to chronic low-grade inflammation, altered adipokine secretion and insulin resistance, and metabolic changes on leukemic cell growth and survival. Despite the limitations of unknown cytogenetic risk in 590 patients and limited mutation data in some studies, our findings suggest that obesity may impact the prognosis of AML. Future research should address these limitations and provide a more comprehensive understanding of the intricate interplay between obesity, cytogenetics, and AML prognosis.

e19543 Background: Primary Bone Lymphoma (PBL) is defined as a lymphoma originating in an osseous site with no systemic disease. It is rare, constituting around 1% of all lymphomas. Due to its rarity, ascertaining natural history and standard of care treatments are based primarily on small case series but there have been no systematic reviews, randomized control trials or meta-analysis to establish optimal treatment strategies. Methods: We searched MEDLINE, Embase, Scopus and other sources, from each database's inception to September 2022. Outcomes of interest included mortality and progression at different time points, as well as complete response and partial response. Meta-analysis was conducted using the random-effects model. Results: The number of studies matching our inquiry was 51 ranging from 1955 to 2019. Total patients studied were 5,847 of which 3,055 were male and the dominant histology was diffuse large B cell lymphoma with 3,816. Treatment primarily consisted of radiation therapy, chemotherapy, or a combination of the two. Overall mortality at 2, 5 and 10 years was 17%, 29% and 39% respectively. Complete response to initial treatment was noted in 73% of patients. Disease progression at 2 and 5 years was 26% and 29% respectively. Patients aged older than 60 years and multiple sites of disease in the skeleton (such as axial and spine etc.) had worse outcomes with RR 1.76 (P value 0.0027) and 1.133 (P value 0.0167) respectively. Additionally, patients who underwent chemotherapy with radiation vs radiation alone had improved outcomes with a relative risk of 0.38 (P value of 0.0001). Patients who underwent radiation treatment in addition to chemotherapy tended to have improved outcomes with a relative risk of 0.60 but this was not statistically significant with a P value of 0.068. Conclusions: We performed a systematic review to determine the characteristics and current treatment of PBL. The analysis demonstrates the rarity and heterogenicity of the disease. The current standard of care is for chemoradiation, but this is based primarily on old case studies. Our study confirms the utility of multimodal treatment with a tendency for improved outcomes. However, further prospective trials are needed to determine the necessity of multimodal treatment given this hypothesis generating study. [Table: see text]

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC). OBJECTIVE: To compare the efficacy and safety of the two most commonly used cisplatin-based regimens; gemcitabine, and cisplatin (GC) vs. accelerated (dose-dense: dd) or conventional methotrexate, vinblastine, adriamycin, and cisplatin (MVAC). METHODS: We searched MEDLINE, Embase, Scopus and other sources. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model. RESULTS: We identified 24 studies. Efficacy outcomes were comparable between MVAC and GC for MIBC. dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95%CI 1.15–1.82) and all-cause mortality at longest follow-up (OR 0.63; 95%CI 0.44–0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95%CI 0.13–0.80), anemia (OR 0.32; 95%CI 0.18–0.54), nausea and vomiting (OR 0.27; 95%CI 0.12–0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3–4 thrombocytopenia (OR 4.70; 95%CI 1.59–13.89) and a lower risk of nausea and vomiting (OR 0.05; 95%CI 0.01–0.31). Certainty in the estimates was very low for most outcomes. CONCLUSIONS: Efficacy and safety outcomes were comparable between MVAC and GC for MIBC. Including non-peer-reviewed studies showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice.

e16522 Background: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC) in cisplatin-eligible patients. This systematic review and meta-analysis provide an updated efficacy and safety comparison between the two most commonly used cisplatin-based regimens; dose-dense (dd) or conventional MVAC versus GC. Methods: We searched different databases for studies comparing MVAC versus GC in the neoadjuvant setting. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model. Results: We identified 24 studies from inception to March 2020; among them 17 were peer reviewed and 7 were only reported as abstracts in national or international meetings, including a phase 3, randomized-controlled clinical trial. Among peer-reviewed published studies, efficacy outcomes such as OS, downstaging and pCR were comparable between conventional MVAC and GC for MIBC. If including non-peer-reviewed studies, dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95% CI 1.15–1.82), and OS at longest follow-up (OR 0.63; 95% CI 0.44–0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95% CI 0.13–0.80), anemia (OR 0.32; 95% CI 0.18–0.54), nausea and vomiting (OR 0.27; 95% CI 0.12–0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3–4 thrombocytopenia (OR 4.70; 95% CI 1.59–13.89) and a lower risk of nausea and vomiting (OR 0.05; 95% CI 0.01-0.31). Certainty in the estimates was very low for most outcomes. Conclusions: Among peer-reviewed published studies, efficacy and safety outcomes were comparable between conventional MVAC and GC for MIBC. However, If including non-peer-reviewed studies, this analysis showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice

e19530 Background: Intensive chemotherapy (IC) regimens are rarely used in patients with myelodysplastic syndromes (MDS) for many reasons including advanced age at diagnosis, the frailty of these patients, the presence of several comorbidities and potentially increased mortality when such regimens are used. Additionally, very little literature exists on its safety and long-term benefit in this population. Aim: To evaluate the safety and effectiveness of IC regimens in patients with MDS. Methods: We searched MEDLINE, Embase, Scopus and Cochrane databases from each database's inception from 1990 to January 27th, 2020. Keywords include: “MDS”, “induction chemotherapy” and “remission induction”. Studies evaluating different IC regimens with MDS were included. IC studies for patients with relapsed/ refractory MDS were excluded. Studies that combined acute myeloid leukemia (AML) and MDS outcomes were excluded. The random-effects model was used to pool relative risks and incidence rates. Main endpoints were overall remission rates (ORR), 30- and 60-days mortality, 1-year, 2-year and 5-year overall survival (OS). Results: Characteristics: From 2001 records, we included 13 studies [1,164 patients, median age 60.1 years (range, 17-88), males 58.9%, 58.4% patients had abnormal cytogenetics, median bone marrow blasts 17.8% (range 4 -29%), 4 studies were randomized]. Induction outcome: IC regimes included “7+3, FLAG, s-HAM, and few other regimens. Response: ORR was 55%, including 52% CR rate. Safety: 30- and 60-days mortality were 7%, 15%, respectively. Survival outcome: median survival was 11.6 months, 1-year, 2-year and 5-year OS were 48%, 21% and 5%, respectively. Randomized studies comparison: adding growth factors to IC did not show statistically significant effects on outcomes regarding induction mortality, ORR and OS (p-value > .05). Conclusions: IC is rarely used in MDS patients and its use is associated with high mortality rates and low long-term survival. Limitations to our studies include the long span of this review over 3 decades and the difficulty of using published studies that combines MDS and AML patients’ outcome. More studies are needed in this population of interest in the future.

Abstract Background Regorafenib at different dosing strategies and TAS-102 are treatment options for refractory metastatic colorectal cancer (mCRC). We aimed to evaluate the comparative effectiveness evidence supporting these different strategies. Materials and Methods We searched different databases for randomized controlled trials evaluating TAS-102 or regorafenib in patients with refractory mCRC who failed prior oxaliplatin, irinotecan, and fluoropyrimidine. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White's multivariate meta-regression to pool evidence from direct and indirect comparisons. Results Six trials at low risk of bias (2,445 patients) were included. Direct comparisons showed that Rego 160 and TAS-102 as monotherapy were superior to best-supportive care (BSC) in terms of PFS (Rego 160: hazard ratio [HR], 0.4; 95% confidence ratio [CI], 0.26–0.63; TAS-102: HR, 0.46 CI, 0.40–0.52) and OS (Rego 160: HR, 0.67; CI, 0.48–0.93; TAS-102: HR, 0.67; CI, 0.57–0.80). Network analysis showed no statistically difference in PFS or OS between Rego 160 and TAS-102. Rego 80+ was superior to BSC in terms of OS (HR, 0.44; CI, 0.23–0.84) and PFS (HR, 0.37; CI, 0.21–0.66). Rego 80+ was associated with statistically nonsignificant improvement in OS and PFS compared with TAS-102 and Rego 160. Conclusion Regorafenib 160 and TAS-102 appear to have similar efficacy. Rego 80+ is shown to be superior to BSC. A trend for improved OS was observed with Rego 80+ versus Rego 160 or TAS 102. Implications for Practice Regorafenib at a dose of 160 mg and TAS-102 appear to have similar efficacy in patients with refractory metastatic colorectal cancer. Regorafenib with a dose escalation strategy is superior to best-supportive care. Given its tolerability and the observed trend in survival benefit compared with regorafenib 160, dose escalation strategy of regorafenib (80+) may be the preferred option in this setting.

Introduction Chronic obstructive pulmonary disease (COPD) is a progressive lung disease, usually caused by tobacco smoking, but other important risk factors include exposures to combustion products of biomass fuels and environmental pollution. The introduction of several new (combination) inhaler therapies, increasing uncertainty about the role of inhaled corticosteroids and a rapid proliferation of the literature on management of stable COPD in general, call for novel ways of evidence synthesis in this area. A systematic review and evidence map can provide the basis for shared decision-making tools and help to establish a future research agenda. Methods and analysis This systematic review will follow an umbrella systematic review design (also called overview of reviews). We plan to conduct a comprehensive literature search of Ovid MEDLINE (including epub ahead of print, in process and other non-indexed citations), Ovid Embase, Ovid Cochrane Database of Systematic Reviews and Scopus from database inception to the present. We will include systematic reviews that assessed the effectiveness of any pharmacological or non-pharmacological intervention on one or more patient-important outcomes and/or lung function in patients with stable COPD. For every intervention/outcome pair, one systematic review will be included. An a priori protocol will guide, which systematic reviews will be chosen, how their credibility will be evaluated, and how the quality of the body of evidence will be rated. Data will be synthesised into an evidence map that will present a matrix that depicts each available treatment for stable COPD with a quantitative estimate on symptoms/outcomes from the patient perspective, along with an indication of the size and certainty in the evidence. Ethics and dissemination Approval by a research ethics committee is not required since the review will only include published data. The systematic review will be published in a peer-reviewed journal. PROSPERO registration number CRD42018095079

Background. This systematic review was commissioned to identify new variables associated with transplant outcomes that are not currently collected by the Organ Procurement and Transplantation Network (OPTN). Methods. We identified 81 unique studies including 1 193 410 patients with median follow-up of 36 months posttransplant, reporting 108 unique risk factors. Results. Most risk factors (104) were recipient related; few (4) were donor related. Most risk factors were judged to be practical and feasible to routinely collect. Relative association measures were small to moderate for most risk factors (ranging between 1.0 and 2.0). The strongest relative association measure for a heart transplant outcome with a risk factor was 8.6 (recipient with the previous Fontan operation), for a kidney transplant 2.8 (sickle cell nephropathy as primary cause of end-stage renal disease), for a liver transplant 14.3 (recipient serum ferritin >500 µg/L), and for a lung transplant 6.3 (Burkholderia cepacia complex infection for 1 y or less). OPTN may consider some of these 108 variables for future collection to enhance transplant research and clinical care. Conclusions. Evidence-based approaches can be used to determine variables collected in databases and registries. Several candidate variables have been identified for OPTN.