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ImportanceTranexamic acid reduces bleeding and blood transfusion in many types of surgery, but its effect in patients undergoing liver resection for a cancer-related indication remains unclear.ObjectiveTo determine whether tranexamic acid reduces red blood cell transfusion within 7 days of liver resection.Design, Setting, and ParticipantsMulticenter randomized clinical trial of tranexamic acid vs placebo conducted from December 1, 2014, to November 8, 2022, at 10 hepatopancreaticobiliary sites in Canada and 1 site in the United States, with 90-day follow-up. Participants, clinicians, and data collectors were blinded to allocation. A volunteer sample of 1384 patients undergoing liver resection for a cancer-related indication met eligibility criteria and consented to randomization.InterventionsTranexamic acid (1-g bolus followed by 1-g infusion over 8 hours; n = 619) or matching placebo (n = 626) beginning at induction of anesthesia.Main Outcomes and MeasuresThe primary outcome was receipt of red blood cell transfusion within 7 days of surgery.ResultsThe primary analysis included 1245 participants (mean age, 63.2 years; 39.8% female; 56.1% with a diagnosis of colorectal liver metastases). Perioperative characteristics were similar between groups. Red blood cell transfusion occurred in 16.3% of participants (n = 101) in the tranexamic acid group and 14.5% (n = 91) in the placebo group (odds ratio, 1.15 [95% CI, 0.84-1.56]; P = .38; absolute difference, 2% [95% CI, −2% to 6%]). Measured intraoperative blood loss (tranexamic acid, 817.3 mL; placebo, 836.7 mL; P = .75) and total estimated blood loss over 7 days (tranexamic acid, 1504.0 mL; placebo, 1551.2 mL; P = .38) were similar between groups. Participants receiving tranexamic acid experienced significantly more complications compared with placebo (odds ratio, 1.28 [95% CI, 1.02-1.60]; P = .03), with no significant difference in venous thromboembolism (odds ratio, 1.68 [95% CI, 0.95-3.07]; P = .08).Conclusions and RelevanceAmong patients undergoing liver resection for a cancer-related indication, tranexamic acid did not reduce bleeding or blood transfusion but increased perioperative complications.Trial RegistrationClinicalTrials.gov Identifier: NCT02261415

84 Background: Local therapies potentially offer a curative approach for patients with oligometastatic colorectal cancer (CRC). The effectiveness of systemic chemotherapy following definitive local treatment in this setting is not well-defined. Tumor-informed circulating tumor DNA (ctDNA) might guide management strategies after curative-intent local treatment. Methods: This is a single institution retrospective study of patients with CRC who underwent curative-intent local therapy to an isolated site of metastatic disease and had post-intervention tumor-informed ctDNA (Signatera) testing. The study was approved by the institutional review board. Clinical characteristics, including ctDNA results, were collected and evaluated. Kaplan-Meier method and log-rank test were used to calculate and compare disease-free survival (DFS). Factors associated with DFS were analyzed using multivariate Cox proportional hazards model. Results: 45 patients were included with median age of 59 years, 62% being male, 91% white, and 53% with stage IV disease at diagnosis. 37% of the patients had RAS mutations, no patient had BRAF mutation, and 2.2% patient had mismatch repair deficient disease. Isolated liver metastases were present in 80% of patients, lung metastases in 11% and other sites in 9%. 44 patients received chemotherapy prior to definitive treatment, with a median treatment duration of 16 weeks. ctDNA tests were done prior to local therapy in 23 patients, with 14 cases (61%) testing positive. Definitive treatment included resection (58%), ablation (13%), radiotherapy (4%), and multimodality (25%). Post-definitive treatment chemotherapy was administered to 24 (53%) patients. ctDNA positivity following definitive therapy was observed in 10 patients (22%), which was associated with a poorer prognosis, with a median DFS of 5.3 months compared to 21.3 months for the ctDNA-negative group (p<0.001). These findings were confirmed on multivariate analysis. In patients who had negative ctDNA after definitive local treatment, median DFS was 14.9 months for those who received post-intervention chemotherapy versus 21.3 months for those without post-intervention chemotherapy (p=0.835). Conclusions: Patients with negative ctDNA results following definitive local therapy for isolated metastatic CRC have better prognosis. Post-intervention chemotherapy in this group of patients was not associated with improved DFS. ctDNA guided omission of post-intervention chemotherapy following curative-intent local treatment of oligometastatic CRC warrants further study. [Table: see text]

Background: Hospitalization represents a major access point for prescription opioids, yet little is known regarding patterns and outcomes of opioid exposures before and after hospitalization for critical illness. Methods: This is an observational, population-based cohort study of adults (≥18 years) hospitalized for critical illness from 2010 to 2019. Multivariable models assess associations between opioid exposures prior to hospitalization, classified according to the Consortium to Study Opioid Risks and Trends, and posthospitalization opioid exposures and clinical outcomes through 1-year posthospitalization. Results: Of 11 496 patients, 6318 (55%) were men with a median age of 66 (51, 79) years and 40% (n = 4623) surgical admissions. Prehospitalization opioid availability included 8449 (73%) none, 2117 (18%) short-term, 471 (4%) episodic, and 459 (4%) long-term. Thirty-nine percent (4144/10 708) of hospital survivors were discharged with opioids, with higher prescribing rates for surgical admissions (55%). Greater preadmission opioid exposures were associated with higher prevalent opioid availability at 1 year (odds ratio [95% confidence interval] 24.1 [18.3-31.8], 9.42 [7.18-12.3], and 2.55 [2.08-3.12] for long-term, episodic, and short-term exposures, respectively, vs none, P < .001). Greater preadmission opioid exposures were associated with longer hospitalizations (1.13 [1.04-1.23], 1.15 [1.06-1.25], and 1.08 [1.04-1.13] multiplicative increase in geometric mean, P < .001), more readmissions (hazard ratio [HR] 2.08 [1.74-2.49], 1.88 [1.56-2.26], and 1.48 [1.33-1.64], P < .001), and higher 1-year mortality (HR 1.59 [1.28-1.98], 1.75 [1.41-2.18], and 1.49 [1.32-1.69], P < .001). Similar associations were observed across surgical and nonsurgical admissions. Conclusions: Prehospitalization opioid exposures in survivors of critical illness are associated with clinical outcomes through 1 year and may serve as important prognostic markers.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan–Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar’s test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

PURPOSE The RECIST guidelines provide a standardized approach for evaluating the response of cancer to treatment, allowing for consistent comparison of treatment efficacy across different therapies and patients. However, collecting such information from electronic health records manually can be extremely labor-intensive and time-consuming because of the complexity and volume of clinical notes. The aim of this study is to apply natural language processing (NLP) techniques to automate this process, minimizing manual data collection efforts, and improving the consistency and reliability of the results. METHODS We proposed a complex, hybrid NLP system that automates the process of extracting, linking, and summarizing anticancer therapy and associated RECIST-like responses from narrative clinical text. The system consists of multiple machine learning–/deep learning–based and rule-based modules for diverse NLP tasks such as named entity recognition, assertion classification, relation extraction, and text normalization, to address different challenges associated with anticancer therapy and response information extraction. We then evaluated the system performances on two independent test sets from different institutions to demonstrate its effectiveness and generalizability. RESULTS The system used domain-specific language models, BioBERT and BioClinicalBERT, for high-performance therapy mentions identification and RECIST responses extraction and categorization. The best-performing model achieved a 0.66 score in linking therapy and RECIST response mentions, with end-to-end performance peaking at 0.74 after relation normalization, indicating substantial efficacy with room for improvement. CONCLUSION We developed, implemented, and tested an information extraction system from clinical notes for cancer treatment and efficacy assessment information. We expect this system will support future cancer research, particularly oncologic studies that focus on efficiently assessing the effectiveness and reliability of cancer therapeutics.

1518 Background: Despite high interest among young women diagnosed with breast cancer (BC) in future fertility, prior research has been hampered by short follow-up and lack of prospective assessment of pregnancy attempts. We sought to describe fertility outcomes among young women participating in a prospective cohort who reported pregnancy attempt post-BC diagnosis. Methods: Women with stage 0-III BC in the Young Women's Breast Cancer Study (YWS, NCT01468246), a multicenter, prospective cohort of women diagnosed at age ≤40 from 2006-2016 who reported attempting pregnancy post-diagnosis were included. Those with prior hysterectomy, bilateral oophorectomy, or metastatic disease at diagnosis were excluded. Data on attempting pregnancy and fertility outcomes were obtained from serial surveys. Multivariable logistic regression with stepwise model selection was used to identify factors associated with pregnancy and live birth. Results: Among 1213 eligible participants, 197 reported any attempt of pregnancy (16%) over a median follow-up of 11 years (range: 3-17). Among attempters, median age at diagnosis was 32 years (range: 17-40); 74% were non-Hispanic White; 41% had stage I, 35% stage II, 10% stage III, and 14% stage 0 BC; 76% had HR+ disease; 68% received chemotherapy; 57% received endocrine therapy within one year post-diagnosis; 13% were BRCA1/2 pathogenic variant (PV) carriers; 51% reported financial comfort at baseline; 51% were nulligravida and 72% nulliparous at diagnosis; 28% had undergone fertility preservation consisting of egg/embryo freezing at diagnosis; 15% reported a history of infertility before BC diagnosis. Most (73%) reported ≥1 pregnancy after diagnosis and 65% reported ≥1 live birth. Median time from diagnosis to first pregnancy was 48 months (range: 6-125). In the multivariable model, greater age at diagnosis (odds ratio [OR] 0.82 per year increase, 95% CI 0.74-0.90, P<0.0001) was negatively associated with pregnancy, while financial comfort at baseline (OR 2.04, 95% CI 1.01-4.12, P=0.047) was predictive of pregnancy. For live births, greater age at diagnosis was negatively associated (OR 0.82 per year increase, CI 95% 0.76-0.90, P<0.0001) while having undergone fertility preservation at diagnosis was predictive (OR 2.78, 95% CI 1.29-6.00, P=0.009). History of infertility, nulliparity at diagnosis, tumor characteristics, cancer treatment, race, ethnicity, and BRCA1/2 PV status were not associated with either outcome. Conclusions: This is the first prospective study with greater than 10 years of follow-up to report fertility outcomes in young BC survivors accounting for attempting pregnancy. The majority achieved a pregnancy and most reported a live birth. Our findings can be incorporated into the counseling of young BC patients and survivors, and highlight the need for accessibility of fertility preservation services for this population. Clinical trial information: NCT01468246 .

11079 Background: Phase 3 randomized clinical trials (RCTs) inform the standard of care in cancer treatment yet have a mixed track record of success. In this study, we sought to 1) determine the overall success rate of phase 3 RCTs; 2) assess whether authorship patterns differ between successful (positive) and unsuccessful (negative) trials; and 3) explore if individual authors have distinct track records of success. Methods: The HemOnc knowledgebase (KB) was queried for initial publications of phase 3 RCTs of systemic anticancer therapy; those without primary outcome described were excluded. RCTs were labeled positive if the primary endpoint was met per HemOnc standard criteria (P value ≤ 0.05 or hazard ratio upper bound ≤ 1 for any experimental arm[s]) and negative if they did not meet these criteria or if the experimental arm was statistically inferior. Trial metadata and author information were extracted from the HemOnc KB. Author positive publication rate (PPR) was defined as % of publications reporting a positive result divided by total number of eligible publications. Prolific authors were defined as those with 6+ eligible publications. Author count for manuscripts reporting positive vs negative results was evaluated with the Mann-Whitney U test; other statistics were descriptive. Results: 3328 studies met criteria as of February 5, 2024; these were associated with 3305 initial publications between 1960-2023, involving 25,412 unique authors. 1474 (44.3%) of the studies were positive. Publications reporting positive trial results had, on average, 3 more authors, median (interquartile range) of 18 (12-23) vs 15 (11-20), p<0.0001. The mean (±SD) PPR for n=1967 prolific authors was 47.7% (±22.3%). The PPR was not related to individual author output; mean PPR for non-prolific authors was 48.0% (SD not reported). Differences in PPR were apparent by the disease under study and the years of publication (Table). Among the 46 prolific authors who had a PPR 2+ SD above the mean, 26 (55%) were from China followed by Italy with 3 (6%). Conclusions: Despite known positive publication bias, the success rate of published phase 3 RCTs remains <50%. Publications reporting positive results had significantly more authors; this finding requires further study including adjustment for trial sample size. Significant variation in PPR amongst fields could be due to watershed therapeutic advances, differential selection of primary endpoints, and/or selective reporting of results. Finally, a signal for geographic association of outlier PPRs suggests the need for further investigation. [Table: see text]

11030 Background: Drug regulators operate on their own timelines to assess the safety and efficacy of new drugs and/or extensions to existing indications, such that there are delays between regulators. During such a gap, patients in the “early” domain have access to the approved drug, while those in the “late” domain do not, outside of compassionate use. Our study aimed to quantify the “opportunity lost” for new therapies approved by FDA and EMA, assuming patients in the late domain receive standard-of-care (SOC) therapy – which is presumably inferior to the new drug – during the gap. Methods: Anticancer drugs approved by both FDA and EMA were identified through the HemOnc knowledgebase. Inclusion criteria included: 1) drugs approved in both domains based on the same randomized clinical trial (RCTs) for the same indication; 2) a primary time-to-event endpoint; and 3) a quantitated median time-to-event for the primary endpoint. For each included trial, the approval gap between FDA and EMA in days and the ratio of approval gap to median control arm time-to-event duration was calculated. A ratio ≥2 implies that, on average, no late domain patients starting treatment in the first half of the gap would be expected to have access to the new drug prior to an event. Results: Of 60 eligible RCTs, 59 had calculable median event durations. 25 (42%) had a primary overall survival endpoint; the most common surrogate endpoint was progression-free survival (PFS; 29/59; 49%). The median (interquartile range [IQR]) approval gap was 186 (124-271) days, with FDA being the first approver in 56/59 (95%) cases. The median (IQR) ratio of approval gap to median control arm event duration was 0.63 (0.35-1.11). Drugs with ratio ≥2 (Table) were targeted or immunotherapies; 7/8 (88%) were approved with PFS endpoint; 5/8 (62.5%) were approved for second line or later. Conclusions: Our study shows that FDA approves most drugs prior to EMA and a nontrivial number of patients may experience progression or death events while awaiting access to anticancer therapies already approved in another domain. The analysis does not take into consideration scenarios in which the new therapy is inferior to SOC or delays in patient access (due to slow uptake; regulatory barriers [in Europe/UK]; or patient affordability [in US]). Further regulatory collaboration (e.g., Project Orbis) between FDA and EMA could help to reduce and potentially ameliorate this differential in access to new cancer drugs in the future. [Table: see text]

11023 Background: Randomized clinical trials (RCTs) in cancer typically compare experimental to control arm regimens. The choice of an appropriate control (ctrl) arm can have a major impact on the expected success of an RCT. The frequency with which cancer RCTs use control arms based on established dosing and scheduling protocols has not been described. Methods: The HemOnc knowledgebase (KB) was used to identify systemic anti-cancer therapy (SACT) regimen variants, defined as regimens with identical components that differ in dosing, scheduling, and/or route. Non-cancer, nonrandomized, and non-SACT studies were excluded. Study publication year was used to define standard variants as those evaluated in the experimental arm of a positive phase 3 RCT >1 year prior to publication as a control arm, regardless of cancer type or context of treatment. Study-variant dyads were evaluated to determine whether the variant was standard. Success rates of RCTs with standard vs non-standard control arms were evaluated with Fisher’s exact test. Results: 5221 studies were associated with ≥1 named variant in the HemOnc KB, as of 2024-02-06. After exclusions, there were 3511 study-variant dyads (2386 studies; 1714 variants). The 9 most common regimens are shown in the Table. The median (IQR) number of variants per regimen was 2 (1-3); carboplatin & paclitaxel (CP) had the most variants (n=33). Across all control arm study-variant dyads, 2228/3492 (64%) utilized non-standard variants. For example, 60/97 studies (62%) of docetaxel as control used the 75 mg/m2 q3wk variant after it was established in 2000, whereas n=27 others used 19 non-standard variants. Trials that used a standard control arm had a numerically higher success rate, 45% vs 42% (OR 1.10, 95% CI 0.92-1.32). Conclusions: Non-standard regimen variants are frequently used in cancer RCTs. Reasons for this could include toxicity, patient convenience, or emerging data from smaller studies that establish comparable efficacy or improved toxicity to standard variants. However, the a priori efficacy of non-standard control arms is less rigorously established, and trials with standard control arms might be more successful. Future directions include quantifying the granular differences between standard and non-standard variants and investigating whether certain types of non-standard variation (e.g. fewer cycles, lower doses) associate with trial success rates. [Table: see text]