Initial Chemotherapy Research Articles

AMH levels after initial cycles of chemotherapy in female adolescents with Ewing sarcoma and implications for preservation of fertility.

10067 Background: Anti-Müllerian hormone (AMH) has been recommended as the primary surveillance modality for evaluation of ovarian insufficiency in females. Patients with Ewing sarcoma receive VDC-IE chemotherapy which is estimated high risk of gonadotoxic injury. Previous studies have shown that only a small part of female patients with Ewing sarcoma show signs of ovarian recovery during long-term follow-up, similar to those treated with SCT or abdominal radiotherapy. Time to start preservation of fertility should be defined in this group of patients. Methods: In this observational study, we prospectively investigated AMH as a measure of ovarian function in female adolescents (less than 18 years old) with Ewing sarcoma who received initial chemotherapy in our hospital. Patients previously treated with systemic treatment were excluded. Serum levels of AMH were measured at the laboratory of Peking University People’s Hospital. Blood samples were collected at the first day of the initial two cycles of VDC-IE treatment, before local therapy including surgical resection and radial radiation, and at the end of chemotherapy. All statistical analyses were performed using SPSS 19.0 version. Results: A total of 53 female adolescents with Ewing sarcoma who received initial chemotherapy in our hospital were analyzed from February 1, 2021 to December 31, 2023, including 35 patients aging from 6 to 12 (group 1), 18 patients aging from 12 to 18 (group 2). 255 blood samples from unique time points were measured. The baseline mean AMH were 4.16 (90% CI, 1.88 – 9.42) ng/mL in all patients, 3.58 (90% CI, 1.40 – 6.91) ng/mL for group1 and 5.28 (90% CI, 3.10 – 9.48) ng/mL for group 2. The mean AMH level after first cycle of chemotherapy was 0.43 (90% CI, 0.03 – 0.81) ng/mL in all patients, 0.40 (90% CI, 0.03 – 0.69) ng/mL and 0.47 (90% CI, 0.12 – 1.09) ng/mL for each group at a mean time of 16.5 days after initial chemotherapy. The mean AMH level before local therapy was 0.17 (90% CI, 0.03 – 0.37) ng/mL and 0.07 (90% CI, 0.01 – 0.32) ng/mL at the end of chemotherapy. Conclusions: Female adolescents with Ewing sarcoma treated by VDC-IE regimen showed a rapid reduction of AMH after initial cycles. Methods for preservation of fertility should be implemented as soon as possible but not at the same time of local therapy.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC.

e20531 Background: First-line pemetrexed-platinum chemotherapy + osimertinib (Pem-Plat-Osi) improves progression free survival as compared to osimertinib (Osi) alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe the outcomes of patients who receive Pem-Plat-Osi after progression on first-line Osi in 2 tertiary cancer centres. Methods: Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line Osi at National Cancer Centre Singapore and Chinese University of Hong Kong were identified. Primary endpoints were time to treatment failure (TTF) and overall survival (OS) by Kaplan-Meier. Results: A total of 60 patients were included. Median age at diagnosis was 62, 53% (32/60) were male and 77% (46/60) were never smokers. Ex19del comprised 57% (34/60) and L858R 43% (26/60). Baseline central nervous system (CNS) metastases were present in 67% (40/60). Median TTF1 on Osi was 12 months (m) and median time to initiation of Pem-Plat-Osi was 41 days (d) (range 0-652) after progression on Osi. CNS failure occurred in 10 patients (16.7%). Partial response (PR) to Pem-Plat-Osi was achieved as best response in 45% (27/60), stable disease in 37% (22/60) and progressive disease in 18% (11/60). Three of 4 patients with CNS PD on Osi who did not undergo brain radiotherapy achieved PR/SD to Pem-Plat-Osi. At median follow up of 31m, median TTF2 on Pem-Plat-Osi was 6m, median TTF1+TTF2 was 20m and median OS was 34m. Comparing ex19del and L858R, there was no significant difference in median TTF1 (10m vs 12m, p=0.63), TTF1+TTF2 (19m vs 21m, p=0.50) and OS (34m vs 36m, p=0.40). Median TTF1+TTF2 (19m vs 20m, p=0.84) and OS (31m vs 36m, p=0.68) were similar in patients with or without baseline CNS metastases. There was no significant difference in TTF2 comparing patients who had TTF1<12m versus TTF1≥12m (both median 6m, p=0.56). Patients who started Pem-Plat-Osi within 20d of progression on Osi had significantly longer TTF2 as compared to patients who started after 20d (median 8m versus 5 months, hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.23-0.89, p=0.016) although there was no significant difference in OS (median 31m versus 34 months, p=0.35). Achieving PR was predictive of superior TTF2 (median 8m vs 5m, HR 0.46, 95% CI 0.26-0.84, p=0.005) but not OS (median 36m vs 32m, p=0.45). Conclusions: Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first line Osi, including among L858R subtype and patients with baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression and achieving PR were significantly associated with superior TTF2. Sequential approach of adding chemotherapy upon osimertinib failure is a plausible treatment option.

Reducing the time to chemotherapy start for planned admissions.

e23201 Background: Planned hospital admissions for chemotherapy should be initiated shortly after arrival. Between January 2022 and May 2023, 25.7% of sarcoma patients at Medstar Washington Hospital Center admitted for chemotherapy experienced initiation of chemotherapy delays of more than 6 hours. Delays in chemotherapy initiation can lead to prolonged hospitalization with associated higher costs, increased risk of hospital acquired conditions, and decreased patient satisfaction. Methods: Discussions with team members involved in the initiation of inpatient chemotherapy process identified the following issues contributing to delay: absence of recent lab results, challenges with IV access, missing chemotherapy consent forms, absence of chemotherapy orders, failure to notify team members of patient arrival, lack of dose adjustments based on lab work, and insufficient pharmacy staffing. As our chemotherapy floor policy is to start pre-medications once the chemotherapy is on the unit, we defined the time to chemotherapy start as the time of the first pre-medication minus the time the patient checked in to the hospital’s admissions office. Patients with unforeseen issues such as a new fever on arrival were excluded. We obtained baseline data for sarcoma admissions between January 2022 to May 2023. Two Plan-Do-Study-Act (PDSA) cycles were implemented. The first cycle involved the introduction of a chemotherapy calendar. The second cycle implemented a group email system to finalize all arrangements for the admission. We collected about 3 months of data for each PDSA cycle. Results: Pre-intervention, there were 101 sarcoma admissions with 14.9% of patients starting chemotherapy in < 3 hours while 25.7% took > 6 hours. In the post-intervention data combining both PDSA cycles, 6.8% of patients started chemotherapy in < 3 hours while 43.2% took > 6 hours. As such, the average time to chemotherapy start was increased in post-intervention groups (table 1) despite improvements in many of the common issues. The median time to chemotherapy start based on the number of agents the patient was receiving was 4.98, 6.4, and 7.18 hours respectively for 1, 2, and 3 agents in the post-intervention group. Conclusions: Despite multiple attempts, the median time to chemotherapy start increased in the post-intervention groups. Our interventions targeted many of the barriers except insufficient pharmacy staff. With the median start time increasing based on the number of agents the patient was receiving, it appears that pharmacy mixing and delivery chemotherapy is likely one of the main causes of the delays. Subsequent discussions with the pharmacy team revealed plans to increase staffing as a proactive measure to address this issue. [Table: see text]

Homologous recombination deficiency score for predicting efficacy of platinum-based chemotherapy and PARPi maintenance therapy in ovarian cancer.

e17543 Background: Currently, homologous recombination deficiency (HRD) has been confirmed to be a predictive biomarker for poly-ADP-ribose-polymerase inhibitors (PARPi) in ovarian cancer, while its effects on the clinical outcomes of platinum-based chemotherapy and PARPi maintenance therapy are not assessed rigorously in ovarian cancer. We developed an HRD assay to evaluate the effect of HRD scores on the platinum-based chemotherapy and PARPi maintenance therapy in Chinese patients with ovarian cancer. Methods: HRD testing was performed on the samples obtained at primary cytoreductive surgery. The progression-free survival (PFS) was observed among the BRCA-mutated/HRD-positive and BRCA wild-type/HRD-negative patients. Univariate and multivariate COX analyses were performed to test the association of PFS with different variables, and hazards ratios (HR) and 95% confidence interval (CI) were calculated. The two-tailed p value less than 0.05 was considered statistically significant. Results: Totally 74 patients who received platinum-based chemotherapy were eligible for the study, among whom 81.1% responded to the initial platinum-based chemotherapy, 33.8% harbored BRCA1/2 mutations and 74.3% were HRD-positive. The median HRD score of platinum-sensitive patients (n=60) was 48.5, significantly higher than the 31 of platinum-resistant patients (n=14, p=0.0035). Analysis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) between platinum-sensitive and platinum-resistant patients showed significant differences in TAI ( p=0.0012) and LST ( p=0.004). Compared with HRD-negative patients, HRD-positive patients had a significantly longer median PFS (10 vs. 15 months, p=0.017), and multivariate analysis further indicated that HRD-positive status (HR, 0.423, 95%CI: 0.191-0.939, p=0.035) was a significant predictor for the improvement of PFS. Conclusions: The HRD assay developed in our study can accurately predict the response to platinum-based chemotherapy and PARPi efficacy in patients with ovarian cancer, providing powerful evidence for implementation of genetic testing and guidance of clinical treatment in ovarian cancer.

Clinical features and prognostic analysis of 247 patients with ovarian clear cell carcinoma (OCCC) and an exploration of the treatment of recurrent OCCC: A single-center study in China.

e17548 Background: Ovarian clear cell carcinoma (OCCC) is relatively resistant to chemotherapy and has a worse prognosis than other ovary cancer. In this study, we reviewed the case files of OCCC in a single center to find its clinical characteristics and explore the treatment of recurrent cases, and the efficacy of immunotherapy. Methods: From August 2007 to August 2023 247 patients with OCCC were retrospectively involved. Univariate and multivariate Cox regression analyses were used to identify independent clinicopathological factors. The relapse OCCC were divided into four groups based on the different treatment who underwent chemotherapy or chemotherapy combined with surgery, bevacizumab, immune checkpoint inhibitors treatment. Kaplan–Meier curves were utilized to compare OS and DFS/PFS between the groups. Results: (1) 247 patients with OCCC were included, CA125 abnormality (> 35 U/ml) 65.2%, ascites cytology positive 10.1%, and the overall satisfactory reduction of tumor was 92.7%, CR and PR were 93.1 and 6.9%, respectively. 16.2% patients received more than 6 cycles of postoperative chemotherapy.(2)Univariate Cox regression analysis identified ascites (HR=4.012, 95% CI: 1.846 - 8.720, P<0.001), initial treatment effect (HR=2.714, 95% CI: 1.132 - 6.506, P=0.025), and chemotherapy cycles (HR=2.564, 95% CI: 1.402 - 4.689, P=0.002) were identified as independent prognostic factors for OS.(3)The patients who received chemotherapy cycles exceeding 6 cycles had worse prognosis(HR=3.01, 95%CI: 1.70-5.33, P<0.001), the result is the first proposal in our study.(4) Kaplan-Meier survival analysis showed that the OS of the chemotherapy combined with surgery relapse OCCC group was significantly better than the other three groups (HR=0.2732, 95%CI: 10.133-0.559, P=0.001). Subgroup analysis showed that relapse patients with satisfactory tumor reduction had more significant survival benefits(HR=3.86, 95%CI: 0.79-18.93, P=0.096).(5)The PFS of the chemotherapy combined with surgery group was also better than the other three groups (median PFS 25 months vs 8.5 months in chemotherapy vs12 months in chemotherapy combined immunotherapy vs 12 months in chemotherapy combined with bevacizumab). (6)4 patients who tested positive for PD-L1 received immune maintenance therapy after chemotherapy for 6-24months. There has been no recurrence since follow-up. Conclusions: Ascites, initial treatment effect and chemotherapy cycles were identified as independent prognostic factors for OCCC OS, chemotherapy combined with surgery for recurrent OCCC was significantly improving patient prognosis. For patients who achieve CR after initial treatment, if PD-L1 expression is positive, maintenance immunotherapy can be considered, but further studies with large samples are needed.

Osimertinib, platinum, etoposide as initial treatment for patients with EGFR mutant lung cancers with TP53 and RB1 alterations.

8565 Background: EGFR-mutant lung adenocarcinomas (EGFR+LC) transform to small cell lung cancer (SCLC) in up to 14% of cases, which creates an aggressive disease phenotype that is treated like de novo small lung cancer with platinum/etoposide chemotherapy. Transformed EGFR+LC molecularly mimic de novo small cell lung cancers and harbor TP53and RB1 loss. We hypothesized that if small cell directed chemotherapy is utilized prior to histologic transformation in EGFR/TP53/RB1 mutant LC, we may eradicate any pre-existing small cell clones, prevent small cell histologic transformation, and improve patient outcomes. Methods: We administered osimertinib, platinum, and etoposide in patients with newly diagnosed EGFR+LC with TP53and RB1alterations. Patients received 3 months of osimertinib induction, then 4 cycles of osimertinib, platinum and etoposide followed by osimertinib until progression. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were assessed. Patients were required to have an on-treatment biopsy prior to initiation of chemotherapy upon which single cell RNA sequencing (scRNAseq) was performed. All patients had pre-treatment and post-progression biopsies that underwent next-generation sequencing. Patients were evaluated for acquired resistance (classified as on-target, off-target, transformation, and unknown). Among patients that transformed, markers of SCLC (ASCL1, NEUROD1, POU2F3, YAP1, synaptophysin, chromogranin, and Ki-67) were analyzed. Results: Eleven patients were enrolled [median age 58 years old range (49-81), 45% female, 73% EGFRexon 19 deletions and 27% EGFR L858R]. Three patients received cisplatin/etoposide, six patients carboplatin/etoposide, and two patients progressed two months on induction osimertinib before they could start chemotherapy. The ORR was 82%, median PFS 15.6 months and median OS was 37.9 months. All patients retained EGFR, TP53, and RB1mutations on post-treatment biopsy. Acquired on-target resistance mechanisms were identified in 9% of patients ( EGFR C797S), off-target in 9% of patients ( CDKN2A), and small cell transformation in 46% of patients. Among the transformed patients, all had high Ki-67 (70-95%) and 80% were positive for synaptophysin and chromogranin. 40% of cases were ASCL1-dominant, 40% were NEUROD1-dominant, and 20% were unknown. Additionally, we utilized copy number inference and CytoTrace to identify subclones within pre-transformed EGFR+LC that potentially harbor features of early plasticity. Further scRNAseq and whole exome sequencing data are forthcoming. Conclusions: In patients with EGFR+LCs with concurrent TP53and RB1alterations, osimertinib plus platinum and etoposide demonstrated activity and no new safety signals were seen. Early addition of small cell directed chemotherapy did not prevent histologic transformation. Clinical trial information: NCT03567642 .

Efficacy of chemotherapy followed by chemoradiation versus initial chemoradiation as part of the total neoadjuvant therapy for patients with locally advanced rectal cancer: An NCDB analysis.

e15629 Background: Results from multiple trials lead to modern management for locally advanced rectal cancer, with total neoadjuvant therapy (TNT) followed by surgery. However, the best sequence of different treatment modalities is unclear. Methods: We used the National Cancer Database (NCDB) to identify patients with locally advanced rectal adenocarcinoma. We divided patients into different categories based on the timing of chemo and radiation therapy relative to surgery. We used chi-square and Wilcoxon rank test for unadjusted comparison. To compare treatment efficacy with initial chemotherapy to concurrent chemoradiation in downstaging (clinical to pathological stage), we used a linear mixed effect model (LME) with adjustments on age, sex, race, facility type, and year of diagnosis. Also, we evaluated the probability of having positive lymph nodes in the pathological specimen (N+) in the multivariable logistic regression model with adjustment on the clinical stage in addition to the previously mentioned variables. All analyses were done using R 4.6.2. Results: A total of 100509 patients were identified. Only 695 patients received six cycles of neoadjuvant chemotherapy before concurrent chemoradiation (TNT chemotherapy), and 8677 patients received upfront radiation therapy with neoadjuvant chemotherapy administered within 12 weeks of neoadjuvant radiation therapy (TNT radiation). Patients whose start date of chemotherapy or radiation after surgery were excluded. The median age of participants was 63 (IQR = 54-63), and 83% were white. Patients who had TNT chemotherapy were younger (56.4 VS 59.5, P-value < 0.01), had clinically and pathologically advanced stage (IIIB, IIIC) compared to TNT radiation (64%VS 37% and 33%VS 29%, P-value < 0.01). Patients who received TNT radiation had an upgrade in their pathological stage compared to their clinical stage by 0.67 points in the LME (P value < 0.01). In multivariable logistic regression. TNT chemotherapy had a 17% lower risk of (N+) with an OR of 0.83 (0.95 CI 0.59-1.16). However, it was not statistically significant. The two groups had no difference in OS, with a median OS of 137 months (0.95 CI 110 -NR) and 143 (0.95 CI 137-151), respectively. Conclusions: Upfront chemotherapy before starting chemoradiation could be associated with more significant downstaging. Future trials to validate our finding is warranted. [Table: see text] [Table: see text]

Molecular and clinical characteristics of patients with non-small-cell lung cancer (NSCLC) harboring KRAS G12V mutations.

8618 Background: KRAS G12V is one of the most common drivers of non-small cell lung cancer (NSCLC), accounting for around 3 percent of cases. Recently, there have been promising approaches in early clinical research to therapeutically target this mutation. However, this subset of patients is poorly characterized both molecularly and clinically, and data on therapy-dependent outcome are lacking. We performed this real world analysis to gain insight into the genomic and clinical characteristics of a large cohort of NSCLC patients with KRAS G12V mutations. Methods: Molecular data of 662 UICC stage I-IV lung cancer patients diagnosed between 2018 and 2023 and harbouring a KRAS G12V mutation in their tumor tissue were linked to the medical record data in the Network Genomic Medicine (NGM) database. The mutational status was determined by next-generation sequencing (NGS) and further immunohistochemistry (IHC) for PD-L1 status was performed. Results: 662 patients with a KRAS G12V mutation were diagnosed between 01/2018 and 03/2023 (stage I: 33 (6.0%), II: 29 (5.3%), III: 89 (16.3%), IV: 396 (72.4%)), which is a proportion of 15.3% among all registered KRAS-mutated lung cancer patients in this period (n=4332). Among the KRASG12V positive primary lung carcinomas, 605 (94.3%) showed an adenocarcinoma and 17 (2.6%) a squamous cell carcinoma. The median age at diagnosis was 67 years (range: 33-91), of which 338 were men (52.6%) and 304 women (47.4%). The majority of the cohort were active or former smokers (active: 289 (54.9%); former: 208 (39.2%)). In the group of never smokers (n=33, 6.2%), there were 5 men (15.2% of never smokers) and 28 women (84.8% of never smokers). The most common mutation site at initial diagnosis in patients with metastatic disease was brain and bone metastases with 41.5% and 37.4%, respectively. The most common co-mutations with a frequency of ≥ 5% were TP53 (40.2%), STK11 (28.3%), KEAP1 (22.6%) and NTRK1-3 (8.7%). Preliminary median overall survival at UICC stage IV was 525 (95% CI: 427 – 579) days. The first PD-L1-independent analysis showed a response rate of 40.9% (18/44) to initial chemotherapy (CTX)/immune-checkpoint blockade (ICB) combination, 66.7% (8/13) to ICB alone and 18.8% (6/32) to CTX alone. Conclusions: The cohort is characterized by heavy tobacco consumption. Among the never-smokers, the high proportion of women is noteworthy and will be analyzed further. Metastases at first diagnosis and concurrent mutations show clear differences to other KRAS subtypes, which highlights the heterogeneity of KRAS subtypes. We will continue to analyze the overall prognosis as well as the first indications of a PD-L1-independent benefit of immunotherapy compared to chemotherapy alone.

Refining the 30-day emergency department visit after initial chemotherapy administration A-PROACCT model.

e23253 Background: This study attempted to address limitations in the A-PROACCT model developed by Stein et al. (JOP, 2023) to predict the rate of acute care events within 30 days (ACE30) of initial chemotherapy administration (ICA). The four most important predictors were drug category (immunotherapy), cancer type (gastrointestinal), age group ( < 40), and BMI category (underweight). Only linear relationships were considered. For patients for whom an ACE30 was predicted by their first and second models, only 0.18 and 0.23 actually had an ACE30, a low positive predictive value (PPV). We attempted to improve the PPV with advanced modeling techniques. Methods: Using Orlando Health data between February of 2012 and April 2021, random sampling was used to split the dataset into training (10,838) and validation (4645). For the training data, resampling was employed to obtain a balanced quota, equal observations followed by an ACE30 and not followed by an ACE30. We included only variables used in Stein (drug category, age group, ED visits and hospitalizations in the prior year, cancer type, insurance category, number of anti-cancer agents, race, and BMI category). Logistic regression with L1-penalty, XGBoost (a non-linear nonparametric tree-based algorithm to account for nonlinear relationships), and artificial neural networks were used to develop and evaluate predictive models. Different sampling methods (bootstrap and SMOTE) as well as cuff-off thresholds for high-risk groups were tested. Results: Based on evaluation with validation data set, the best performing approach was an XGBoost model with SMOTE resampling in the training data. The four most important predictors were ED visits in the prior year, payor category (self-insured), cancer type (genitourinary) and hospitalization in past year. This model reported a PPV of 0.27. Many other combinations of methodologies described above were performed, and the PPV varied between 0.19 to 0.27. Of the 282 ICAs identified as high-risk by the best model, 76 (27.0%) had an ACE30. Of the 4346 ICAs identified as low-risk, 533 (12.3%) had an ACE30. The differences between high risk and low risk ACE30 rates were statistically significant (p < 0.0001). In comparison, using Stein et al. models with our data reported a PPV of 0.27 and 0.25 which are basically at the same level of our best trained model. Conclusions: Using the variables included in A-PROACCT and a variety of machine learning models, advanced sampling methodologies and threshold cut-off limits, the best results were similar to those obtained using basic logistic regression. This suggests improvement in predicting acute care events following chemotherapy administration need to incorporate more extensive multimodal data, such as vital signs, performance status, patient reported outcomes, socioeconomic factors, laboratory and radiology results, remote patient monitoring and wearable device data.

OSIRAM-1/TORG1833: Overall survival results of a randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer.

8613 Background: Dual inhibition of the EGFR/VEGF pathways has demonstrated superior efficacy with 1st generation EGFR tyrosine kinase inhibitor (TKI) in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study aims to evaluate the efficacy and safety of combining osimertinib (Osi), a 3rd generation TKI considered the standard of care, with ramucirumab (Ram). We have previously shown the result of progression free survival (PFS) as a primary endpoint, the median PFS was 20.0 months for Osi+Ram and 24.0 months for Osi, hazard ratio of 1.054 (95% CI 0.674-1.648). In further analyses, we aimed to examine the effects of this combination therapy on overall survival (OS). Methods: Previously untreated EGFR mutation-positive advanced non-squamous NSCLC patients with a performance status of 0 or 1 were eligible. Asymptomatic and/or treated brain metastases were included. Eligible patients were randomized at a 1:1 ratio to receive Osi (80mg) every day either without or with Ram (10mg/kg) every 2 weeks until disease progression or unacceptable toxicity, stratified according to gender and the type of EGFR mutation (exon 19 deletion, L858R). The primary endpoint was PFS assessed by the independent blinded radiologic reviewer. Secondary endpoints included PFS assessed locally, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), OS and safety. Results: Between November 2018 and April 2020, 122 patients (Osi+Ram: 59, Osi: 63) were enrolled. The patients' characteristics were well balanced. 59% were females, and 61% had an exon 19 deletion. Median age was 70 years old (range, 29-86). With a median follow up of 36.0 months, the median OS was 43.4 months (95% CI 36.5-N.R.) for Osi+Ram and N.R. (95% CI 41.3-N.R.) for Osi, resulting in a hazard ratio of 1.159 (95% CI 0.645-2.083, p = 0.62). Median treatment duration for Ram was 140 (14-1239) days. Ram was discontinued in 45 patients (76%) by the treatment related adverse effects. Common reasons for Ram discontinuation were platelet count decreased (n=14), proteinuria (n=12), neutrophil count decreased (n=11), pneumonitis (n=3), bleeding (n=3) and infection (n=3). Pneumonitis was observed in 16% in Osi, 9% in Osi+Ram, with grade 3 observed in 2% of both arms. Conclusions: Both treatment arms demonstrated sustained OS over 43 months. However, this study did not show an advantage of biweekly Ram administration with Osi in terms of PFS and OS. Notably, there was surpassed increase of early discontinuation of Ram due to higher adverse events. Clinical trial information: 2080224085 .

Current management practices of de novo oligometastatic breast cancer: Real-world data from a physician survey.

1104 Background: De novo oligometastatic breast cancer (oligo-mBC) is generally defined as < 5 lesions at the time of diagnosis and represent a steadily increasing subset of metastatic cancers. Several retrospective studies demonstrated prolonged overall survival (OS) for select patients with oligo-mBC when treated with multimodality therapy (chemotherapy, surgery, and radiation). However, randomized trials that tested surgical resection of the primary tumor, or radiation of oligometastases (including recurrent and de novo disease) showed no OS benefit. No randomized trials to date have tested all 3 treatment modalities combined (as used with curative intent in early-stage disease). Current NCCN guidelines do not include specific recommendations for de novo oligo-mBC, the St Gallen International guidelines allow multimodality therapy for carefully selected patients. We surveyed practicing medical oncologists through the ASCO survey pool regarding their use of multimodality therapy in de novo oligo-mBC. Methods: An online survey was sent to the ASCO Research survey pool (N=999) between 11/14/23 – 12/29/23, 193 ASCO members completed the survey. Data was confidential and anonymous. Results: The majority (76-79%) of respondents recommend starting with palliative systemic chemotherapy. If patients have a response to initial chemotherapy, 42-54% recommend ablative radiation to all residual lesions, and 38-52% recommended surgical resection of the primary tumor. Overall, multimodality therapy is recommended sometimes by 29-36%, often by 19-29%, almost never by 32-41%, and never by 2-7% of respondents. Recommendations varied by disease subtype (Table). Conclusions: These survey data indicate varied practices in the treatment of de novo oligo-mBC. This highlights the need for future randomized clinical trials to investigate whether there may be survival benefit by receptor subtype in de novo oligo-mBC treated with curative intent multimodality therapy as used in locally advanced cancers. [Table: see text]

Continuous glucose monitoring and rates of hyperglycemia during chemotherapy for early-stage breast cancer.

e24134 Background: Diabetes (DM) and hyperglycemia (HG) during chemotherapy increase the risk of treatment-related toxicities. The prevalence of HG and daily patterns of HG over the course of chemotherapy in patients with early-stage breast cancer (ESBC) are currently unknown. Methods: We conducted a prospective single-arm pilot study of continuous glucose monitoring in patients with ESBC receiving chemotherapy from 12/2020 – 2/2022. Eligibility criteria included: diagnosis of Stage I-III BC, age ≥18, and planned chemotherapy with concurrent corticosteroid supportive care use. Patients were excluded if they were receiving other systemic corticosteroids or insulin. Patients wore FreeStyle Libre Pro continuous glucose monitoring sensors from the time of chemotherapy initiation (± 7 days) through completion. The sensors detected interstitial glucose levels every 15 minutes and were reapplied by the study team every 2-3 weeks. Primary endpoints were: (1) prevalence of HG, defined as number of patients with ≥1 glucose reading ≥140 mg/dL and (2) among those who developed HG, the proportion of time spent hyperglycemic, defined as number of readings ≥140 mg/dL divided by total number of readings. Key secondary endpoints included prevalence of prediabetes (pre-DM) and diabetes (DM) at baseline and changes in A1c from baseline to weeks 12 and 24. The analysis was stratified by baseline A1c (euglycemia [A1c < 5.7%], pre-DM [A1c 5.7%-6.4%], or DM [A1c ≥6.5% and clinical diagnosis of DM prior to study enrollment]). Results: Among 20 evaluable patients, the median age at baseline was 59 (range 34-78) and median body mass index (BMI) was 29.5 kg/m2 (range 19.5-41.6). The most common chemotherapy regimens included docetaxel/cyclophosphamide (25%), weekly paclitaxel ± trastuzumab (20%), paclitaxel followed by doxorubicin/cyclophosphamide (15%), docetaxel/carboplatin/trastuzumab/pertuzumab (15%), and cyclophosphamide/methotrexate/fluorouracil (15%). All 20 patients developed HG. Of 124,165 total readings, 17% were ≥140 mg/dL and mean glucose was 112.7 mg/dL. At baseline, n = 10 were euglycemic, n = 7 had pre-DM, and n = 3 had DM. By cohort, the proportion of time spent hyperglycemic was 3.9% (euglycemia group), 10% (pre-DM group), and 73.3% (DM group) (p < .0001). Mean glucose values were 95.5 mg/dL (euglycemia group), 104.5 mg/dL (pre-DM group), and 183.0 mg/dL (DM group) (p < .0001). Change in mean A1c from baseline to weeks 12 and 24 varied significantly across groups. Conclusions: Among patients receiving chemotherapy for ESBC, we found evidence of HG in all patients, and the proportion of time spent hyperglycemic during chemotherapy varied significantly by baseline A1c. Further interventions should evaluate the benefits of improved glucose control among patients with baseline A1c > 5.7%. Clinical trial information: NCT04473378 .

The influence of sarcopenia and myosteatosis on severe laboratory toxicity and overall mortality in older adults with cancer receiving chemotherapy.

12131 Background: Older adults with cancer often present with suboptimal muscle quantity and quality prior to treatment due to disease-related catabolic effects combined with the aging process. Muscle catabolism is further exacerbated by cancer treatments leading to worse metabolic health, patient quality of life, and clinical outcomes. Our objective was to examine the impact of sarcopenia and myosteatosis on severe laboratory toxicity and overall mortality in older adults with cancer receiving chemotherapy. Methods: This was a retrospective cohort study of older adults who had undergone chemotherapy at the Princess Margaret Cancer Centre, Toronto, Canada from June 2015 to June 2022. A computed tomography scan after diagnosis but prior to treatment was used to assess skeletal muscle index (SMI) and skeletal muscle density (SMD) for each participant. Sarcopenia was defined as the presence of low muscle strength (grip strength <35.5kg for males and <20kg for females), low SMI, and low physical performance (walking speed <0.8m/s or a total Short Physical Performance Battery score of ≤8) prior to chemotherapy initiation. Myosteatosis was assessed through SMD in Hounsfield Units using previously published cut-offs. Severe laboratory toxicity was defined as occurrence of a grade ≥3 adverse event per the Common Terminology Criteria for Adverse Events (version 4.0). Severe laboratory toxicity and overall mortality were assessed from treatment initiation until treatment termination or loss to follow up. Multivariable logistic regression was used to determine the role of sarcopenia and myosteatosis in predicting occurrence of severe laboratory toxicity. Multivariable Cox regression was used to assess the risk of overall mortality. Results: A total of 115 older adults (mean age: 77.1 y) were included, of whom 63.5% had metastatic disease. Sarcopenia was identified in 27% of the cohort, whereas 80% had myosteatosis. A total of 132 severe laboratory toxicities occurred during the study period in 41 participants (35.7%). Sarcopenia was a significant predictor of severe laboratory toxicity (adjusted odds ratio (aOR)=3.19, 95%CI= 1.19 to 8.52, p= 0.012) after adjusting for sex, body mass index, and hemoglobin. Myosteatosis was significantly associated with overall mortality (adjusted hazard ratio (aHR)= 2.51, 95%CI= 1.12-5.61, p=0.025) after adjusting for albumin, alkaline phosphatase, and treatment intent. Conclusions: Sarcopenia may be used to inform the risk of severe laboratory toxicity in older adults prior to chemotherapy. Pre-treatment myosteatosis defined by low SMD predicts overall mortality in the same cohort. Optimization of skeletal muscle health through targeted exercise and nutritional interventions may improve patient quality of life and clinical outcomes in older adults with cancer receiving chemotherapy.

Lymphocyte counts predict optimal timing of chemotherapy reinitiation after antivirus treatment for herpes zoster in children with leukemia.

Herpes zoster (HZ) is rare in healthy children, but more prevalent in those with leukemia. Optimal timing of chemotherapy reinitiation after HZ treatment is challenging because chemotherapy suppresses immunity and increases risk of HZ relapse. We aimed to optimize the timing of chemotherapy reinitiation after HZ therapy in children with leukemia. The study included 31 children with acute leukemia and HZ infection. General information, clinical symptoms, laboratory test results, duration of HZ treatment, and prognosis were compared with those of children with leukemia alone. Correlation analysis was performed for 20 children who restarted chemotherapy after HZ treatment. Of 31 children with leukemia and HZ, 67.74% had lesions at multiple sites. The median time from chemotherapy initiation to HZ onset was 14.1 (1.5-29.5) months. Among 27 children included in the follow-up, there was one case of HZ relapse. After excluding children who did not continue chemotherapy after HZ treatment, the median interval between completion of HZ therapy and chemotherapy reinitiation in the remaining 20 children was 8.00 (-3 to 27) days. Lymphocyte counts (LY#) on restarting chemotherapy correlated inversely with HZ lesion healing time (p < 0.05). LY# at the time of HZ onset were lower than those pre- and post-onset, and lower than those in the control group (p < 0.05). In conclusion, children with leukemia have a good HZ prognosis, but an increased risk of HZ recurrence. LY# at the time of chemotherapy reinitiation may be a useful indicator for selecting the optimal interval between antiviral therapy completion and chemotherapy reinitiation.

Factors associated with delays in receipt of neoadjuvant chemotherapy in patients with operable breast cancer.

e13541 Background: Delays in neoadjuvant chemotherapy initiation (NACTI) after breast cancer (BC) diagnosis have been associated with worse outcomes. We evaluated incidence and predictors of delays of NACTI among high clinical risk patients treated with NACT on a national level. Methods: We conducted a retrospective cohort study using the National Cancer Database. Eligibility included age ≥18 years, diagnosis of non-metastatic BC between 1/1/2010 – 12/31/2020, who were treated with NACT within 180 days of diagnosis. Patients who received neoadjuvant endocrine therapy were excluded. Time to chemotherapy (TTC) in days was recorded. Patients were categorized into sub-cohorts by receptor status and clinical stage: 1) Hormone Receptor positive/HER-2 negative (HR+/HER2-) and were lymph node (LN) LN+; 2) HER-2 positive (HER2+) cT2+ or LN+; and 3) triple negative BC (TNBC) cT2+ or LN+. Multivariable logistic regression, adjusted for demographic, socioeconomic and tumor characteristics, was used to identify characteristics associated with delays &gt; 60 days from diagnosis to NACTI. Multiple imputation was used for missing data. Results: We identified 145,697 eligible patients, 74% were White, 18% were Black, 3.3% were Asian, and 4.6% were Other/Unknown. Across all racial categories, 9.2% were Hispanic. Median age at diagnosis was 52 years (range 18-90), median TTC was 32 days (range 0-180), and 10% had a delay &gt; 60 days. There were 40,345 patients in the HR+/HER2- cohort, 56,868 in the HER2+ cohort, and 48,484 in the TNBC cohort; 12%, 9.0%, and 8.9% (p &lt;0.001) had a delay in NACTI, respectively. In multivariable analysis among the HR+/HER2- sub-cohort, characteristics associated with delays in NACTI included Black race (OR 1.71, 95%CI 1.57-1.86) and Hispanic ethnicity (OR 1.76, 95%CI 1.60-1.94) compared to White and non-Hispanic patients. Patients with Medicare, Medicaid, or who were uninsured were more likely to be delayed (OR 1.44 95%CI 1.30-1.58, 2.10, 95%CI 1.92-2.29, 2.28, 95%CI 1.99-2.61) compared to those with commercial insurance. Results were similar in the HER2+ and TNBC cohorts, as seen in Table. Conclusions: Among patients with operable BC who received NACT, patients who were Black, Hispanic, had Medicaid or no insurance had as high as a twofold increase in odds of a delay in NACTI. Targeted interventions to address these racial and socioeconomic disparities are necessary to ensure equitable care. Multivariable logistic regression adjusted for demographic, socioeconomic and tumor characteristics variables (n= 145,697). [Table: see text]

Current diagnostic guidelines and perpetuation of inequities in ovarian cancer: A National Cancer Database study.

11027 Background: International guidelines use cancer antigen 125 (CA-125) thresholds to recommend which patients with pelvic masses should undergo evaluation by gynecologic oncologists for ovarian cancer and which patients can be observed without intervention. However, CA-125 thresholds were developed from white populations, and CA-125 levels have been shown to be 10-29% lower in healthy Black women than white women. If CA-125 levels also differ among patients with cancer, current guidelines may contribute to missed or delayed ovarian cancer diagnoses among Black women. Our objective was to examine CA-125 levels at cancer diagnosis by patient race and associations of CA-125 elevation with timely treatment. Methods: We conducted a retrospective cohort study of patients with ovarian cancer ages 0 to 90+ years diagnosed from 2018-2020 using the National Cancer Database. CA-125 was defined as positive/borderline or negative/normal by each site. We report descriptive CA-125 elevated by patient characteristics. We use multivariate logistic regression models to examine the association of patient characteristics with CA-125 level overall and for epithelial and high-grade serous cancers. We used generalized linearized models to examine the association of CA-125 with days from diagnosis to chemotherapy start for patients with Stage II-IV disease. Results: Of 38,707 patients diagnosed with ovarian cancer and with reported CA-125, 13.4% of patients did not have an elevated CA-125 at diagnosis. Patients who identified as Black, Asian, or Hispanic were less likely to have an elevated CA-125 at ovarian cancer diagnosis as were patients with early-stage disease. Among patients with high-grade serous cancer (n=18,151), 8% of Black patients had normal CA-125 at diagnosis compared to 6% of white patients. In multivariate analyses, being Black remained associated with lower odds of elevated CA-125 (OR 0.71, 95%CI 0.63-0.81), after adjustment for menopausal status, comorbidities, and stage. Even among patients with high-grade serous ovarian cancer, being black was associated with lower odds of having an elevated CA-125 (OR 0.78, 95%CI 0.64-0.96). Patients with Stage II-IV ovarian cancer who had a normal CA-125 at diagnosis had 12 days longer on average to chemotherapy initiation compared to patients with elevated CA-125. Conclusions: Current thresholds for CA-125 and gynecologic oncology referral likely miss Black patients with ovarian cancer and may delay timely treatment. Work is needed to develop inclusive CA-125 thresholds and guidelines for ovarian cancer diagnosis and not compound disparities.

Implementing geriatric assessment for dose optimization of CDK 4/6 inhibitors in older breast cancer patients (IMPORTANT trial): A pragmatic randomized-controlled trial.

TPS1132 Background: Current evidence from both randomized trials and real-world evidence studies suggests that older patients with advanced hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer derive clinical benefit from the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy. However, a higher risk for adverse events due to CDK4/6 inhibitors among older patients is evident, leading to a trend of initiating CDK4/6 inhibitors at a lower dose in clinical practice, though without evidence. The aim of the present randomized trial is to investigate whether lower initial dose of CDK4/6 inhibitors combined with endocrine therapy is comparable to full dose in older patients with advanced HR+/HER2-breast cancer that are assessed as vulnerable/frail based on comprehensive geriatric assessment (CGA). Methods: We designed a multi-national, open-label, pragmatic randomized controlled trial with non-inferiority approach. Patients ≥70 years old with advanced HR+/HER2- breast cancer with no curative intention, no prior treatment in an advanced setting, and suitable to receive a combination of CDK4/6 inhibitors plus endocrine therapy according to treating physician, are eligible for study inclusion. After informed consent, included patients fill out a self-administered CGA tool and categorized accordingly to fit, vulnerable, or frail, depending on the number of impaired CGA domains. Fit patients receive full dose of CDK4/6 inhibitors and endocrine therapy whereas vulnerable/frail patients are randomized to either -1 level lower CDK4/6 inhibitor dose or full dose and endocrine therapy. The randomization is stratified by type of CDK 4/6 inhibitor, type of endocrine therapy, and level of vulnerability. The treating physician decides on the choice of CDK4/6 inhibitor (abemaciclib, ribociclib, palbociclib) and endocrine therapy (aromatase inhibitors, fulvestrant). The primary endpoint is time to treatment failure whereas secondary endpoints include overall treatment utility, progression-free survival, overall survival, time to chemotherapy initiation, toxicity, quality-of-life, time to quality-of-life deterioration and cost-effectiveness. The evaluation of disease progression, toxicity assessment, and the follow-up strategy resembles clinical practice to enhance the pragmatic design approach of IMPORTANT trial. The trial also enables a hybrid decentralized approach where the initial patient visit is in-person whereas the visits for efficacy and toxicity evaluation can be performed digitally according to local practices. In total, 495 patients are planned to be included to allow 346 vulnerable/frail patients to be randomized. Enrollment: The trial is open for recruitment since February 2024 with a recruitment period of 30 months. Clinical trial information: NCT06044623 .

Implementing DPYD/UGT1A1testing to prevent treatment related adverse events (TRAE) in patients with gastrointestinal (GI) cancer: Results of a pragmatic implementation trial.

10599 Background: Fluoropyrimidines (FP), 5-FU and capecitabine, are standard treatments for many GI cancers. Irinotecan may be used with FPs in both the curative and palliative settings. 30-40% of patients experience severe TRAEs which can lead to treatment interruption and hospitalization. TRAE risk is higher in patients with pharmacogenetic variants in DPYD and/or UGT1A1. Methods: This is a non-randomized, open-label implementation study at 3 cancer care sites within an academic health system to determine feasibility of integrating DPYD/UGT1A1 testing into clinical care (IMPACT-GI; NCT#04736472). Test ordering and discrete variant resulting were available within the Electronic Health Record. The lab detected 5 DPYD variants with reduced or no function (c.1905+1G&gt;A, c.2846A&gt;T, c.1679T&gt;G, c.1236G&gt;A, c.557A&gt;G) and 2 UGT1A1 (*6, *28) alleles. Patients with a GI cancer initiating treatment with 5-FU, capecitabine, or irinotecan underwent testing along with preemptive chemotherapy dose modifications. Carriers of 1 DPYD variant (i.e., intermediate metabolizers [IM]) and UGT1A1 homozygous carriers (i.e., poor metabolizers [PM]) were recommended a 50% and 30% dose reduction, respectively. The primary endpoints were feasibility (proportion of results available prior to cycle 1) and fidelity (genotype concordant dose modifications). Secondary endpoints included severe TRAE (requiring emergency room visit or hospitalization) comparing variant carriers vs. wildtype over the first 6 cycles. Results: From 3/2021- 12/2022, 224 patients received testing (54% male, 74% White, 18% Black, mean age 62 ±17 years. The most common diagnoses were 47% colorectal and 30% pancreatic cancers. The median lab turnaround time was 10 (IQR 9-13) calendar days with 57.2% of results available prior to cycle 1. Results available prior to cycle 1 varied by distance to lab (64.7% near sites vs. 32.7% far site, p&lt;0.001). We identified 7 (3%) DPYD intermediate metabolizers (IM) and 33 (15%) UGT1A1 poor metabolizers (PM). Four (2%) patients carried a variant in both DPYD and UGT1A1. Chemotherapies were preemptively dose reduced for 6 of 7 DPYD carriers receiving FP and 5 of 8 UGT1A1 PMs receiving irinotecan. 2 (28%) DPYD carriers vs. 71 (33%) wildtype carriers had a severe TRAE. 4 (50%) UGT1A1 PMs vs. 11 (36%) UGT1A1 wildtype carriers experienced a severe TRAE. Conclusions: DPYD/UGT1A1 testing is feasible with oncology providers following the genotype guided dose reductions when results were available prior to cycle 1. Pretreatment DPYD/UGT1A1 testing in conjunction with preemptive dose reductions resulted a similar proportion of severe TRAE as compared with wild-type patients. Further workflow modifications are required to decrease test turnaround time to ensure results are available prior to chemotherapy initiation. Clinical trial information: NCT04736472 .

The Trends and Outcomes of Initial Palliative Chemotherapy in Patients with Pancreatic Cancer in Korea Based on National Health Insurance Service Data.

Background/Objectives: The survival rate of patients with pancreatic cancer (PC) has improved gradually since the introduction of FOLFIRINOX (FFX) and gemcitabine + albumin-bound paclitaxel (GnP) regimens. However, the trends and outcomes of initial palliative chemotherapy before and after the advent of these regimens and their contribution to survival rates are not well understood. This study aimed to investigate this in patients with PC in Korea using claims data from the National Health Insurance Service (NHIS). Methods: Patients diagnosed with PC who underwent initial palliative chemotherapy between 2007 and 2019 were identified from the NHIS database. Patient demographics, comorbidities, chemotherapy regimens, and survival rates were analyzed using follow-up data up to 2020. Results: In total, 14,760 patients (mean age, 63.78 ± 10.18 years; men, 59.19%) were enrolled. As initial palliative chemotherapy, 3823 patients (25.90%) received gemcitabine alone; 2779 (18.83%) received gemcitabine + erlotinib; 1948 (13.20%) received FFX; and 1767 (11.97%) received GnP. The median survival values were 15.00 months for FFX; 11.04 months for GnP; 8.40 months for gemcitabine alone; and 8.51 months for gemcitabine + erlotinib. The adjusted hazard ratio (aHR) for GnP vs. FFX was 1.291 (95% CI, 1.206-1.383) in the multivariate Cox regression analysis of mortality. Radiation therapy (aHR, 0.667; 95% CI, 0.612-0.728) and second-line chemotherapy (aHR, 0.639; 95% CI, 0.597-0.684) were significantly associated with improved survival. Conclusions: Our study found that first-line chemotherapy with FFX was associated with significantly longer survival than the other regimens, although caution is needed in interpreting the results.

Identification of symptom clusters and sentinel symptoms during the first cycle of chemotherapy in patients with lung cancer

PurposeTo identify symptom clusters (SCs) in patients with lung cancer who are undergoing initial chemotherapy and to identify the sentinel symptoms of each SC.MethodsA convenience sampling method was used to recruit patients with lung cancer who were undergoing their initial chemotherapy treatment. Patient information was collected using the General Demographic Questionnaire, MD Anderson Symptom Inventory (including the lung cancer module) and a schedule documenting the initial occurrence of symptoms. The Walktrap algorithm was employed to identify SCs, while sentinel symptoms within each SC were identified using the Apriori algorithm in conjunction with the initial occurrence time of symptoms.ResultsA total of 169 patients with lung cancer participated in this study, and four SCs were identified: the psychological SC (difficulty remembering, sadness, dry mouth, numbness or tingling, and distress), somatic SC (pain, fatigue, sleep disturbance, and drowsiness), respiratory SC (coughing, expectoration, chest tightness, and shortness of breath), and digestive SC (nausea, poor appetite, constipation, vomiting, and weight loss). Sadness, fatigue, and coughing were identified as sentinel symptoms of the psychological, somatic, and respiratory SCs, respectively. However, no sentinel symptom was identified for the digestive SC.ConclusionPatients with lung cancer who are undergoing chemotherapy encounter a spectrum of symptoms, often presenting as SCs. The sentinel symptom of each SC emerges earlier than the other symptoms and is characterized by its sensitivity, significance, and driving force. It serves as a vital indicator of the SC and assumes a sentry role. Targeting sentinel symptoms might be a promising strategy for determining the optimal timing of interventions and for mitigating or decelerating the progression of the other symptoms within the SC.