Combination Of Carboplatin Research Articles

In Vitro Methylene Blue and Carboplatin Combination Triggers Ovarian Cancer Cells Death.

Ovarian cancer presents a dire prognosis and high mortality rates, necessitating the exploration of alternative therapeutic avenues, particularly in the face of platinum-based chemotherapy resistance. Conventional treatments often overlook the metabolic implications of cancer, but recent research has highlighted the pivotal role of mitochondria in cancer pathogenesis and drug resistance. This study delves into the metabolic landscape of ovarian cancer treatment, focusing on modulating mitochondrial activity using methylene blue (MB). Investigating two epithelial ovarian cancer (EOC) cell lines, OV1369-R2 and OV1946, exhibiting disparate responses to carboplatin, we sought to identify metabolic nodes, especially those linked to mitochondrial dysfunction, contributing to chemo-resistance. Utilizing ARPE-19, a normal retinal epithelial cell line, as a control model, our study reveals MB's distinct cellular uptake, with ARPE-19 absorbing 5 to 7 times more MB than OV1946 and OV1369-R2. Treatment with 50 µM MB (MB-50) effectively curtailed the proliferation of both ovarian cancer cell lines. Furthermore, MB-50 exhibited the ability to quell glutaminolysis and the Warburg effect in cancer cell cultures. Regarding mitochondrial energetics, MB-50 spurred oxygen consumption, disrupted glycolytic pathways, and induced ATP depletion in the chemo-sensitive OV1946 cell line. These findings highlight the potential of long-term MB exposure as a strategy to improve the chemotherapeutic response in ovarian cancer cells. The ability of MB to stimulate oxygen consumption and enhance mitochondrial activity positions it as a promising candidate for ovarian cancer therapy, shedding light on the metabolic pressures exerted on mitochondria and their modulation by MB, thus contributing to a deeper understanding of mitochondrial dysregulation and the metabolic underpinnings of cancer cell proliferation.

Targeting the Epidermal Growth Factor Receptor Pathway in Chemotherapy-Resistant Triple-Negative Breast Cancer: A Phase II Study.

Epidermal growth factor receptor (EGFR) pathway activation causes chemotherapy resistance, and inhibition of the EGFR pathway sensitizes triple-negative breast cancer (TNBC) cells to chemotherapy in preclinical models. Given the high prevalence of EGFR overexpression in TNBC, we conducted a single-arm phase II study of panitumumab (anti-EGFR monoclonal antibody), carboplatin, and paclitaxel as the second phase of neoadjuvant therapy (NAT) in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02593175). Patients with early-stage, AC-resistant TNBC, defined as disease progression or ≤80% reduction in tumor volume after four cycles of AC, were eligible for this study and received panitumumab (2.5 mg/kg i.v., every week × 13), paclitaxel (80 mg/m2 i.v. every week × 12), and carboplatin (AUC = 4 i.v., every 3 weeks × 4) as the second phase of NAT. A two-stage Gehan-type design was used to detect an improvement in the pathological complete response (pCR)/residual cancer burden class I (RCB-I) rate from 5% to 20%. Whole-exome sequencing was performed on diagnostic tumor biospecimens, where available. From November 3, 2016, through August 23, 2021, 43 patients with AC-resistant TNBC were enrolled. The combined pCR/RCB-I rate was 30.2%. The most common treatment-related adverse events were neutropenia (72%) and anemia (61%), with 7 (16%), 16 (37%), and 8 (19%) patients experiencing grade 4 neutropenia, grade 3 neutropenia, and grade 3 anemia, respectively. No new safety signals were observed. This study met its primary endpoint (pCR/RCB-I = 30.2% vs. 5% in historical controls), suggesting that panitumumab should be evaluated as a component of NAT in patients with chemotherapy-resistant TNBC in a larger, randomized clinical trial. The epidermal growth factor receptor (EGFR) pathway has been implicated as a driver of chemotherapy resistance in triple-negative breast cancer (TNBC). Here, we evaluate the combination of panitumumab, carboplatin, and paclitaxel as the second phase of neoadjuvant therapy (NAT) in patients with AC-resistant TNBC. This study met its primary efficacy endpoint, and molecular alterations in EGFR pathway genes did not seem to influence response to the study regimen.

Eribulin plus carboplatin combination for HER2-negative metastatic breast cancer: a multicenter, real-world cohort study

BackgroundPre-clinical data suggests a potential synergistic effect of eribulin and platinum. However, clinical data on the combination for metastatic breast cancer (mBC) is lacking. We evaluated the efficacy and safety of eribulin plus carboplatin (ErCb) in patients with mBC.Patients and methodsThis multicenter, real-world cohort study included patients with pre-treated metastatic triple negative breast cancer (TNBC) or endocrine-refractory hormone receptor (HR) positive, HER2-negative mBC who received ErCb. Eribulin (1.4 mg/m2) and carboplatin (target AUC = 2) were administered intravenously on day 1 and 8 of 21-day cycle. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated.ResultsFrom March 2022 to December 2023, a cohort of 37 patients were recruited to the study. Among them, 22 patients have TNBC and 15 have HR + HER2 − mBC. Of the 22 patients with TNBC, 8 had an initial diagnosis of the HR + HER2 − subtype. The median treatment was 6 cycles (range, 2 − 8 cycles). In the full cohort, TNBC, and HR + HER2 − subgroup, the ORR were 51.4%, 54.5% and 46.7%, the DCR were 81.1%, 81.8% and 80%, and the median PFS were 5 months, 5 months, and 5.2 months, respectively. The median OS was 12.7 months in the entire cohort and 12.8 months in TNBC subgroup. The most common grade 3/4 hematological AEs were neutropenia (37.8%), leukopenia (35.1%), febrile neutropenia (10.8%), thrombocytopenia (5.4%), and anemia (2.7%). No grade 3/4 non-hematological AEs were observed.ConclusionErCb demonstrated favorable efficacy and tolerability in patients with heavily pre-treated mBC, especially TNBC. The findings of the current study warrant further investigation of the application of this combination in earlier lines of mBC treatment.

Outcomes comparison of patients with nasopharyngeal carcinoma who treated with combination of carboplatin and paclitaxel with other regimens: A systematic review

Outcomes comparison of patients with nasopharyngeal carcinoma who treated with combination of carboplatin and paclitaxel with other regimens: A systematic review

Optimizing Outcomes: Bevacizumab with Carboplatin and Paclitaxel in 5110 Ovarian Cancer Patients-A Systematic Review and Meta-Analysis.

The study aimed to evaluate the efficacy and safety of incorporating bevacizumab into the combination therapy of carboplatin and paclitaxel for epithelial ovarian cancer and other clinical applications. A systematic review was conducted following PRISMA guidelines using keyword searches in PubMed, Embase, Cochrane Library, CINAHL, ClinicalTrials.gov, and ICTRP until February 2024. Randomized controlled trials (RCTs) comparing carboplatin and paclitaxel with and without bevacizumab in ovarian cancer patients were included. Efficacy outcomes were overall survival (OS) and progression-free survival (PFS), as described by hazard ratios (HRs). Safety outcomes were analyzed with risk ratios (RRs) for 16 adverse events. Seven RCTs (n = 5110) were included. The combination with bevacizumab significantly improved PFS (HR: 0.73; 95% confidence interval: 0.58, 0.92; p = 0.008). The chemotherapy group receiving bevacizumab with carboplatin and paclitaxel showed a significantly higher incidence of hypertension, non-CNS bleeding, thromboembolic events, GI perforation, pain, and proteinuria. The combination of carboplatin, paclitaxel, and bevacizumab improves PFS compared to the regimen without bevacizumab, but it raises significant safety concerns. Clinical management should consider adverse event prevention by vigilantly monitoring blood pressure, signs and symptoms of bleeding, thromboembolism, GI perforation, and pain to balance the therapeutic benefits with the potential risks of this combination therapy.

Combination Therapy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel for Metastatic Non-squamous Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Resistance and EGFR Mutations.

Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapyhas a potential efficacy in a specific subset of non-squamous non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations following tyrosine kinase inhibitor (TKI) treatment. However, there is a dearth of investigations on the effectiveness of ABCP therapy as the primary outcome of EGFR-TKI use. A single-center retrospective analysis was performed on 24 cases of stage IV EGFR-positive non-squamous NSCLC patients who received one or more lines of EGFR-TKItherapy and subsequently initiated ABCP therapy within the timeframe of April 1, 2019, to April 30, 2023. This study assessed overall survival and progression-free survival associated with ABCP therapy, further analyzing the overall survival data based on EGFR subgroups. The mean age of the cohort was 65 ± 9 years with 14 females (58%). The performance status (PS) was recorded as 0 in 13 out of 24 patients (54%) and 1 in 11 out of 24 patients (46%). Thirteen (54%) patients had a history of smoking. Adenocarcinoma histology was prevalent in all cases. The EGFR mutations included Ex19del in 14 patients (58%) and L858R in 10 (42%) patients. At ABCP therapy initiation, liver metastases were evident in three cases (13%) and brain metastases in eight (33%). Programmed death ligand 1 (22C3) expression levels varied, with <1%, 1-49%, and ≥50% observed in five, 11, and five cases, respectively, while data were missing for three cases. The median follow-up duration was 14.1 months, with median overall survival estimated at 23.6 months (95% CI: 14.5 months - not reached) and median progression-free survival at 5.6 months (95% CI: 4.9-11.5 months). The EGFR L858R mutation showed a favorable trend in overall survival compared with the EGFR Ex19del mutation (not evaluated vs. 23.6 months). ABCP therapy for EGFR-positive non-squamous NSCLC is a promising option, similar to immune checkpoint inhibitor-free platinum-based combination therapy. Therefore, prospective trials are necessary to confirm the efficacy of these treatments.

Reduction in chemotherapy relative dose intensity decreases overall survival of neoadjuvant chemoradiotherapy in patients with locally advanced esophageal carcinoma

BackgroundMany patients undergo dose reduction or early termination of chemotherapy to reduce chemoradiotherapy-related toxicity, which may increase their risk of survival. However, this strategy may result in underdosing patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This study aimed to analyze the relationship between the relative dose intensity (RDI) and survival outcomes in patients with LA-ESCC.MethodsThis retrospective study assessed patients with LA-ESCC (cT2N + M0, cT3-4NanyM0) receiving neoadjuvant chemoradiotherapy (NCRT) with curative-intent esophagectomy. The patients received 2 courses of paclitaxel plus carboplatin (TC) combination radiotherapy prior to undergoing surgery. During NCRT, RDI was computed, defined as the received dose as a percentage of the standard dose, and the incidence of dose delays was estimated (≥ 7 days in any course cycle). The best RDI cutoff value (0.7) was obtained using ROC curve. The Kaplan–Meier survival curves were compared using the log-rank test, the treatment effect was measured using hazard ratios (HR) and 95% confidence intervals (CI).ResultsWe included 132 patients in this study, divided into RDI < 0.7 and RDI ≥ 0.7 groups using cut-off value of 0.7. RDI grade was an independent prognostic factor for OS. Baseline demographic and clinical characteristics were well balanced between the groups. There was no evidence that patients with RDI < 0.7 experienced less toxicity or those with RDI ≥ 0.7 resulted in more toxicity. However, patients with RDI < 0.7 who were given reduced doses had a worse overall survival [HR 0.49, 95% CI 0.27–0.88, P = 0.015]. The risk of a lower RDI increased with a longer dose delay time (P < 0.001).ConclusionThe RDI below 0.7 for avoiding chemoradiotherapy toxicity administration led to a reduction in the dose intensity of treatment and decreased overall survival.

Weekly paclitaxel, carboplatin and cetuximab (PCC) combination followed by nivolumab in platinum-sensitive recurrent and /or metastatic squamous cell carcinoma of head and neck: a retrospective analysis from two institutions in India

Background: First line (1L) TP-Ex-like regimen followed by 2nd-line (2L) immunotherapy represents one of the standards of care in platinum-sensitive recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN). We report our experience from 2 tertiary care institutions of India. Methods: This is a retrospective analysis of consecutive patients of platinum-sensitive R/M SCCHN treated with 1L weekly paclitaxel, carboplatin, and cetuximab (PCC) regimen followed by cetuximab maintenance (if non-progressive) or 2L nivolumab or oral metronomic chemotherapy (OMCT) on progression. Overall response rates (ORR), progression-free survival after 1L and 2L (PFS-1 &amp; PFS-2), overall survival (OS), and safety were evaluated. Results: The study included 54 patients; median age 56.5 years; 89% men; 11% had cardiac dysfunction; 13% had renal dysfunction. After 1L PCC, ORR was 59.3%; median PFS-1 was 7.031 months; 61% had progression; 35% were treated with nivolumab and 18% with OMCT. The ORR was 26.3% (nivolumab) and 10% (OMCT). Median PFS-2 was 6.5 months (nivolumab) and 2 months (OMCT). The median OS was 15.01 months (entire cohort), 20.6 months (nivolumab), and 7 months (OMCT). Grade III/IV adverse events on PCC included neutropenia (31.4%), anaemia (35.1%), thrombocytopenia (7.4%), febrile neutropenia (11.1%), and skin reaction (16.6%); no Grade-III/IV treatment-related toxicities on 2L. Conclusions: 1L weekly PCC is an effective regimen for palliative therapy of platinum- sensitive R/MSCCHN with an acceptable toxicity profile. The addition of 2L nivolumab on progression further improves the outcomes.

A DPC Database Study on the Safety of Atezolizumab/Bevacizumab/Carboplatin/Paclitaxel in Non-small Cell Lung Cancer in Japanese Patients.

Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapy is a standard of care for advanced non-squamous non-small cell lung cancer (NSQ-NSCLC); however, the lack of safety data limits its clinical application in Japan. This study compared the safety of ABCP with that of bevacizumab, carboplatin, and paclitaxel (BCP) combination for the treatment of advanced NSQ-NSCLC in Japanese patients by evaluating the clinical background and incidence of adverse events (AEs) based on data extracted from the Diagnosis Procedure Combination (DPC) database. Incidence rates and restricted mean survival times (RMSTs) for up to 1 year were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method. A search conducted using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes identified 350,987 patients, of whom 202 were included in the ABCP cohort and 232 in the BCP cohort. Among the 19 AEs, the incidence of skin disorder and febrile neutropenia (FN) was significantly higher in the ABCP cohort versus the BCP cohort. The adjusted incidence rate ratios were 2.65 [95%confidence interval (CI) 1.43-4.91] for skin disorder and 1.70 (95% CI 1.01-2.85) for FN. The adjusted RMST differences were-64.2 days (95% CI-93.0 to-35.4 days) and-46.0days (95% CI-73.5 to-18.5 days) for skin disorder and FN, respectively. These results were comparable to those of other pivotal clinical trials. The findings of this DPC database study highlight the safety of ABCP in Japanese clinical practice, and this methodology may facilitate more efficient research in real-world settings. UMIN Clinical Trials Registry ID UMIN000041507.

Comparison of the efficacy of taxanes with carboplatin and anthracyclines with taxanes in neoadjuvant chemotherapy for stage II–III triple negative breast cancer: a retrospective analysis

PurposeThe neoadjuvant chemotherapy (NACT) regimen for triple negative breast cancer (TNBC) primarily consists of anthracyclines and taxanes, and the addition of platinum-based drugs can further enhance the efficacy. However, it is also accompanied by more adverse events, and considering the potential severe and irreversible toxicity of anthracyclines, an increasing number of studies are exploring nonanthracycline regimens that combine taxanes and platinum-based drugs.MethodsThe retrospective study included 273 stage II–III TNBC patients who received NACT. The AT group, consisting of 195 (71.4%) patients, received a combination of anthracyclines and taxanes, while the TCb group, consisting of 78 (28.6%) patients, received a combination of taxanes and carboplatin. Logistic regression analysis was performed to evaluate the factors influencing pathological complete response (pCR) and residual cancer burden (RCB). The log-rank test was used to assess the differences in event-free survival (EFS) and overall survival (OS) among the different treatment groups. Cox regression analysis was conducted to evaluate the factors influencing EFS and OS.ResultsAfter NACT and surgery, the TCb group had a higher rate of pCR at 44.9%, as compared to the AT group at 31.3%. The difference between the two groups was 13.6% (OR = 0.559, 95% CI 0.326–0.959, P = 0.035). The TCb group had a 57.7% rate of RCB 0–1, which was higher than the AT group's rate of 42.6%. The difference between the two groups was 15.1% (OR = 0.543, 95% CI 0.319–0.925, P = 0.024), With a median follow-up time of 40 months, the TCb group had better EFS (log-rank, P = 0.014) and OS (log-rank, P = 0.040) as compared to the AT group. Clinical TNM stage and RCB grade were identified as independent factors influencing EFS and OS, while treatment group was identified as an independent factor influencing EFS, with a close-to-significant impact on OS.ConclusionIn stage II–III triple TNBC patients, the NACT regimen combining taxanes and carboplatin yields higher rates of pCR and significant improvements in EFS and OS as compared to the regimen combining anthracyclines and taxanes.

314P Real-world experience of carboplatin and gemcitabine combination chemotherapy in advanced biliary tract cancer: A single centre experience from Nottingham University Hospitals (UK)

314P Real-world experience of carboplatin and gemcitabine combination chemotherapy in advanced biliary tract cancer: A single centre experience from Nottingham University Hospitals (UK)

Adverse Event Profile of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel Combination Therapy Based on JADER.

There have been advances in the development of immune checkpoint inhibitors for monotherapy and combination therapy with other anticancer agents in recent years. The combination of bevacizumab, carboplatin, and paclitaxel with atezolizumab, an anti-programmed death ligand 1 antibody (ABCP therapy), has been reported to be effective for treating non-small cell lung cancer. However, reports on its adverse events are limited. In this study, a survey and disproportionality analysis based on the Japanese Adverse Drug Event Report (JADER) database was conducted to elucidate the adverse event profile of ABCP therapy. The reporting odds ratio (ROR) and information component were used as indicators for the disproportionality analysis. The ROR was also used to assess the changes in the reporting intensity with combination therapy, and the mutual exclusivity of the 95% confidence interval between the compared groups was considered. The reported adverse events of ABCP therapy mirrored those of the individual drugs that constituted it. ABCP therapy enhanced the reporting intensity of adverse events related to leukocytes and the skin, while decreased those related to interstitial lung disease and hepatic function abnormality as immune-related adverse events caused by atezolizumab, and gastrointestinal perforation caused by bevacizumab. Our analysis of data from the JADER database has revealed the adverse event profile of ABCP therapy. Our findings emphasize the importance of effectively managing febrile neutropenia and skin-related adverse events in ABCP therapy.

Chemotherapy in pediatric low-grade gliomas (PLGG).

Pediatric low-grade gliomas (PLGG) are commonly treated with a combination of surgery, radiotherapy, and chemotherapy. Recent trends prioritize reducing long-term morbidities, particularly in younger patients. While historically chemotherapy was reserved for cases progressing after radiotherapy, evolving recommendations now advocate for its early use, particularly in younger age groups. The carboplatin and vincristine (CV) combination stands as a standard systemic therapy for PLGG, varying in dosage and administration between North America and Europe. Clinical trials have shown promising response rates, albeit with varying toxicity profiles. Vinblastine has emerged as another effective regimen with minimal toxicity. TPCV, a regimen combining thioguanine, procarbazine, lomustine, and vincristine, was compared to CV in a Children's Oncology Group trial, showing comparable outcomes, but more toxicity. Vinorelbine, temozolomide, and metronomic chemotherapy have also been explored, with varied success rates and toxicity profiles. Around 40-50% of PLGG patients require subsequent chemotherapy lines. Studies have shown varied efficacy in subsequent lines, with NF1 patients generally exhibiting better outcomes. The identification of molecular drivers like BRAF mutations has led to targeted therapies' development, showing promise in specific molecular subgroups. Trials comparing targeted therapy to conventional chemotherapy aim to delineate optimal treatment strategies based on molecular profiles. The landscape of chemotherapy in PLGG is evolving, with a growing focus on molecular subtyping and targeted therapies. Understanding the role of chemotherapy in conjunction with novel treatments is crucial for optimizing outcomes in pediatric patients with low-grade gliomas.

Ozone Therapy in the Integrated Treatment of Female Dogs with Mammary Cancer: Oxidative Profile and Quality of Life.

Considering the high frequency of malignant breast tumors, there is a growing search for new therapeutic strategies that control neoplastic growth and dissemination, combined with fewer adverse reactions. Therefore, this study evaluated the effects of ozone therapy in female dogs with mammary cancer undergoing chemotherapy treatment. Twenty-five canines diagnosed with malignant mammary neoplasia were divided into two groups: one treated with carboplatin alone (n = 11) and the other with carboplatin associated with ozone therapy (n = 14). Clinical and laboratory evaluations, mastectomy, analysis of the oxidative profile based on total antioxidant capacity (TAC) and serum concentrations of malondialdehyde (MDA), survival rate, and quality of life were performed. Animals in the ozone therapy group had higher concentrations of red blood cells and platelets, significantly improving the survival rate and quality of life. Furthermore, adverse reactions were less intense and frequent in this group, which was associated with an increase in TAC and a reduction in MDA. These results indicate that the combination of carboplatin and ozone therapy represents a promising complementary treatment for female dogs with mammary cancer, as it was associated with fewer adverse reactions and a better oxidative profile.

Abstract PO2-06-07: A Randomized Phase II Comparison of Single-Agent Carboplatin versus the Combination of Carboplatin and Everolimus for the Treatment of Advanced Triple Negative Breast Cancer

Abstract Background: Both TNBC and BRCA-1 associated breast cancers are sensitive to DNA cross-linking agents such as platinum compounds due to defective DNA repair by homologous recombination. TNBCs are also associated with a high frequency of PTEN loss, which can lead to activation of the mTOR pathway resulting in tumor cell growth and proliferation. mTOR activation can confer resistance to platinum agents, and this phenomenon may be reversible by the addition of an mTOR inhibitor, such as everolimus. A prior phase II single arm trial of carboplatin and everolimus in patients (pts) with advanced TNBC demonstrated good tolerability and preliminary efficacy. Methods: We conducted a phase II, multicenter, randomized trial in pts with advanced TNBC, who had received 0-3 prior lines of therapy. Pts were randomly assigned (in a 2:1 ratio) to carboplatin and everolimus or carboplatin alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. We planned to enroll 72 pts which would provide &amp;gt; 80% power for a one-sided log-rank test at the 5% level of significance, to detect a 2.5 month improvement in median PFS between treatment groups, assuming a median PFS of 2.5 months in the control group. An interim analysis for futility was planned after 36 events with a stopping boundary of P &amp;lt;0.375 for the comparison of PFS, using an Obrien-Fleming spending function. Of note, the trial was stopped earlier than planned based on a sensitivity/tipping point analysis which indicated that terminating the trial 3 months ahead of schedule would have no substantial impact on the primary endpoint. Results: A total of 56 pts were randomized between 2015 and 2022, of whom 36 received carboplatin/everolimus and 20 carboplatin alone. The median age of the population was 62.8 years (range: 33-87) and about 20% of pts had BRCA-1 or BRCA-2 mutations. In the overall population, pts had received a median of 1 (range 1-3) prior line of therapy in the metastatic setting, with 75% of pts receiving prior chemotherapy and 47% prior carboplatin. The median PFS was significantly improved in pts who received carboplatin and everolimus (4.7 months) versus those who received carboplatin alone (2.1 months; HR: 0.37; 95% CI: 0.19-0.72; p=0.0042). Overall survival was 22.1 months in pts on the combination versus 14.4 months on carboplatin alone (HR: 0.73; 95% CI: 0.30-1.72; p=0.3106). CBR was 61% with the combination vs 50% with carboplatin monotherapy, as shown in Table 1. Most common adverse events (AEs) on carboplatin and everolimus included thrombocytopenia (81%), anemia (69%), leukopenia (67%), fluid retention (64%), and neutropenia (61%). Overall, Grade 3/4 events occurred in 75% of pts (83% of pts on combination vs 60% on carboplatin alone) and were primarily anemia (40% vs 17%), thrombocytopenia (47% vs 0%), and neutropenia (20% vs 0%). Of note, there was an increase in thrombocytopenia with the addition of everolimus (All Grades: 81% vs 35%, Grade 3/4: 39% vs 0%). Conclusions: Treatment options for TNBC are limited due to a lack of targeted therapies. The combination of carboplatin and everolimus in this study was associated with a 63% reduction in risk of progression or death in pts with metastatic TNBC. The regimen was well tolerated and provides a promising treatment option for pts with advanced TNBC. Table 1. Results in Patients on Carboplatin and Everolimus versus Carboplatin Alone NE= Not Estimable; 1Unevaluable patients treated as non-responders in CBR and ORR calculations. Citation Format: Rima Patel, Jami Fukui, Paula Klein, Erin Moshier, Charles Shapiro, Anupama Goel, Julie Fasano, Theresa Shao, Aarti Bhardwaj, Rita Vaccaro, Gargi Atul Joshi, Joseph Sparano, Amy Tiersten. A Randomized Phase II Comparison of Single-Agent Carboplatin versus the Combination of Carboplatin and Everolimus for the Treatment of Advanced Triple Negative Breast Cancer [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 PO2-06-07.

Top advances of the year: Uterine cancer.

Endometrial cancer continues to be the only gynecologic malignancy with a rising incidence and mortality, with both regional and global implications. Combination carboplatin and paclitaxel has been the recognized chemotherapy backbone for the treatment of advanced-stage or recurrent disease, with modest clinical outcomes. Over the last year, significant advances were achieved in improving oncologic outcomes by capitalizing on the molecular characterization of this heterogenous disease. These advances include incorporation of immunotherapy, identification of effective hormonal approaches, the evolution of antibody drug conjugates, and utilization of alternate targeted therapies. PLAIN LANGUAGE SUMMARY: The molecular characterization of endometrial cancer has been critical in informing novel treatment strategies. Over the past year, significant gains have been made via the incorporation of immunotherapy, hormonal combinations as well as antibody drug conjugates.

A single arm Phase I/II trial on the combination of carboplatin, nab-paclitaxel and avastin as first-line treatment for advanced non-squamous non-small cell lung cancer (TORG1424/OLCSG1402: CARNAVAL).

Bevacizumab with platinum doublet therapy including paclitaxel+carboplatin improves the survival of patients with non-squamous non-small cell lung cancer. However, in a previous trial (CA031), paclitaxel+carboplatin led to Grade>3 neutropenia in a Japanese population. Nanoparticle albumin-bound paclitaxel exhibits an improved toxicity profile. We evaluated the safety, dosage and response rate of the nanoparticle albumin-bound paclitaxel+carboplatin + bevacizumab combination in a Japanese population. Chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer were included. The dosage schedule was established in the Phase I trial as follows: 4-6cycles of carboplatin (area under the concentration-time curve=6 on Day 1)+nanoparticle albumin-bound paclitaxel (100mg/m2 on Days 1, 8 and 15)+bevacizumab (15mg/kg on Day 1), followed by maintenance therapy (nanoparticle albumin-bound paclitaxel+bevacizumab). The response rate and presence of adverse effects were evaluated in the Phase II trial. The overall response rate was 56.5% (90% confidence interval: 44.5-68.5), and 93% of patients (43/46) showed tumor shrinkage or maintained a stable disease course. The primary endpoint was achieved. At the median follow-up duration of 42months, the median overall survival was 18.9 (range: 10.5-32.4) months. The most frequently observed Grade≥3 adverse effects were neutropenia (72%), leukopenia (50%) and anemia (30%). All adverse effects were manageable and none resulted in patient death. In conclusion, the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination is favorable and well tolerated in Japanese patients as first-line treatment for advanced non-squamous non-small cell lung cancer.

Efficacy and safety of paclitaxel liposome versus paclitaxel in combination with carboplatin in the first-line chemotherapy for ovarian cancer: a multicenter, open-label, non-inferiority, randomized controlled trial

BackgroundThe paclitaxel liposome formulation, encapsulating paclitaxel within a phospholipid bilayer, addresses the insolubility of traditional paclitaxel formulations, thereby reducing toxicity without compromising its antitumor efficacy. MethodsThis multicenter, open-label, non-inferiority randomized controlled trial (ChiCTR2000038555) evaluates the efficacy and safety of paclitaxel liposome in comparison to the standard regimen of paclitaxel combined with carboplatin (PLC vs. PC) as first-line therapy in patients with epithelial ovarian cancer. ResultsAn analysis of median progression-free survival (PFS) revealed non-inferior outcomes between 263 patients in the PLC group and 260 patients in the PC group (32.3 vs. 29.9 months, hazard ratio [HR], 0.89 [95% CI, 0.64−1.25]), using a non-inferior margin of 1.3. Although the overall incidence of treatment-related adverse events was comparable between groups, the PLC group experienced significantly fewer non-hematologic toxicities than those treated with the PC regimen. ConclusionThe findings affirm the non-inferiority of paclitaxel liposome compared to the combination of paclitaxel and carboplatin regarding therapeutic efficacy, with an enhanced safety profile marked by reduced non-hematologic toxicities.

High-dose ascorbate exerts anti-tumor activities and improves inhibitory effect of carboplatin through the pro-oxidant function pathway in uterine serous carcinoma cell lines

ObjectiveUterine serous carcinoma is a highly aggressive non-endometrioid subtype of endometrial cancer with poor survival rates overall, creating a strong need for new therapeutic strategies to improve outcomes. High-dose ascorbate (vitamin C) has been shown to inhibit cell proliferation and tumor growth in multiple preclinical models and has shown promising anti-tumor activity in combination with chemotherapy, with a favorable safety profile. We aimed to study the anti-tumor effects of ascorbate and its synergistic effect with carboplatin on uterine serous carcinoma cells. MethodsCell proliferation was evaluated by MTT and colony formation assays in ARK1, ARK2 and SPEC2 cells. Cellular stress, antioxidant ability, cleaved caspase 3 activity and adhesion were measured by ELISA assays. Cell cycle was detected by Cellometer. Invasion was measured using a wound healing assay. Changes in protein expression were determined by Western immunoblotting. ResultsHigh-dose ascorbate significantly inhibited cell proliferation, caused cell cycle arrest, induced cellular stress, and apoptosis, increased DNA damage, and suppressed cell invasion in ARK1 and SPEC2 cells. Treatment of both cells with 1 mM N-acetylcysteine reversed ascorbate-induced apoptosis and inhibition of cell proliferation. The combination of ascorbate and carboplatin produced significant synergistic effects in inhibiting cell proliferation and invasion, inducing cellular stress, causing DNA damage, and enhancing cleaved caspase 3 levels compared to each compound alone in both cells. ConclusionsAscorbate has potent antitumor activity and acts synergistically with carboplatin through its pro-oxidant effects. Clinical trials of ascorbate combined with carboplatin as adjuvant treatment of uterine serous carcinoma are worth exploring.

Abstract 3237: KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer

Abstract Background: Ovarian cancer (OCa) is the deadliest of all gynecological cancers. The standard treatment for OCa is platinum-based chemotherapy, such as carboplatin or cisplatin in combination with paclitaxel. Most patients are initially responsive to these treatments; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. Recent studies have revealed that the epigenetic modifier lysine-specific histone demethylase (KDM1A/LSD1) is highly overexpressed in OCa. However, whether KDM1A plays a role in chemoresistance and whether its inhibition enhances chemotherapy response in OCa is unknown. In this study, we explored the hypothesis that KDM1A inhibition will sensitize OCa cells to standard-of-care chemotherapy. Methods: Transduction of KDM1A-specific shRNA was used to generate KDM1A knockdown (KD) cells. Cell viability, colony formation, and apoptosis assays were used to determine the impact of KDM1A KD on sensitization of SKOV3, OVCAR8, and OVCAR5 OCa cells to cisplatin, carboplatin, and paclitaxel. The combination effect of KDM1A inhibitors (NCD38 and SP2509) and chemotherapy drugs was further determined. Mechanistic studies were conducted using RNA-sequencing, RT-qPCR, and Western blotting. In vivo efficacy ofKDM1A knockdown with or without chemotherapy was determined using OCa orthotopic xenograft models. Results: Analysis of TCGA datasets revealed that KDM1A expression is negatively correlated with OCa survival, and its expression is high in patients who do not respond to chemotherapy. Further, Western blotting results show that treatment with chemotherapy drugs cisplatin, carboplatin, and paclitaxel increased KDM1A expression in OCa cells. KDM1A-KD or KDM1A inhibition sensitized OCa cells to chemotherapy drugs in reducing cell viability, survival, and enhancing apoptosis. Moreover, knockdown of KDM1A sensitized carboplatin-resistantA2780-CP70 cells to carboplatin treatment. RNA-seq studies revealed that KDM1A-KD and cisplatin-regulated genes showed negative correction with epithelial-mesenchymal transition (EMT) and positive correlation with apoptosis-related pathways. Importantly, KDM1A KD in combination with cisplatin significantly reduced the tumor growth in the orthotopic OCa xenograft model. Conclusion: These results suggest that the combination of KDM1A inhibitors with chemotherapy is a viable therapeutic approach for the treatment of OCa Citation Format: Jessica D. Johnson, Yihong Chen, Sridharan Jayamohan, Yi He, Diksha Jamwal, Neetesh Pandey, Edward Kost, Ratna K. Vadlamudi, Gangadhara R. Sareddy. KDM1A/LSD1 inhibition enhances chemotherapy response in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3237.