Paclitaxel and Carboplatin for Uterine Carcinosarcoma: A Path to Inclusion.
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SUBMITTER: Roque DR
PROVIDER: S-EPMC8937007 | biostudies-literature | 2022 Mar
REPOSITORIES: biostudies-literature
Publications
Paclitaxel and Carboplatin for Uterine Carcinosarcoma: A Path to Inclusion.
Roque Dario R DR Matei Daniela D
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20220119 9
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Project description:BackgroundUterine serous carcinoma and carcinosarcoma are aggressive forms of endometrial cancer with poor survival outcomes. Trastuzumab, a human epidermal growth factor receptor-2 (HER2)-directed monoclonal antibody, has demonstrated tumoricidal efficacy. However, clinical data regarding its efficacy in uterine serous carcinoma are limited, and there are no clinical data available for uterine carcinosarcoma. Therefore, this study aimed to ascertain the efficacy and safety of adding trastuzumab to carboplatin and paclitaxel as a frontline treatment for advanced-stage HER2-overexpressing uterine serous carcinoma and carcinosarcoma.MethodsThis retrospective study used deidentified data from electronic health records from the TriNetX Research Network. Participants were identified using International Classification of Diseases codes, and HER2 positivity was confirmed through immunohistochemistry or fluorescence in situ hybridisation. Propensity score matching was employed to reduce confounders, and survival outcomes and adverse events were assessed.ResultsFollowing propensity score matching, 280 patients with advanced HER2-positive uterine serous carcinoma or carcinosarcoma were analysed. The group of patients treated with carboplatin/paclitaxel + trastuzumab (CP + T) showed a significantly prolonged median overall survival compared to those treated exclusively with CP (41 months versus 25.2 months, hazard ratio [HR] = 0.51, p = 0.002) in both advanced-stage uterine carcinosarcoma and serous carcinoma. Specifically, patients with uterine carcinosarcoma experienced a prolonged survival benefit (HR = 0.39, p < 0.0001) when trastuzumab was added to their chemotherapy regimen, which surpassed the survival benefit observed in patients with uterine serous carcinoma (HR = 0.56, p = 0.04). However, patients who received trastuzumab experienced increased rates of hypertension, diarrhoea, and left ventricular systolic dysfunction.ConclusionsThe addition of trastuzumab to frontline chemotherapy is effective in treating HER2-overexpressing uterine serous carcinoma and carcinosarcoma, particularly uterine carcinosarcoma. However, careful monitoring of adverse cardiac events is needed.
| S-EPMC11846311 | biostudies-literature
Project description:PurposeThis phase III randomized trial (NCT00954174) tested the null hypothesis that paclitaxel and carboplatin (PC) is inferior to paclitaxel and ifosfamide (PI) for treating uterine carcinosarcoma (UCS).Patients and methodsAdults with chemotherapy-naïve UCS or ovarian carcinosarcoma (OCS) were randomly assigned to PC or PI with 3-week cycles for 6-10 cycles. With 264 events in patients with UCS, the power for an overall survival (OS) hybrid noninferiority design was 80% for a null hazard ratio (HR) of 1.2 against a 13% greater death rate on PI with a type I error of 5% for a one-tailed test.ResultsThe study enrolled 536 patients with UCS and 101 patients with OCS, with 449 and 90 eligible, respectively. Primary analysis was on patients with UCS, distributed as follows: 40% stage I, 6% stage II, 31% stage III, 15% stage IV, and 8% recurrent. Among eligible patients with UCS, PC was assigned to 228 and PI to 221. PC was not inferior to PI. The median OS was 37 versus 29 months (HR = 0.87; 90% CI, 0.70 to 1.075; P < .01 for noninferiority, P > .1 for superiority). The median progression-free survival was 16 versus 12 months (HR = 0.73; P = < 0.01 for noninferiority, P < .01 for superiority). Toxicities were similar, except that more patients in the PC arm had hematologic toxicity and more patients in the PI arm had confusion and genitourinary hemorrhage. Among 90 eligible patients with OCS, those in the PC arm had longer OS (30 v 25 months) and progression-free survival (15 v 10 months) than those in the PI arm, but with limited precision, these differences were not statistically significant.ConclusionPC was not inferior to the active regimen PI and should be standard treatment for UCS.
| S-EPMC8937015 | biostudies-literature
Project description:PurposePlatinum and taxane compounds have demonstrated activity in uterine carcinosarcoma (malignant mixed Mullerian tumor). Ifosfamide plus paclitaxel is the regimen with established superiority based on a randomized phase III trial conducted through the Gynecologic Oncology Group. However, the toxicity, multiday schedule, and limited activity of this regimen support further development of novel regimens. Our primary objective was to estimate the antitumor activity and toxicity of paclitaxel plus carboplatin in patients with uterine carcinosarcomas.Patients and methodsEligible patients had advanced stage (III or IV), persistent or recurrent measurable disease, and no prior chemotherapy. Patients received paclitaxel at 175 mg/m(2) intravenously (IV) over 3 hours plus carboplatin (area under the serum concentration-time curve = 6) IV over 30 minutes every 3 weeks until disease progression or until adverse effects occurred. Common Terminology Criteria for Adverse Events v3.0 was used to grade adverse events.ResultsFifty-five patients were entered onto the study with nine being excluded from analysis, leaving 46 evaluable for analysis. Treatment was well tolerated with expected hematologic toxicity and minimal nonhematologic grade 4 toxicity (one cardiovascular and two pain) with 59% of patients completing six or more cycles of chemotherapy. The proportions of patients with confirmed complete and partial responses were 13% and 41%, respectively, resulting in a total overall response rate of 54% (95% CI, 37% to 67%).ConclusionPaclitaxel plus carboplatin demonstrates antitumor activity against uterine carcinosarcoma with acceptable toxicity and warrants further evaluation in phase III randomized trials.
| S-EPMC2881851 | biostudies-literature
Project description:We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.
| S-EPMC5599133 | biostudies-literature
Project description:Carcinosarcoma is a rare histological type of non-small cell carcinoma (NSCLC), and its prognosis has been reported to be worse compared with other NSCLCs. Nanoparticle albumin-bound paclitaxel (nab-PTX) + carboplatin (CBDCA) achieves a favorable response rate in patients with non-small cell lung cancer (NSCLC). We administered nab-PTX + CBDCA to a 68-year-old man with postoperative recurrent carcinosarcoma with interstitial lung disease (ILD). A partial response was evident after four cycles of chemotherapy. To the best of our knowledge, the present study is the first to report the safety and efficacy of nab-PTX + CBDCA for treating carcinosarcoma with ILD.
| S-EPMC5925955 | biostudies-literature
Project description:Uterine carcinosarcoma (UCS) is a relatively infrequent, but extremely aggressive endometrial malignancy. Although surgery and chemotherapy have improved outcomes, overall survival (OS) remains dismal due to the lack of targeted therapy and biphasic (epithelial and mesenchymal) nature that renders the tumor aggressive and difficult to manage. Here we report a role of transforming growth factor-β (TGFβ) in maintaining epithelial to mesenchymal transition (EMT) phenotype and aggressiveness in UCS. Using a 3D-culture system, we evaluated the efficacy of the transforming growth factor-β receptor-I (TGFβR1) kinase inhibitor Galunisertib (GLT), alone and in combination with standard chemotherapeutic drugs used for the management of UCS. We demonstrate that GLT by inhibiting canonical and non-canonical signaling emanating from transforming growth factor-β1 (TGFβ1) reduces cellular viability, invasion, clonal growth and differentiation. Interestingly, GLT sensitizes UCS cells to chemotherapy both in vitro and in in vivo preclinical tumor model. Hence, targeting TGFβ signaling, in combination with standard chemotherapy, may be exploited as an important strategy to manage the clinically challenging UCS.
| S-EPMC7590842 | biostudies-literature
Project description:PurposeUterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002.Patients and methodsEligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints.ResultsSixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28-0.76; P = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23-0.83; P = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03-0.48; P = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34-0.99; P = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25-0.97; P = 0.041). Toxicity was not different between arms.ConclusionsAddition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.
| S-EPMC8792803 | biostudies-literature
Project description:Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) are two rare histologic variants of uterine carcinoma, with distinct molecular profiles and aggressive metastatic potential. As the effectivity of traditional platinum-based chemotherapy for USC and UCS is low, and there are high rates of resistance and recurrence, the development of novel targeted therapeutics is needed. Human epidermal growth factor receptor 2 (HER2) has proven to be an oncogene of increasing interest in these cancers, as HER2 protein overexpression and/or c-ERBB2 gene amplification ranges from ~30 to 35% in USC, and between ~15 and 20% in UCS. This review summarizes the existing clinical and preclinical evidence, as well as ongoing clinical trials of HER2-targeting therapeutics, and identifies potential areas of further development and inquiry.
| S-EPMC10452357 | biostudies-literature
Project description:Uterine carcinosarcoma (UCS) is a rare but lethal neoplasm with high metastasis and recurrence rate, and to date, no molecular classification of UCS has been defined to achieve targeted therapies. In this study, we identified two distinct molecular subtypes of UCS with distinct gene expression patterns and clinicopathologic characteristics. Subtype I UCS recapitulates low-grade UCS, in contrast subtype II UCS represents high-grade UCS with higher tumor invasion rate and tumor weight. Interestingly, subtype I UCS is characterized by cell adhesion and apoptosis pathways, whereas genes over-expressed in subtype II UCS are more involved in myogenesis/muscle development. We also proposed certain potential subtype specific therapeutic targets, such as SYK (spleen tyrosine kinase) for subtype I and cell-cycle proteins for subtype II. Our findings provide a better recognition of UCS molecular subtypes and subtype specific oncogenesis mechanisms, and can help develop more specific targeted treatment options for these tumors.
| S-EPMC5362530 | biostudies-literature
Project description:Uterine carcinosarcomas are rare and extremely aggressive undifferentiated carcinomas which include both carcinomatous and sarcomatous elements. A 52-year-old female presented with heavy irregular menstrual bleeding for several years and new right elbow pain and swelling. Ultrasound and computed tomography showed a large uterine mass with regional and distant metastatic lymphadenopathy and suspicious findings of osseous metastasis to the right elbow. A biopsy confirmed uterine carcinosarcoma, and the patient underwent chemotherapy and then surgical resection of the uterine mass with palliative radiotherapy of the right elbow. The postoperative imaging showed new metastasis, and the patient was scheduled to start on immunotherapy. Considering the highly invasive nature of uterine carcinosarcomas, timely detection of this cancer using characteristic imaging and pathology findings is of extreme importance to improve the patient's survival.
| S-EPMC7455848 | biostudies-literature