Dataset Information

Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy.

ABSTRACT: There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recurrent endometrial cancer from 1992 to 2011. Diagnosis of diabetes, metformin use, demographics, endometrial cancer clinico-pathologic parameters, and survival duration were abstracted. The primary outcome was overall survival. The final cohort included 349 patients, 31 (8.9%) had diabetes and used metformin, 28 (8.0%) had diabetes but did not use metformin, and 291 (83.4%) did not have diabetes. The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes (log-rank test comparing the three groups P = 0.006). In a model adjusted for confounders, the difference in survival between the three groups remained statistically significant (P = 0.023). The improvement in survival among metformin users was not explained by better baseline health status or more aggressive use of chemotherapy. Overall, the findings in this retrospective cohort of endometrial cancer patients with stage III-IV or recurrent disease treated with chemotherapy indicate that patients with diabetes who were concurrently treated with metformin survived longer than patients with diabetes who did not use metformin.

SUBMITTER: Ezewuiro O

PROVIDER: S-EPMC4720394 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy.

Ezewuiro Obiageli O Grushko Tatyana A TA Kocherginsky Masha M Habis Mohammed M Hurteau Jean A JA Mills Kathryn A KA Hunn Jessica J Olopade Olufunmilayo I OI Fleming Gini F GF Romero Iris L IL

PloS one 20160120 1

There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recur ...[more]

PMID: 26788855

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Project description:: Level I evidence exists for use of adjuvant chemotherapy in stage IIIC endometrial cancer (positive lymph nodes), although results of randomized trials have varied. Chemotherapy is also often recommended for high-risk subsets of stage I disease, such as serous carcinomas, although prospective trial data to validate this practice are lacking. Carboplatin plus paclitaxel is the current standard regimen, based on extrapolation of data from the metastatic setting. Several clinical trials have compared adjuvant pelvic radiotherapy alone to a combination of radiotherapy and chemotherapy with mixed results. One of the largest of these trials, Postoperative Radiation Therapy in Endometrial Carcinoma 3 (PORTEC-3), has completed accrual and is awaiting data maturation. Metastatic disease is not curable. For tumors of low-grade endometrioid histology with a prolonged time to recurrence, endocrine therapy with a progestin-based regimen is appropriate. Chemotherapy will be used in most other cases, and the standard first-line regimen is carboplatin and paclitaxel. Few chemotherapy agents have been shown to produce meaningful response rates in the second-line setting. Molecularly targeted therapies such as mTOR inhibitors and antiangiogenic agents including bevacizumab have been studied but their role in the armamentarium remains uncertain.Following surgical resection and staging for endometrial cancer, adjuvant chemotherapy with carboplatin and paclitaxel can be administered to patients with a high risk for recurrence. This includes patients with stage IIIC disease with positive lymph nodes, and high-risk subsets of stage I disease such as serous carcinomas. In the metastatic setting, endocrine therapy can be considered, particularly for patients with lower-grade disease and a prolonged time to recurrence. Combined therapy with carboplatin and paclitaxel is the standard of care used for front-line chemotherapy. Antiangiogenic agents are clearly active, but how they should be integrated into treatment is not yet determined. Immunotherapy is a promising direction for patients with mismatch repair-deficient or polymerase ?-mutated tumors.

Project description:Second-line therapy has consistently demonstrated survival benefit if compared with best supportive care; however, there is limited evidence whether further lines of treatment may improve the prognosis of advanced gastric cancer (AGC) patients.Starting from a real-world cohort of 868 AGC patients, we retrospectively analyzed baseline parameters, tumor characteristics, and treatment data of those treated with at least three lines. Categorical features were described through cross-tables and chi-square test. We explored the impact of treatment intensity and progression-free survival (PFS) experienced in previous lines on PFS and overall survival in third-line by uni- and multivariate Cox regression models and described by Kaplan-Meier estimator plot with log-rank test.Overall, 300 patients were included in the analysis. The most common site of primary tumor was gastric body; 45.3% of cancers had an intestinal histotype, 14% were human epidermal growth receptor 2 positive. In third-line, 45.7% of patients received a single-agent chemotherapy, 49.7% a combination regimen. Patients who had experienced a first-line PFS ?6.9 months had a better prognosis compared with those who had achieved a shorter one. Consistently, a second-line PFS ?3.5 months positively influenced the prognosis. Patients receiving a third-line combination regimen had better outcomes compared with those treated with a single-agent chemotherapy.Our real-world study confirms that selected AGC patients may receive third-line treatment. Longer PFS in previous lines or a more intense third-line treatment positively influenced prognosis. Further efforts are warranted to define the best therapeutic sequences, and to identify the optimal candidate for treatment beyond second-line.The benefit of third-line treatment to advanced gastric cancer patients is controversial. This study depicts a real scenario of the clinical practice in Italy, confirming that a non-negligible proportion of patients receive a third-line therapy. Longer progression-free survival in previous treatment lines or higher third-line treatment intensity positively influenced prognosis. Including a large number of real-world patients, this study provides information on third-line treatment from the daily clinical practice; moreover, its results help in defining the best therapeutic sequence and offer some hints to select the optimal candidate for treatment beyond second-line.

Project description:ObjectiveWhile primary cytoreductive surgery (PCS) is considered the standard of care for women who present with stage IV endometrial cancer, neoadjuvant chemotherapy (NACT) followed by interval cytoreductive surgery (ICS) has emerged as an alternative treatment strategy. We summarized the literature and compared outcomes of PCS compared to NACT and ICS.MethodsWe conducted a systematic search on PubMed, Embase, Web of Science, and Scopus for articles published from January 1, 1990 to December 31, 2020. Key search terms included multiple descriptors of advanced disease status in combination with "endometrial cancer" and "neoadjuvant chemotherapy". Our review included studies that examined survival and surgical outcomes of patients with stage III or IV endometrial cancer treated with neoadjuvant chemotherapy followed by interval cytoreductive surgery versus those who received primary cytoreductive surgery. We excluded studies examining only patients with leiomyosarcomas, carcinosarcomas, and stromal sarcomas due to the biologic heterogeneity of these malignancies.ResultsThe nine included studies encompassed 5,844 patients, of which 1,317 (22.5%) received NACT and 4,527 received PCS (77.5%). With the exception of a single study, all were retrospective observational studies or case series. Use of NACT in patients with stage IV EC increased from 16.0% in 2010 to 23.9% in 2015. Five studies analyzed median overall survival and all but one reported no significant difference between NACT + ICS vs. PCS. Optimal cytoreduction (<1 cm of residual disease) rates were similar across both treatment groups in three separate analyses, however pooled data suggest improved rates of optimal cytoreduction for NACT + ICS vs. PCS patients (81.9% vs. 51.5% respectively). Patients receiving NACT experienced significantly shorter hospital admissions and lower operative times compared to PCS counterparts.ConclusionsNACT followed by ICS reduces perioperative morbidity while offering similar overall survival.

Project description:Highlights • Among subjects who underwent hysterectomy for endometrial cancer, 19% received adjuvant chemotherapy.• Platinum and taxane based chemotherapy is the most commonly used adjuvant chemotherapy.• Platinum and taxane combination therapy was used in 48% of patients at first recurrence. Objective The objective of this study was to describe patterns of utilization of cytotoxic, hormonal, and immunotherapy in patients with endometrial cancer in the adjuvant setting and at the time of first recurrence. Methods We identified patients in the IBM MarketScan database with endometrial cancer who underwent hysterectomy from 2011 to 2019. The use of clinically relevant therapeutic agents and combination regimens was determined in the adjuvant setting and at the time of first recurrence. Results A total of 22,632 patients were identified. Of these, 7,147 patients (31.6%) received adjuvant radiation and 4,381 (19.4%) received adjuvant chemotherapy following surgery. Of those who received adjuvant chemotherapy, the most commonly utilized agents were carboplatin (90.3%), paclitaxel (85.8%), cisplatin (9.4%), docetaxel (9.3%), gemcitabine (3.8%), and doxorubicin (2.0%), while bevacizumab was utilized in 1.5% of patients. A combination of platinum and a taxane were utilized as adjuvant therapy in 88.8% of women. Of the cohort, 1,825 patients (8.1%) recurred, of whom 1,017 patients had already received adjuvant chemotherapy. The median time from hysterectomy to initiation of chemotherapy for recurrence was 13.3 months (IQR: 7.6–23.1 months). Overall, platinum and taxane combination therapy was used in 788 (46.8%) of patients with recurrent disease, platinum alone or with other drugs in 194 (11.5%), taxanes alone or with other drugs in 145 (8.6%), and non-platinum and non-taxane based therapy in 31.3%. Conclusions Among patients with endometrial cancer who underwent hysterectomy, platinum-taxane combination chemotherapy was used in almost 90% of patients who received adjuvant chemotherapy while nearly 70% of patients who recurred were treated with platinum or taxane based therapy at first recurrence.

Project description:BackgroundAn extensive crosstalk co-regulates the Hippo and Wnt pathway. Preclinical studies revealed that the Hippo transducers YAP/TAZ mediate a number of oncogenic functions in gastric cancer (GC). Moreover, comprehensive characterization of GC demonstrated that the Wnt pathway is targeted by oncogenic mutations. On this ground, we hypothesized that YAP/TAZ- and Wnt-related biomarkers may predict clinical outcomes in GC patients treated with chemotherapy.MethodsIn the present study, we included 86 patients with advanced GC treated with first-line chemotherapy in prospective phase II trials or in routine clinical practice. Tissue samples were immunostained to evaluate the expression of YAP/TAZ. Mutational status of key Wnt pathway genes (CTNNB1, APC and FBXW7) was assessed by targeted DNA next-generation sequencing (NGS). Survival curves were estimated and compared by the Kaplan-Meier product-limit method and the log-rank test, respectively. Variables potentially affecting progression-free survival (PFS) were verified in univariate Cox proportional hazard models. The final multivariate Cox models were obtained with variables testing significant at the univariate analysis, and by adjusting for all plausible predictors of the outcome of interest (PFS).ResultsWe observed a significant association between TAZ expression and Wnt mutations (Chi-squared p = 0.008). Combined TAZ expression and Wnt mutations (TAZpos/WNTmut) was more frequently observed in patients with the shortest progression-free survival (negative outliers) (Fisher p = 0.021). Uni-and multivariate Cox regression analyses revealed that patients whose tumors harbored the TAZpos/WNTmut signature had an increased risk of disease progression (univariate Cox: HR 2.27, 95% CI 1.27-4.05, p = 0.006; multivariate Cox: HR 2.73, 95% CI 1.41-5.29, p = 0.003). Finally, the TAZpos/WNTmut signature negatively impacted overall survival.ConclusionsCollectively, our findings indicate that the oncogenic YAP/TAZ-Wnt crosstalk may be active in GC, conferring chemoresistant traits that translate into adverse survival outcomes.

Project description:BackgroundAlthough endometrial adenocarcinoma is a common gynaecological cancer, a comparatively small proportion of patients present with, or develop, recurrent or advanced disease. However, for those women whose disease does progress or recur the prognosis is poor and the best treatment is yet to be identified. Co-morbidity, including obesity and cardiac disease, and concerns over toxicity have prevented more extensive studies of cytotoxic chemotherapy, although there are a number of active agents.ObjectivesTo assess any benefits or adverse effects of cytotoxic chemotherapy in women with advanced, recurrent or metastatic endometrial adenocarcinoma.Search methodsSystematic searches of MEDLINE, EMBASE, CENTRAL and the Cochrane Gynaecological Cancer specialist trials register were conducted to identify all eligible randomised controlled trials (RCTs).Databases were searched from 1966 to January 2012. Literature searches were supplemented with searches of relevant trials registers and conference proceedings.Selection criteriaRCTs comparing chemotherapy versus another intervention (including different chemotherapy) in advanced disease were considered. Trials of adjuvant treatment or for sarcomatous tumours were excluded.Data collection and analysisData were extracted from the papers by review authors and authors of included studies contacted for further information.Main resultsFourteen eligible trials, which recruited patients between 1974 and 2005, were identified, eight of which compared 'more' with 'less' chemotherapy. Results from these eight trials, including 1519 patients, showed that treatment consisting of 'more' chemotherapy was associated with longer overall survival (OS) (hazard ratio (HR) 0.86; 95% confidence intervals (CI) 0.77 to 0.96; P = 0.005) and with longer progression-free survival (PFS) (n = 1526; HR 0.82; 95% CI 0.74 to 0.90; P < 0.0001). However, serious acute toxicities were more common in women randomised to the more-intense chemotherapy regimens.There was no evidence to suggest that any particular doublet chemotherapy was better (or worse) than any other, or that any single-agent chemotherapy was better (or worse) than another; however, data for these two comparisons were limited. There were no comparative trials of chemotherapy with endocrine therapy or best supportive care alone.Authors' conclusionsThis review suggests that more-intense chemotherapy regimens may improve both OS and PFS for women with advanced or recurrent endometrial cancer. However, owing to inconsistencies between cytotoxic drug combinations that have been assessed in randomised trials to date, the optimum regimen has still to be defined. Future trials should aim to include measures of quality of life (QoL) and symptom control in addition to survival and progression outcomes.

Project description:ObjectiveIn the double-blind, phase III, placebo-controlled RUBY randomized clinical trial, dostarlimab plus carboplatin-paclitaxel significantly increased survival among patients with primary advanced or recurrent endometrial cancer (EC). We conducted a cost-effectiveness analysis of dostarlimab in combination with chemotherapy in these patients stratified by mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) subgroups from the perspective of a United States payer.Materials and methodsA Markov model with three states was employed to simulate patients who were administered either dostarlimab in combination with chemotherapy or chemotherapy based on the RUBY trial. Quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER) were calculated with a willingness-to-pay (WTP) threshold of $150,000 per QALY. Both univariate and probabilistic sensitivity analyses were carried out to explore the robustness of the model.ResultsIn dMMR EC, the combination of dostarlimab and chemotherapy achieved an additional 5.48 QALYs at an incremental cost of $330,747 compared to chemotherapy alone, resulting in an ICER of $60,349.30 per QALY. In pMMR EC, there were 1.51 additional QALYs gained at an extra cost of $265,148, yielding an ICER of $175,788.47 per QALY. With a 15.2% discount on dostarlimab, the ICER decreased to $150,000 per QALY in the pMMR EC. The univariate sensitivity analysis revealed that the cost of dostarlimab, utility of progression-free survival (PFS), and progressive disease (PD) had the most significant impacts on the outcomes. Probabilistic sensitivity analysis revealed that dostarlimab had a 100% likelihood of being considered cost-effective for patients at a WTP threshold of $150,000 per QALY for dMMR EC, whereas this likelihood was only 0.5% for pMMR EC.ConclusionDostarlimab in combination with chemotherapy was cost-effective for primary advanced or recurrent dMMR EC from the perspective of a United States payer at a WTP threshold of $150,000 per QALY, but not for pMMR EC. Lowering the prices of dostarlimab could potentially enhance the cost-effectiveness of treatment for pMMR EC.

Dataset Information

Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy.

Publications

Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy.

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