Evaluation of the management of PARP inhibitor toxicities in ovarian and endometrial cancer within a multi-institution health-system

2021 ◽  
pp. 107815522110247
Author(s):  
Rachel V Hatch ◽  
Sweta U Patel ◽  
Christine Cambareri ◽  
Tanya Uritsky ◽  
Lainie P Martin
Keyword(s):  
Observational Study ◽  
Health System ◽  
Dose Reduction ◽  
Parp Inhibitor ◽  
Management Strategies ◽  
Progression Free Survival ◽  
Adenosine Diphosphate ◽  
University Of Pennsylvania ◽  
The Status ◽  
Health System Data

Introduction Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) have become a cornerstone of therapy in the management ovarian cancer and other cancers. PARPi are associated with significant toxicities and management strategies are primarily founded on clinical trial experience. This study aimed to provide an evaluation of patients receiving PARPi therapy within an academic health-system. Methods A retrospective, observational study of adult patients with gynecologic malignancy was conducted at the University of Pennsylvania Health System. Data was collected on patients prescribed a PARPi between December 2014 and October 2019. The primary endpoint was the status of PARPi therapy at the end of the study period. Key secondary endpoints included toxicity management strategies, time to discontinuation due to toxicity, progression free survival (PFS), and overall survival (OS). Results Of the 85 patients included, 45 (53%) received olaparib, 24 (28%) niraparib, and 16 (19%) rucaparib. Twenty-nine patients (34%) continued on therapy, 15 (18%) discontinued due to toxicity, and 41 (48%) discontinued due to progression. Fifty-one percent of patients required a dose reduction due to toxicities. The median time to discontinuation due to toxicity was 69 days (9-353). Median PFS was 181 days (9-365) and median OS was 338 days (9-365). Conclusion PARPi therapy is associated with numerous toxicities that are best managed through a multi-modal approach. Importantly, about half the patients in the current study required a dose reduction. Overall, this observational study outlines the incidence of PARPi toxicities and reviews potential management strategies, further guiding practitioners in an area with limited real-world experience.

Evaluation of the occurrence and management of PARP inhibitor toxicities.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18073-e18073
Author(s):  
Rachel Hatch ◽  
Sweta Patel ◽  
Christine Cambareri ◽  
Tanya Uritsky ◽  
Lainie P. Martin
Keyword(s):  
Adverse Events ◽  
Observational Study ◽  
Health System ◽  
Dose Reduction ◽  
Median Time ◽  
Management Strategies ◽  
Elevated Serum ◽  
Pharmacologic Therapy ◽  
One Year

e18073 Background: Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) have become a major cornerstone of therapy in the management of patients with ovarian cancer and other cancer types. The most common adverse events with PARPi therapy include bone marrow suppression, gastrointestinal (GI) toxicity, and fatigue. Currently, information is scarce regarding the management of some of these adverse events. Methods: A retrospective, descriptive observational study of adult patients with gynecologic malignancy, who received at least 2 weeks of PARPi therapy, was conducted at the University of Pennsylvania Health System. Data was collected on patients prescribed a PARPi between December 2014 and October 2019, from initiation of therapy through one-year post-initiation or last follow-up. The primary endpoint was the status of PARPi therapy at the end of the study period. Secondary endpoints included time to toxicity, progression free survival (PFS), and overall survival (OS). Descriptive statistics were used to analyze all endpoints. Results: Of the 85 patients included in the study, 45 (53%) received olaparib, 24 (28%) niraparib, and 16 (19%) rucaparib. Twenty-nine patients (34%) continued on PARPi therapy, 16 (19%) discontinued the due toxicity, and 40 (47%) discontinued due to progression. Of 147 unique toxicities, 67 (46%) were GI-related, 48 (33%) were hematologic, and 32 (22%) were other toxicities, including fatigue, elevated serum creatinine, hypertension, and rash. Twenty-three percent of all toxicities were categorized as grade 3 or 4 per the Common Terminology Criteria for Adverse Events v5.0. The median number of management strategies required for GI toxicities was 1 (range 1-7), hematologic toxicities was 2 (1-8), and fatigue was 1.5 (1-4). Primary management strategies included pharmacologic therapy (96%) for GI toxicities; transfusion support (65%), holding PARPi therapy (67%), and dose reduction (52%) for hematologic toxicities; and dose reduction (78%) for fatigue. Hospital admission due to PARPi toxicity occurred in 12% of patients. The median time to toxicity was 29 days (1-330) and the median time to discontinuation due to toxicity was 72.5 days (9-353). Fifty-four patients (64%) had progression of disease and 18 (21%) died within one-year of initiation. Median PFS was 181 days and median OS was 338 days, censored for time to last follow-up. Conclusions: This observational study outlines the incidence of PARPi toxicity and some of the management strategies within an academic health system, further guiding practitioners in an area with limited information.

scholarly journals Poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors as maintenance therapy in women with newly diagnosed ovarian cancer: a systematic review and meta-analysis

2021 ◽  
Author(s):  
Hongyan Cheng ◽  
Junjun Yang ◽  
Huixin Liu ◽  
Yang Xiang
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Meta Analysis ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
Cochrane Library ◽  
Newly Diagnosed ◽  
Gynecology And Obstetrics

Abstract Purpose To investigate the efficacy and safety of poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors (including their different types) as maintenance therapy in women with newly diagnosed ovarian cancer, and to explore whether this therapy produces a survival benefit in a subgroup population with specific clinical characteristics. Methods We searched MEDLINE, EMBASE, the Cochrane Library, Web of Science and relevant clinical research registry platforms on October 1, 2019, and included randomized controlled trials (RCTs) that compared PARP inhibitors with placebo in women (aged ≥ 18 years) with newly diagnosed epithelial ovarian cancer. Results We identified four RCTs with 3,070 participants. Compared with placebo, PARP inhibitor maintenance therapy showed a clinically significant benefit on progression free survival (PFS) in homologous recombination deficiency (HRD) positive population (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.29–0.53). In contrast, no clear differences were identified between the groups in the HRD negative population (HR, 0.83; 95% CI 0.67–1.03). Further, there was no clear difference between the groups in terms of other outcomes (overall survival, health-related quality of life, and adverse events). Conclusions PARP inhibitor maintenance therapy significantly prolongs the PFS of patients with newly diagnosed ovarian cancer, especially in HRD positive patients. The diagnostic test used to determine HRD status plays an important role in guiding PARP inhibitor maintenance therapy. Compared with placebo, the effect of PARP inhibitors on ovarian cancer was probably not affected by the International Federation of Gynecology and Obstetrics stage status, response to first-line chemotherapy, and residual macroscopic disease after debulking surgery.

scholarly journals Association between virtual care modality, utilization, and anxiety outcomes: retrospective observational study (Preprint)

2020 ◽  
Author(s):  
Sarah Kunkle ◽  
Manny Yip ◽  
Justin Hunt ◽  
Watson Ξ ◽  
Dana Udall ◽  
...  
Keyword(s):  
Mental Health ◽  
Observational Study ◽  
Health System ◽  
Mental Health System ◽  
Anxiety Symptoms ◽  
Retrospective Observational Study ◽  
Public Health Perspective ◽  
On Demand ◽  
Clinically Significant ◽  
Health System Data

BACKGROUND Anxiety is an extremely prevalent condition, but has received notably less attention than depression and other mental health conditions from a research, clinical, and public health perspective. Growing concerns about the burden of anxiety have only been exacerbated by the Coronavirus (COVID-19) pandemic due to the confluence of physical health risks, economic stressors, social isolation, and general disruption of daily activities OBJECTIVE This study aimed to examine differences in anxiety outcomes by care modality (coaching, teletherapy and telepsychiatry, and collaborative) within an on-demand mental health system. We also explored the association between levels of engagement within each care modality and odds of improvement in symptoms of anxiety METHODS We conducted a retrospective observational study of individuals who accessed Ginger, an on-demand mental health system. Data were collected from 1611 Ginger members between January 1, 2018 and December 31, 2019. We used logistic regression to assess the association between care modality and improvement in anxiety symptoms. Within each modality, we assessed the association between level of engagement and improvement. RESULTS 761/1611 (47.0%) experienced a decrease in anxiety symptoms as measured by a change from positive to negative GAD-2 screen. Among members who still screened positive (n=865; 53%) at follow up, a total of 192 members (11.9%) experienced a clinically significant reduction in score on the full GAD-7 (i.e. a score reduction of >5 points), even though their GAD-2 scores were still positive. All modalities showed increased odds of improvement compared to those who were not engaged with coaching or clinical services (“app only”). Higher GAD-7 intake score was also associated with decreased odds of improvement. CONCLUSIONS This study found increased odds of anxiety improvement for all care modalities compared to those who did not engage in care with larger effect sizes for higher utilization within all care modalities. Additionally, there is a promising observation that those engaged in collaborative care (teletherapy and text-based coaching) have the greatest odds of anxiety improvement. Future directions include more detailed classifications of utilization patterns and exploring explanations and solutions for lower utilization members.

scholarly journals Role of caregiver factors in outpatient medical follow-up post-stroke: observational study in Singapore

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shilpa Tyagi ◽  
Gerald Choon-Huat Koh ◽  
Nan Luo ◽  
Kelvin Bryan Tan ◽  
Helen Hoenig ◽  
...  
Keyword(s):  
Observational Study ◽  
Management Strategies ◽  
Stroke Survivor ◽  
Stroke Survivors ◽  
Post Stroke ◽  
Memory Problems ◽  
Healthcare Needs ◽  
Stroke Study

Abstract Background Outpatient medical follow-up post-stroke is not only crucial for secondary prevention but is also associated with a reduced risk of rehospitalization. However, being voluntary and non-urgent, it is potentially determined by both healthcare needs and the socio-demographic context of stroke survivor-caregiver dyads. Therefore, we aimed to examine the role of caregiver factors in outpatient medical follow-up (primary care (PC) and specialist outpatient care (SOC)) post-stroke. Method Stroke survivors and caregivers from the Singapore Stroke Study, a prospective, yearlong, observational study, contributed to the study sample. Participants were interviewed 3-monthly for data collection. Counts of PC and SOC visits were extracted from the National Claims Database. Poisson modelling was used to explore the association of caregiver (and patient) factors with PC/SOC visits over 0–3 months (early) and 4–12 months (late) post-stroke. Results For the current analysis, 256 stroke survivors and caregivers were included. While caregiver-reported memory problems of a stroke survivor (IRR: 0.954; 95% CI: 0.919, 0.990) and caregiver burden (IRR: 0.976; 95% CI: 0.959, 0.993) were significantly associated with lower early post-stroke PC visits, co-residing caregiver (IRR: 1.576; 95% CI: 1.040, 2.389) and negative care management strategies (IRR: 1.033; 95% CI: 1.005, 1.061) were significantly associated with higher late post-stroke SOC visits. Conclusion We demonstrated that the association of caregiver factors with outpatient medical follow-up varied by the type of service (i.e., PC versus SOC) and temporally. Our results support family-centred care provision by family physicians viewing caregivers not only as facilitators of care in the community but also as active members of the care team and as clients requiring care and regular assessments.

scholarly journals Quantitative MRI-based radiomics for noninvasively predicting molecular subtypes and survival in glioma patients

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Jing Yan ◽  
Bin Zhang ◽  
Shuaitong Zhang ◽  
Jingliang Cheng ◽  
Xianzhi Liu ◽  
...  
Keyword(s):  
Image Fusion ◽  
Molecular Subtypes ◽  
Progression Free Survival ◽  
Quantitative Mri ◽  
Promoter Mutation ◽  
Fusion Model ◽  
Free Survival ◽  
Contrast Enhanced ◽  
Apparent Diffusion ◽  
The Status

AbstractGliomas can be classified into five molecular groups based on the status of IDH mutation, 1p/19q codeletion, and TERT promoter mutation, whereas they need to be obtained by biopsy or surgery. Thus, we aimed to use MRI-based radiomics to noninvasively predict the molecular groups and assess their prognostic value. We retrospectively identified 357 patients with gliomas and extracted radiomic features from their preoperative MRI images. Single-layered radiomic signatures were generated using a single MR sequence using Bayesian-regularization neural networks. Image fusion models were built by combing the significant radiomic signatures. By separately predicting the molecular markers, the predictive molecular groups were obtained. Prognostic nomograms were developed based on the predictive molecular groups and clinicopathologic data to predict progression-free survival (PFS) and overall survival (OS). The results showed that the image fusion model incorporating radiomic signatures from contrast-enhanced T1-weighted imaging (cT1WI) and apparent diffusion coefficient (ADC) achieved an AUC of 0.884 and 0.669 for predicting IDH and TERT status, respectively. cT1WI-based radiomic signature alone yielded favorable performance in predicting 1p/19q status (AUC = 0.815). The predictive molecular groups were comparable to actual ones in predicting PFS (C-index: 0.709 vs. 0.722, P = 0.241) and OS (C-index: 0.703 vs. 0.751, P = 0.359). Subgroup analyses by grades showed similar findings. The prognostic nomograms based on grades and the predictive molecular groups yielded a C-index of 0.736 and 0.735 in predicting PFS and OS, respectively. Accordingly, MRI-based radiomics may be useful for noninvasively detecting molecular groups and predicting survival in gliomas regardless of grades.

scholarly journals MODL-15. THE COMBINATION TREATMENT OF PARP INHIBITOR AND TMZ, OR DAG WILL BE PROMISING TREATMENT IN SF8628

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii414-iii414
Author(s):  
Shigeo Ohba ◽  
Yuichi Hirose
Keyword(s):  
Combination Treatment ◽  
Dna Methyltransferase ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Adenosine Diphosphate ◽  
Promoter Hypermethylation ◽  
Methylguanine Dna Methyltransferase ◽  
Dna Crosslinks ◽  
Promising Treatment ◽  
Base Excision

Abstract Diffuse midline glioma, H3 K27M-mutant (DMG) is a newly defined entity. The prognosis of DMG is poor. Because surgical resection is often incomplete for DMG, radiotherapy and chemotherapy are important. Temozolomide (TMZ) is an alkylating agent that adds a methyl group to DNA (O6-guanine, N7-guanine, and N3-adenine). TMZ-induced cytotoxicity is mainly derived from O6-methylguanine, which is repaired by O6-methylguanine DNA methyltransferase (MGMT). It has been reported that most of DMG lacked MGMT promoter hypermethylation, which is thought to contribute to less effectiveness of TMZ to DMG. The purpose of the study is to explore the way to inhibit the proliferation of DMG. A DMG cell line, SF8628, was used for the experiments. SF8628 had the expression of MGMT and was revealed to be resistant to TMZ. Because N7-methylguanine and N3-methyladenine are repaired via base excision repair, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor combined with TMZ was considered to be effective to suppress the proliferation of SF8628. As expected, PARP inhibitor enhanced TMZ-induced cytotoxicity in SF8628. Dianhydrogalactiol (DAG) is a bifunctional DNA-targeting agent forming N7-alkylguanine and inter-strand DNA crosslinks. DAG reduced the clonogenicity of SF8628. Moreover, inhibition of homologous recombination enhanced the DAG-induced cytotoxicity in SF8629. The combination treatment of PARP inhibitor and TMZ, or DAG were revealed to be promising treatments in SF8628.

Assessing the impact of Queensland's late‐night alcohol restrictions using health system data

2021 ◽  
Author(s):  
Michael Livingston ◽  
Kerri Coomber ◽  
Dominique de Andrade ◽  
Nicholas Taylor ◽  
Jason Ferris ◽  
...  
Keyword(s):  
Health System ◽  
Late Night ◽  
System Data ◽  
Health System Data ◽  
The Impact

Lonsurf (trifluridine/tipiracil): Assessing the impact of dose related toxicities and progression free survival in (refractory) metastatic colorectal cancer

2021 ◽  
pp. 107815522110179
Author(s):  
Olivia R Court
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Reduction ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Free Survival ◽  
Length Of Treatment ◽  
Common Grade ◽  
Grade 3 ◽  
The Impact

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73–3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian cancer (HGOC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5537-5537
Author(s):  
Tanya Kwan ◽  
Amit M. Oza ◽  
Domenica Lorusso ◽  
Carol Aghajanian ◽  
Ana Oaknin ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Maintenance Treatment ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Molecular Characteristics ◽  
Brca Mutations ◽  
Molecular Features ◽  
Brca1 Promoter Methylation ◽  
Genome Wide ◽  
To Receive

5537 Background: ARIEL3 is a placebo-controlled randomized trial of the PARP inhibitor (PARPi) rucaparib as maintenance treatment in HGOC patients (pts) who responded to the latest line of platinum therapy (NCT01968213). Rucaparib improved progression-free survival (PFS) across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. Methods: Pts were randomized 2:1 to receive rucaparib 600 mg BID or placebo. At the data cutoff of Dec 31, 2019, 33/375 (9%) and 1/189 (0.5%) pts were still ongoing and receiving rucaparib or placebo, respectively. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were compared between pts who derived exceptional benefit (PFS ≥2 yrs), and those with disease progression on first scan (≈12 wks; the short-term [ST] subgroup) within each treatment arm. Results: Of 564 pts, 83 (15%) showed exceptional benefit: 79/375 (21%) in the rucaparib arm and 4/189 (2%) in the placebo arm. Within the rucaparib arm, exceptional benefit pts had more favorable clinical prognostic factors at baseline compared with the ST subgroup (Table). While BRCA mutations were enriched in the rucaparib exceptional benefit subgroup, 34/79 (43%) of these pts were BRCA wild type. Among other biomarkers, RAD51C/D mutations were associated with exceptional benefit; low genome-wide loss of heterozygosity was enriched within the ST subgroup; and high BRCA1 methylation was present at similar fractions. Trends were similar in the placebo arm (Table). Conclusions: Exceptional benefit in ARIEL3 was more common in, but not exclusive to, pts with favorable clinical characteristics and known mechanisms of PARPi sensitivity. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of HGOC pts. Clinical trial information: NCT01968213. [Table: see text]

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