Risk of secondary hematologic malignancies and tolerability in patients with ovarian cancer treated with PARP inhibitors: A systematic review and meta-analysis of four phase III randomized controlled trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e23056-e23056
Author(s):  
Kyaw Zin Thein ◽  
Somedeb Ball ◽  
Anita Sultan ◽  
Sriman Swarup ◽  
Myo Zaw ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Synthetic Lethality ◽  
Meta Analysis ◽  
Group Versus ◽  
Hematologic Malignancies ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Control Group ◽  
Study Group ◽  
Significant Drop

e23056 Background: Poly adenosine diphosphate ribose polymerase (PARP) inhibitors have shown to improve survival in ovarian cancer (OC) through synthetic lethality with potentiation of double-strand breaks in tumor cells. Yet, there are concerns of secondary hematologic malignancies (SHM) and notable adverse events (AE) leading to treatment discontinuation (TD), interruption (TI), or dose reduction (DR). Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2019 were queried. Phase 3 RCTs utilizing PARP inhibitors maintenance in OC were eligible. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: A total of 1792 patients from four phase III RCTs were included. The study arm used olaparib or niraparib or rucaparib while the control arm utilized placebo. Almost all patients in the SOLO-2 & -1 trials had a gBRCA mutation, while there were patients with and without the said mutation in the other two studies. The SHM incidence was 1.25% in PARP inhibitors group vs 0.83% in control group (RR, 1.15; 95% CI: 0.41–3.22, p = 0.79). TI due to AE was 59.71% in study group versus 11.39% in control arm (RR, 4.94; 95% CI: 2.44 – 9.96, P < 0.001). DR was reported in 47.73% in PARP inhibitors arm versus 6.86% in control group (RR, 7.73; 95% CI: 4.17 – 14.31, P < 0.001). TD rate was 10.97% higher in study group compared to control arm (RR, 6.63; 95% CI: 3.55 – 11.31, P < 0.001). Conclusions: The risk of SHM was not significantly increased in PARP inhibitors group. However, patients on PAPR inhibitors arm experienced significant drop outs due to AE, despite showing significant improvement in PFS in studies. Proper supportive care may enhance compliance.

Risk of secondary hematologic malignancies in patients with ovarian cancer treated with PARP inhibitors: A combined meta-analysis of seven phase III randomized controlled trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 12076-12076
Author(s):  
Thura Htut ◽  
Somedeb Ball ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
Myat M. Han ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Hematologic Malignancies ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Control Group ◽  
Controlled Trials ◽  
Strand Breaks ◽  
Randomized Controlled

12076 Background: Ovarian cancer (OC) is a leading cause of death from gynecologic cancers in women worldwide. Poly adenosine diphosphate ribose polymerase (PARP) inhibitors prevent the repair of single-strand breaks and generate double-strand breaks in tumor cells and have recently shown survival benefits in OC. Yet, the impact on the risk of secondary hematologic malignancies (SHM) remains uncertain. We performed a combined meta-analysis of randomized controlled trials (RCT) to determine the risk of SHM in patients with advanced OC treated with PARP inhibitors. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2020 were queried. Phase III RCTs utilizing PARP inhibitors maintenance in advanced OC were eligible. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with I2 and Cochran's Q- statistic. Fixed effects model was applied. Results: A total of 4,445 patients with advanced OC from seven phase III RCTs were included. The study arm used olaparib or niraparib or rucaparib or veliparib or olaparib +bevacizumab while the control arm utilized placebo or bevacizumab. Randomization ratio was 2:1 in all studies. The I2 statistic for heterogeneity was 0, suggesting some heterogeneity among RCTs. The overall SHM incidence was 0.80% in PARP inhibitors group vs 0.47% in control group (RR 1.45; 95% CI: 0.68 – 3.07, P = 0.34). In patients with newly diagnosed OC (n = 3,044), the incidence was 0.59% vs 0.09% in control group (RR 2.7; 95% CI: 0.7—10.37, P = 0.15). In recurrent OC subset (n = 1,401), 1.28% were reported in both study and control arms (RR 0.96; 95% CI: 0.38-2.46, P = 0.94). SHM was noted in 1.3% in the olaparib subgroup compared to 1% in the control with RR of 1.24 (95% CI: 0.46 –3.31, P = 0.67). SHM occurred in 0.7% in the niraparib subgroup compared to 0.47% in the control with RR of 1.28 (95% CI: 0.30-5.45, P = 0.74). Conclusions: Our study demonstrated that the risk of SHM was not significantly increased in patients who received PARP inhibitors compared to control arm, despite attaining survival benefits. Further studies and long term follow up are necessary to define the actual relation and definitive incidence.

Risk of gastrointestinal and hepatic toxicities in patients with cancer treated with poly adenosine diphosphate ribose polymerase inhibitors: A meta-analysis of seven phase III trials.

2018 ◽  
Vol 36 (34_suppl) ◽  
pp. 219-219
Author(s):  
Myo Zaw ◽  
Anita Sultan ◽  
Sriman Swarup ◽  
Myat M. Han ◽  
Yin Mon Myat ◽  
...  
Keyword(s):  
Side Effects ◽  
Synthetic Lethality ◽  
Meta Analysis ◽  
Single Agent ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Control Group ◽  
Patients With Cancer ◽  
Phase Iii Trials

219 Background: Inhibition of poly adenosine diphosphate ribose polymerase (PARP) enzymes terminates an alternative DNA repair pathway, resulting in synthetic lethality in homologous recombination deficient tumors. Many PARP inhibitors have shown to improve survival in many solid tumors with noteworthy safety concerns. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2018. Phase III RCTs that mention GI toxicities and elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: 3188 patients from 7 phase III RCTs with breast, ovarian and gastric cancer were eligible. Studies compared olaparib or niraparib or rucaparib versus placebo, olaparib versus single agent chemotherapy, iniparib + gemcitabine / carboplatin (GC) versus GC, veliparib + C versus C and olaparib + paclitaxel versus paclitaxel. The RR of all-grade side effects were as follows: diarrhea, 1.24 (95% CI: 1.08 – 1.42, P = 0.002); nausea, 1.53 (95% CI: 1.16 – 2.02, P = 0.002); vomiting, 1.46 (95% CI: 1.02 – 2.08, P = 0.03); elevated AST, 1.25 (95% CI: 0.58 – 2.67, P = 0.55); and elevated ALT, 1.61 (95% CI: 0.81 – 3.20, P = 0.16). The RR of high-grade side effects were as follows: diarrhea, 1.08 (95% CI: 0.52 – 2.24, P = 0.82); nausea, 1.81 (95% CI: 0.79 – 4.12, P = 0.15); vomiting, 1.99 (95% CI: 1.06 – 3.73, P = 0.03); elevated AST, 1.86 (95% CI: 0.45 – 7.55, P = 0.38); and elevated ALT, 1.33 (95% CI: 0.42 – 4.18, P = 0.62). Conclusions: Our study showed that the risk of developing all grades of vomiting as well as any-grade nausea and diarrhea was high in PARP inhibitors arm, compared to control group. Timely recognition and prompt intervention with good supportive care are entailed.

scholarly journals Niraparib in ovarian cancer: results to date and clinical potential

2017 ◽  
Vol 9 (9) ◽  
pp. 579-588 ◽  
Author(s):  
Davide Caruso ◽  
Anselmo Papa ◽  
Silverio Tomao ◽  
Patrizia Vici ◽  
Pierluigi Benedetti Panici ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Repair System ◽  
Gynaecological Malignancy ◽  
Platinum Based Chemotherapy ◽  
Base Excision

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.

Discontinuation of poly(adenosine diphosphate-ribose) polymerase inhibitors due to adverse events in patients with recurrent ovarian cancer: A meta-analysis of three phase III trials.

2018 ◽  
Vol 36 (34_suppl) ◽  
pp. 118-118
Author(s):  
Kyaw Zin Thein ◽  
Anita Sultan ◽  
Myo Zaw ◽  
Sriman Swarup ◽  
Myat M. Han ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Adverse Events ◽  
Dose Reduction ◽  
Meta Analysis ◽  
Adenosine Diphosphate ◽  
Recurrent Ovarian Cancer ◽  
Treatment Interruption ◽  
Parp Inhibitors ◽  
Treatment Discontinuation ◽  
Phase Iii

118 Background: Ovarian cancer is the fifth leading cause of cancer-related death among women. Poly adenosine diphosphate ribose polymerase (PARP) inhibitors maintenance has shown to improve survival in patients with recurrent ovarian cancer. Yet, there are notable adverse events which led to treatment discontinuation, interruption, or dose reduction. We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of PARP inhibitors discontinuation due to adverse events. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through June 2018 were queried. Phase III RCTs which employed PARP inhibitors maintenance in ovarian cancer and mentioned treatment interruption, dose reduction and treatment discontinuation due to adverse events were included. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Random effects model was applied. Results: Three phase III RCTs with a total of 1,401 patients with recurrent ovarian cancer were eligible. The study arm used olaparib or niraparib or rucaparib while the control arm utilized placebo. The randomization ratio was 2:1 in all studies. The incidence of treatment interruption due to adverse events was 578 (61.8%) in study group versus 46 (9.8%) in control arm. The relative risk for treatment interruption was statistically significant at 5.87 (95% CI: 2.24 – 15.36, P < 0.001). The reduction in dose was reported in 496 (53.1%) in PARP inhibitors arm versus 37 (7.9%) in control group. The pooled RR for dose reduction was 7.49 (95% CI: 3.44 – 16.29, P < 0.001). The treatment discontinuation rate was 11.4% higher with PARP inhibitors than with control arm (RR - 6.84; 95% CI: 3.51 – 13.34, P < 0.001). Conclusions: Our study showed that patients on PARP inhibitors experienced some adverse events which led to significant drop outs although the definitive advantage to PARP inhibitors is still shown in the studies. Preemptive measures with proper supportive care will aide in reducing those toxicities, improve patients’ quality of life and may probably affect patients’ compliance.

Poly adenosine diphosphate ribose polymerase inhibitors maintenance in patients with ovarian cancer: A systematic review and meta-analysis of randomized controlled trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17081-e17081
Author(s):  
Thura WIN Htut ◽  
Aung Tun ◽  
Anita Sultan ◽  
Sriman Swarup ◽  
Myo Zaw ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
The Other ◽  
Phase Iii ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
Platinum Based Chemotherapy

e17081 Background: Ovarian cancer is the deadliest of gynecologic cancers and many recur despite achieving a clinical response to initial platinum-based chemotherapy. The use of poly adenosine diphosphate ribose polymerase (PARP) inhibitors maintenance has shown to improve survival in ovarian cancer. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2019 were queried. Phase 3 randomized controlled trials (RCT) which employed PARP inhibitors maintenance in ovarian cancer were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to some heterogeneity among studies. Results: Four phase III RCTs with a total of 1792 patients were eligible. The study arm used olaparib or niraparib or rucaparib while the control arm utilized placebo. The randomization ratio was 2:1 in all studies. Participants were sensitive to platinum-based chemotherapy, as newly diagnosed in SOLO-1 trial and had been previously on two such regimens in the other trials, with an objective response. Almost all patients in the SOLO-2 and SOLO-1 trials had a gBRCA mutation, while there were patients with and without the said mutation in the other two studies. The pooled HR for PFS was statistically significant at 0.32 (95% CI: 0.27-0.38; P < 0.0001), including gBRCA cohort (HR, 0.28; 95% CI: 0.24-0.33; P < 0.0001) and non-gBRCA cohort (HR, 0.39; 95% CI: 0.32-0.48; P < 0.0001). Conclusions: Our meta-analysis demonstrated that the use of maintenance therapy with PARP inhibitors significantly improved PFS compared to placebo, regardless of the presence or absence of gBRCA mutation.

scholarly journals Updated Meta-Analysis to Evaluate the Incidence of Atrial Fibrillation and Major Bleeding in Patients with Hematologic Malignancies Treated with Ibrutinib

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2200-2200
Author(s):  
Sriman Swarup ◽  
Anita Sultan ◽  
Lukman Tijani ◽  
Thura Win Htut ◽  
Nicholas D'Cunha ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
B Cell ◽  
Major Bleeding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Phase Iii ◽  
Control Group ◽  
Study Group ◽  
Susceptible Population

Introduction: Bruton's tyrosine kinase (BTK) is a kinase involved in cellular signaling downstream of the B cell receptor and is involved in B-cell survival and proliferation. Hence, BTK inhibitors have become an attractive therapeutic target for a multitude of B cell malignancies, mainly chronic lymphocytic leukemia. Ibrutinib is an oral potent covalent inhibitor of BTK and hence employed in many hematologic malignancies for BTK inhibition. Yet, the risk of atrial fibrillation and major bleeding remains considerable. We undertook an updated analysis of phase III trials to assess the incidence of atrial fibrillation and major bleeding associated with ibrutinib in this susceptible population. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with hematologic malignancies that mention atrial fibrillation and major bleeding were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,920 patients with CLL/SLL, mantle-cell lymphoma, Waldenstrom's macroglobulinemia and diffuse large b-cell lymphoma, from 10 phase III RCTs were eligible. Studies compared ibrutinib+ obinutuzumab vs chlorambucil+ obinutuzumab, ibrutinib vs chlorambucil, bendamustine+ rituximab vs ibrutinib vs ibrutinib+ rituximab, ibrutinib+ rituximab vs fludarabine+ cyclophosphamide+ rituximab, ibrutinib vs rituximab, ibrutinib vs ofatumumab, ibrutinib+ bendamustine+ rituximab vs bendamustine+ rituximab, ibrutinib vs temsirolimus, ibrutinib+ rituximab+ cyclophosphamide+ doxorubicin+ vincristine+ prednisone vs rituximab+ cyclophosphamide+ doxorubicin+ vincristine+ prednisone were included in the analysis. The randomization ratio was 2:1 in E1912 study and Huang et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 32, suggesting some heterogeneity among RCT. The atrial fibrillation incidence was 142 (6.52%) in study group vs 17 (0.97%) in control group. The RR for atrial fibrillation was 5.37 (95% CI: 2.74 - 10.54; P < 0.0001) and RD was 0.06 (95% CI: 0.04 to 0.08; P = < 0.0001). Major bleeding was reported in 50 (2.29%) in ibrutinib arm vs 21 (1.20%) in control arm with the RR of 1.73 (95% CI: 1.03 -2.91; P = 0.04). In a subset of patients with CLL/SLL treated with ibrutinib (n= 2658), atrial fibrillation rate was 6.29% higher in study group compared to control arm (RR, 6.14; 95% CI: 2.49 - 15.14; P < 0.0001) and major bleeding rate was 1.32% higher in ibrutinib arm (RR, 2.16; 95% CI: 1.02 - 4.55; P = 0.04). Conclusions: Our study again demonstrated that ibrutinib increases the risk of atrial fibrillation in patients with hematologic malignancies, significantly with a RR of 5.37. Ibrutinib also contributed to higher risk of major bleeding by 1.73. These results are concordant with our previous findings on ibrutinib and remain persistent. Hence, caution is advised with the use of ibrutinib amongst patients who are predisposed to these conditions. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Role of Coconut Oil in Treating Patients Affected by Plaque-Induced Gingivitis: A Pilot Study

2020 ◽  
Vol 14 (04) ◽  
pp. 558-565
Author(s):  
Francesca Ripari ◽  
Federica Filippone ◽  
Giulia Zumbo ◽  
Francesco Covello ◽  
Francesca Zara ◽  
...  
Keyword(s):  
Coconut Oil ◽  
Mean Value ◽  
Plaque Formation ◽  
Control Group ◽  
Study Group ◽  
Clinical Parameters ◽  
Significant Drop ◽  
Significance Level ◽  
Student’S T

Abstract Objectives The aim of the study was to evaluate the coconut oil pulling efficacy as adjuvant in reducing plaque formation and in treating plaque-induced gingivitis. Materials and Methods A sample of 20 patients was divided into two groups: a study and a control group. In the study group, coconut oil, in form of mouthwash, was administered to a sample of patients affected by gingivitis, aged between 18 and 35. The protocol established a daily application of the product for 30 days, where clinical parameters for plaque formation and gingivitis—plaque index (PI), bleeding index (BI)—will be evaluated during the recalls on a specific periodontal chart. The control group did not associate a coadjuvant to the normal daily oral health procedures and the same clinical parameters were evaluated at t0 and after 30 days (t1). The data were statistically analyzed using Student’s t-test, establishing the significance level as p < 0.05. Results PI and BI decreased in both groups, with a more relevant and significant drop in the study group, from a mean value of PI of 58.0 to 19.3 and a mean value of BI of 33.5 to 5.0. In the control group, the values decreased, respectively, from 53.9 to 29.1 for PI, and from 33.5 to 16.2. Furthermore, no significant side effect was reported during coconut oil pulling therapy. Conclusions The collected data showed significant and promising improvements in reducing plaque formation and gingivitis. However, further researches have to be performed to have more consistent and statistically significant data on larger samples and to fully understand the mechanisms of action and effectiveness.

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