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.

Risk of health-related quality-of-life events and pulmonary 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. 213-213
Author(s):  
Sriman Swarup ◽  
Anita Sultan ◽  
Myo Zaw ◽  
Rachana Yendala ◽  
Myat M. Han ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Side Effects ◽  
Meta Analysis ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Health Related Quality ◽  
Related Quality ◽  
Health Related

213 Background: Poly adenosine diphosphate ribose polymerase (PARP) enzymes aide in the repair of DNA damage. PARP inhibitors showed synthetic lethality in cancer cells and were utilized in many solid tumors with notable toxicities. Fatigue and pain are the major determinants of health-related quality of life (HRQOL) in cancer patients undergoing chemotherapy. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of HRQOL events and pulmonary toxicities. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through June 2018 were queried. Phase III RCTs that mention HRQOL events and pulmonary toxicities as adverse effects 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: 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 vs 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: fatigue, 1.26 (95% CI: 1.07 – 1.49, P = 0.006); decreased appetite, 1.42 (95% CI: 1.18 – 1.71, P < 0.001); arthralgia, 1.05 (95% CI: 0.83 – 1.34, P = 0.65); headache, 1.35 (95% CI: 0.99 – 1.84, P = 0.05); cough, 1.75 (95% CI: 1.17 – 2.62, P = 0.006); dyspnea, 1.40 (95% CI: 0.90 – 2.18, P = 0.12); and upper respiratory infections, 1.70 (95% CI: 0.97 – 3.00, P = 0.06). The RR of high-grade side effects were as follows: fatigue, 1.94 (95% CI: 1.24 – 3.04, P = 0.004); arthralgia, 1.37 (95% CI: 0.29 – 6.51, P = 0.68); headache, 1.09 (95% CI: 0.47 – 2.55, P = 0.83); and dyspnea, 1.02 (95% CI: 0.44 – 2.36, P = 0.95). Conclusions: The risk of developing all grades of fatigue as well as any-grade cough and decreased appetite was high in PARP inhibitors group, compared to control arm. Recognizing these toxicities and providing good supportive care is vital in enhancing patients’ quality of life.

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.

scholarly journals First-Line PARP Inhibitors—Emerging Side Effects Require Caution: A Case of PARPi-Induced Pneumonitis

2021 ◽  
Author(s):  
Alistair McLaren ◽  
Douglas Cartwright ◽  
Ewen Ross ◽  
Patricia Roxburgh
Keyword(s):  
Side Effects ◽  
Progression Free Survival ◽  
Adenosine Diphosphate ◽  
The United States ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
First Line ◽  
Platinum Based Chemotherapy ◽  
Phase Iii Trials ◽  
Relapsed Disease

ABSTRACT Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) 1 and 2, has been shown to improve progression free survival in patients when used as maintenance treatment after first-line platinum-based chemotherapy in advanced stage (III to IV) high-grade ovarian cancer, and after platinum-based chemotherapy for relapsed disease. For grades greater than III, commonly reported side effects include bone marrow suppression (thrombocytopenia, neutropenia, and anemia) and hypertension. However, pneumonitis is not listed as a side effect in the summary of product characteristics, or reported in phase III trials (PRIMA or NOVA). We present a case of life-threatening niraparib-induced pneumonitis. With recent approval for use of first-line maintenance niraparib in the United States and Europe, knowledge of the side effects and how to manage them is vital.

A systematic review and meta- analysis of randomized controlled trials to evaluate the risk of hematological toxicities in patients with cancer treated with poly adenosine diphosphate ribose polymerase (PARP) inhibitors.

2018 ◽  
Vol 36 (34_suppl) ◽  
pp. 217-217
Author(s):  
Anita Sultan ◽  
Sriman Swarup ◽  
Myo Zaw ◽  
Myat M. Han ◽  
Yin Mon Myat ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Effects ◽  
Randomized Controlled Trials ◽  
Meta Analysis ◽  
Single Agent ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Controlled Trials ◽  
Randomized Controlled

217 Background: Poly adenosine diphosphate ribose polymerase (PARP) inhibitors have shown to benefit in DNA repair-deficient tumors by enhancing synthetic lethality in cancer cells and are currently employed in many solid tumors. Nevertheless, the risk of hematological toxicities remains significant. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of hematological 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 hematological toxicities 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: Seven phase III RCTs with a total of 3,188 patients with breast, ovarian and gastric cancer were eligible. Studies compared olaparib or niraparib or rucaparib versus placebo, olaparib vs single agent chemotherapy, iniparib + gemcitabine / carboplatin (GC) versus GC, veliparib + C versus C and olaparib + paclitaxel vs paclitaxel. The RR of all-grade side effects were as follows: anemia, 2.38 (95% CI: 1.42 – 4.00, p = 0.001); thrombocytopenia, 2.96 (95% CI: 1.37 – 6.40, p = 0.006); neutropenia, 1.47 (95% CI: 1.06 – 2.05, p = 0.02); and leukopenia, 1.08 (95% CI: 0.77 – 1.50, p = 0.63). The RR of high-grade adverse effects were as follows: anemia, 3.63 (95% CI: 1.53 – 8.57, p = 0.003); thrombocytopenia, 2.65 (95% CI: 0.89 – 7.85, p = 0.07); neutropenia, 1.27 (95% CI: 0.87 – 1.86, p = 0.21); and leukopenia, 1.20 (95% CI: 0.90 – 1.58, p = 0.19). Conclusions: Our meta-analysis demonstrated that patients on PARP inhibitors experienced a significant increase in the risk of all grades of anemia with a relative risk of 3.63 for grade 3 and 4 anemia, along with any-grade thrombocytopenia and neutropenia. Proper supportive care is essential, and it will ultimately reduce drug dosing inconsistencies and financial burden among patients undergoing treatment.

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.

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.

Comparison between gemcitabine-based combination (G) and single-agent chemotherapy (S) for elderly patients (EP) with advanced non-small cell lung cancer (NSCLC): A literature-based meta-analysis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 19586-19586
Author(s):  
I. Carreca ◽  
F. Bellomo ◽  
G. Bronte ◽  
M. Burgio ◽  
A. Carreca ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Meta Analysis ◽  
Single Agent ◽  
Haematological Toxicity ◽  
Phase Iii ◽  
Cochrane Library ◽  
Combination Regimen ◽  
Random Effects Models ◽  
Significant Difference ◽  
Phase Iii Trials

19586 Background: It was estimated that a quarter of all patients who have a diagnosis of NSCLC worldwide are more than 70 years old. This meta-analysis tries to shed light on the controversial results of phase III trials evaluating in NSCLC EP doublets against third generation S. Methods: We performed a literature search using MEDLINE and Cochrane Library. We selected only clinical trials responding to the question of our meta-analysis. Outcomes recorded were 1-year survival rate (1-y SR), overall response rate (ORR) and haematological toxicity (HT). Fixed-effects and random-effects models were used to calculate pooled odds ratios (OR). An OR greater than 1 indicates that doublet is more effective for 1-y SR and ORR and more toxic for HT. Results: Three published randomized controlled phase III trials (SICOG 9909; MILES; AISCAP-SICOG) were selected yielding a total of 1082 patients (G: 426; S: 655) clustered in seven comparisons. Drugs delivered to randomized patients included gemcitabine, vinorelbine and paclitaxel. EP treated with doublets showed respect to control patients a pooled estimate for 1-y SR advantage of 36%, not statistically significant (OR=1.356; 95% CI=0.925–1.990; p>0.05). The pooled estimate for ORR advantage was 57% and statistically significant (OR=1.559; 95% CI=1.220–2.015; p<0.05). However G showed not significant difference for HT (OR=1.168; 95% CI=0.685–1.992; p>0.05). Conclusions: These data confirm in EP superior efficacy and equal tolerability of G in comparison with S previously demonstrated for adult patients. Anyway G seems to not change prognosis of NSCLC EP. It is worthy to note that all the trials analysed showed some biases: early closure of the study, second-line therapy or crossover, lower dosage of drugs in combination regimen, inclusion of unfit or strongly comorbid patients. This meta-analysis doesn’t solve troubles in decision-making of treatment for EP, but suggest to design a better phase III trial including more patients and improving accrual criteria for reducing biases. An indication of a potentially active combination regimen (gemcitabine + paclitaxel) is suggested in SICOG 9909 trial. No significant financial relationships to disclose.

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