Search Results

Background: VEGFR, KIT, RET, and MET pathways are implicated in several solid tumors. Cabozantinib is an oral inhibitor of these kinase pathways, and hence has found its use in treatment of multiple malignancies. However, it has several side effects that can limit tolerance amongst patients. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of health-related quality of life (HRQOL) events in patients with advanced solid tumors treated with cabozantinib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through September 30, 2018. Phase 3 trials that mention HRQOL events like pain, arthralgia, fatigue, and reduced appetite as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: 4 phase 3 RCTs with a total of 2,703 patients with medullary thyroid cancer, prostate cancer, renal cell carcinoma, and hepatocellular carcinoma were eligible. Studies comparing cabozantinib (C) vs everolimus, C vs placebo, C vs prednisone were included in the analysis. The relative risks of all-grade side effects were as follows: fatigue, 1.378 (95% CI: 1.236–1.536; P<.0001); asthenia, 1.704 (95% CI: 1.190–2.441; P=.004); reduced appetite, 2.088 (95% CI: 1.471–2.964; P<.0001); back pain, 1.047 (95% CI: 0.871–1.259; P=.626); pain in limbs, 1.444 (95% CI: 1.128–1.847; P=.004); arthralgia, 0.982 (95% CI: 0.707–1.363; P=.912). The RR of high-grade side effects were as follows: fatigue, 1.937 (95% CI: 1.483–2.528; P<.0001); asthenia, 2.211 (95% CI: 1.536–3.184; P<.0001); reduced appetite, 4.329 (95% CI: 2.372–7.900; P<.0001); back pain, 1.227 (95% CI: 0.738–2.040; P=.431); pain in limbs, 2.933 (95% CI: 1.127–7.635; P=.028); arthralgia, 0.820 (95% CI: 0.394–1.709; P=.597). Conclusion: Our meta-analysis showed that cabozantinib contributed to significant toxicity of all grades of fatigue, asthenia, pain in limbs, and reduced appetite. Identifying and addressing these toxicities will be important in improving quality of life for these patients.

Background: Breast cancer is the most common cancer in women, and the majority of breast cancers express the estrogen receptor or progesterone receptor. Inhibition of CDK4/6 signaling pathway has shown survival benefit in advanced breast cancer by overcoming endocrine therapy resistance. Yet, there are considerable hematologic toxicities associated with CDK 4/6 inhibitors and hence, we performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk. Methods: MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018 were queried. RCTs that mention anemia, thrombocytopenia, leukopenia, neutropenia, and neutropenic fever as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) and risk difference (RD) with 95% CI. Random effects model was applied. Results: 8 RCTs (7 phase III and 1 phase II studies) with a total of 4,557 patients were eligible. The study arms used palbociclib/ribociclib/abemaciclib with letrozole or anastrozole or fulvestrant or other hormonal agent while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agent. The RR of all-grade side effects were as follows: anemia, 3.494 (95% CI: 2.535–4.814; P<.0001); thrombocytopenia, 6.066 (95% CI: 3.055–12.046; P<.0001); leukopenia, 10.376(95% CI: 7.236–14.879; P<.0001); and neutropenia, 14.387 (95% CI: 10.877–19.031; P<.0001). The RR of high-grade adverse effects were as follows: anemia, 2.251 (95% CI: 1.393–3.637; P=.001); thrombocytopenia, 3.696 (95% CI: 1.417–9.642; P=.008); leukopenia, 22.083(95% CI: 12.126–40.217; P<.0001); neutropenia, 33.527(95% CI: 17.271–65.082; P<.001). Neutropenic fever was noted in 71 (3.73%) in CDK 4/6 inhibitors group vs 28 (2.18%) in control arm. The pooled RR was statistically significant at 12.056 (95% CI: 1. 352–3.127; P=.001) and RD was 0.014 (95% CI: −0.002–0.029; P=.078) Conclusion: CDK 4/6 inhibitors–based regimen significantly contributed to all hematologic toxicities as well as febrile neutropenia. The improved efficacy outcomes and manageable toxicities with CDK 4/6 inhibitors are observed with proper supportive care and close monitoring.

Background: Pain, fatigue, hot flushes, and rash significantly contribute to quality of life in breast cancer patients undergoing chemotherapy. Hormone receptor-positive breast cancer is a common entity among women worldwide. In cancer cells, CDK4/6 activity is over expressed, which can lead to amplification or overexpression of the genes encoding for CDK 4/6 or the cyclin D, ultimately leading to endocrine therapy resistance. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of health-related quality of life (HRQOL) events associated with CDK 4/6 inhibitors. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018. RTCs that mention HRQOL events as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95%CI. Random effects model was applied. Results: 8 RCTs (7 phase III and 1 phase II) with a total of 4,557 patients were eligible. The study arms used palbociclib/ribociclib/abemaciclib with letrozole or anastrozole or fulvestrant or other hormonal agent while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agent. The RR of all-grade side effects were as follows: fatigue, 1.226 (95% CI: 1.079–1.393; P=.002); back pain, 0.971 (95% CI: 0.844–1.117; P=.681); arthralgia, 0.978 (95% CI: 0.830–1.152; P=.790); headache, 1.046 (95% CI: 0.928–1.179; P=.459); alopecia, 2.635 (95% CI: 1.966–3.533; P<.001); hot flushes, 0.901 (95% CI: 0.766–1.060; P=.210); and rash, 2.068 (95% CI: 1.604–2.666; P<.001). The RR of high-grade side effects were as follows: fatigue, 3.487 (95% CI: 1.765–6.889; P<.001); back pain, 1.364 (95% CI: 0.695–2.679; P=.367); arthralgia, 1.148 (95% CI: 0.509–2.593; P=.740); headache, 0.807 (95% CI: 0.303–2.147; P=.667); and rash, 3.018(95% CI: 0.954–9.554; P=.060). Conclusions: Our study showed that the risk of developing all grades of fatigue and any-grade alopecia and rash was significantly with CDK 4/6 inhibitors. Prompt intervention with good supportive care is required.

Background: CDK4 and CDK6 are cyclin-dependent kinases that control transition between G1 and S phases of the cell cycle, hence controlling cell cycle progression by reversible combination with cyclin D1. In cancer cell, CDK4/6 activity is overexpressed, which can lead to amplification or overexpression of the genes encoding for CDK 4/6 or the cyclin D. Additionally, loss of endogenous INK4 inhibitors can also lead to over activity of CDK4 and CDK6. We undertook a meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities associated with CDK 4/6 inhibitors. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts from inception through September 2018. In our analysis, we incorporated RCTs that mention GI toxicities and elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) as adverse effects. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: A total of 4,557 patients with advanced breast cancer from 7 phase III and 1 phase II RCTs were eligible. The study arms used were palbociclib/ribociclib/abemaciclib or placebo in combination with letrozole or anastrozole or fulvestrant or other hormonal agents. The RR of all-grade side effects were as follows: diarrhea, 1.691 (95% CI: 1.220–2.345; P=.002); nausea, 1.632 (95% CI: 1.447–1.840; P<.001); vomiting, 1.684 (95% CI: 1.256–2.259, P=.001); stomatitis, 2.160 (95% CI: 1.332–3.503; P=.002); elevated AST, 1.832 (95% CI: 1.312–2.558; P<.001); and elevated ALT, 2.150 (95% CI: 1.649–2.803; P<.001). The RR of high-grade side effects were as follows: diarrhea, 2.592 (95% CI: 0.853–7.877; P=.093); nausea, 1.326 (95% CI: 0.589–2.988; P=.496); vomiting, 1.089 (95% CI: 0.479–2.476; P=.839); stomatitis, 2.097 (95% CI: 0.502–0.753; P=.310); elevated AST, 2.274 (95% CI: 1.173–4.410; P=.015); and elevated ALT, 3.988 (95% CI: 2.387–6.663; P<.001). Conclusions: Our study demonstrated that the risk of developing all grade GI toxicities and all grades of hepatic side effects including grade 3 and 4, was high in CDK 4/6 inhibitors group, compared to control arm, and prompt intervention with good supportive care is required.

Background: Cabozantinib is an oral inhibitor of multiple tyrosine kinases and is used in treatment of multiple solid tumors, targeting several pathways such as vascular endothelial growth factor signaling pathway and proto-oncogenes MET, KIT, RET. These pathways are implicated in several tumor development and progression. We performed a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of gastrointestinal (GI) and hepatic toxicities among patients with metastatic solid tumors treated with cabozantinib. Methods: MEDLINE, EMBASE databases, and meeting abstracts from inception to September 2018 were queried. Phase 3 RCTs that mention GI and elevation of liver enzymes as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% CI. Random effects model was applied. Results: We included 4 phase 3 RCTs with a total of 2,703 patients with various solid tumors. The study arm used cabozantinib while the control arm utilized everolimus or placebo or prednisone. The relative risks of all-grade side effects were as follows: diarrhea, 2.495 (95% CI: 2.149–2.897, P<.0001); nausea, 1.849 (95% CI: 1.649–2.072; P<.0001); vomiting, 2.335 (95% CI: 1.724–3.163; P<.0001); stomatitis, 4.541 (95% CI: 0.908–22.696; P=.065); dysgeusia, 4.428 (95% CI: 2.67–7.343; P<.0001); elevated AST, 2.002 (95% CI: 1.331–3.011; P=.001); and elevated ALT, 1.988 (95% CI: 0.936–4.222; P=.074). The RR of high-grade side effects were as follows: diarrhea, 5.913 (95% CI: 3.655–9.566; P<.0001); nausea, 3.098 (95% CI: 1.266–7.581; P=.013); vomiting, 1.298 (95% CI: 0.395–4.265; P=.668); stomatitis, 3.837 (95% CI: 0.749–19.665; P=.107); dysgeusia, 1.522 (95% CI: 0.159–14.574; P=.716); elevated AST, 1.733 (95% CI: 1.101–2.728; P=.018); and elevated ALT, 2.489 (95% CI: 1.164–5.326; P=.019). Conclusion: The risk of developing all grades of diarrhea, nausea, elevated AST, and any-grade vomiting, dysgeusia as well as high-grade elevated ALT, was high in cabozantinib group. Timely recognition and providing good supportive care will enhance patients’ quality of life.