Omar Abdel-Rahman

Risk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis

BACKGROUND We performed a meta-analysis of the risk of endocrine adverse events associated with immune check point inhibitors. METHODS Eligible studies included randomized trials of cancer patients on immune checkpoint inhibitors; describing events of hypothyroidism, hyperthyroidism, hypophysitis and adrenal insufficiency. RESULTS A total of ten clinical trials were eligible for the meta-analysis. The relative risk of all-grade hypothyroidism, hyperthyroidism, hypophyisitis and adrenal insufficiency were 8.26 (95% CI: 4.67-14.62; p < 0.00001), 5.48 (95% CI: 1.33-22.53; p = 0.02); 22.03 (95% CI: 8.52-56.94; p < 0.00001), 3.87 (95% CI: 1.12-13.41; p = 0.03), respectively. CONCLUSION Our meta-analysis has demonstrated that the use of immune check point inhibitors is associated with an increased risk of hypothyroidism, hyperthyroidism, hypophysitis and adrenal insufficiency compared with control.

Risk of cardiovascular toxicities in patients with solid tumors treated with sunitinib, axitinib, cediranib or regorafenib: an updated systematic review and comparative meta-analysis.

BACKGROUND We performed a systematic review and comparative meta-analysis of cardiovascular toxicities associated with sunitinib, axitinib, cediranib or regorafenib; oral multi tyrosine kinase inhibitors. PATIENTS AND METHODS Eligible studies included randomized phase II and III trials of patients with solid tumors on sunitinib, axitinib, cediranib or regorafenib describing daily events of hypertension, left ventricular dysfunction, bleeding or thrombosis. RESULTS Patients treated with these four agents had a significantly increased risk of all-grade hypertension and bleeding. The RR of all-grade hypertension, bleeding, thrombosis and cardiac dysfunction were 2.78 (95% CI 2.03-3.81; p<0.00001), 1.93 (95% CI 1.41-2.64; p<0.00001), 0.85 (95% CI 0.60-1.19; p=0.50), 2.36 (95% CI 0.95-5.87; p=0.06), respectively. Exploratory subgroup analysis showed no effect of the agent used (sunitinib vs. axitinib vs. cediranib) in the risk of hypertension; while for bleeding, only the sunitinib subgroup RR was significant compared to axitinib or cediranib. CONCLUSIONS Our meta-analysis has demonstrated that sunitinib, axitinib, cediranib and regorafenib are associated with a higher risk of developing all grade and high grade hypertension compared with control. While for bleeding, only the sunitinib subgroup RR was significant compared to axitinib or cediranib. Clinicians should be aware of these risks and perform regular cardiovascular monitoring.

Systemic therapy for hepatocellular carcinoma (HCC): from bench to bedside.

Primary liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. For patients with early resectable disease, surgical resection or transplantation is considered a potentially curative modality for hepatocellular carcinoma (HCC); on the other hand, for patients with unresectable or metastatic disease, treatment is essentially palliative and prior to the approval of sorafenib, there was no globally approved systemic treatment for patients presenting with unresectable or metastatic HCC. Sorafenib is the only systemic treatment to demonstrate a statistically significant but modest overall survival benefit in a large phase III trial. Thus, novel systemic approaches represent a high unmet medical need in advanced HCC. In this review article, we will try to take a journey through the history of systemic therapeutic options for HCC passing through the current standard options and exploring the potential new systemic options for this disease.

Risk of pneumonitis in cancer patients treated with immune checkpoint inhibitors: a meta-analysis

Background: A meta-analysis of the risk of pneumonitis associated with the use of immune checkpoint inhibitors in cancer patients has been conducted. Methods: Eligible publications included randomized trials of cancer patients on immune checkpoint inhibitors, describing events of all-grade and high-grade pneumonitis. Results: After exclusion of noneligible citations, a total of 11 clinical trials were eligible for the meta-analysis. The odds ratio was 3.96 [95% confidence interval (CI): 2.02–7.79; p < 0.0001] for all-grade pneumonitis and 2.87 (95% CI: 0.90–9.20; p = 0.08) for high-grade pneumonitis. Moreover, the odds ratio of all-grade pneumonitis with a nivolumab/ipilimumab combination versus ipilimumab monotherapy was 3.68 (95% CI: 1.59–8.50; p = 0.002) and, for high-grade pneumonitis, it was 1.86(95% CI: 0.36–9.53; p = 0.46). Subgroup analysis did not reveal a difference between lung cancer patients and other cancer patients in the risk of pneumonitis. Conclusions: Our analysis provided evidence that the use of immune checkpoint inhibitors is associated with an increased risk of all-grade pneumonitis compared with chemotherapy or placebo controls.

Risk of cutaneous toxicities in patients with solid tumors treated with immune checkpoint inhibitors: a meta-analysis.

BACKGROUND We performed a meta-analysis of the risk of cutaneous toxicities associated with immune checkpoint inhibitors. METHODS Eligible studies included randomized trials of patients with solid tumors on immune checkpoint inhibitors (ipilimumab, nivolumab, tremelimumab, pidlizumab and pembrolizumab); describing events of rash, vitiligo and pruritus. RESULTS A total of nine clinical trials were considered eligible for the meta-analysis. The relative risk of all-grade rash, vitiligo and pruritus was 4.06 (95% CI: 3.35-4.91; p < 0.0001), 16.3 (95% CI: 3.21-82.8; p = 0.0008) and 3.4 (95% CI: 2.24-5.16; p < 0.00001), respectively. CONCLUSION Our meta-analysis demonstrates that immune checkpoint inhibitors are associated with an increased risk of all grade skin rash, vitiligo and pruritus. Clinicians should perform regular clinical cutaneous monitoring.

Targeting vascular endothelial growth factor (VEGF) pathway in gastric cancer: Preclinical and clinical aspects

The prognosis of advanced gastric cancer has been dreadful with the majority of patients dying of their disease within 1 year of the diagnosis. In the advanced stage several therapeutic options can be discussed, including molecular targeted agents, but biological predicting factors are lacking. A number of molecular targets have been studied over the last decade bringing to several phase II studies; however very few agents moved into phase III clinical trials. The VEGFR-2 inhibitor monoclonal antibody ramucirumab has been recently approved in advanced progressing gastric cancer. This article reviews the basic science as well as clinical data of VEGF signaling in advanced gastric cancer with special emphasis on the different VEGF targeting agents tested previously in this disease.

Correlation between PD-L1 expression and outcome of NSCLC patients treated with anti-PD-1/PD-L1 agents: A meta-analysis

BACKGROUND A meta analysis of the correlation between PD-L1 levels and outcomes of PD-1/PD-L1 inhibitors in advanced non small cell lung cancer (NSCLC) has been performed. METHODS Eligible studies included those evaluating PD-1/PD-L1 inhibitors in advanced NSCLC and correlating the outcomes to PD-L1 levels. RESULTS The search strategy yielded 250 potentially relevant citations from searched databases. After preclusion of ineligible studies, 12 studies were included. Comparing PD-1/PD-L1 inhibitors to docetaxel in second line treatment, the pooled hazard ratio (HR) for progression free survival (PFS) and overall survival (OS) was 0.75 (95% CI 0.62-0.90; p=0.002) and 0.61 (95% CI 0.50-75; p=0.00001) respectively; while the pooled odds ratio (OR) for objective response rate (ORR) was 1.98 (95% CI 1.28-3.07; p=0.002) in the PD-L1>1% population. Moreover, for PD-L1>1% patients versus PD-L1<1% patients treated with PD-1/PD-L1 targeted agents, the OR of ORR was 2.18 (95% CI 1.45-3.29; p=0.0002); while for PD-L1>5% patients versus PD-L1<5% patients, it was 2.66 (95% CI 1.74-4.07; p<0.00001); and for PD-L1>10% versus PD-L1<10% patients, it was 3.38 (95% CI 2.23-5.13; p<0.00001); and for PD-L1>50% versus PD-L1<50% patients, it was 3.99 (95% CI 2.81-5.66; p<0.00001). CONCLUSIONS The current analysis of data indicates that the benefit from PD-1 inhibitors versus docetaxel in second line treatment of NSCLC is limited to the PD-L1>1% subpopulation. Moreover, a possible dose effect relationship between the intensity of PD-L1 staining and the potential benefit from PD-1/PD-L1 targeted agents does exist with higher intensity associated with higher ORR.

Risk of gastrointestinal complications in cancer patients treated with immune checkpoint inhibitors: a meta-analysis

AIM We performed a meta-analysis of the risk of selected gastrointestinal toxicities associated with immune checkpoint inhibitors. PATIENTS & METHODS Eligible studies included randomized trials of patients with solid tumors on ipilimumab, nivolumab, pembrolizumab, tremelimumab, pidilizumab and atezolizumab, describing events of diarrhea, vomiting or colitis. RESULTS After exclusion of ineligible studies, a total of ten clinical trials were considered eligible for the meta-analysis. The relative risk of all-grade diarrhea, vomiting and colitis was 1.64 (95% CI: 1.19-2.26; p = 0.002), 0.72 (95% CI: 0.49-1.07; p = 0.1), 10.35 (95% CI: 5.78-18.53; p < 0.00001), respectively. CONCLUSION Our meta-analysis has demonstrated that immune checkpoint inhibitors are associated with a significantly increased risk of all grade and high-grade colitis.

Correlation of cetuximab-induced skin rash and outcomes of solid tumor patients treated with cetuximab: A systematic review and meta-analysis

BACKGROUND We performed a systematic review and meta-analysis of the correlation between cetuximab-induced skin rash and outcomes of solid tumor patients treated with cetuximab. PATIENTS AND METHODS Eligible studies included phase I, II and III trials of patients with solid tumors on cetuximab; describing events of skin rash and correlating skin rash with overall survival (OS), progression free survival (PFS) and/or overall response rate (ORR). RESULTS Our search strategy yielded 409 potentially relevant citations on CETUXIMAB from Pubmed/Medline, CENTRAL Cochrane registry and ASCO meeting library. After exclusion of ineligible studies, a total of 13 clinical trials were considered eligible for the meta-analysis, including 4 phase III trials, 8 phase II trials and one phase I trial. The occurrence of cetuximab-induced rash in patients was highly associated with improvements in PFS (HR=0.74; 95% CI: 0.63-0.86, P<0.0002), OS (HR=0.60; 95% CI: 0.47-0.76, P<0.0001), and ORR (RR=1.51, 95% CI: 1.26-1.81, P<0.00001), as compared to patients without rash. Exploratory subgroup analysis showed no effect of tumor types on the RR of ORR. CONCLUSIONS Our meta-analysis has demonstrated that cetuximab-induced rash is associated with a significantly improved OS, PFS and ORR. Cetuximab-induced skin rash may represent a prognostic factor in patients with advanced solid tumors.

Immune checkpoints aberrations and gastric cancer; assessment of prognostic value and evaluation of therapeutic potentials

Till now, the prognosis of advanced gastric cancer looked dreadful; thus the search for newer better approaches for this lethal disease has been a strategic target for cancer researchers. In recent years, important immunobiological aspects of the tumor have been revealed with the subsequent proposal of immune check point inhibitors to target these pathways. Clinically, unselected use of immune checkpoint inhibitors in gastric cancer has been deemed with failure; in contrast to the clear success of more recent studies reporting on the use of pembrolizumab in molecularly selected patients. This may illustrate that any future use of immune checkpoint inhibitors in gastric cancer has to be molecularly supported. This review provides a delicate dissection of the clinical and immunobiological considerations underlying the use of these agents in addition to a thorough review of the published clinical data of immune checkpoint inhibitors in gastric cancer.