Targeted Therapies for Renal Cell Carcinoma: Review of Adverse Event Management Strategies

Eisen, Tim; Sternberg, Cora N.; Robert, Caroline; Mulders, Peter F.A.; Pyle, L; Zbinden, Stephan; Izzedine, Hassan; Escudier, Bernard

doi:10.1093/jnci/djr511

Cited by 194 publications

(192 citation statements)

References 113 publications

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“…In the case of present anti-angiogenic agents, the inhibitory effect on angiogenesis in normal tissue, except for tumor tissue, can lead to an unfavorable influence. For example, Avastin can induce mortal side effects, such as bowel perforation and pulmonary hemorrhages because Avastin can inhibit VEGF signaling in normal tissue, which is required for the maintenance of healthy blood vessels [40,41]. In contrast, since the RGD-MEND could selectively suppress gene expression in tumor tissue, its use should be safer than the currently used anti-angiogenic agents.…”

Section: Discussionmentioning

confidence: 99%

RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system

Sakurai

Hatakeyama

Sato

et al. 2014

Journal of Controlled Release

101

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Angiogenesis is one of crucial processes associated with tumor growth and development, and consequently a prime target for cancer therapy. Although tumor endothelial cells (TECs) play a key role in pathological angiogenesis, investigating phenotypical changes in neovessels when a gene expression in TEC is suppressed is a difficult task. Small interfering RNA (siRNA) represents a potential agent due to its ability to silence a gene of interest. We previously developed a system for in vivo siRNA delivery to cancer cells that involves a liposomal-delivery system, a MEND that contains a unique pH-sensitive cationic lipid, YSK05 (YSK-MEND). In the present study, we report on the development of a system that permits the delivery of siRNA to TECs by combining the YSK-MEND and a ligand that is specific to TECs. Cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) is a well-known ligand to α V β 3 integrin, which is selectively expressed at high levels in TECs.We incorporated cRGD into the YSK-MEND (RGD-MEND) to achieve an efficient gene silencing in TECs. Quantitative RT-PCR and the 5' rapid amplification of cDNA ends PCR indicated that the intravenous injection of RGD-MEND at a dose of 4.0 mg/kg induced a significant RNAi-mediated gene reduction in TEC but not in endothelial cells of other organs. Finally, we evaluated the therapeutic potency of the RGD-MEND encapsulating siRNA against vascular endothelial growth factor receptor 2. A substantial delay in tumor growth was observed after three sequential RGD-MEND injections on alternate days. In conclusion, the RGD-MEND represents a new approach for the characterization of TECs and for us in anti-angiogenic therapy.

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Section: Discussionmentioning

confidence: 99%

RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system

Sakurai

Hatakeyama

Sato

et al. 2014

Journal of Controlled Release

101

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“…Surveillance must be performed in HCC patients with high-grade oesophageal varices, RCC patients with brain metastases, patients with coagulopathies or congenital bleeding disorders [54] and particularly in patients given simultaneous treatment with anticoagulants [55].…”

Section: Bleedingmentioning

confidence: 99%

The Adverse Effects of Sorafenib in Patients with Advanced Cancers

Gao

2015

Basic Clin Pharma Tox

126

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Sorafenib is the first multi-kinase inhibitor (TKI) approved for the treatment of advanced hepatocellular cancer (HCC) and metastatic renal cell cancer (RCC) and is increasingly being used to treat patients with well-differentiated radioiodine-resistant thyroid cancer (DTC). Sorafenib demonstrates targeted activity on several families of receptor and non-receptor tyrosine kinases that are involved in angiogenesis, tumour growth and metastatic progression of cancer. Sorafenib treatment results in longterm efficacy and low incidence of life-threatening toxicities. Although sorafenib has demonstrated many benefits in patients, the adverse effects cannot be ignored. The most common treatment-related toxicities include diarrhoea, fatigue, hand-foot skin reaction and hypertension. Most of these toxicities are considered mild to moderate and manageable to varying degrees; however, cardiovascular events might lead to death. In this MiniReview, we summarize the adverse effects of sorafenib that commonly occur in patients with advanced cancers.Over the past few years, targeted therapy utilizing multi-tyrosine kinase inhibitors (TKIs) has been widely used for treatment of cancers. TKIs are designed to block specific cancer cell processes and are usually better tolerated than most conventional chemotherapeutic drugs. Sorafenib is the first orally active TKI approved by the Food and Drug Administration (FDA). Sorafenib mainly targets vascular endothelial growth factor (VEGFR1-3) and Raf kinases. Other reported targets include K-Ras, BRAF, V599E mutant BRAF, platelet-derived growth factor receptor-b (PDGFR-b), FMS-like tyrosine kinase 3 (FLT3), c-Kit and RET, and several other receptor tyrosine kinases (RTKs) via various modes of action, such as inhibition of the Ras/Raf/MAPK and PI3K/AKT/mTOR signalling pathways [1][2][3]. The anticancer activity of sorafenib thus results from a dual inhibitory effect towards angiogenesis and tumour cell proliferation. Sorafenib also possesses the function of inducing apoptosis in cancer cells by inhibiting the phosphorylation of initiation factor eIF4E and loss of the antiapoptotic protein myeloid cell leukaemia-1(Mcl-1) [4].In 2007, sorafenib was approved by the FDA for the treatment of advanced hepatocellular cancer (HCC) [5,6] and metastatic renal cell cancer (RCC) [7,8]. Oral administration of sorafenib is associated with improved quality of life and prolonged overall survival of patients [9]. Recently, the most positive phase III results were observed in well-differentiated radioiodine-resistant thyroid cancer (DTC) [10], resulting in the increased use of sorafenib to treat patients with DTC.

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“…Also, the occurrence rate of sorafenib-related toxicities in older patients is similar to that in younger patients. In the TARGET study, except for fatigue, the incidence of treatment-related toxicities in elderly patients was similar to that in younger patients (Eisen et al, 2012). Porta et al evaluated the efficacy of EVE in elderly patients enrolled in the RECORD-1 trial (Porta et al, 2012).…”

Section: Discussionmentioning

confidence: 90%

Favorable Outcome in Elderly Asian Patients with Metastatic Renal Cell Carcinoma Treated with Everolimus: The Osaka Urologic Oncology Group

Inamoto¹,

Azuma²,

Nonomura³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: In clinical trials with no upper age limit, the proportion of older patients is usually small, probably reflecting the more conservative approach adopted by clinicians when treating the elderly. An exploratory analysis of elderly patients in the RECORD-1 Trial showed that patients ≥ 65 y.o. had superior median PFS than overall RECORD-1 population (5.4 months and 4.9 months, respectively). We investigated the efficacy, relative benefit and safety of Everolimus (EVE) as sequential therapy after failure of VEGFr-TKI therapy for older patients with metastatic renal cell cancer (mRCC), in daily practice. Materials and Methods: 172 consecutive IRB approved patients with mRCC (median age 65, M:F 135/37, 78% clear cell) who received salvage EVE at 39 tertiary institutions between October 2009 and August 2011 were included in this analysis. Some 31% had progressed on sunitinib, 22% on sorafenib, 1% on axitinib, 41% on sequential therapy, and 5% had received other therapy. Patients with brain metastases were not included and 95% of the patients had a ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0 or 1. Previous radiotherapy was an exclusion criterion, but prior chemotherapy was permitted. Adequate organ function and hematologic parameters were mandatory. EVE administration was approved by the institutional review board at each participating institution and signed informed consent was obtained from all patients. Results: Median time of the whole cohort to last follow-up was 3.5 months (range 0.4-15.2 months). Forty four percent were continuing to take EVE at last followup. There were 86 (50%) patients ≥ 65 y.o. and 86 (50%) <65 y.o. The percentage of patients who showed PR/ SD was higher in the older group than in the younger one (5.9%/61.2% vs 1.2%/46.5%, respectively). Median survival of older patients was also significantly longer (3.5 +/-0.31 vs 3.1 +/-0.34, hazard ratio=0.45, CI; 0.255-0.802). Analysis using Cox regression model adjusted for gender, PS, number of metastases, site of metastases, histology, smoking history and age detected an association between age and PFS (p=0.011). The frequency of adverse events in elderly patients treated with EVE was no greater than that in younger patients, although such toxicity may have had a greater impact on their quality of life. Conclusions: Older patients should not generally be excluded from accepted therapies (mTOR inhibitors after failure of VEGFr-TKI therapy) for mRCC.

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Targeted Therapies for Renal Cell Carcinoma: Review of Adverse Event Management Strategies

Cited by 194 publications

References 113 publications

RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system

RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system

The Adverse Effects of Sorafenib in Patients with Advanced Cancers

Favorable Outcome in Elderly Asian Patients with Metastatic Renal Cell Carcinoma Treated with Everolimus: The Osaka Urologic Oncology Group

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