Toxicities Associated with the Administration of Sorafenib, Sunitinib, and Temsirolimus and Their Management in Patients with Metastatic Renal Cell Carcinoma

Bhojani, Naeem; Jeldres, Claudio; Patard, Jean Jacques; Perrotte, Paul; Suardi, Nazareno; Hutterer, Georg C.; Patenaude, François; Oudard, Stéphane; Karakiewicz, Pierre I.

doi:10.1016/j.eururo.2007.11.037

Cited by 226 publications

(143 citation statements)

References 30 publications

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“…However, it is interesting to note that in a phase II trial of sunitinib in cytokine-refractory mRCC patients; only 35% needed a dosereduction. Sunitinib-induced skin toxicity has been reported in several studies, but none of the studies reported any cases of perianal abscesses (8,16). Patients included in our study represent an unselected group with mRCC and therefore the results demonstrate the reproducibility of clinical trial results in the general population, albeit with a slightly higher toxicity, as may be expected with less stringent patient selection criteria than is typical in the clinical trials setting.…”

Section: Discussionsupporting

confidence: 52%

Sunitinib in patients with metastatic renal cell carcinoma: Birmingham experience

Ansari

Fatima²,

Fernando³

et al. 2010

Oncol Rep

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Abstract. Sunitinib is a novel, multi-targeted receptor tyrosine kinase inhibitor, which has demonstrated evidence of improved survival when compared to interferon (IFN)-· in patients with metastatic renal cell carcinoma (RCC). Recently published National Institute for Health and Clinical Excellence guidance recommends sunitinib as a first-line treatment option for patients with advanced and/or metastatic RCC. We assessed the efficacy and toxicity of sunitinib in an unselected group of patients with metastatic RCC, and compared outcomes in clinical practice with published clinical trial results. Between June 2006 and March 2008, 56 patients with metastatic RCC gave informed consent for commencement of sunitinib treatment at our institution. Median age was 61 years (range: 33-78); 68% had clear-cell histology; 86% had undergone prior nephrectomy; and 50% had progressed on IFN-· prior to commencement of sunitinib. Sunitinib was administered orally at a dose of 50 mg once daily, in 6-week cycles consisting of 4 weeks of treatment followed by a 2-week break. All patients were evaluable for toxicity, and 49 for response. The mean dose of sunitinib was 38.15 mg/cycle (range: 25-50); and 402 cycles of sunitinib were delivered. Partial response and stable disease were observed in 41 and 37% of patients, respectively. Median progression-free survival and overall survival were 12.2 and 18.2 months, respectively. The most common adverse events (all grades) were mucositis (79%) and fatigue (75%). Grade 3/4 neutropenia was observed in 13%, and treatmentrelated hypothyroidism in 20%, of patients. Dose-reduction was necessary in 75% of patients, and 32% needed hospital admission for treatment-related toxicities. The results from this study confirm the efficacy of sunitinib in the first-and second-line treatment of an unselected group of patients with metastatic RCC. Compared to published data, there was a higher incidence of treatment-related toxicities and a greater necessity for dose-reductions. Despite the increase in toxicity, these results are encouraging and imply that the clinical trial results seen with sunitinib can be translated into routine clinical practice.

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Section: Discussionsupporting

confidence: 52%

Sunitinib in patients with metastatic renal cell carcinoma: Birmingham experience

Ansari

Fatima²,

Fernando³

et al. 2010

Oncol Rep

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“…As hyperamylasaemia was not associated with clinical symptoms and no patient developed acute pancreatitis, it is possible that the asymptomatic increase in amylase should not be considered as a relevant DLT. Notably, asymptomatic increases in serum levels of amylase and lipase have been observed with the antiangiogenic agents such as sorafenib, sunitinib, and temsirolimus and may represent a class effect (Escudier et al, 2006;Bhojani et al, 2008). However, other side effects noted with VEGFR inhibitors and agents targeting VEGF such as skin rashes, hand -foot skin reactions, diarrhoea, hypertension and neuropathic changes (Kane et al, 2006;Rock et al, 2007) were not observed with tasquinimod.…”

Section: Discussionmentioning

confidence: 96%

Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer

et al. 2009

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BACKGROUND: Tasquinimod is a quinoline-3-carboxamide derivative with anti-angiogenic activity. Two open-label phase I clinical trials in patients were conducted to evaluate the safety and tolerability of tasquinimod, with additional pharmacokinetic and efficacy assessments. METHODS: Patients with castration-resistant prostate cancer with no previous chemotherapy were enrolled in this study. The patients received tasquinimod up to 1 year either at fixed doses of 0.5 or 1.0 mg per day or at an initial dose of 0.25 mg per day that escalated to 1.0 mg per day. RESULTS: A total of 32 patients were enrolled; 21 patients were maintained for X4 months. The maximum tolerated dose was determined to be 0.5 mg per day; but when using stepwise intra-patient dose escalation, a dose of 1.0 mg per day was well tolerated. The dose-limiting toxicity was sinus tachycardia and asymptomatic elevation in amylase. Common treatment-emergent adverse events included transient laboratory abnormalities, anaemia, nausea, fatigue, myalgia and pain. A serum prostate-specific antigen (PSA) decline of X50% was noted in two patients. The median time to PSA progression (425%) was 19 weeks. Only 3 out of 15 patients (median time on study: 34 weeks) developed new bone lesions. CONCLUSION: Long-term continuous oral administration of tasquinimod seems to be safe, and the overall efficacy results indicate that tasquinimod might delay disease progression.

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“…18 Sunitinib has been associated with many side effects, including severe cutaneous toxicities and cardiotoxicity. 11,[19][20][21][22] To avoid these side effects, targeted delivery of sunitinib to the target cells, ie, the proximal tubular cells of the kidneys, is a comprehensive approach. We have shown that small-molecule inhibitors can be delivered to the kidney by conjugation to lysozyme, [23][24][25] a low molecular weight protein that is rapidly filtered through the glomeruli of the kidneys and subsequently taken up at the apical membrane of proximal tubular cells via megalin receptor-mediated internalization.…”

Section: Introductionmentioning

confidence: 99%

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

Dolman¹,

Harmsen²,

Pieters³

et al. 2012

IJN

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Background: Activated proximal tubular cells play an important role in renal fibrosis. We investigated whether sunitinib and a kidney-targeted conjugate of sunitinib were capable of attenuating fibrogenic events in tubulointerstitial fibrosis. Methods: A kidney-targeted conjugate was prepared by linkage of a sunitinib analog (named 17864) via a platinum-based linker to the kidney-specific carrier lysozyme. Pharmacological activity of 17864-lysozyme was evaluated in human kidney proximal tubular cells (HK-2); the capability of the kidney-directed conjugate to accumulate in the kidneys was studied in mice. Potential antifibrotic effects of a single-dose treatment were evaluated in the unilateral ureteral obstruction (UUO) model in mice. Results: The 17864-lysozyme conjugate and its metabolites strongly inhibited tyrosine kinase activity. Upon intravenous injection, 17864-lysozyme rapidly accumulated in the kidneys and provided sustained renal drug levels for up to 3 days after a single dose. Renal drug level area under the curve was increased 28-fold versus an equimolar dose of sunitinib malate. Daily treatment of UUO mice with a high dose of sunitinib malate (50 mg/kg) resulted in antifibrotic responses, but also induced drug-related toxicity. A single dose of 17864-lysozyme (equivalent to 1.8 mg/kg sunitinib) was safe but showed no antifibrotic effects. Conclusion: Multikinase inhibitors like sunitinib can be of benefit in the treatment of fibrotic diseases, provided that their safety can be improved by strategies as presented in this paper, and sustained renal levels can be achieved.

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Toxicities Associated with the Administration of Sorafenib, Sunitinib, and Temsirolimus and Their Management in Patients with Metastatic Renal Cell Carcinoma

Cited by 226 publications

References 30 publications

Sunitinib in patients with metastatic renal cell carcinoma: Birmingham experience

Sunitinib in patients with metastatic renal cell carcinoma: Birmingham experience

Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

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