Sunitinib is an oral multi-targeted tyrosine kinase inhibitor approved for first line treatment for metastatic renal cell carcinoma and imatinib-resistant metastatic gastrointestinal stromal tumors. Sunitinib administration can cause myelosuppression resulting in neutropenia and thrombocytopenia. Here we present the case of a patient with metastatic renal cell carcinoma who developed sunitinib-induced immune-mediated thrombocytopenia and who was treated with withdrawal of sunitinib and administration of intravenous immunoglobulin and steroids.
This case report describes a 70-year-old Aboriginal Australian with a diagnosis of metastatic renal cell carcinoma. Three weeks after the initiation of sunitinib he developed epistaxis and was admitted with thrombocytopenia (platelets 7 × 109/L) which was found to be refractory to platelet transfusion. Sunitinib was stopped and he was treated with intravenous immunoglobulin and steroids. His platelet count rapidly improved and returned to baseline in three weeks. Only two cases of sunitinib-induced immune-mediated thrombocytopenia have been described in the literature.
Clinicians should have a high index of suspicion for the potential of immune-mediated thrombocytopenia after the initiation of multi-targeted tyrosine kinase inhibitors such as sunitinib. This is a diagnosis of exclusion and can be safely treated by drug withdrawal.
Metastatic renal cell carcinoma; Sunitinib; Thrombocytopenia
Sunitinib malate is a novel oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Sunitinib was recently approved in first-line treatment for patients with advanced renal cell carcinoma (RCC) and for the treatment of patients with gastrointestinal stromal tumors (GIST) after disease progression or intolerance to imatinib mesylate therapy. We report the very interesting results of the phase II trials after cytokin failure and of the randomized recent trial of sunitinib versus cytokin-based therapy in first-line treatment for patients with metastatic RCC, as well as the promising results of the recent trials on patients with GIST after disease progression or intolerance to imatinib mesylate therapy. Oral sunitinib demonstrates a high level of efficacy with acceptable tolerability with the 50 mg daily for 4 weeks followed by 2 weeks off schedule; a continuous schedule could be of interest. Hypertension and asthenia are the most common side effects with sunitinib. Regardless of these encouraging results, studies investigating sunitinib in first-line treatment (for patients with GIST), adjuvant and neoadjuvant settings are awaited, as well as trials using sunitinb in combination with chemotherapy or other targeted therapies. Clinical trials investigating sunitinib in other tumor types are ongoing.
sunitinib; renal cell carcinoma; GIST; review; targeted therapy
Sunitinib is an oral receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity that is approved for the treatment of advanced renal cell carcinoma (RCC), malignant gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. Well-known side effects of sunitinib include hypertension, fatigue, thyroid dysfunction, cardiotoxicity, gastrointestinal toxicity and skin toxicity. In this study, we report the case of a 61-year-old male with papillary metastatic RCC who responded to sunitinib but developed generalized tonic-clonic seizures during the third cycle. Magnetic resonance imaging (MRI) was compatible with reversible posterior leukoencephalopathy syndrome (RPLS). After the administration of anti-epileptic drugs and the withdrawal of sunitinib there was rapid clinical improvement. Notably, radiological characteristics of RPLS persisted during second-line therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and only resolved when everolimus was terminated due to disease progression. Although sunitinib-induced RPLS has been reported previously, our case is the first to additionally suggest that everolimus may sustain and therefore potentially contribute to the occurrence of RPLS.
renal cell cancer; sunitinib; reversible posterior leukoencephalopathy syndrome
Sunitinib is a protein tyrosine kinase-inhibitor targeting VEGFR, c-kit and PDGFR. It has been approved for the treatment of metastatic renal-cell carcinoma and gastrointestinal stromal tumors. Although it has been shown to prolong disease-free and overall survival in renal-cell carcinoma patients, only 70% of the treated population receive a clinical benefit (CB) from the treatment. Markers that could predict clinical benefit to sunitinib would be an important aid in monitoring and following their treatment. We assessed the outcome and plasma proangiogenic factors in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib in our institution.
We have treated 42 patients with metastatic clear-cell renal carcinoma with sunitinib. Plasma concentrations of VEGF-A, sVEGFR2 and PDGF were determined by ELISA.
At the time of analysis 39 patients were evaluable for response and 30 patients had obtained a clinical benefit (CB). Median progression-free survival was 268 days (8.93 months) and median overall survival was 487 days (16.23 months). Interestingly, disease stabilization or objective response resulted in comparable overall survival. Most treatment-related adverse events were of mild-to-moderate intensity with one treatment-related death. Plasma sVEGFR2 and PDGF levels had no predictive value. Fold-increase in plasma VEGF was significantly lower in patients that obtained a CB as compared to patients that progressed after two cycles of treatment. Plasma VEGF did not increase in patients with initial CB at the time of progression.
Sunitinib showed substantial activity in mRCC. Disease stabilization or objective response resulted in comparable overall survival and both outcomes should be considered positive. Fold-increase in plasma VEGF predicts for CB and could be a candidate marker. Progression after initial CB is not associated with elevated plasma VEGF, implying a different mechanism of resistance.
Tyrosine kinase inhibitors (TKIs) have advanced cancer treatment. Sunitinib, a recently-approved, multi-targeted TKI, prolongs survival for patients with metastatic renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST), but concerns about cardiac safety have arisen with this agent.
To determine the cardiovascular risk associated with sunitinib, we reviewed all cardiovascular events in patients with imatinib-resistant, metastatic GIST at the Dana-Farber Cancer Institute enrolled in a Phase I/II protocol evaluating the efficacy of the drug (n=75). Sunitinib’s effects on left ventricular ejection fraction (LVEF) and blood pressure (BP) were also examined. Studies in isolated cardiomyocytes and mice investigated potential mechanisms of sunitinib-associated cardiac effects.
Eleven percent (8/75) of subjects suffered a cardiovascular event with congestive heart failure (CHF) occurring in 8% (6/75) of the population. Twenty-eight percent (10/36) of patients treated at the FDA-approved dose had LVEF declines of ≥ 10 EF%, and nineteen percent (7/36) experienced LVEF declines of ≥ 15 EF%. Sunitinib induced significant increases in mean systolic and diastolic BP in patients, and 47% (35/75) of individuals developed hypertension (HTN) (>150/100 mmHg). CHF and LV dysfunction generally responded to withholding drug and instituting medical management. In mice and cultured cardiomyocytes, sunitinib caused mitochondrial injury and cardiomyocyte apoptosis.
Sunitinib treatment can lead to HTN, LVEF decline, and/or CHF. Experimental studies suggest that this is due, at least in part, to direct cardiomyocyte toxicity which may be exacerbated by HTN. Patients treated with sunitinib should receive close monitoring and prompt treatment for HTN and/or LVEF decline.
Sunitinib, a multitargeted tyrosine-kinase inhibitor, extends survival of patients with metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumours. Between October 2005 and March 2007, we retrospectively reviewed blood glucose level variations associated with sunitinib therapy in patients treated for mRCC. Nineteen of the patients had type II diabetes. All 19 patients had a decrease in blood glucose level (mean 1.77 mmol l−1) after 4 weeks of treatment. This was followed by re-elevation in the 2-week rest period. After two cycles of sunitinib administration, two patients had stopped blood glucose-lowering drugs whereas five other patients had normalised their blood glucose level. On the basis of pre-clinical data, we hypothesise that several mechanisms could be involved in this process, such as capillary regression of pancreatic islets, IGF-1 modulation through HIF1-α or NF-κB activation. In addition, a decrease of glucose uptake in the context of concomitant gastrointestinal toxicity cannot be excluded. Glycaemic control should be carefully evaluated in diabetic patients treated with sunitinib, and routine monitoring is warranted.
renal cell carcinoma; sunitinib; diabetes; glucose level; tyrosine-kinase inhibitor; VEGF
The novel multitargeted tyrosine kinase inhibitor sunitinib is used as an anti-angiogenic agent for the treatment of several types of cancer, including metastatic renal cell carcinoma (RCC). Sunitinib was shown to positively change the immunosuppressive phenotype in RCC patients. In order to improve its antitumor efficacy, and offer strategies for its combination with other approaches, it is critical to fully elucidate its mechanisms of action. We show that sunitinib induces tumor cell apoptosis and growth arrest in RCC tumor cells, which correlates with Stat3 activity inhibition. Sunitinib-mediated direct effects on tumor cells occur regardless of von Hippel-Lindau tumor suppressor gene status and hypoxia-inducible transcription factor-2α levels. Reduction of Stat3 activity enhances sunitinib’s antitumor effects, whereas expression of a constitutively-activated Stat3 mutant rescues tumor cell death. Intravital multi-photon microscopy data show that sunitinib induces mouse Renca tumor cell apoptosis in vivo before tumor vasculature collapse. Sunitinib also inhibits Stat3 in Renca tumor–associated myeloid derived suppressor cells (MDSCs), downregulates angiogenic gene expression, and reduces MDSCs and tumor T regulatory cells. These results suggest that Stat3 activity is important for RCC response to sunitinib, and Stat3 inhibition permits sunitinib’s direct proapoptotic activity on tumor cells and positive effects on tumor immunologic microenvironment.
The broad spectrum kinase inhibitor sunitinib is a first-line therapy for advanced clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Unfortunately, most patients develop sunitinib resistance and progressive disease after about 1 year of treatment. In this study, we evaluated the mechanisms of resistance to sunitinib to identify the potential tactics to overcome it. Xenograft models were generated that mimicked clinical resistance to sunitinib. Higher microvessel density was found in sunitinib-resistant tumors, indicating that an escape from antiangiogenesis occurred. Notably, escape coincided with increased secretion of interleukin-8 (IL-8) from tumors into the plasma, and coadministration of an IL-8 neutralizing antibody resensitized tumors to sunitinib treatment. In patients who were refractory to sunitinib treatment, IL-8 expression was elevated in ccRCC tumors, supporting the concept that IL-8 levels might predict clinical response to sunitinib. Our results reveal IL-8 as an important contributor to sunitinib resistance in ccRCC and a candidate therapeutic target to reverse acquired or intrinsic resistance to sunitinib in this malignancy.
Sunitinib malate (Sutent; Pfizer, New York, NY, USA) is a highly selective multi-targeted agent and has been reported to have potent anti-tumor effects against various tumors, including renal cell carcinoma and gastrointestinal stromal tumors. In this study, we explored in vitro the anti-tumor effect and related molecular mechanisms of sunitinib malate against human bladder cancer cell lines. We also determined the synergistic anti-tumor effect between sunitinib and conventional cytotoxic drugs, cisplatin and gemcitabine, in bladder cancer cells.
Materials and Methods
Six human cancer cell lines (HTB5, HTB9, T24, UMUC14, SW1710, and J82) were exposed to an escalating dose of sunitinib alone or in combination with cisplatin/gemcitabine, and the cytotoxic effect of the drugs was examined by CCK-8 assay. The synergistic effect between sunitinib and cisplatin/gemcitabine was determined by the combination index (CI) and clonogenic assay. Alterations in cell cycle (cyclin D, B1), survival (p-Akt, t-Akt), and apoptosis (Bax, Bad) regulator expression were analyzed by Western blotting.
Like cisplatin and gemcitabine, sunitinib exerted a dose- and time-dependent anti-tumor effect in bladder cancer cells. However, sunitinib exhibited entirely different sensitivity profiles from cisplatin and gemcitabine. Sunitinib suppressed the expression of cyclin B1, p-Akt, and t-Akt while augmenting the expression of cyclin D and pro-apoptotic Bax and Bad in HTB5 cells. Analysis of the drug combination by the isobolic method and clonogenic assay revealed that sunitinib acts in synergy with gemcitabine in HTB5 cells.
These results indicate that sunitinib malate has a potent anti-tumor effect and may synergistically enhance the anti-tumor effect of gemcitabine in human bladder cancer cells.
Carcinoma; Cisplatin; Gemcitabine; Sunitinib; Urinary bladder
Purpose of review
Gastrointestinal stromal tumors are the most common sarcoma of the gastrointestinal tract. A decade ago, the only therapy for gastrointestinal stromal tumors was surgery. Treatment paradigms changed with the discovery that gastrointestinal stromal tumor cells express KIT, a tyrosine kinase growth factor receptor, which is mutated in 85% of cases. Imatinib and sunitinib are tyrosine kinase inhibitors with activity against advanced gastrointestinal stromal tumors. This review will discuss the available data on the use of imatinib in the adjuvant setting and the role of imatinib and sunitinib in the neoadjuvant setting.
Retrospective series and prospective studies have demonstrated the benefit of adjuvant imatinib. Randomized data show improved recurrence free survival in patients receiving imatinib for 1 year postoperatively. Ongoing studies are further defining the length of adjuvant therapy. The neoadjuvant treatment decreases tumor size to allow for surgical resection with less morbidity. The imatinib neoadjuvant therapy in a prospective randomized study was safe with encouraging outcomes. This approach for palliating advanced disease also appears to be safe following imatinib, sunitinib, or other tyrosine kinase inhibitors therapy.
Treatment for gastrointestinal stromal tumors, formerly limited to surgery, now is a combination of surgery and tyrosine kinase inhibitors therapy. Combination therapy is safe and improves outcomes, particularly in the adjuvant setting.
adjuvant; gastrointestinal stromal tumors; imatinib; neoadjuvant; sunitinib
Renal cell carcinoma (RCC) represents approximately 3% of all adult cancers and is more common in males. Systemic treatment for RCC has improved following the introduction of tyrosine kinase inhibitors, such as sunitinib. The molecular targets of sunitinib are receptor tyrosine kinases (RTKs). Moreover, sunitinib has an additional anti-angiogenic effect through its inhibition of the vascular endothelial growth factor receptor activation.
We present a case of intra-abdominal abscess formation mimicking disease progression, in a patient with metastatic renal cell carcinoma during sunitinib treatment.
In the advancing era of molecular therapy of solid tumours, sunitinib has demonstrated significant efficacy in the post-cytokine setting treatment of metastatic renal cancer. Concurrently, however, increasing evidence has emerged to indicate that this class of drugs exert profound immunomodulatory effects on T cells and play major roles in immune tumor surveillance.
Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor of targets such as vascular endothelial growth factor and platelet derived growth factor receptor. It is used for the treatment of metastatic renal cell carcinoma (RCC). Use of sunitinib has been associated with renal dysfunction and nephrotic syndrome. However, simultaneous occurrence of nephrotic syndrome and renal dysfunction in a patient treated with sunitinib is rare. We report a case of metastatic RCC treated with sunitinib for 22 months who presented with nephrotic syndrome and renal dysfunction. Renal biopsy was diagnostic of thrombotic microangiopathy with diffuse effacement of podocytic foot process.
Nephrotic syndrome; receptor tyrosine kinase inhibitor; sunitinib; thrombotic microangiopathy
A patient with advanced gastrointestinal stromal tumor (GIST) receiving second-line treatment with sunitinib developed edema, increase of the serum creatinine, weight gain, nephrotic syndrome with proteinuria of 12 g/24 h, dyslipidemia, hypoalbuminemia and also presented with hypertension. A kidney biopsy showed an immunocomplex glomerulonephritis. Steroid treatment was started, but the clinical conditions and laboratory values did not improve. So in the hypothesis that the nephrotic syndrome was induced by sunitinib, sunitinib was temporarily discontinued with a subsequent reduction of proteinuria and improvement in blood pressure control. In the last years, the introduction of sunitinib has modified the natural history of advanced GIST. However, due to chronic and prolonged intake of this drug, there is increasingly frequent detection of late and unknown toxicities in clinical practice. In particular, the late renal toxicity from sunitinib may be the primary clinical problem with this drug in the case of prolonged treatment. Monitoring of kidney function and blood pressure should be performed for early detection of side effects such as hypertension and kidney dysfunction in advanced GIST patients receiving long-term treatment with sunitinib. A clinical collaboration between oncologists and nephrologists could be useful with the objective to optimize the management of sunitinib.
Gastrointestinal stromal tumor; Sunitinib; Nephrotic syndrome; Vascular endothelial growth factor; Proteinuria; Renal toxicity
Sorafenib and sunitinib are multi-kinase inhibitors with antitumor activity in patients with advanced renal cell carcinoma (RCC). Several studies have evaluated the effect of sorafenib/sunitinib in combination with chemotherapeutic agents in different types of tumor. However, few studies have addressed the activity of fluorinated pyrimidine in combination with sorafenib/sunitinib. In this study, we examined the potential of combination therapy with 5FU and sorafenib/sunitinib in human RCC cell lines. Three human RCC cell lines, ACHN, Caki-1 and Caki-2, were used to assess sensitivity to 5-fluorouracil (5FU), sorafenib and sunitinib alone or in combination using an in vitro cell survival assay. Caki-2 cells demonstrated significantly higher resistance to 5FU and sorafenib as compared to ACHN and Caki-1. Additive antitumor effects of the combination therapy were observed in the in vitro study. There was a tendency for a positive correlation between the sensitivity to sunitinib and platelet-derived growth factor β (PDGFR-β) expression levels, which were examined by reverse transcription polymerase chain reaction. Caki-1 xenograft models were prepared by inoculating cells subcutaneously into nude mice, which were divided randomly into six groups: control, 5FU (8 mg/kg/day, intraperitoneally), sorafenib (15 mg/kg/day, orally), sunitinib (20 mg/kg/day, orally), and 5FU with sorafenib or sunitinib. The treatments were administered on 5 days each week, and tumor growth was monitored for 42 days following inoculation of cells. Synergistic antitumor effects of the combination therapy were observed in an in vivo study. The resected tumors were evaluated using the Ki-67 labeling index and microvessel density. Both the Ki-67 labeling index and microvessel density were decreased in tumors treated with the combination therapy compared to those treated with sorafenib/sunitinib alone. These findings suggest that the combination therapy of 5FU with sorafenib/sunitinib may be an effective therapeutic modality for advanced RCC patients.
renal cell carcinoma; 5-fluorouracil; sorafenib; sunitinib; angiogenesis
We report a case of nephrotic syndrome and acute renal failure apparently induced by sunitinib. A 67-year-old man with a history of metastatic renal cell carcinoma presented with progressive kidney dysfunction with proteinuria, general edema, and body weight gain of 21 kg after undergoing 3 weeks of sunitinib therapy. The patient had taken no other over-the-counter medications, and all other possible causes of nephrotic syndrome were excluded. The Naranjo Adverse Drug Reaction Probability Scale score for this event was 6, indicating a high probability that the observed presentations were associated with use of the drug. However, despite the discontinuation of sunitinib, his condition deteriorated, and hemodialysis was initiated for respiratory distress. A renal biopsy was performed, which revealed ischemic acute tubular necrosis with minimal change nephropathy. In conclusion, nephrologists and oncologists should be aware that nephrotic syndrome with ischemic acute tubular necrosis is a possible adverse effect of sunitinib. For early diagnosis of this condition and to avoid renal damage, we recommend differential diagnosis of serum creatinine and proteinuria in patients undergoing sunitinib therapy.
Sunitinib; Nephrotic syndrome; Ischemic acute tubular necrosis
Following approval of the oral, multitargeted tyrosine kinase inhibitor sunitinib malate for the treatment of patients with metastatic renal cell carcinoma (mRCC) in Europe and the USA in 2006, the agent has had a substantial impact on the treatment landscape in this setting. Sunitinib is now recommended in international treatment guidelines for the first-line treatment of favourable- or intermediate-risk mRCC and as an alternative option in poor-risk mRCC. In the 6 years since the approval of sunitinib, the range of agents available for the treatment of mRCC has expanded substantially, and this, together with a number of additional therapies in late-stage development, has increased the treatment options available to patients. Results from a phase III trial and a global expanded access study have provided robust data to support the efficacy of sunitinib in mRCC, including in real-world populations. Data also suggest a significant quality of life benefit with sunitinib, with superior patient-reported outcomes observed with this agent compared with interferon-α therapy. Both clinical and real-world study data also support the safety profile of sunitinib; most treatment-associated adverse events are mild to moderate in severity and can be managed effectively with close monitoring and proactive management. Clinical experience with sunitinib has demonstrated that therapy management, involving optimal dosing, maximum treatment duration and prompt and effective adverse event management, supports optimal patient outcomes with sunitinib. In this review we discuss clinical experience with sunitinib in mRCC, with an emphasis on real-world data, and utilize clinical case studies to examine the successful implementation of therapy management strategies for optimal patient outcomes. An increasing body of evidence suggests that side effects associated with sunitinib therapy, including hypertension, hand–foot syndrome and hypothyroidism, may represent effective markers of treatment response, and these will also be discussed.
case studies; metastatic renal cell carcinoma; sunitinib; therapy management; tyrosine kinase inhibitor
In an attempt to develop better therapeutic approaches for metastatic renal cell carcinoma (RCC), the combination of the antiangiogenic drug sunitinib with gemcitabine was studied. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), we have previously determined that a sunitinib dosage of 20 mg/kg per day increased kidney tumor perfusion and decreased vascular permeability in a preclinical murine RCC model. This sunitinib dosage causing regularization of tumor vessels was selected to improve delivery of gemcitabine to the tumor. DCE-MRI was used to monitor regularization of vasculature with sunitinib in kidney tumors to schedule gemcitabine. We established an effective and nontoxic schedule of sunitinib combined with gemcitabine consisting of pretreatment with sunitinib for 3 days followed by four treatments of gemcitabine at 20 mg/kg given 3 days apart while continuing daily sunitinib treatment. This treatment caused significant tumor growth inhibition resulting in small residual tumor nodules exhibiting giant tumor cells with degenerative changes, which were observed both in kidney tumors and in spontaneous lung metastases, suggesting a systemic antitumor response. The combined therapy caused a significant increase in mouse survival. DCE-MRI monitoring of vascular changes induced by sunitinib, gemcitabine, and both combined showed increased tumor perfusion and decreased vascular permeability in kidney tumors. These findings, confirmed histologically by thinning of tumor blood vessels, suggest that both sunitinib and gemcitabine exert antiangiogenic effects in addition to cytotoxic antitumor activity. These studies show that DCE-MRI can be used to select the dose and schedule of antiangiogenic drugs to schedule chemotherapy and improve its efficacy.
Sunitinib is approved for the treatment of metastatic renal cell carcinoma (RCC) and imatinib-resistant or -intolerant gastrointestinal stromal tumours (GIST). Several studies have identified unexpected rates of thyroid dysfunction with sunitinib treatment. We performed a prospective observational study with the aim of more accurately defining the incidence and severity of hypothyroidism in RCC or GIST patients receiving sunitinib. Thyroid function was assessed at baseline and on days 1 and 28 of each treatment cycle. Thyroid antibodies were assessed at baseline and during follow-up if abnormal thyroid function tests were recorded. Sixteen patients (27%) developed sub- or clinical hypothyroidism and required hormone replacement and 20 patients (34%) showed at least one elevated thyroid-stimulating hormone not requiring therapeutic intervention. Twenty patients (34%) did not develop any biochemical thyroid abnormality. Thus, sunitinib can induce (sub-) clinical hypothyroidism, warranting close monitoring of thyroid function. We propose a new algorithm for managing this side effect in clinical practise.
sunitinib; prospective study; hypothyroidism; gastrointestinal stromal tumour; renal cell carcinoma
Sorafenib and sunitinib are used for renal cell carcinoma (RCC). The objective was to study the treatment duration and time to death in Swedish RCC patients on sorafenib or sunitinib as first-line or monotherapy or as sequential therapy. Patients with an RCC diagnosis were identified in the Swedish Cancer Register. Information on treatment with sorafenib and sunitinib was collected from the Swedish Prescribed Drug Register, and time of death from the Cause of Death Register. Outcome measures were duration of treatment and time to death on sorafenib or sunitinib as first-line or monotherapy and sequential therapy (sorafenib–sunitinib versus sunitinib–sorafenib). Poisson regression models were used to estimate hazard ratios (HR) with 95 % confidence intervals (CI). No difference was observed for sorafenib (n = 123 patients) versus sunitinib (n = 261 patients) in treatment duration (HR 1.00; CI 0.80–1.24) or risk for death (HR 1.30; CI 0.91–1.85) when used as first-line or monotherapy. The same applied for sequential therapy with sorafenib–sunitinib (n = 43 patients) versus sunitinib–sorafenib (n = 54 patients), HR 1.47 (CI 0.71–3.02) and HR 2.01 (CI 0.86–4.68), respectively. There was a difference between the two treatments in how the duration of first-line treatment influenced the duration of second-line treatment and time to death, in favor of starting with sorafenib. In conclusion, no difference was detected between sorafenib and sunitinib in the duration of treatment or time to death when used as first-line or monotherapy. The impact of the duration of first-line treatment differed between the two sequences, and the results indicated that sorafenib as first-line treatment is a favorable choice.
Electronic supplementary material
The online version of this article (doi:10.1007/s12032-012-0331-8) contains supplementary material, which is available to authorized users.
Sorafenib; Sunitinib; Sequential; Register; Renal cell cancer
The multitargeted tyrosine-kinase inhibitor sunitinib has emerged as one of the standards of care for good and intermediate metastatic renal cell carcinoma. Fatigue, diarrhea, anorexia, oral changes, hand-foot syndrome and other skin toxicity, thyroid dysfunction, myelotoxicity, and hypertension seem to be the most common and clinically relevant toxicities of sunitinib. The proactive assessment and consistent and timely management of sunitinib-related side effects is critical to ensure optimal treatment benefit by allowing appropriate drug dosing and prolonged treatment periods.
The multitargeted tyrosine-kinase inhibitor sunitinib has emerged as one of the standards of care for good- and intermediate-risk metastatic renal cell carcinoma. Although generally associated with acceptable toxicity, sunitinib exhibits a novel and distinct toxicity profile that requires monitoring and management. Fatigue, diarrhea, anorexia, oral changes, hand-foot syndrome and other skin toxicity, thyroid dysfunction, myelotoxicity, and hypertension seem to be the most common and clinically relevant toxicities of sunitinib. Drug dosing and treatment duration are correlated with response to treatment and survival. Treatment recommendations for hypertension have been published but, currently, no standard guidelines exist for the management of noncardiovascular side effects. To discuss the optimal management of noncardiovascular side effects, an international, interdisciplinary panel of experts gathered in November 2009. Existing literature on incidence, severity, and underlying mechanisms of side effects as well as on potential treatment options were carefully reviewed and discussed. On the basis of these proceedings and the thorough review of the existing literature, recommendations were made for the monitoring, prevention, and treatment of the most common noncardiovascular side effects and are summarized in this review. The proactive assessment and consistent and timely management of sunitinib-related side effects are critical to ensure optimal treatment benefit by allowing appropriate drug dosing and prolonged treatment periods.
Sunitinib; Toxicity; Side effect management; Treatment optimization
Acalculous cholecystitis accounts for 10–15% of cases of cholecystitis. It is often associated with critical illness and has a high morbidity and mortality.
PRESENTATION OF CASE
We report an unusual case of an elderly lady who presented with acalculous cholecystitis as the herald event for subsequent fatal intestinal ischaemia. She demonstrated classical radiological features of pneumatosis coli and hepatic porto-venous gas (HPVG).
The pathogenesis of acalculous cholecystitis remains uncertain but theories including biliary stasis, sepsis and ischaemia have been proposed. The gallbladder is particularly vulnerable to ischaemia which may precipitate the inflammatory process. In this case, we propose that acute acalculous cholecystitis was triggered by ischaemia and was a herald sign of the ischaemia that would later affect the entire gastrointestinal tract. We suggest that the gallbladder's tenuous blood supply made it more vulnerable to the ischaemia that the rest of the bowel subsequently suffered from.
Intramural and hepatic porto-venous gas are classical, though rarely seen, CT findings in acute intestinal ischaemia. In these situations HPVG is often associated with poor outcome. In this case the acute acalculous cholecystitis may have been a herald sign of mesenteric ischaemia.
Acalculous cholecystitis; Mesenteric ischaemia; Pneumatosis intestinalis
Sunitinib is a receptor tyrosine kinase inhibitor (TKI) that is front-line therapy for metastatic renal cell carcinoma (mRCC). Its antitumor activity is related to its ability to block tumor cell and tumor vasculature cell signaling via several TKI receptors (i.e. vascular endothelial growth factor receptors VEGFRs, platelet-derived growth factors (PDGFs), stem cell factors). Sunitinib also targets myeloid derived suppressor cells (MDSCs) significantly reducing their accumulation in the peripheral blood and reversing T cell (IFNγ) suppression in both mRCC patients and in murine tumor models. This reduction in immune suppression provides a rationale for combining sunitinib with immunotherapy for the treatment of certain tumor types. Despite these encouraging findings, however, we have observed that sunitinib has variable impact at reducing MDSCs and restoring T cell function within the tumor microenvironment. Given the immunosuppressive and proangiogenic activities of MDSC, it seems plausible that their persistence may contribute to the resistance that develops in sunitinib-treated patients. While sunitinib reduced tumor infiltrating MDSCs in Renca and CT26-bearing mice, coinciding with strong to modest decreases in tumor size respectively, it was ineffective at ‘reducing MDSCs (<35% reduction in Gr1+CD11b+) or tumor burden in 4T1-bearing mice. Persistence of intratumor MDSCs was paralleled by depressed intratumor T cell IFNγ response and increased GM-CSF expression. Additionally, in vitro and in vivo experiments showed that GM-CSF prolongs survival of MDSCs, thus protecting them from the effects of sunitinib via a pSTAT5-dependent pathway. Although preliminary, there is evidence of intratumor MDSC resistance in some mRCC patients following sunitinib treatment. Intratumor MDSC persistence and T cell IFNγ response post nephrectomy in patients receiving sunitinib in a neoadjuvant setting is being compared to RCC patients undergoing nephrectomy without prior sunitinib treatment. Tumors from untreated patients showed suppressed T cell IFNγ response along with substantial expression of MDSCs (5% of total digested cells). Thus far, tumors from 5/8 neoadjuvant patients showed persistence of intratumor MDSCs and low T cell IFNγ production post sunitinib treatment, findings that parallel results from untreated tumors. In the remaining 3 neoadjuvant patients, intratumor MDSCs were detected at low levels which coincided with a T cell IFNγ response similar to that observed with normal donor peripheral T cells. GM-CSF’s role in promoting MDSC survival in patient tumors is supported by the observation that GM-CSF is produced in short-term RCC cultures at levels capable of protecting MDSCs from sunitinib-induced cell death. Additionally, persistence of MDSC also may be associated with increased expression of proangiogenic proteins, such as MMP9, MMP8, and IL-8 produced by tumor stromal cells or infiltrating MDSCs. Indeed our findings suggest that the most dominate MDSC subset in RCC patients is the neutrophilic population that produces proangiogenic proteins. We propose that the development of sunitinib resistance is partly mediated by the survival of MDSCs intratumorally, thereby providing sustained immune suppression and angiogenesis.
The anti-angiogenic drug sunitinib is a receptor tyrosine-kinase inhibitor with significant, yet not curative, therapeutic impacts in metastatic renal cell carcinoma (mRCC). Sunitinib is also an immunomodulator, potently reversing myeloid-derived suppressor cell (MDSC) accumulation and T-cell inhibition in the blood even of non-responder RCC patients. We observed that sunitinib similarly prevented MDSC accumulation and restored normal T-cell function to spleens of tumor-bearing mice, independent of sunitinib's capacity to inhibit tumor progression (RENCA>CT26>4T1). Both monocytic and neutrophilic splenic MDSC were highly repressible by sunitinib. In contrast, MDSC within the microenvironment of 4T1 tumors or human RCC tumors proved highly resistant to sunitinib, and ambient T-cell function remained suppressed. Proteomic analyses comparing tumor to peripheral compartments demonstrated that GM-CSF predicted sunitinib resistance, and recombinant GM-CSF conferred sunitinib resistance to MDSC in vivo and in vitro. MDSC conditioning with GM-CSF uniquely inhibited STAT3 and promoted STAT5 activation, and STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. We conclude that compartment-dependent GM-CSF exposure in resistant tumors may account for sunitinib's regionalized impact upon host MDSC modulation, and hypothesize that ancillary strategies to decrease such regionalization will enhance sunitinib's potency as an immunomodulator and a cancer therapy.
RCC; myeloid derived suppressor cells (MDSC); sunitinib; STAT; GM-CSF
The oral multi-kinase inhibitor sunitinib malate improves the survival of patients with gastrointestinal stromal tumors (GIST) after the disease progresses or intolerance to imatinib mesylate develops. Urinary fistulae arising during treatment with sunitinib for GIST have not been described.
We describe a 62-year-old female patient diagnosed with unresectable GIST that involved the abdominal wall, urinary bladder wall, bowel, mesentery and peritoneum in the pelvic cavity. Intestinocutaneous fistulae developed on a surgical lesion after orally administered imatinib was supplemented by an arterial infusion of 5-flurouracil. Sunitinib was started after the patient developed resistance to imatinib. On day 4 of the fourth course of sunitinib, a widely dilated cutaneous fistula discharged large amounts of fluid accompanied by severe abdominal pain. Urinary communication was indicated based on the results of an intravenous injection of indigo carmine. Computed tomography findings suggested a small opening on the anterior urinary bladder wall and fistulous communication between the bladder and abdominal walls bridged by a subcutaneous cavity. The fistula closed and the amount of discharge decreased when sunitinib was discontinued. Therefore, sunitinib might have been associated with the development of the vesicocutaneous fistula in our patient.
This is the first description of a vesicocutaneous fistula forming while under sunitinib treatment. Clinicians should be aware of the possible complication of vesicocutaneous fistula formation during treatment with molecular targeting agents in patients with extravesical invasion and peritoneal dissemination of GIST.
Angiogenesis is tightly linked to inflammation and cancer. Regulation of angiogenesis is mediated primarily through activation of receptor tyrosine kinases, thus kinase inhibitors represent a new paradigm in anti-cancer therapy. However, these inhibitors have broad effects on inflammatory processes and multiple cell types. Sunitinib is a multitarget receptor tyrosine kinase inhibitor, which has shown promise for the treatment of glioblastoma, a highly vascularized tumor. However, there is little information as to the direct effects of sunitinib on brain-derived neurons. The objective of this study is to explore the effects of sunitinib on neuronal survival as well as on the expression of inflammatory protein mediators in primary cerebral neuronal cultures.
Primary cortical neurons were exposed to various doses of sunitinib. The drug-treated cultures were assessed for survival by MTT assay and cell death by lactate dehydrogenase release. The ability of sunitinib to affect NF-κB, COX2 and NOS2 expression was determined by western blot. The NF-κB inhibitors dicoumarol, SN50 and BAY11-7085 were employed to assess the role of NF-κB in sunitinib-mediated effects on neuronal survival as well as COX2 and NOS2 expression.
Treatment of neuronal cultures with sunitinib caused a dose-dependent increase in cell survival and decrease in neuronal cell death. Exposure of neurons to sunitinib also induced an increase in the expression of NF-κB, COX2 and NOS2. Inhibiting NF-κB blunted the increase in cell survival and decrease in cell death evoked by sunitinib. Treatment of cell cultures with both sunitinib and NF-κB inhibitors mitigated the increase in COX2 and NOS2 caused by sunitinib.
Sunitinib increases neuronal survival and this neurotrophic effect is mediated by NF-κB. Also, the inflammatory proteins COX2 and NOS2 are upregulated by sunitinib in an NF-κB-dependent manner. These data are in agreement with a growing literature suggesting beneficial effects for inflammatory mediators such as NF-κB, COX2 and NOS2 in neurons. Further work is needed to fully explore the effects of sunitinib in the brain and its possible use as a treatment for glioblastoma. Finally, sunitinib may be useful for the treatment of a range of central nervous system diseases where neuronal injury is prominent.
COX2; NOS2; Sunitinib; NF-κB; Glioblastoma; Tyrosine kinase inhibitor; Neuron; Neuronal injury