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1.  Acute Acalculous Cholecystitis in Patients With Clear Cell Renal Cell Carcinoma Treated With Sunitinib: Report of Two Cases 
Although sunitinib is associated with a variety of adverse events, cases of sunitinib-related acute cholecystitis have rarely been reported. We herein report two cases of sunitinib-related acute acalculous cholecystitis in patients with clear cell renal cell carcinoma. In both cases, the gallbladder was surgically removed because it was difficult to improve the patient’s condition with the cessation of sunitinib and non-surgical treatment only. Attention must be paid to the possibility of sunitinib-related acute cholecystitis, which, although uncommon, can be life-threatening.
PMCID: PMC4039104  PMID: 24883158
Sunitinib; Clear cell renal cell carcinoma; Acute acalculous cholecystitis; Cholecystectomy; Adverse event
2.  Sunitinib treatment enabling resection of massive liver metastasis: a case report 
Sunitinib was developed as a molecular-targeted drug to treat advanced renal cell carcinoma. It is not yet known whether liver damage occurs in patients with liver metastases of renal cell carcinoma after sunitinib administration. Here, we report the case of a patient with an inoperable massive liver metastasis of renal cell carcinoma for whom sunitinib administration was dramatically effective with no obvious evidence of liver damage. As a result, the liver metastasis could be resected. We emphasize the dramatic reduction in liver metastasis with sunitinib treatment, and the histopathological effects of sunitinib on the non-tumorous liver parenchyma.
Case presentation
A 54-year-old Japanese woman was diagnosed with right renal cell carcinoma and underwent right nephrectomy 12 years earlier. She presented to a local clinic with right abdominal pain. A computed tomography scan showed a massive liver metastasis occupying her right hepatic lobe, and she was referred to our hospital for treatment. The diagnosis was not only liver metastasis, but also left renal metastasis. Oral administration of tyrosine kinase inhibitor sunitinib was started. Adverse events due to sunitinib included liver dysfunction, thrombocytopenia, and decreased hemoglobin, but she completed eight courses with the help of drug holidays and dose adjustments. Post-treatment computed tomography showed a dramatic reduction in size of her liver metastasis, enabling right lobectomy of her liver. Histopathological findings showed no obvious liver damage due to chemotherapy in non-cancerous parenchymal areas.
With the availability of sunitinib, some patients with potentially unresectable massive liver metastases of renal cell carcinoma may be able to undergo major hepatectomy curatively and safely with little histopathological damage to non-tumorous liver parenchyma, thus improving their prognosis.
PMCID: PMC3874753  PMID: 24090151
Chemotherapy; Liver damage; Liver metastasectomy; Liver metastasis; Renal cell carcinoma; Sunitinib
3.  Sunitinib Malate Synergistically Potentiates Anti-Tumor Effect of Gemcitabine in Human Bladder Cancer Cells 
Korean Journal of Urology  2011;52(1):55-63.
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.
PMCID: PMC3037508  PMID: 21344032
Carcinoma; Cisplatin; Gemcitabine; Sunitinib; Urinary bladder
4.  MDSC as a Mechanism of Tumor Escape from Sunitinib Mediated Anti-Angiogenic Therapy 
International immunopharmacology  2011;11(7):853-858.
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.
PMCID: PMC3109226  PMID: 21315783
5.  Drug-induced immune-mediated thrombocytopenia secondary to sunitinib in a patient with metastatic renal cell carcinoma: a case report 
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.
Case presentation
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.
PMCID: PMC3599754  PMID: 23442444
Metastatic renal cell carcinoma; Sunitinib; Thrombocytopenia
6.  Sunitinib-induced severe toxicities in a Japanese patient with the ABCG2 421 AA genotype 
BMC Cancer  2014;14(1):964.
Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand–foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects.
Case presentation
A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient’s genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient.
The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-964) contains supplementary material, which is available to authorized users.
PMCID: PMC4301945  PMID: 25515134
Renal cell carcinoma; Sunitinib; Pharmacokinetics; Pharmacogenetics; Single-nucleotide polymorphism; ABCG2
7.  Acute Acalculous Cholecystitis in a Patient with Metastatic Renal Cell Carcinoma Treated with Sunitinib 
Clinics and Practice  2014;4(1):635.
A 55-year old man was treated with sunitinib 50 mg/day for 4 weeks on and 2 weeks off, as a first-line therapy for metastatic renal cell carcinoma. During the fourth week of the first cycle, he was admitted to the Emergency Department with abdominal pain and vomiting. Acute acalculous cholecystitis was diagnosed. Sunitnib-associated cholecystitis is a rare adverse event previously reported in few cases. The mechanism behind this complication is not fully understood, although vascular endothelial dysfunction may play a role. The use of this drug is expanding in clinical oncology, and physicians should be aware of this life-threating adverse event.
PMCID: PMC4019924  PMID: 24847435
acalculous cholecystitis; sunitinib malate; angiogenic agents; receptor tyrosine kinase
8.  Sunitinib: a novel tyrosine kinase inhibitor. A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST) 
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.
PMCID: PMC1936316  PMID: 18360643
sunitinib; renal cell carcinoma; GIST; review; targeted therapy
9.  An unusual case of acalculous cholecystitis heralding presentation of acute mesenteric ischaemia with typical radiological findings 
Acalculous cholecystitis accounts for 10–15% of cases of cholecystitis. It is often associated with critical illness and has a high morbidity and mortality.
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.
PMCID: PMC3356553  PMID: 22580081
Acalculous cholecystitis; Mesenteric ischaemia; Pneumatosis intestinalis
10.  Experience with sunitinib in the treatment of metastatic renal cell carcinoma 
Therapeutic Advances in Urology  2012;4(5):253-265.
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.
PMCID: PMC3441135  PMID: 23024706
case studies; metastatic renal cell carcinoma; sunitinib; therapy management; tyrosine kinase inhibitor
11.  Guillain-Barré Syndrome following Treatment with Sunitinib Malate 
Sunitinib malate (Sutent, SU011248) is an oral multitargeted tyrosine kinase inhibitor (TKI) used for the treatment of metastatic renal cell carcinoma and imatinib (Gleevec)—resistant gastrointestinal stromal tumor (GIST) with few reported side effects including asthenia, myelosuppression, diarrhea, and mucositis. Scarce literature exists regarding the rare but often serious toxicities of sunitinib. Autoimmune and neurological side effects have been linked to sunitinib's inhibition of VEGF receptors with a corresponding increase in VEGF levels, which is associated with development of different neuropathies. We hereby report an interesting case of Guillain-Barré syndrome in a middle-aged patient with metastatic renal cell carcinoma following sunitinib treatment.
PMCID: PMC4074976  PMID: 25018885
12.  Sunitinib treatment for patients with clear-cell metastatic renal cell carcinoma: clinical outcomes and plasma angiogenesis markers 
BMC Cancer  2009;9:82.
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.
PMCID: PMC2662874  PMID: 19284623
13.  Cardiotoxicity Associated with the Tyrosine Kinase Inhibitor Sunitinib 
Lancet  2007;370(9604):2011-2019.
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.
PMCID: PMC2643085  PMID: 18083403
14.  A phase 2 trial of sunitinib in patients with advanced non-clear cell renal cell carcinoma 
European urology  2012;62(6):10.1016/j.eururo.2012.06.043.
Sunitinib is a standard of care treatment in advanced clear-cell renal cell carcinoma (ccRCC). Retrospective and expanded access data suggest sunitinib has activity in advanced non-clear cell RCC (nccRCC).
To prospectively determine the clinical efficacy and safety of sunitinib in patients with advanced nccRCC.
Design, Setting, and Participants
This is a single-arm phase 2 trial with a two-stage design. Eligibility criteria included pathologically confirmed nccRCC or ccRCC with ≥ 20 percent sarcomatoid histology, performance status 0–2, measurable disease, maximum 2 prior systemic therapies, and no prior treatment with tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptors.
Patients received sunitinib 50 mg daily on a 4-week on, 2-week off schedule.
Outcome Measurements and Statistical Analysis
Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints were safety and overall survival (OS).
Results and Limitations
Fifty-seven patients were eligible [papillary (27), chromophobe (5), unclassified (8), collecting duct or medullary carcinoma (6), sarcomatoid (7), others (4)]. Median PFS for 55 evaluable patients was 2.7 months [95% CI: 1.4, 5.4]. Two patients with chromophobe and one patient with unclassified histology had a confirmed partial response (5% ORR). Median PFS for patients with papillary histology was 1.6 months (95% CI: 1.4, 5.4). Median PFS for patients with chromophobe histology was 12.7 months (95% CI: 8.5, NA). Median OS for all patients was 16.8 months (95% CI: 10.7, 26.3). Treatment emergent adverse events were consistent with sunitinib’s mechanism of action. The non-randomized design and small number of patients are limitations of this study.
The differential response of chromophobe histology to sunitinib suggests a therapeutically relevant biological heterogeneity exists within nccRCC. The low ORR and short PFS with sunitinib in the other nccRCC subtypes underscore the need to enroll patients with these diverse tumors on clinical trials.
PMCID: PMC3882163  PMID: 22771265
15.  Sunitinib Induced Thrombotic Thrombocytopenic Purpura in addition to Severe Hypothyroidism: A Case Report and Review of the Literature 
Case Reports in Medicine  2014;2014:958414.
Introduction. Sunitinib malate is an oral multitargeting tyrosine kinase inhibitor approved for the first line treatment of metastatic renal cell carcinoma. Sunitinib administration is associated with several adverse events including fatigue, diarrhea, skin toxicity, hypothyroidism, and cytopenia. Herein, we present a case of thrombotic thrombocytopenic purpura and clinical hypothyroidism presenting within 4 weeks of starting sunitinib therapy. Case Presentation. A 72-year-old woman with metastatic renal cell carcinoma presented with generalized fatigue 28 days after starting sunitinib 50 mg daily. She was found to have severe hypothyroidism, in addition to significant thrombocytopenia and anemia. The latter were explained by a clinical and laboratory diagnosis of thrombotic thrombocytopenic purpura. Sunitinib was stopped and she recovered completely after plasmapheresis. Conclusion. To our knowledge, this is the fourth case report of thrombotic thrombocytopenic purpura secondary to sunitinib. Oncologists should be aware of this rare but potentially fatal adverse event. We highly suggest to routinely test for platelet count and thyroid stimulating hormone level as early as two weeks after initiating sunitinib.
PMCID: PMC4202279  PMID: 25349620
16.  Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells 
Cancer research  2009;69(6):2506-2513.
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.
PMCID: PMC2664264  PMID: 19244102
17.  Characterizing fatigue associated with sunitinib and its impact on health-related quality of life in patients with metastatic renal cell carcinoma 
Cancer  2014;120(12):1871-1880.
Using phase 3 trial data for sunitinib versus interferon (IFN)-α in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life (HRQoL).
Patients received sunitinib at a dose of 50 mg/day on a schedule of 4 weeks on/2 weeks off (375 patients) or IFN-α at a dose of 9 MU subcutaneously 3 times per week (360 patients). HRQoL was self-assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom Index–15-item (FKSI-15) questionnaire, with fatigue assessed using its Disease-Related Symptoms subscale. Fatigue was also assessed by providers using Common Terminology Criteria for Adverse Events (CTCAE). A repeated-measures model (M1) and random intercept-slope model (M2) characterized sunitinib-associated fatigue over time. Another repeated-measures model examined the relationship between HRQoL scores and CTCAE fatigue grade.
M1 demonstrated that the initial increase in patient-reported fatigue with sunitinib was worst during cycle 1, with mean values numerically better at subsequent cycles; most pairwise comparisons of consecutive CTCAE fatigue cycle means were not found to be statistically significant. M2 demonstrated that the overall trend (slope) for patient-reported and CTCAE fatigue with sunitinib was not statistically different from 0. The relationship between most HRQoL scores and CTCAE fatigue was close to linear regardless of treatment, with lower scores (worse HRQoL) corresponding to higher fatigue grade. The majority of HRQoL scores were better with sunitinib versus IFN-α for the same CTCAE fatigue grade.
Patients reported worse fatigue during the first sunitinib cycle. However, in subsequent consecutive cycles, less fatigue was reported with no statistically significant worsening. CTCAE fatigue assessment may not fully capture patient treatment experience. Cancer 2014;120:1871–1880. © 2014 American Cancer Society.
Using phase 3 trial data for sunitinib versus interferon-α in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life. Patients reported worse fatigue during the first sunitinib cycle, but in subsequent consecutive cycles less fatigue was reported with no statistically significant worsening; provider-assessed fatigue did not appear to fully capture patient treatment experience.
PMCID: PMC4231253  PMID: 24634003
sunitinib; metastatic renal cell carcinoma; fatigue; health-related quality of life; phase 3
18.  Sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects 
Canadian Urological Association Journal  2007;1(2 Suppl):S41-S54.
Sunitinib, a new vascular endothelial growth factor receptor inhibitor, has demonstrated high activity in renal cell carcinoma (RCC) and is now widely used for patients with metastatic disease. Although generally well tolerated and associated with a low incidence of common toxicity criteria grade 3 or 4 toxicities, sunitinib exhibits a distinct pattern of novel side effects that require monitoring and management. This article summarizes the most important side effects and proposes recommendations for their monitoring, prevention and treatment, based on the existing literature and on suggestions made by an expert group of Canadian oncologists. Fatigue, diarrhea, anorexia, oral changes, skin toxicity and hypertension seem to be the most clinically relevant toxicities of sunitinib. Fatigue may be partly related to the development of hypothyroidism during sunitinib therapy for which patients should be observed and, if necessary, treated. Hypertension can be treated with standard antihypertensive therapy and rarely requires treatment discontinuation. Neutropenia and thrombocytopenia usually do not require intervention, in particular no episodes of neutropenic fever have been reported to date. A decrease in left ventricular ejection fraction is a rare, but potentially life-threatening side effect. Because of its metabolism by cytochrome P450 3A4 a number of drugs can potentially interact with sunitinib. Clinical response and toxicity should be carefully observed when sunitinib is combined with either a cytochrome P450 3A4 inducer or inhibitor and doses adjusted as necessary. Knowledge about side effects, as well as the proactive assessment and consistent management of sunitinib-related side effects, is critical to ensure optimal benefit from sunitinib treatment.
PMCID: PMC2422945  PMID: 18542784
19.  A case of severe acalculous cholecystitis associated with sorafenib treatment for advanced hepatocellular carcinoma 
Sorafenib, a multikinase inhibitor, is the first and only drug, which improves significantly the overall survival in patients with advanced hepatocellular carcinoma (HCC). However, many patients experience diverse side effects, some of them severe and unexpected. To date, acute acalculous cholecystitis has not been documented in association with a HCC patient treated with sorafenib. Here, we report the case of a 43-year-old woman with hepatitis C virus-related advanced HCC. She received sorafenib, and later complained of a sudden onset of severe right hypocondrial pain with rebound tenderness and muscle defense. Laboratory examination showed mild elevation of transaminases, biliary enzymes, bilirubin, inflammation markers, and a marked peripheral eosinophilia. Abdominal computed tomography (CT) revealed a swollen gallbladder with exudate associated with severe inflammation without stones or debris. Consequently, sorafenib treatment was stopped immediately, and steroid-pulse therapy was performed. Steroid therapy drastically improved all clinical manifestations along with normalization of CT findings, eosinophilia, and liver functions. In summary, we herein report a rare case of acute severe acalculous cholecystitis associated with sorafenib in the patient with advanced HCC.
PMCID: PMC3360105  PMID: 22645635
Hepatocelluar carcinoma; Sorafenib; Acalculous cholecystitis
20.  Reversible posterior leukoencephalopathy syndrome during sunitinib therapy for metastatic renal cell carcinoma 
Oncology Letters  2012;3(6):1293-1296.
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.
PMCID: PMC3392579  PMID: 22783436
renal cell cancer; sunitinib; reversible posterior leukoencephalopathy syndrome
21.  Transformation of Nonfunctioning Pancreatic Neuroendocrine Carcinoma Cells into Insulin Producing Cells after Treatment with Sunitinib 
Endocrinology and Metabolism  2013;28(2):149-152.
We report a rare case of severe hypoglycemia after sunitinib treatment for pancreatic neuroendocrine carcinoma. We describe the initial clinical presentation, laboratory results, pathologic findings, and managment in a patient with a nonfunctioning pancreatic neuroendocrine carcinoma with liver metastases who developed life threatening hypoglycemia after 2 months of sunitinib therapy. A 46-year-old woman presented to the emergency department with loss of consciousness from hypoglycemia. Serum C-peptide and insulin levels at fasting state revealed that the hypoglycemia resulted from endogenous hyperinsulinemia. She had been diagnosed with nonfunctioning pancreatic neuroendocrine carcinoma based on a biopsy of metastatic cervical lymph node and was being treated with sunitinib, a small molecule tyrosine kinase inhibitor. Immunohistochemical stain of the metastatic liver mass demonstrated that the initially nonfunctioning neuroendocrine carcinoma cells had changed into insulin-producing cells after sunitinib therapy. Transarterial chemoembolization of the liver masses and systemic chemotherapy with streptozotocin/adriamycin relieved the hypoglycemia. A nonfunctioning pancreatic neuroendocrine carcinoma was transformed into an insulin-producing tumor after treatment with sunitinib, causing endogenous hyperinsulinemia and severe hypoglycemia.
PMCID: PMC3811707  PMID: 24396670
Sunitinib; Tyrosine kinase inhibitor; Pancreatic neuroendocrine tumor; Insulinoma; Hypoglycemia
22.  Clinical response to sunitinib as a multitargeted tyrosine-kinase inhibitor (TKI) in solid cancers: a review of clinical trials 
OncoTargets and therapy  2014;7:719-728.
Angiogenesis is an integral process in carcinogenesis, and molecular inhibitors of angiogenic factors are currently being tested as treatments for cancer. Sunitinib is an oral multitargeted tyrosine-kinase inhibitor that blocks activation through the stem cell-factor receptor (Kit) and platelet-derived growth-factor receptor. Sunitinib has shown potent antitumor activity against several solid tumors, including renal cell carcinoma, gastrointestinal stromal tumors, and neuroendocrine tumors in several Phase II/III trials. Recently, sunitinib has been used to treat other solid cancers, such as lung cancer, pancreatic cancer, chondrosarcoma, esophageal cancer, bladder cancer, glioma, and aggressive fibromatosis, and also showed potential efficacy in progression-free survival and overall survival. In this review, we examine the efficacy of sunitinib as a molecular-targeted therapy in patients with different types of solid cancers.
PMCID: PMC4026584  PMID: 24872713
anti-angiogenic therapy; molecular-targeted therapy; tumor; antitumor activity
23.  Active Smoking May Negatively Affect Response Rate, Progression-Free Survival, and Overall Survival of Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib 
The Oncologist  2013;19(1):51-60.
An international multicenter retrospective study of sunitinib-treated metastatic renal cell carcinoma patients was performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. The results showed that active smoking may negatively affect the progression-free and overall survival of these patients.
Learning Objectives
Describe the association between risk factors for renal cell carcinoma and the outcome of sunitinib treatment for metastatic disease.Explain the impact of active smoking on the outcome of sunitinib-treated metastatic renal cell carcinoma.Discuss obesity, hypertension, and diabetes in relation to the outcome of sunitinib-treated metastatic renal cell carcinoma.
Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC).
An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors.
Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002).
Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.
PMCID: PMC3903056  PMID: 24309979
Active smoking; Metastatic renal cell carcinoma; Outcome; Sunitinib treatment
24.  Ultrasound guided percutaneous cholecystostomy in high-risk patients for surgical intervention 
AIM: To assess the efficacy and safety of ultrasound guided percutaneous cholecystostomy (PC) in the treatment of acute cholecystitis in a well-defined high risk patients under general anesthesia.
METHODS: The data of 27 consecutive patients who underwent percutaneous transhepatic cholecystostomy for the management of acute cholecystitis from January 1999 to June 2003 was retrospectively evaluated. All of the patients had both clinical and sonographic signs of acute cholecystitis and had comorbid diseases.
RESULTS: Ultrasound revealed gallbladder stones in 25 patients and acalculous cholecystitis in two patients. Cholecystostomy catheters were removed 14-32 d (mean 23 d) after the procedure in cases where complete regression of all symptoms was achieved. There were statistically significant reductions in leukocytosis, (13.7 × 103 ± 1.3 × 103 μg/L vs 13 × 103 ± 1 × 103 μg/L, P < 0.05 for 24 h after PC; 13.7 × 103 ± 1.3 × 103 μg/L vs 8.3 × 103 ± 1.2 × 103 μg/L, P < 0.0001 for 72 h after PC), C -reactive protein (51.2 ± 18.5 mg/L vs 27.3 ± 10.4 mg/L, P < 0.05 for 24 h after PC; 51.2 ± 18.5 mg/L vs 5.4 ± 1.5 mg/L, P < 0.0001 for 72 h after PC), and fever (38 ± 0.35°C vs 37.3 ± 0.32°C, P < 0.05 for 24 h after PC; 38 ± 0.35°C vs 36.9 ± 0.15°C, P < 0.0001 for 72 h after PC). Sphincterotomy and stone extraction was performed successfully with endoscopic retrograde cholangio-pancreatography (ERCP) in three patients. After cholecystostomy, 5 (18%) patients underwent delayed cholecystectomy without any complications. Three out of 22 patients were admitted with recurrent acute cholecystitis during the follow-up and recovered with medical treatment. Catheter dislodgement occurred in three patients spontaneously, and two of them were managed by reinsertion of the catheter.
CONCLUSION: As an alternative to surgery, percutan-eous cholecystostomy seems to be a safe method in critically ill patients with acute cholecystitis and can be performed with low mortality and morbidity. Delayed cholecystectomy and ERCP, if needed, can be performed after the acute period has been resolved by percutaneous cholecystostomy.
PMCID: PMC4087782  PMID: 17131483
Percutaneous cholecystostomy; Acute cholecystitis; Ultrasound; High risk; Elderly
25.  Reversible Posterior Leukoencephalopathy Syndrome Induced by Pazopanib 
BMC Cancer  2012;12:489.
The reversible posterior leukoencephalopathy syndrome is a clinical/radiological syndrome characterized by headache, seizures, impaired vision, acute hypertension, and typical magnetic resonance imaging findings. There are several reports in the literature that depict its occurrence in cancer patients. The list of common anticancer and supportive care drugs that predispose to reversible posterior leukoencephalopathy syndrome is expanding and includes not only a large number of chemotherapeutic agents but also an increased number of new targeted drugs, particularly angiogenesis inhibitors such as bevacizumab,sorefenib and sunitinib. Pazopanib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit which after a positive phase III randomized clinical trial in patients with advanced renal cell cancer received FDA approval for the treatment of advanced renal cell carcinoma. Until now no cases of reversible posterior leukoencephalopathy syndrome induced by pazopanib have been reported.
Case report
We present the case of a 40 years old female patient with heavily pre-treated metastatic renal cell carcinoma who received pazopanib as salvage treatment. After 21 days of pazopanib therapy the patient referred to the emergency department with epileptic seizure, impaired vision at both eyes and headache. MRI of the brain revealed subcortical oedema at the occipital and parietal lobes bilaterally. She was treated with anticonvulsants, i.v. administration of mannitol and antihypertensives and she recovered completely from her symptoms and was discharged on the tenth hospital day. A brain MRI performed 3 weeks after showed that the subcortical oedema had been subsided.
In conclusion this is the first case of pazopanib induced reversible posterior leukoencephalopathy syndrome. Although usually reversible, this syndrome is a serious and potentially life threatening adverse effect, if untreated, that should be considered by physicians treating metastatic renal cell carcinoma patients with pazopanib.
PMCID: PMC3487903  PMID: 23088634
Reversible posterior leukoencephalopathy syndrome; Pazopanib; Renal cell carcinoma

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