Tokio Rationale and Protocol: A Phase II Study to Evaluate the Activity and Safety of Third-line Tyrosine Kinase Inhibitor after 2 Tyrosine Kinase Inhibitors in Patients with Metastatic Renal Cell Carcinoma

Introduction Sunitinib is a tyrosine kinase inhibitor that binds to vascular endothelial factor receptor currently used for the treatment of renal cell carcinoma, as well as for several other conditions such as gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. We present a patient with invasive diarrhea who was treated with sunitinib for metastatic renal cell carcinoma. Case report Drug induced colitis was confirmed with colonoscopy from histopathological specimens. Clinical recovery of diarrhea was achieved with oral budesonide. Remarkably, the pathologic findings were observed in both the macroscopically normal mucosa and the mucosa with aphthous ulcers in the colon. Management & outcome The patient was treated for sunitinib associated diarrhea, after exclusion of the other reasons. Metronidazole and piperacillin/tazobactam treatment were prescribed. Discussion Diarrhea is a frequent symptom in patients treated with tyrosine kinase inhibitors, however the described pathologic findings have rarely been reported. Our aim is to emphasize the importance of close follow-up in patients treated with tyrosine kinase inhibitors, and to raise awareness on the management of sunitinib induced colitis.

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Real-world chart review study of adverse events management in patients taking tyrosine kinase inhibitors to treat metastatic renal cell carcinoma

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155217719583 ◽

2017 ◽

Vol 24 (8) ◽

pp. 574-583 ◽

Cited By ~ 6

Author(s):

Sandy Srinivas ◽

Dara Stein ◽

Dana Y Teltsch ◽

Sunning Tao ◽

Laura Cisar ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Adverse Events ◽

Tyrosine Kinase ◽

Cell Carcinoma ◽

Tyrosine Kinase Inhibitors ◽

Metastatic Renal Cell Carcinoma ◽

Special Interest ◽

Renal Cell ◽

Kinase Inhibitors ◽

Kinase Inhibitor

Purpose The purpose is to describe management of adverse events of special interest across tyrosine kinase inhibitors approved for metastatic renal cell carcinoma. Methods We conducted a retrospective chart review in metastatic renal cell carcinoma patients initiating tyrosine kinase inhibitor monotherapy between 15 November 2010 and 15 November 2013, and experiencing ≥ 1 adverse events of special interest (diarrhea, fatigue, hand-foot syndrome, hypertension, or stomatitis/mucositis) within 3 months of initiation. Demographics, medical history, treatment regimens, and adverse events of special interest management data for 3.5 months postonset were collected. Results In 220 charts from 27 centers, tyrosine kinase inhibitors prescribed included sunitinib (55%), pazopanib (27%), axitinib (9%), and sorafenib (8%). During the study period, patients experienced 376 adverse events of special interest (13% serious). Fatigue was most common (62% of patients), followed by hypertension (37%), diarrhea (30%), stomatitis/mucositis (29%), and hand-foot syndrome (12%). Over half (56%) the adverse events of special interest were resolved or resolving. Treatment discontinuation due to adverse events of special interest occurred in 15% of patients. Prophylaxis was rarely provided (8%), whereas 59% of patients received adverse events of special interest treatment (pharmacologic (55%) and/or nonpharmacologic (7%)), 27% received tyrosine kinase inhibitor dose management, 23% received both adverse events of special interest treatment and dose management, and 31% received neither. Hypertension was the most treated (72% of all events), and fatigue was the least treated (9%); only 4% of patients received pharmacologic treatment for fatigue. Conclusions Most adverse events of special interest were nonserious and more than half of the patients received pharmacologic and/or nonpharmacologic treatment. Fatigue was the most common yet least frequently treated adverse event of special interest, and few patients received prophylaxis or nonpharmacologic treatment. More emphasis on treatment and prophylaxis options for bothersome adverse events is warranted.

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Pharmacotherapy Options in Advanced Renal Cell Carcinoma: What Role for Pazopanib?

Clinical Medicine Insights Oncology ◽

10.4137/cmo.s6087 ◽

2011 ◽

Vol 5 ◽

pp. CMO.S6087 ◽

Cited By ~ 6

Author(s):

Michael R. Harrison

Keyword(s):

Renal Cell Carcinoma ◽

Tyrosine Kinase ◽

Cell Carcinoma ◽

Tyrosine Kinase Inhibitors ◽

Renal Cell ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Treatment Options ◽

Tumor Biology ◽

Mammalian Target Of Rapamycin

Over the last 6 years, the treatment of metastatic renal cell carcinoma (mRCC) has undergone dramatic changes. A better understanding of the pathogenesis and tumor biology of sporadic renal cell carcinoma has led to the approval of 6 drug regimens: 3 oral multi-targeted tyrosine-kinase inhibitors (sorafenib, sunitinib, and pazopanib), 2 inhibitors of the mammalian target of rapamycin (temsirolimus and everolimus), and 1 monoclonal antibody against the vascular endothelial growth factor (bevacizumab). Pazopanib, a multi-targeted tyrosine kinase inhibitor that targets VEGFR-1, -2, and-3; PDGFR-α and PDGFR-β, and c-Kit, was approved for the treatment of mRCC in October 2009, several years after the other drugs in its class. The efficacy and safety of pazopanib in Phase I, II, and III trials will be examined and its role in mRCC treatment will be described. Future studies that may clarify pazopanib's role in mRCC will be discussed. Based on pazopanib's demonstrated efficacy in treatment-naïve and cytokine-refractory patients, along with a seemingly favorable toxicity profile compared with other multi-targeted tyrosine-kinase inhibitors, pazopanib may have a unique niche in the armamentarium of treatment options for mRCC. Results from ongoing studies are awaited to confirm pazopanib's favorable efficacy-toxicity ratio, especially in comparison with the previous first-line standard-of-care, sunitinib.

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A phase II study of S-1 for the treatment of cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal cell carcinoma: Updated results.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.393 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 393-393

Author(s):

Yoshihiko Tomita ◽

Nobuo Shinohara ◽

Atsushi Mizokami ◽

Masato Fujisawa ◽

Katsuyoshi Hashine ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Cell Carcinoma ◽

Mrna Expression ◽

Phase Ii ◽

Renal Cell ◽

Kinase Inhibitor ◽

Phase Ii Study

393 Background: S-1 is an oral anticancer agent combining tegafur, a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine and potassium oxonate. S-1 has shown efficacy for cytokine and/or tyrosine-kinase inhibitor (TKI) refractory metastatic renal-cell carcinoma (mRCC). We report the final results of a phase II study and evaluate 5-FU-related enzymes as a predictor of the response to S-1. Methods: 45 patients received S-1 at a dose of 40 mg/m2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR). The secondary endpoints of progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Formalin-fixed, paraffin-embedded specimens obtained by radical nephrectomy were used for mRNA expression assay, performed by reverse-transcriptase polymerase chain reaction. Results: 45 patients including 6 were progressed after TKI were enrolled from April 2006. 24 patients received more than 5 cycles, and 2 continued to receive S-1 as of October 2011. Two (4.4%) of the 45 patients had complete responses to S-1, 9 (20.0%) had partial responses, and 28 (62.8%) had stable disease. The final PFS and OS were 9.2 and 42.8 months, respectively, and the PFS of TKI refractory patients was approximately two times of final PFS (18.0 months). The most common grade 3-4 adverse events according to CTCAE v.3.0 were similar to the previous report except for hemoglobin decreased and fatigue. On mRNA expression analysis, the expression level of thymidylate synthase correlated with ORR and PFS. On the other hand, OS did not differ significantly between patients with low expression and those with high expression of 5-FU-related enzymes. Conclusions: S-1 is effective and well tolerated in patients with cytokine and/or TKI refractory mRCC. Moreover, long-term treatment with S-1 is safe in mRCC patients enabling long-term disease control, especially in TKI refractory patients. Clinical trial with large number of TKI refractory patients is warranted to determine the efficacy of S-1.

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