Influence of genetic polymorphisms in vascular endothelial-related genes on the clinical outcome of axitinib in patients with metastatic renal cell carcinoma.

OBJECTIVE: Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated with axitinib, patients often need dose reductions or discontinue its use, highlighting the need for effective biomarkers to assess efficacy and/or AEs. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in the pharmacodynamic action of axitinib and clinical prognosis and AEs in metastatic RCC (mRCC) patients. METHODS: This study included 80 mRCC patients treated with first-, second-, or third-line axitinib (5 mg orally twice daily). Clinical parameters and genetic polymorphisms were examined in 75 cases (53 males and 22 females). We assessed three SNPs in each of three candidate genes namely, angiotensin-converting enzyme (ACE), nitric oxide synthase 3 (NOS3), and angiotensin II receptor type 1 (AT1R), all of which are involved in axitinib effects on vascular endothelial function. RESULTS: Axitinib-treated patients carrying the ACE deletion allele suffered more frequently from hand-foot syndrome and a deterioration in kidney function (p = .045 and p = 0.005, respectively) whereas those carrying the NOS3 G allele suffered more frequently from proteinuria and multiple AEs (p = .025 and p = 0.036, respectively). CONCLUSIONS: Our study found that the ACE deletion allele and the NOS3 G allele are associated with increased AEs.

Real clinical outcomes of nivolumab plus ipilimumab for renal cell carcinoma in patients over 75 years old.

BACKGROUND: Although nivolumab plus ipilimumab is the standard treatment for metastatic renal cell carcinoma (RCC), its efficacy and safety in older patients remain unclear. Therefore, this study aimed to assess the clinical outcomes of nivolumab plus ipilimumab for metastatic RCC in patients aged ≥ 75 years. METHODS: We enrolled 120 patients with metastatic RCC treated with nivolumab plus ipilimumab from August 2015 to January 2023. Objective response rates (ORRs) were compared between patients aged < 75 and ≥ 75 years. Progression-free survival (PFS), overall survival (OS), and adverse events were compared between the groups. Adverse events were evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1. RESULTS: Among the patients, 57 and 63 were classified as intermediate and poor risk, respectively, and one could not be classified. The median follow-up duration after the initiation of treatment was 16 months. The patient characteristics between the groups, except for age, were not significantly different. Intergroup differences in ORR (42% vs. 40%; p = 0.818), PFS (HR: 0.820, 95% CI 0.455-1.479; p = 0.510), and median OS (HR: 1.492, 95% CI 0.737-3.020; p = 0.267) were not significant. The incidence of adverse events (50% vs. 67%; p = 0.111) and nivolumab plus ipilimumab discontinuation due to adverse events was not significantly different between the groups (14% vs. 13%; p = 0.877). CONCLUSIONS: The effectiveness of nivolumab plus ipilimumab was comparable between patients with metastatic RCC aged < 75 and those ≥ 75 years with respect to their ORRs, PFS, OS, and adverse event rates.

Complete remission of brain metastases in renal cell carcinoma treated with axitinib after failure with nivolumab and ipilimumab treatment.

Introduction: Complete remission of cerebral metastasis is a rare consequence of tyrosine kinase inhibitor monotherapy in patients with metastatic renal cell carcinoma. Case presentation: A 68-year-old woman, who presented with dyspnea, was diagnosed with left renal cell carcinoma with multiple brain and pleural metastases. Although nivolumab and ipilimumab combination treatment was initiated, it was discontinued because of an immune-related adverse event. Two months after treatment cessation, brain metastases progressed regardless of shrinkage of primary renal tumor and pleural metastases. Therefore, axitinib was started as a second-line treatment, which resulted in the complete disappearance of the brain metastases along with the stable disease of the other tumor lesions. Conclusion: This is the first report of complete remission of brain metastases in renal cell carcinoma treated by axitinib.

Short-term outcomes of risk-adapted upfront docetaxel administration in patients with metastatic hormone-sensitive prostate cancer: a multicenter prospective study in Japan.

We conducted a risk-adapted upfront docetaxel (DOC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Here, we reported an interim analysis of the study. The study enrolled 68 patients with newly diagnosed mHSPC between 2016 and 2018. According to the presence of visceral metastasis, an EOD score ≥ 3, or prostate-specific antigen (PSA) level at 3 months of ≥ 1 ng/mL, patients were divided into low- and high-risk groups. Patients were treated with androgen deprivation therapy (ADT) with or without bicalutamide; those in the high-risk group received upfront treatment involving six cycles of DOC (70 mg/m2). Short-term treatment effect, adverse events, and quality of life (QOL) were evaluated. Fifty (73.5%) were classified in the high-risk group, and 46 (67%) received upfront ADT + DOC. In the ADT + DOC group, 43.5% (20/46) patients achieved a PSA level ≤ 0.2 ng/mL. PSA nadir and time to PSA nadir were 0.291 ng/mL and 288 days, respectively. In the ADT + DOC group, 76.1% (35/42) patients had adverse events (AEs) of grade ≥ 3. During a median follow-up of 18.5 months, 36.4% (8/22) patients in the ADT group and 43.5% (20/46) in the ADT + DOC group had CRPC. Two QOL scores including the physical status and appetite loss at 6 months significantly worsened in the ADT + DOC group but was resolved by 12 months. Upfront DOC achieved high PSA responses without long-term QOL deterioration. However, the short-term outcomes were limited. Longer follow-up is needed to determine the survival advantage.

[Advanced Adrenocortical Carcinoma with Vena Caval Tumor Thrombus Treated with Extended Surgery and Subsequent Chemotherapy].

A 36-year-old female was referred to our hospital for a giant abdominal mass found by ultrasound examination. A computed tomographic scan showed a large retroperitoneal mass measuring 11 cm in diameter suspected to be liver invasion,a right atrial and inferior vena cava (IVC) tumor thrombus with obstruction of hepatic vein junction of IVC,and small lung metastases. She was diagnosed with cT4N0M1 adrenocortical carcinoma (ACC) by a needle biopsy and radiographic examination. Right adrenalectomy and thrombectomy were successfully performed without cardiac arrest and without liver dissection. The operative time was 485 minutes,and the estimated blood loss was 7,533 ml. No major peri- or postoperative complications were observed. For the residual lung mass,a first line combination chemotherapy with etoposide,doxorubicin,cisplatin and mitotane followed by a second line chemotherapy with gemcitabine and capecitabine were administered. She has been alive with disease for 45 months under mitotane treatment against residual lung metastases. In conclusion,extended surgery could be successfully performed for advanced ACC with right atrium and IVC tumor thrombus. Although careful planning is needed for successful surgery,combination therapy with extended surgery and subsequent systematic chemotherapy may provide a substantial benefit in patients with advanced ACC.

Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients.

In this study, we examined the association between the pharmacokinetics (PK) level of sunitinib malate (SU) and its metabolite N-desethyl-sunitinib (DSU) in terms of adverse events (AEs) and clinical outcomes in patients with metastatic renal cell carcinoma (mRCC). The PK of sunitinib (SU and DSU) was examined in 26 patients (20 men and 6 women) with mRCC. The associations between SU/DSU C0 and AE occurrence, best response rate, time to treatment failure, progression-free survival (PFS), and overall survival (OS) were investigated. Occurrence of grade 1 or higher hand-foot syndrome and thrombocytopenia (p = 0.002 and 0.024, respectively) was associated with a high concentration before morning intake (C0) level of SU. Low C0 levels of DSU were significantly associated with drug discontinuation due to disease progression (p = 0.035). Patients with DSU C0 level higher than 15.0 ng/mL showed a tendency toward increased PFS (61 weeks vs 12 weeks, p = 0.004) and OS (36 months vs 8 months, p = 0.040). The C0 level of SU and SU + DSU were not associated with prognosis. The higher level of C0 of SU may predict developing AEs and DSU C0 >15.0 ng/mL may lead to better prognosis of patients treated with sunitinib. PK of sunitinib may be useful for determining adequate dosages and prevention of severe AEs. Further studies are required to establish the utility of the PK of sunitinib in patients with mRCC.

Contribution of UGT1A1 genetic polymorphisms related to axitinib pharmacokinetics to safety and efficacy in patients with renal cell carcinoma.

Axitinib is a potent second-line molecular-targeted agent for metastatic renal cell carcinoma (mRCC). Axitinib pharmacokinetics and its relation with genetic polymorphisms were evaluated to predict the adverse events (AEs) and efficacy of axitinib. We analyzed 46 patients with mRCC who were treated with axitinib. The plasma axitinib level was measured at 0, 2, 4, 8, and 12 h after administration (C0, C2, C4, C8, and C12; ng/mL) on day 7 of the treatment. Genetic polymorphisms related to axitinib pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed. Axitinib C0 and AUC0-12 in patients with UGT1A1 poor metabolisers (*6/*6, *6/*28, and *28/*28; n = 10) were significantly higher than those in patients with UGT1A1 extensive metabolisers (*1/*1, *1/*6,*1/*28, and *27/*28; n = 36) (23.6 vs. 7.8 ng/mL, p = 0.030, and 441.3 vs. 217.1 ng h/mL, p = 0.007). The cutoff levels of C0 to predict ≥ G2 hypothyroidism and ≥ G2 anorexia were 6.6 and 7.1 ng/mL, respectively (p = 0.005 and p = 0.035). The overall survival (OS) in patients with C0 > 5 ng/mL was significantly better than that in patients with C0 < 5 ng/mL (p = 0.022). Genetic polymorphisms in UGT1A1 were significantly associated with the plasma axitinib level. The plasma axitinib level was significantly associated with the frequency of AEs and OS in patients with mRCC. No direct relationship was observed between UGT1A1 genotypes and the frequency of AEs or OS.

[Tuberous Sclerosis Complex Detected by Spontaneous Rupture of a Giant Renal Angiomyolipoma : A Case Report].

A woman in her 30s was admitted with abdominal pain and nausea. CT scan revealed a spontaneous rupture of the right giant renal angiomyolipoma, and trans-arterial embolization was performed successfully. With further examination, she was found to be affected with tuberous sclerosis complex (TSC) and she finally wastreated with everolimusfor prevention of recurrent spontaneous-rupture of renal angiomyolipoma.