Axitinib for preoperative downstaging of renal cell carcinoma with sarcomatoid differentiation and direct invasion of the duodenum and inferior vena cava: a case report
In November 2012, a 73-year-old man presented with a right renal mass and the chief complaints of anorexia, fatigue, and melena. Laboratory tests revealed anemia (hemoglobin, 6.2 g/dL) and hypercalcemia (corrected calcium, 11 mg/dL). The Karnofsky performance status was 50%–60%. Computed tomography (CT) showed a large right renal tumor with a diameter of 13 cm that had invaded the second part of the duodenum and had involved multiple regional lymph nodes without distant metastasis ().\nPositron emission tomography (PET) scans showed accumulation of fluorine-18-deoxyglucose in the tumor, with the maximum standardized uptake value being >40 (). Esophagogastroduodenoscopy detected direct invasion of the tumor into the second part of the duodenum with bleeding (). Biopsy of the protruding tumor revealed histologic features that were highly suggestive of sarcoma (). Accordingly, the clinical diagnosis was right RCC with sarcomatoid differentiation (cT4N1M0). It seemed to be difficult to safely perform radical nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy. In comparison with the first-generation vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) like sorafenib and sunitinib, axitinib is a more potent and selective second-generation VEGFR-TKI with better safety and tolerability, which has a higher affinity for the tyrosine kinase of VEGFR and a stronger inhibitory effect on its kinase activity with fewer serious adverse events, such as thrombocytopenia. At present, axitinib is generally recommended as a second-line therapy for advanced RCC, because the phase III axitinib versus sorafenib in advanced RCC (AXIS) trial demonstrated that axitinib treatment achieved longer progression-free survival than sorafenib in patients with metastatic RCC after failure of approved first-line systemic therapy, including sunitinib and cytokines.\nOur patient was unable to take food orally and had become emaciated. His classification was poor risk, according to the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria. To decrease the tumor burden and improve the feasibility of surgery, we selected preoperative treatment with axitinib. If the patient showed a poor response to axitinib, we intended to perform palliative gastrojejunostomy to allow oral intake.\nThis study was conducted in accordance with the World Medical Association Inc’s Declaration of Helsinki and was approved by the Institutional Review Board of the Ethical Committee of Dokkyo Medical University Hospital. In addition, the patient signed a consent form that was approved by our institutional Committee on Human Rights in Research. Axitinib administration (10 mg/day) was started in December 2012; it was scheduled to continue for 4–6 weeks until the patient underwent radical surgery, comprising nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy.\nDuring axitinib treatment, there were no adverse events > grade 3. After 2 weeks, the dose of axitinib was increased to 14 mg/day; then, it was raised to 20 mg/day after 2 more weeks. Attenuation of the tumor contrast uptake and enlargement of the duodenal lumen were observed on CT after 5 weeks of administration ().\nAfter 6 weeks of treatment, we decided to perform definitive surgery, and successfully carried out radical nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy. The resected tumor was an invasive whitish and yellowish mass with partial necrosis. Pathological examination confirmed that the lesion was RCC with sarcomatoid differentiation with necrotic areas (pT4pN1M0, Fuhrman grade 4) (). The pathological treatment effect of axitinib was grade 2 (two-thirds necrosis). The patient has been doing well since the operation. Western blotting and immunohistochemistry of the resected specimen was performed to detect phosphorylated Akt (Ser-473), using a rabbit antihuman antibody (PhosphoPlus® Akt (Ser-473) Antibody Kit; #9270, Cell Signaling Technology, Inc., Danvers, MA, USA), according to the method described previously.,\nThese studies showed that expression of phosphorylated Akt (Ser-473) in the tumor was heterogeneous ( and ). Axitinib therapy (10 mg/day) was resumed because microscopic invasion was detected at the resection margin, and some of the tumor tissues showed viability and expression of phosphorylated Akt (Ser-473). The patient has been asymptomatic without apparent disease progression for 6 months after resuming treatment with axitinib.