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A 52-year-old man complained of asymptomatic gross hematuria and cough. Chest and abdominal computed tomography (CT) revealed a right renal tumor, mediastinal lymph node metastasis, and right endobronchial metastasis. The right endobronchial metastasis was causing obstructive atelectasis in the lower lobe of the right lung. After tumor biopsy, the pathological diagnosis was clear cell renal cell carcinoma. Combination immunotherapy with ipilimumab and nivolumab was initiated, but CT showed enlargement of the metastatic lesion and lung abscess after two courses of treatment. The therapy was then switched to axitinib. Six days after initiation of axitinib, the lung abscess perforated into the pleural cavity, which resulted in the formation of pleural empyema with fistula. Ten days after initiation of axitinib, obstruction of the bronchus was relieved due to shrinkage of the right endobronchial metastasis, which resulted in development of a pneumothorax. Placement of a thoracic drainage tube and administration of an antimicrobial agent improved the pneumothorax and inflammatory response, but the drainage tube could not be removed. Long-term insertion of the thoracic drainage tube considerably diminished the patient's quality of life, and after 4 months, he was transferred to another hospital to receive the best supportive care.

This case is a 62-year-old man diagnosed with metastatic renal cell carcinoma. He was referred to our department due to the left renal mass pointed with ultra sound examination. Radiographical examination showed left-side 42 mm renal tumor with multiple lung tumors, suggesting renal cell carcinoma, cT1bN0M1 (pul). As an induction therapy, we selected Pembrolizumab plus Axitinib combination therapy. After 4 course of the therapy, the left kidney tumor shrank to 27 mm, and the lung metastasis disappeared with computed tomography imaging. For the next step, we performed laparoscopic partial nephrectomy. The pathological diagnosis was clear cell carcinoma, grade 2 with central necrosis. Since then, complete remission has been maintained without any treatment for 21 months.

A 46-year-old woman was referred to our hospital with a left-sided renal tumor pointed out by ultrasonography at the time of a medical checkup．Computed tomography revealed a mass measuring 88×77×68 mm on the upper pole of the left kidney. She was diagnosed with cT2aN0M0 clear cell renal cell carcinoma. Laparoscopic left nephrectomy was performed uneventfully. Histopathological diagnosis was clear cell renal cell carcinoma, G2, v1, pT2. Four months after surgery, lung metastases appeared, and systemic therapy was given sequentially as follows ; sunitinib for 2 months, nivolumab for 8 months, axitinib for 17 months, and pazopanib for 2 months．However, metastases progressed, and a re-administration of nivolumab was planned. The nivolumab re-treatment resulted in a marked reduction in multiple lung metastases despite the previous failure by nivolumab treatment. There are few reports on the therapeutic effect of re-administration of nivolumab. We report a case of successful treatment by re-administration of nivolumab.

A man in his 60s was diagnosed with clear cell carcinoma of the right kidney with multiple lung metastases, tumor thrombus of the inferior vena cava (IVC), and invasion of the duodenum and pancreas. Ipilimumab plus nivolumab was administered as first-line therapy. After 3 treatment courses, computed tomography (CT) demonstrated a slight decrease in the size of the primary tumor and lung metastases. However, the patient became hemodynamically unstable due to persistent duodenal bleeding during treatment despite frequent blood transfusions. Axitinib was then initiated as second-line therapy. The duodenal bleeding ceased 10 days after starting axitinib and his anemia remissed. Subsequent CT showed further decrease in the size of the primary tumor and lung metastases. The patient underwent right nephrectomy after improvement of nutrition. IVC thrombectomy, and pancreaticoduodenectomy. The lung metastases disappeared on postoperative imaging and no additional treatment was provided. Twelve months after surgery, he was in good health and showed no signs of recurrence.

The patient a 48-year-old male, underwent nephrectomy for clear cell renal cell carcinoma. After surgery, the patient was treated sequentially with sunitinib, axitinib, and everolimus for multiple pulmonary metastases and iliopsoas muscle metastasis. After 16 months, subcutaneous metastasis and left ventricular myocardial metastasis developed without any symptoms. He was treated with pazopanib for these metastases. However, no shrinkage was seen and bone metastasis in right acetabulum appeared. After radiation therapy (20 Gy/5 Fr) for right acetabulum, nivolumab was administered for myocardial metastasis and subcutaneous metastasis. Significant shrinkage of metastases was seen after 3 courses of nivolumab and the patient's condition remained stable after 31 courses of nivolumab.

A 56-year-old man with advanced RCC and a past medical history of type 2 diabetes underwent a radical left nephrectomy following a histological diagnosis of papillary RCC, G2, INF b, pT3, V1 in 1999. In 2008, sorafenib was started to treat multiple pulmonary metastases of RCC. In 2011, sorafenib was switched to sunitinib when radiologic progression was observed. In 2014, sunitinib was switched to axitinib when further radiologic progression was observed. In 2015, the patient was referred to Yazawa clinic for homecare urology when hospital visits became difficult due to cancer pain and bilateral lower-extremity muscle weakness. Cancer pain was controlled using acetaminophen and a fentanyl patch. During the administration of axitinib, a CTCAE grade 1 vocal disorder was detected. We reduced the axitinib dose from 10 mg to 6 mg, and valsartan and an antiflatulent were administered due to CTCAE grade 2 hypertension and diarrhea, respectively. Axitinib administration continued until the patient died. He had survived more than 11 years following the detection of lung metastasis. In this patient, a good balance between cancer treatment and palliative care was achieved through the application of homecare urology. In a super-aged society such as Japan, urologists with an awareness of Zaitaku Medicine, a Japanese style of homecare that provides continuing appropriate medical treatment and welfare support to patients with access barriers to hospital treatment to enable them to live out the remainder of their lives with dignity, may play a key role in the development of Zaitaku Medicine.

We report a case of hydrocephalus due to brain metastasis from renal cell carcinoma treated with axitinib. A 65-year-old man had undergone right radical nephrectomy for renal cell carcinoma in 2010. The pathological diagnosis indicated clear cell carcinoma G3, pT1a. After adjuvant treatment with interferon-α, computed tomography, in 2011, revealed multiple lung metastases. He was administered sorafenib. Because of progressive lung metastases, sunitinib was administered. The lung metastases were progressive and bone scan revealed multiple bone metastases. The patient was administered axitinib 10 mg/day in February 2014. Brain metastases were found in both the lateral ventricles in the same month and were controlled using axitinib. The patient, however, experienced adverse events such as diarrhea and hand foot syndrome, and the axitinib dosage was titrated. Cognitive function declined rapidly in August 2015. Brain magnetic resonance imaging revealed hydrocephalus due to brain metastasis from renal cell carcinoma. Axitinib was administered again. Cognitive function improved within approximately 10 days. Furthermore, hydrocephalus improved, and the patient was discharged on the 21st day.

A 36-year-old woman had undergone left radical nephrectomy followed by interferon-α and sunitinib for the treatment of renal cell carcinoma with para-aortic lymph node and lung involvements (papillary renal cell carcinoma, G3, cT3aN1M1) in the previous hospital. She was referred to our hospital for further treatment and received serial molecular targeted agents (everolimus, sorafenib, sunitinib) and radiation therapy for right ischial and femoral bone metastases. Then she was found to have multiple metastatic lesions in the lungs and carcinomatous pleural effusion associated with dyspnea. After failure of pleurosclerosis with OK-432, the pleural effusion markedly reduced by axitinib administration, but the pleural effusion relapsed a few days after axitinib was discontinued. For this reason, axitinib was maintained in spite of appearance of new metastatic lesions in the brain. The pleural effusion was well-controlled for 16 months but she died of progressive disease, including metastatic lesions in the brain and in the lungs.

A 73-year-old male patient underwent a right nephrectomy for renal cell carcinoma in 2008, and interferon-alpha was initiated as adjuvant treatment. Computed tomography (CT) scans showed lymphadenopathy above the left diaphragm, and treatment with interferon-2 was subsequently initiated in 2009. Nasal bleeding manifested in February 2010, and CT scans showed a soft-tissue density mass mainly located in the ethmoid sinus. A biopsy of the lesion was performed, and metastatic renal cell carcinoma was diagnosed. Treatment with sorafenib was consequently initiated and the paranasal metastasis showed a temporary partial response (PR). However, the metastatic lesion increased in size and caused repeated nasal bleeding that required blood transfusion. Although treatment with everolims was initiated, adverse events, such as rush, hypertensionnemia, and anemia due to nasal bleeding, developed. Treatment with axitinib was subsequently initiated. However, because adverse events, such as severe diarrhea, renal dysfunction and proteinuria manifested, the dose of axitinib was gradually decreased, and a periodic drug withdrawal schedule (11 days on, 3 days off) was finally initiated, which controlled these adverse events. The metastatic lesions showed a PR for 31months following axitinib administration.

In cases of advanced renal cell carcinoma with inferior vena cava (IVC) thrombus, surgical resection of both tumor and thrombus contributes to the improvement of patient's prognosis, but the risk of perioperative complication is still high. We experienced two cases of advanced renal tumors with IVC tumor thrombus down-sized by presurgical treatment of axitinib. Axitinib treatment showed a marked tumor reduction effect without any severe adverse event. We could remove both tumor and thrombus without perioperative complications. In these two cases, downsizing of IVC thrombus enabled us to reduce the extent of the surgery.

According to previous studies, papillary renal cell carcinoma (pRCC) type 2 is known to have a poor prognosis, especially in cases with metastases. We report a case of pRCC that responded well to axitinib administered as second line therapy. The patient was a 52-year-old woman who presented at our hospital with an incidental tumor on the left kidney. She underwent laparoscopic radical nephrectomy, and the pathological diagnosis was pRCC type 2, grade 3 pT1b. Multiple lung and bone metastases were observed following the four months, and histological findings of lung metastases was metastatic RCC. Although sunitinib was administered as first line therapy, tumor progression was observed after the first cycle of treatment. Therefore, axitinib (10 mg/day) was administrated as second-line therapy and was gradually increased to 14 mg/day. Five months after the administration of axitinib, the maximum tumor diameter of the lung metastases reduced by 83%. At present, eight months have passed since the start of axtinib administration, but the response was still maintained and the adverse events were generally tolerable.

The standard treatment for renal cell carcinoma (RCC) is surgery. Partial nephrectomy is often performed for treatment of small RCC. Radiofrequency ablation (RFA) offers another nephron-sparing minimally invasive approach. It is most successful for tumors not larger than 3 cm in diameter. The rate of severe complications of RFA is low. Further studies are necessary to determine the long-term efficacy of RFA in RCC. Metastatic RCC is currently mainly treated with cytokine-based therapy. Transient responses and moderate survival advantages have been achieved in a subset of patients. New therapies such as targeted molecular therapies are being developed to improve efficacy and treat those patients who are resistant to systemic immunotherapy. Targeted molecular therapies include inhibition of the Raf kinase pathway, inhibition of its receptor kinases, anti-vascular endothelial growth factor monoclonal antibody or the mammalian target of rapamycin pathway. Further clinical research will be required to develop a more effective therapy and the application of combined treatment modalities.