EORTC) The differences in disease-free survival, time to disease progression, and overall survival between the 2 groups with and without lymph node dissection for resectable limited renal cell carcinoma (N0M0) were not statistically significant. Therefore, regional or extensive lymph node dissection is generally not routinely performed in patients with renal cell carcinoma undergoing RN. If preoperative imaging shows enlarged regional lymph nodes or enlarged lymph nodes are palpated intraoperatively, regional lymph node dissection or resection is feasible to clarify pathologic staging.

• Management of positive tumor margins: The greatest concern of patients undergoing partial nephrectomy is the recurrence of tumor The most important concern of partial nephrectomy patients is the recurrence of tumor. The rate of ipsilateral renal tumor recurrence after partial nephrectomy is 1∼6, mostly due to multifocal or positive cut margins of the primary renal cell carcinoma. There is controversy as to whether a positive surgical margin for partial nephrectomy increases the patient’s risk of tumor recurrence and its prognostic impact. Studies have shown that even with positive margins for partial nephrectomy, there is no increase in tumor recurrence at midterm follow-up. Even some studies have shown no evidence of residual tumor in the vast majority of patients undergoing remedial nephrectomy immediately after surgery or later. Literature Reports 3
  

  ∼ 8 of NSS will have positive postoperative pathological margins, but only those patients with higher pathological grading (grade III-IV) will have an increased risk of postoperative recurrence.

  style=”margin-left: 72pt”>
  • Management of venous tumor emboli
    

  About 10 of patients with renal cell carcinoma

  Evaluation: preoperative enhanced MRI or CT scan and angiography to understand the extent and degree of venous aneurysm, the presence of venous wall invasion, etc. The extent and degree of venous thrombosis and the presence or absence of venous wall invasion are evaluated to develop further surgical treatment plans.

  Surgery: The surgical approach to locally advanced renal cell carcinoma with venous thrombosis varies depending on the extent of the venous thrombosis. The first step of surgery is to separate the vessels. The renal artery on the tumor side is ligated at the root of the aorta, followed by control of the vein and removal of the aneurysmal embolus. For better control of bleeding and tumor exposure, branch vessels of the inferior vena cava (lumbar veins, small branches of hepatic veins, etc.) can be ligated. It is important not to ligate all the branches in order to ensure smooth venous return. The kidney and the tumor should be touched as little as possible during the operation to reduce the risk of dislodging the tumor embolus. Surgery for a neoplastic thrombus confined to the renal vein or a neoplastic thrombus that has just entered the inferior vena cava is similar to a routine radical nephrectomy. When the thrombus is between the opening of the renal vein and the hepatic vein, the inferior vena cava is blocked above and below the thrombus, and the contralateral renal vein needs to be blocked. Usually, a blood shunt technique is not required. The vessel is incised anterior to the inferior vena cava and the kidney and tumor, the ipsilateral renal vein, and the aneurysmal vein are removed together. The lining of the inferior vena cava is carefully inspected and flushed to avoid residual tumor. When the tumor embolus is between the hepatic vein and the diaphragm, a blood shunt technique is required, and the decision to use the shunt technique is based on the degree of inferior vena cava blockage required intraoperatively and the status of the resulting hemodynamic changes.

  Prognosis: The relationship between the degree of venous aneurysm embolism and survival prognosis is not clearly established. A retrospective study including 422 cases showed that patients with inferior vena cava aneurysms had a worse survival prognosis than those with aneurysms confined to the renal veins. Another study showed that the prognosis was worse in patients with a tumor that invaded the wall of the renal vein than in those without wall invasion.
  .

  

  Table 8 Mayo clinical classification of tumor emboli in a five-level classification
  

  Grading Criteria and Content
  

  
  

   

  Grade 0 Tumor thrombus confined to renal vein
  

   

  Grade I Tumor thrombus invades the inferior vena cava and the tip of the tumor thrombus is ≤2 cm from the opening of the renal vein
  

   

  Grade II Tumor embolus invades the inferior vena cava below the level of the hepatic vein, with the tip of the embolus >2cm from the opening of the renal vein Grade III Tumor embolus grows to the level of the inferior vena cava in the liver, below the diaphragm
  

  Grade IV Invasion of tumor thrombus into the inferior vena cava above the diaphragm
  

  • Management of stage T4 renal cell carcinoma: A stage T4 tumor occurs when renal cell carcinoma invades beyond the renal fascia and involves the surrounding organs. It may involve the ascending colon, duodenum, descending colon, pancreas, diaphragm, liver, spleen, adrenal gland, ureter, etc. Early studies have shown that stage T4 tumors have poor surgical outcome and surgical treatment is not recommended. However, some subsequent studies have shown that surgery for stage T4 renal cell carcinoma can benefit patients. the MDACC study reported 30 patients with preoperative clinical stage T4NxM0 who underwent surgery with intraoperative resection of the tumor and invaded adjacent organs with negative margins.
    

    60 Patients showed a downstaging of their staging, with The pathological stage was T2 in 2 patients. Multifactorial regression analysis showed that pT4 and lymph node metastasis were independent predictors of survival prognosis. The 3-year overall survival rate for lymph node negative patients was 66, while the 3-year overall survival rate for patients with lymph node metastasis was 12. The 3-year overall survival rate was 66 for lymph node negative patients and 12 for lymph node metastatic patients. This study suggests that preoperative and intraoperative staging is not entirely accurate and that staging is overestimated in a significant number of patients. Therefore, for patients with clinical local staging of T4 and no distant metastases

  Patients may be considered for surgery if their medical condition allows for a manageable perioperative risk. In patients with renal cell carcinoma with stage T3 or T4 pathology combined with adjacent organ resection, approximately 1/4 patients had lymph node metastases and the majority had negative margins (36 positive margins). Survival time was significantly shorter in patients with positive margins. The median survival time for the entire group of patients was

  • months. Capitanio retrospectively analyzed the SEER database of renal cell carcinomas with clinical stage T4N0 to 2M0, 246 underwent surgery, and 64 did not undergo surgery. The median survival time for patients in the operated group was 48 months, compared with 6 months for patients in the non-operated group. The 10-year tumor-specific mortality rate for the 125 patients in the surgical group with pathologic stage T4N0 was 40. However, in patients with lymph node metastases, no significant benefit was seen. Multidisciplinary collaboration is important in the management of patients with clinical stage T4 renal cell carcinoma, as it involves the resection and reconstruction of adjacent organs. In summary, aggressive surgery in patients with clinical T4N0M0 renal cell carcinoma may provide a significant benefit if conditions allow.
    

    (ii) Interventional treatment.

    style=”margin-left: 48pt”>
    • Embolytic therapy
      
  • Renal artery embolization: Renal artery embolization can be used as a palliative treatment for renal tumors to relieve clinical symptoms and improve quality of life.
    
  • Indications: (1) pain due to renal tumor; (2) bleeding events related to renal tumor, such as renal tumor rupture or partial renal resection, hematuria (3) Pre-surgical embolization of some large, blood-rich renal tumors: it is not recommended for routine use because its benefit in prolonging patient survival, reducing intraoperative bleeding, and decreasing postoperative complications is unclear.
    
  style=”margin-left: 90pt”>
  • Contraindications: (i) uncorrectable coagulation dysfunction; (ii) severe infection.
    

  ③ Significant reduction in peripheral blood leukocytes and platelets (not absolutely contraindicated, e.g. in hypersplenism): leukocytes <3.0×109/L, platelets < 50×109/L; ④ Severe renal dysfunction.

  • Key points of the procedure: 1) Renal arteriography, usually by Seldinger’s method, is performed by percutaneous puncture of the femoral or radial artery, and the catheter is placed in the renal artery for digital subtraction angiography (DSA). The catheter is placed in the renal artery for digital subtraction angiography (DSA) and, if necessary, adrenal artery angiography to search for collateral blood supply. (2) Carefully analyze the angiographic manifestations to clarify the location, size, number and blood supplying arteries of the tumor. ③Embolization of the tumor blood supply artery is performed. For bleeding after partial nephrectomy, embolization should be performed as super-selective as possible to the relevant vessels, with attention to preserving normal renal units.
    
  • Postoperative complications: Post-embolization syndrome, the most common adverse reaction after renal artery embolization, mainly manifests as fever, Post-embolization syndrome is the most common adverse effect after renal artery embolization. The cause is local tissue ischemia and necrosis caused by embolization of the renal artery, and most patients recover completely after symptomatic treatment.
    
  • Pulmonary metastasis embolism: Lung is the most common site of metastasis for renal tumors. The first symptom is hemoptysis. Bronchial artery embolization can be used to treat pulmonary metastases, prevent complications associated with pulmonary metastases, and improve quality of survival.
    
  • Indications: 1) pain due to pulmonary metastases, such as pleural metastases; 2) dyspnea due to pulmonary metastases, such as airway compression; and 3) aspiration. Respiratory distress, such as airway compression stenosis; ③ Hemorrhagic events associated with lung metastases, such as hemoptysis, hemothorax, etc.
    
    style=”margin-left: 55pt”>
    • Contraindications: (i) uncorrectable coagulation dysfunction; (ii) severe infection.
      

  ③Significant reduction in peripheral blood leukocytes and platelets (not an absolute contraindication, e.g. spleen function)

  hyperactive): leukocytes <3.0×109/L and platelets <50×109/L; ④ Severe renal dysfunction.

  • ) Key points of the procedure: ① Bronchial arteriography, usually using the Seldinger method, with percutaneous puncture of the femoral artery or The catheter is placed in the bronchial artery and DSA is performed. If necessary, intercostal arteries can be used to find the collateral blood supply if they are adjacent to or located in the pleura. If necessary, intercostal arteries can be used to find the collateral blood supply. ② Carefully analyze the imaging performance to clarify the location, size, number and blood supplying arteries of the tumor. (3) Super-select the tumor-supplying artery for embolization, paying attention to avoid the spinal artery. ④For metastatic non-clear cell carcinoma, chemoembolization of the bronchial artery can be considered.
    
  • Postoperative complications: post-embolization syndrome, the most common adverse reaction after bronchial artery embolization, mainly manifests as fever, pain, cough, hemoptysis, and so on. It occurs because of local tissue ischemia and necrosis caused by embolization, and most patients can fully recover after symptomatic treatment.
    
  • Embolization of liver metastases: The liver is also a common site of metastasis for renal tumors. Selective hepatic artery embolization can be used to treat liver metastases, prevent deterioration of liver function, and improve the quality of survival.
    
    style=”margin-left: 55pt”>
    • Contraindications: (i) uncorrectable coagulopathy; (ii) severe infection.
      

    ③ Significant reduction in peripheral blood leukocytes and platelets (not absolutely contraindicated, e.g. in hypersplenism): leukocytes <3.0×109/L, platelets < 50×109/L; ④ severe renal dysfunction; ⑤ severe hepatic dysfunction (Child-Pugh grade C), including jaundice, hepatic encephalopathy, refractory ascites, or hepatorenal syndrome.

  • Key points of the procedure: ① Hepatic arteriography, usually using the Seldinger method, with percutaneous puncture of the femoral artery for cannulation. The catheter is placed in the abdominal trunk or common hepatic artery to perform
    

  DSA, image acquisition should include the arterial, parenchymal, and venous phases; it should be done The superior mesenteric artery angiography should be done, and attention should be paid to finding the collateral blood supply. (2) Carefully analyze the imaging performance to clarify the site, size, number and blood supplying artery of the tumor. ③Hepatic artery embolization: super-select to tumor blood supply artery for embolization. ④For metastatic non-clear cell carcinoma, hepatic artery chemoembolization can be considered.

  • Postoperative complications: post-embolization syndrome, the most common adverse reaction after hepatic artery embolization, mainly manifests as fever, pain, Post-embolization syndrome is the most common adverse effect after hepatic artery embolization. It occurs because of local tissue ischemia and necrosis caused by embolization of the hepatic artery, and most patients recover completely after symptomatic treatment.
    
    style=”margin-left: 48pt”>
    • Ablation therapy
      

    The widespread use of ablative therapy in recent years has allowed some patients with renal cell carcinoma who do not undergo or are intolerant of surgical resection to have access to radical treatment.

    Ablation therapy is a type of treatment that uses physical or chemical methods to directly kill tumor tissue by targeting the tumor with the guidance of medical imaging technology. The ablation of renal tumors and oligometastases mainly includes radiofrequency ablation and cryoablation. The ablation is most often guided by ultrasound, which is convenient, real-time, and efficient. CT and MRI combined with multimodal imaging systems can be used to visualize lesions that are not accessible by ultrasound. CT and MRI-guided techniques can also be used to ablate metastases in the lung, liver, adrenal glands, and bone.

  • Radiofrequency ablation: The routes of radiofrequency ablation are usually divided into percutaneous ablation and transablative ablation, and in patients with stage T1a renal tumors, the postoperative complication rates of both are higher. There is no difference in the incidence of postoperative complications, recurrence rate and tumor-specific survival between the two. One study showed that in patients with stage T1a renal tumors, radiofrequency ablation compared with partial nephrectomy
    

  There was no difference in overall survival and tumor-specific survival between the two, and the radiofrequency ablation The incidence of complications and transfusion rates were lower than those of partial nephrectomy, and the local recurrence rate of radiofrequency ablation was higher than that of partial nephrectomy but there was no difference in the distant metastasis rate between the two.

  • Cryoablation: The routes of cryoablation are usually divided into percutaneous ablation and trans-laparoscopic ablation, with overall survival, tumor-specific survival, and recurrence-free survival. survival, recurrence-free survival, and complication rates did not differ. When comparing cryoablation with partial nephrectomy, some studies showed no difference in overall survival, tumor-specific survival, recurrence-free survival, disease-free survival, local recurrence, and distant metastasis rates, and some studies showed that partial nephrectomy was superior to cryoablation in the above metrics.
    

    Indications for ablation therapy: ①In stage T1a, in advanced age or with comorbidities.

    ②Recurrence or unresectable in stage IV, combined with ablation of oligometastases on the basis of systemic therapy; ③Those who do not accept or tolerate surgery; ④Those who need to preserve renal units as much as possible; ⑤Those with renal insufficiency; ⑥Those with contraindications to general anesthesia.

    Contraindications to ablation therapy: (i) uncorrectable coagulation dysfunction; (ii) severe infection; (iii) significant reduction in peripheral blood leukocytes and platelets (not an absolute contraindication, e.g., in hypersplenism): leukocytes <3.0×109< /span>/L and platelets <50×109/L.

    Key points of the operation procedure: ① Puncture biopsy is required before ablation to provide support for subsequent treatment and follow-up; ② The size, location, and number of tumors should be comprehensively and adequately evaluated before treatment; attention should be paid to the relationship between tumors and adjacent organs, and a reasonable puncture path and ablation range should be formulated, with the premise of ensuring safety. achieve a sufficient safe range; ③ according to the size and location of the tumor, choose a suitable image guidance technique (ultrasound or CT) and ablation means (radiofrequency or freezing); ④ the ablation range should

  including 5 mm of paracancerous tissue to obtain a “safe margin” and completely kill the tumor, and for infiltrating or metastatic cancer foci with unclear borders and irregular shapes, if the adjacent tissues and structures allow, the ablation should be performed in a safe manner. For infiltrating or metastatic cancer foci with unclear borders and irregular shapes, it is recommended to extend the ablation area if the adjacent tissues and structures allow.

  Postoperative complications: fever, pain, bleeding, infection, etc., most of which are mild. Most patients recover completely after symptomatic treatment.

  • Other technologies: Other ablative treatments for renal tumors include microwave ablation, high-intensity focused ultrasound ablation, irreversible electroporation, and combined high and low temperature ablation. The above methods have also been gradually applied in the ablative treatment of renal cell carcinoma.
    

    (iii) Active monitoring.

    Active surveillance (AS) involves monitoring changes in the size of the renal tumor by performing regular abdominal imaging and receiving delayed interventional therapy if tumor progression occurs during follow-up. Awaiting surveillance differs from active surveillance in that the patient has more severe comorbidities that are not amenable to active treatment, and awaits observation until symptoms develop and then is treated symptomatically without the need for regular imaging.

    A multicenter prospective registry study, DISSRM (Delayed Intervention and Surveillance for Small Renal Masses), of small renal masses (SRMs, tumors ≤4 cm in largest diameter), showed that active surveillance versus active treatment was more effective in patients with small renal masses. treatment compared to 2 year overall survival in patients with small renal tumors

    The rates were similar, at 98 and 96, respectively. https://www.kiraspecialist.com/wp-content/uploads/2022/06/062222_1307_202245.png” alt=””/>; the 5-year overall survival rate was slightly lower in the active surveillance group, with

    The 5-year overall survival rates were slightly lower in the active monitoring group, 92 and 75(P=0.06); 7-year total survival was worse in the active monitoring group, the

    with 91.7 and 65.9, respectively. https://www.kiraspecialist.com/wp-content/uploads/2022/06/062222_1307_202249.png” alt=””/>(P= 0.01). However, in terms of tumor-specific survival

  in terms of active surveillance compared with active treatment at 5 years (99to 100, P=0.3) and 7 years (99to 100, P=0.5) were not different. patients in the AS group were older, had worse ECOG scores, more severe comorbidities, smaller tumors, and a higher proportion of multiple and bilateral renal tumors.

  For most patients with advanced age and comorbidities in SRMs, the risks associated with surgical anesthesia and other comorbidities are often higher than the tumors themselves. Prospective study: 5-year overall survival rate for patients with SRMs in the AS group 53∼90, 5-year tumor-specific mortality 0.2∼1.9 , 5-year progression-free survival rate 97

  ∼ 99. AS is a viable option for patients with older or frail SRMs. American Urologic Surgery

  The American College of Urologists recommended AS as a treatment option for patients with high-risk surgical factors and comorbidities in its 2009 guidelines for the management of stage T1 renal tumors. 2017, the American Society of Clinical Oncology recommended AS as a treatment option of choice for patients with SRMs with high-risk factors and poor life expectancy, and clarified its scope. The American Society of Clinical Oncology recommended AS as the preferred treatment option for patients with SRMs with high-risk factors and poor life expectancy, and defined its scope of application as absolute indications: high risk of surgical anesthesia or life expectancy<5 years; relative indications: risk of end-stage renal disease if treated, SRM<1cm or life expectancy<10 years. However, long-term AS is not advocated in young patients without comorbid other disease SRMs.

  (iv) Drug therapy.

  Since 2005, when sorafenib was approved for the treatment of metastatic renal cell carcinoma, the treatment of metastatic renal cell carcinoma has entered the era of targeted therapy. To date, the U.S. Food and Drug Administration has approved more than a dozen drugs and regimens for the treatment of metastatic renal cell carcinoma. These drugs are divided into, in terms of mechanism of action.

  1) anti-vascular endothelial growth factor or vascular endothelial growth factor receptor (vascular

  endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) pathway, mainly including sunitinib, pegaptanib sorafenib, axitinib, cabozantinib, lenvatinib, bevacizumab, etc.; ② Inhibition of mammalian target of rapamycin (mTOR) pathway: including everolimus and tesilimus; ③ Immune checkpoint inhibitors: including nabritumomab, pabrolizumab and epirimusumab; ④ Other: including cytokines [interleukin-2 and interferon-α (IFN-α)] and chemotherapy (gemcitabine and doxorubicin). Chemotherapy is primarily used as treatment for patients with metastatic renal cell carcinoma with sarcomatoid differentiation.

  Combination regimens include pablizumab in combination with axitinib, pablizumab in combination with lenvatinib, nabritumomab in combination with cabozantinib, nabritumomab in combination with ibritumomab (for intermediate-to-high-risk advanced clear cell-dominant renal cell carcinoma), avelumab in combination with axitinib, lenvatinib in combination with everolimus (for second-line treatment of advanced clear cell-dominant renal cell carcinoma), bevacizumab + erlotinib (for some patients with progressive papillary renal cell carcinoma, including hereditary smooth muscle disease and renal cell carcinoma), bevacizumab + everolimus (for some patients with progressive papillary renal cell carcinoma, including hereditary smooth muscle disease and renal cell carcinoma), and bevacizumab + everolimus (for some patients with progressive papillary renal cell carcinoma, including hereditary smooth muscle disease and renal cell carcinoma). smooth muscle tumor disease and patients with renal cell carcinoma), and others.

  The drugs approved for advanced renal cell carcinoma in China include pegaptanib, sunitinib, axitinib, sorafenib, everolimus, interleukin-2, IFN-α, and others.

  Recommended for patients with bone metastases and creatinine clearance ≥30 ml/min with dual

  phosphonates or RANK ligand inhibitors.

  (v) Traditional Chinese medicine treatment.

  TCM can help promote the recovery of body function after renal cell carcinoma surgery, reduce the toxic side effects of immunotherapy and targeted drug therapy, relieve patients’ symptoms, improve patients’ quality of life, and possibly prolong survival time, and can be used as one of the means of renal cell carcinoma treatment It can be applied alone or in combination with other antitumor drugs.

  There are few modern traditional Chinese medicines approved by the Chinese drug regulatory authorities for the treatment of renal cell carcinoma, and the indications for treatment are mostly for a variety of tumors, including renal cell carcinoma, but these drugs have been on the market for many years, and early experimental and clinical studies are weak. The early experimental and clinical studies are weak and lack sufficient high-level evidence-based support, and require active and in-depth research.

  In addition to these marketed proprietary Chinese medicines, the use of Chinese herbal compound therapy in accordance with the principles of dialectical treatment in Chinese medicine is one of the most common approaches in Chinese medicine, which can be individualized according to the differences of patients and has certain advantages; it can reduce tumor-related complications, improve patients’ quality of life and prolong their survival. It has certain efficacy in reducing tumor-related complications, improving patients’ quality of life, and prolonging their survival.

  (vi) Radiotherapy.

  Renal cell carcinoma is a tumor that is not sensitive to conventional radiotherapy, and previous clinical studies of postoperative radiotherapy for high-risk renal cell carcinoma have shown no survival benefit with adjuvant radiotherapy, so adjuvant radiotherapy after radical surgery is not recommended.

  Radiotherapy is mainly used for palliative treatment of renal cell carcinoma, such as palliative radiotherapy for patients with local recurrence of tumor bed, regional or distant lymph node metastasis, bone, brain or lung metastasis, to relieve pain and improve survival quality.

  Radiotherapy has evolved rapidly in the last decade or so, and in a number of retrospective and clinical

  Stage I or II studies should be treated with stereotactic radiotherapy

  Stereotactic body radiation therapy (SBRT, a split irradiation pattern with one or more single high-dose irradiations) techniques are gradually being used to treat renal cell carcinoma. Retrospective analyses have shown that SBRT can achieve better treatment outcomes than conventional radiotherapy. In several retrospective and clinical phase I or II studies, SBRT has achieved good near-term local control rates and has a good treatment safety profile. In the last two years, several studies of SBRT combined with immune checkpoint inhibitors for advanced renal cell carcinoma have shown high efficiency and local control rates, but the number of reported cases is small and long-term follow-up results are lacking. There are no randomized subgroup studies demonstrating the efficacy of SBRT over conventional fractionated radiotherapy or other local therapies. Therefore, SBRT should only be used as an alternative palliative treatment for renal cell carcinoma in medical centers with technical support for precision radiotherapy and physicians and physiatrists with extensive radiotherapy experience, or in related clinical studies.

  (vii) Common adverse reactions to targeted drugs and their management.

  style=”margin-left: 83pt”>
  • Hypertension
    

  is one of the most common toxic reactions to targeted drug therapy and is common to the VEGR/VEGFR inhibitor class of drugs (Table 9). The incidence of hypertension associated with VEGFR tyrosine kinase inhibitor drug class therapy has been reported in the literature to be 24 to 40, with 8~16 of patients with grade III or higher hypertension. The incidence reported in China is similar to that abroad, with an incidence of all grades of hypertension ranging from 15 to 37 < img src="https://www.kiraspecialist.com/wp-content/uploads/2022/06/062222_1307_202265.png" alt=""/>. Baseline blood pressure should be assessed before starting targeted therapy, and for patients with pre-existing hypertension the target blood pressure should be controlled below 140/90 mmHg during treatment. When hypertension reaches grade II or higher or grade I with symptoms, it must be controlled with medication. The best choice of antihypertensive medication is blood

  Tubulin-converting enzyme inhibitors. Avoid calcium antagonists that inhibit CYP3A4 to avoid drug-drug interactions, and consider adjusting the drug dose if concomitant administration with drugs affecting CYP3A4 is required. During the interval between treatments, suspend or reduce the dose of antihypertensive drugs and monitor blood pressure closely.

  

  Table 9 Grading of hypertension associated with targeted therapeutic agents for renal cell carcinoma
  

  Severity grading Clinical features
  

  
  

   

  Class I Prehypertension (systolic blood pressure 120-139 mmHg, or diastolic blood pressure 80-89 mmHg.
  

   

  Stage I hypertension (systolic blood pressure 140 to 159 mmHg, or diastolic blood pressure 90 to
  

   

  Class II 99mmHg); requires medical intervention; recurrent or persistent (>24 hours) hypertension with symptomatic diastolic elevation >20mmHg, or blood pressure >140/ 90mmHg
  

  (in those with previously normal blood pressure); requires monotherapy.
  

   

  Class III Stage II hypertension (systolic blood pressure ≥ 160 mmHg, diastolic blood pressure ≥ 100 mmHg), requiring medical intervention and multiple medications.
  

  Grade IV Life-threatening (e.g., hypertensive crisis), requiring urgent treatment.
  

   

  < span style="font-size:12pt">V Level Death.
  

   

  Note: The grading scale uses the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE 4.0); 1 mmHg = 0.133 kPa .
  

   

  style=”margin-left: 83pt”>
  • Hematologic toxicity
    

  The common hematologic toxicities associated with targeted therapy for advanced renal cell carcinoma are neutropenia, thrombocytopenia, and anemia (Table 10). The incidence of hematologic toxicity due to sunitinib is high and is the main reason for dose reduction or discontinuation in Chinese patients. Routine blood monitoring and attention to signs of infection are required before and during treatment.

  If neutropenia is ≥ grade I, leukocyte-raising drugs should be given until they rise to normal levels. For thrombocytopenia, routine platelet-raising therapy can be given. Patients with dizziness, blurred vision, shortness of breath or other symptoms of anemia should be taken seriously and given vitamin B12 and iron if necessary. Targeted drug doses should be reduced in cases of grade I or higher hematologic toxicity. Grade III/IV hematologic toxicity should be discontinued until the hematologic toxicity is reduced to baseline levels before restarting therapy. If the patient recovers rapidly from grade III/IV hematologic toxicity during conventional therapy, no dose adjustment is necessary, but close monitoring is required and dosing regimen adjustments may be considered.

   

  

  Table 10 Grading of hematologic toxicity of targeted therapies for renal cell carcinoma
  

   

  style=”border-bottom: solid black 0.5pt”>

  Anemia

  < /tr>

  Anemia

  < /tr>

  Severity grading	Neutrophil count reduction	Reduced platelet count
  Class I	1.5×109/L to lower limit of normal	75×109/L to lower limit of normal	Hemoglobin 100g/L
  				to the lower limit of normal
  Class II	1.0×109 to 1.5×109/L	50×109 to 75×109/L	Blood Red Egg White 80 to
  						100g/L
  Class III	0.5×109 to 1.0×109/L	25×109～50×109/L	Hemoglobin<80 g/L
  Class IV	<0.5 ×109/L	<25×109/L	Life-threatening and requires urgent
  <			Emergency treatment

   

  < span style="font-size:10pt">V – – Death
  

   

   

  style=”margin-left: 83pt”>
  • Hand-foot syndrome and skin toxicity
    

  Hand-foot syndrome (HFS) usually presents as a bilateral palmoplantar rash with pain and dullness of sensation, with a tendency for mechanical pulling on the area.

  There is hyperkeratosis, erythema, and desquamation (Table 11). The literature reports a high incidence of Sorafenib-induced HFS, with an incidence of 51.0 for all grades of HFS, with an incidence of 16.1 for grade ≥III HFS. Cutaneous reactions in the hands and feet are more common in Chinese patients, with the literature reporting an incidence of 55 for all levels of HFS > to 68 . Clinical manifestations of skin toxicity are dry skin, rash, pruritus, blistering, molting, localized thickening of skin keratin, or seborrheic dermatitis with skin sagging. It usually appeared 3 to 8 weeks after the start of treatment. In targeted therapy, the incidence of all graded rashes was 13 to 37 and 0.1 for grade III or higher ~4.0 Examine the palms and soles of the feet prior to treatment to exclude pre-existing areas of skin keratinization. Intervene immediately when symptoms appear with an ointment or lotion containing a 10urea component; if hyperkeratosis occurs, then use an oil or lotion containing

  35 to 40 Urea for exfoliation treatment. For grade II or higher, use an ointment containing 0.05 clobetasol; for pain, use a topical analgesic such as 2 clobetasol. Topical analgesics such as 2lidocaine may be used if pain is present. If severe symptoms occur, a dermatologic consultation is recommended. When grade II or higher HFS occurs, consider interrupting dosing until symptom severity resolves to less than grade I. Reduce or restart treatment at the same dose.

  

  Table 11 Grading of hand-foot syndrome and skin toxicity with targeted therapy for renal cell carcinoma
  

  Severity grading Hand-foot syndrome Skin rash
  

  
  

   

  Grade I Painless mild skin changes or skin inflammation (e.g., erythema, edema, hyperkeratosis)
  

  Patchy rash, papules or erythema without other symptoms
  

  Grade II Painful skin changes (e.g., flaking, blistering, bleeding, macules, papules, or erythema, without
  

   

  edema, hyperkeratosis) that interfere with activities of daily living
  

  With other symptoms, localized flaking and skin lesions involving<50 body surface area
  

  Grade III Severe skin changes (exfoliation, blistering, bleeding, edema, hyperkeratosis) with pain, affecting personal activities of daily living.
  

  Generalized red rash, macules, papules or herpes, desquamation and lesions involving>50 body surface area
  

  Grade IV – generalized exfoliative, ulcerative
  

   

  or blistering dermatitis
  

   

  < span style="font-size:12pt">Class V – Death
  

   

  Note: The hand-foot syndrome grading scale uses the National Cancer Institute Common Terminology Criteria for Adverse Events
  

   

  (NCI-CTCAE 4.0), and the rash grading criteria use NCI-CTCAE 3.0.
  

   

   

  style=”margin-left: 83pt”>
  • Gastrointestinal Adverse Reactions
    

  Diarrhea, nausea, and vomiting (Table 12) are common. Mild diarrhea can be treated with electrolyte replacement, and severe diarrhea should be treated with intravenous fluids and electrolyte replacement, along with loperamide and difenoxycarb. Proton pump inhibitors or H2 receptor antagonists may be beneficial in preventing dyspepsia with symptoms similar to nausea, but should be avoided while patients are on axitinib. Antiemetic treatment with a dopamine antagonist such as metoclopramide or alizapride is recommended. Gastrointestinal adverse reactions and dietary habits

  related to which patients are advised to eat small, frequent meals, ensure adequate fluid intake, eat a light diet, avoid spices, avoid laxatives, and avoid hyperosmolar food Additives. For grade I and II gastrointestinal adverse reactions there is usually no need to adjust the dose of the target drug; in the presence of grade III and IV adverse reactions, the dose should be reduced or discontinued.

  

  Table 12 Grading of gastrointestinal adverse reactions to targeted therapy for renal cell carcinoma
  

   

  >

  < td>

  Mouth exclusion increases heavily, affecting

  Severity grading	Diarrhea	Nausea	vomiting
  Class I	Increase in stool frequency from baseline<4 times	Decreased appetite, eating habits	Onset within 24 hours
  	/day, compared to baseline, fistula	no change in inertia.	1 to 2 times at intervals
  	Mild increase in exclusions.		5min.
  Class II	Increase in stool frequency from baseline 4 to 6	Decreased oral intake, body	Onset within 24 hours
  	times/day, intravenous rehydration less than 24	weight without significant decrease, decompensation	style=”margin-left: 5pt”>3 to 5 times at 5
  	hours to fistula	water or malnutrition.	min.
  	Moderate increase in oral exclusion.
  Class III	Increase in stool frequency by 7 stools/	from baseline left: 2pt”>Ability to ingest orally and	Ability to ingest orally and	24 hours to issue
  	“font-family:Arial; font-size:12pt”>day, bowel incontinence, required hospitalization	Inadequate hydration, requiring nasal	action>6 times at 5
  	treatment. Compared to baseline, fistula	feeding, total parenteral nutrition or	feeding, total parenteral nutrition or	minutes, requiring nasal
  	persons were admitted to the hospital.	Feeding, total parenteral nutrition
  	Patients’ personal activities of daily living.		or hospital admission.
  Grade IV	Life-threatening, requiring urgent treatment.	–	Life-threatening, requiring
  			< /td>	Emergency treatment.
  V class	Death	–	Death

  Note: The grading scale uses the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE 4.0).
  

  style=”margin-left: 83pt”>
  • Hypothyroidism
    

  There are 12 patients with advanced renal cell carcinoma treated with VEGFR inhibitors~

  19There were varying degrees of hypothyroidism (Table 13), and the incidence increased progressively with the duration of treatment. The results of the domestic study showed a slightly higher incidence of hypothyroidism than in the Western population, ranging from 14.0 to 24.9 . ～to 24.9 . Transient hyperthyroidism may occur in some patients, usually without intervention, and most will progress to hypothyroidism on subsequent treatment. The classification of hypothyroidism for targeted therapy in renal cell carcinoma is shown in Table 5. thyroid function tests are performed at the beginning of treatment and thyroxine and thyroid stimulating hormone (TSH) are monitored closely during targeted therapy. Patients with mildly elevated TSH without symptoms need only continued monitoring, while patients with TSH>10 mU/L or clinical signs of hypothyroidism require thyroid hormone replacement therapy. In most cases, thyroid hormone replacement therapy is effective in controlling symptoms and does not require suspension of targeted drug therapy or dose adjustment.

  

  Table 13 Grading of hypothyroidism for targeted therapy in renal cell carcinoma
  

  Severity grading Clinical features
  

  
  

   

  Class I Asymptomatic, seen only on clinical examination or diagnosis, no treatment needed.
  

   

  Grade II Symptomatic; interferes with activities of daily living; thyroid hormone replacement therapy. Grade III Severe; interferes with activities of daily living; requires hospitalization.
  

  Grade IV Life-threatening, requiring urgent treatment.
  

   

  < span style="font-size:12pt">V Death
  

   

  Note: Grading criteria are based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE 4.0).
  

   

   

  style=”margin-left: 83pt”>
  • Hepatotoxicity
    

  Liver function should be closely monitored during treatment with pegaptanib. For patients with hepatic impairment, hepatoprotective drugs are recommended, and for patients at risk of liver damage, aggressive treatment for primary liver disease is required before starting targeted therapy

  (e.g., hepatitis B, cirrhosis, etc.). If a rise in ALT above 8 times the upper limit of normal occurs during treatment, the drug should be discontinued promptly and resumed until it returns to baseline levels; if a rise in ALT above 3 times the upper limit of normal occurs again after resumption of treatment, the drug should be permanently discontinued; if complicated by a rise in ALT above 3 times the upper limit of normal, the drug should be discontinued.

  Rises in transaminases above 3 times the upper limit of normal and in bilirubin above 2 times the upper limit of normal should be discontinued permanently.

  style=”margin-left: 83pt”>
  • Interstitial lung disease
    

  Interstitial lung disease (ILD) is a group of diffuse lung diseases that primarily involve the interstitial lung, alveoli, or fine bronchi, with a high incidence of second-line drug mTOR inhibitor therapy at 19.8. The use of

  mTOR inhibitors should be used with particular attention to co-morbid ILD and infection during mTOR inhibitor therapy and should be used with caution in cases of multiple metastases in both lungs, poor lung function, patients with obstructive pneumonia or other active infections. Prior to initiating therapy, patients with advanced renal cell carcinoma with respiratory symptoms should be evaluated, and lung imaging and lung function should be monitored regularly. In milder ILD, no action is required and close monitoring is sufficient. In severe ILD, targeted drug therapy should be discontinued and shock therapy with a hormone (eg, methylprednisolone).

  style=”margin-left: 83pt”>
  • Cardiac toxicity
    

  VEGFR inhibitor-induced cardiac adverse events with an incidence of 2~10 , as evidenced by decreased left ventricular ejection fraction (1eft ventricular ejection fraction (LVEF)) and myocardial ischemia. In patients without cardiac risk factors, baseline LVEF testing should be considered. Patients with cardiac risk factors or recent cardiovascular adverse events should be closely monitored for vital signs and LVEF. target therapy should be suspended if congestive heart failure occurs; if symptomatic congestive heart failure does not occur, but LVEF<50, or a decrease in LVEF of 20, the targeted drug dose should be reduced or treatment suspended. Patients with a previous history of long Q-T intervals, antiarrhythmic drugs, bradycardia, and electrolyte abnormalities should have regular electrocardiograms and blood potassium and magnesium tests.

  (H) Treatment of limited renal cell carcinoma.

  Limited renal cell carcinoma refers to renal cell carcinoma with tumor confined to the peritoneum of the kidney, including TNM stage T1 to 2N0M0 and clinical stage I and II. With the improvement of imaging technology and the popularity of health checkups, the proportion of confined renal cell carcinoma has exceeded 50 . A growing number of studies have shown that in most stage T1, some stage T2, and even some stage T3a renal cell carcinomas, partial nephrectomy is associated with

  RN has similar oncologic outcomes and better renal function protection.

  NSS is recommended for patients with stage T1a renal cell carcinoma when technology allows, and RN is feasible for those with complex anatomy that makes partial nephrectomy difficult and normal contralateral renal function. For patients with stage T1a tumor who cannot accept or tolerate surgery, ablation therapy can be chosen, and active surveillance can be recommended for those with high-risk factors and poor life expectancy; for patients with stage T1b renal cell carcinoma, NSS or RN is recommended. individual differences, etc. NSS can also be chosen for some appropriate patients with stage T2 renal cell carcinoma who otherwise receive RN.

  Postoperative adjuvant therapy: Adjuvant radiotherapy, chemotherapy, immunotherapy, and targeted therapy after surgery for limited renal cell carcinoma do not reduce tumor recurrence and metastasis rates. Therefore, patients with stage T1 to 2N0M0 renal cell carcinoma should be observed postoperatively on a follow-up basis and may participate in clinical trials without the routine use of adjuvant therapy.

  (ix) Treatment of locally progressive renal cell carcinoma.

  Locally progressive renal cell carcinoma is defined as renal cell carcinoma that breaks through the renal tegument and involves the perinephric fat or sinus fat but remains confined to the renal fascia, may be associated with regional lymph node metastasis or/and venous tumor emboli, and has no distant metastasis, including TNM staging of T1 to The clinical stage of renal cell carcinoma is stage III, including TNM stage T1~2N1M0/T3N0~1M0. RN is preferred for locally progressive renal cell carcinoma, and partial nephrectomy is only technically

  Patients in whom partial nephrectomy is technically feasible and clinically indicated. Several retrospective or prospective phase II studies have shown that preoperative neoadjuvant targeted therapy for stage T2 to T3 renal cell carcinoma has a

  has some shrinking effect and can be tried in cT3 stage tumors that are difficult to resect locally, but there is a lack of high-level studies to confirm this. In recent years, neoadjuvant therapy studies with immune checkpoint inhibitors as single agents or in combination regimens have become widely available.

  The choice of whether to remove regional lymph nodes or angiosarcoma plugs is based on the extent of the lesion and the patient’s medical condition. In patients with locally progressive renal cell carcinoma, regional or expanded lymph node dissection is only meaningful for determining the stage of the tumor (cN0) and does not improve patient survival. In contrast, lymph node dissection is feasible for patients with positive lymph nodes (cN+), but lymph node dissection is only beneficial for some patients and the extent of dissection is still controversial. (2) Surgical treatment of renal vein or/and vena cava thrombosis: For patients with renal cell carcinoma combined with venous thrombosis without distant metastasis, surgical resection of the affected kidney and thrombosis should be pursued if technically feasible. The length of the renal cell carcinoma venous thrombus and whether the thrombus infiltrates the vena cava wall are closely related to the patient’s prognosis. (3) The affected adrenal gland should be resected together for patients with preoperative imaging or intraoperative exploration for adrenal tumors.

  Adjuvant therapy after surgery for locally progressive renal cell carcinoma: There is no standard adjuvant therapy regimen for locally progressive renal cell carcinoma after surgery, and enrollment in clinical trials is recommended first, otherwise observation follow-up is given. In patients with limited high-risk clear cell renal cell carcinoma, a randomized, double-blind, placebo-controlled phase III clinical study (S-TRAC trial) enrolled 615 high-risk clear cell renal cell carcinomas (stage III-IV and/or regional lymph node metastases) on sunitinib (50 mg/d, 4/2 regimen) or placebo for 1 year. Compared with placebo, adjuvant sunitinib prolonged disease-free survival in patients with limited high-risk renal clear cell carcinoma after surgery (6.8 years vs.

  style=”margin-left: 63pt”>
  • years, HR 0.76, P=0.03), but failed to improve overall survival. However, it failed to improve overall survival, while patients with
    

  Patients need to bear clear drug-related side effects and economic burden. Therefore, at this stage only for patients with renal clear cell carcinoma at high risk of recurrence, postoperative adjuvant maintenance of adequate (full dose), adequate (reduced dose interruption), and prolonged (at least 1 year) targeted sunitinib therapy may be an option, with full knowledge of the risks and possible benefits associated with adjuvant therapy. The Chinese Expert Consensus (2020) on adjuvant therapy after surgery for high-risk non-metastatic renal cell carcinoma states that the available evidence-based medical evidence does not support adjuvant cytokine therapy after surgery for renal cell carcinoma. Clinical trials of adjuvant immunotherapy with immune checkpoint inhibitors and immune combination targeting after surgery for high-risk non-metastatic renal cell carcinoma are ongoing and results are promising.

  (J) Treatment of advanced/metastatic renal cell carcinoma.

  Advanced/metastatic renal cell carcinoma refers to renal cell carcinoma that has broken through the renal fascia with extra-regional lymph node metastases or distant metastases, including TNM stage T4N0 to 1M0/T1 to 4N0 to 1M1, and clinical stage IV.

  Systemic drug therapy is the mainstay, supplemented by palliative surgery or radiotherapy for the primary or metastatic foci. The treatment of metastatic renal cell carcinoma requires comprehensive consideration of the primary and metastatic foci, tumor risk factor scores, and the patient’s physical status score to select an appropriate comprehensive treatment plan.

  style=”margin-left: 83pt”>
  • Surgical treatment
    

  Surgery as an adjuvant treatment for metastatic renal cell carcinoma, including reduction surgery of the primary site and palliative resection of the metastases, is usually required in addition to systemic systemic therapy to improve clinical symptoms and survival. Longer-term survival can be achieved with surgery in highly selected patients.

  style=”margin-left: 107pt”>
  • Surgical treatment of renal primary lesions: surgical reduction should be performed in the context of effective
    

  based on systemic therapy. Retrospective studies have shown that subtractive nephrectomy and metastasectomy may still provide a survival benefit in the era of targeted therapy for renal cell carcinoma. The current implementation of subtractive nephrectomy is more appropriate for patients with good general condition (ECOG score) and for patients with metastases.

  Attractive nephrectomy is usually not recommended before systemic therapy for patients with metastatic renal cell carcinoma with no or mild associated symptoms, low metastatic load, and moderate risk factors for significant reduction in tumor load with surgery. In addition, palliative nephrectomy or renal artery embolization is feasible for patients with severe hematuria or pain from renal tumors to relieve symptoms and improve quality of life.

  • Surgical treatment of metastases: For isolated metastases, metastases can be surgically removed if the patient’s behavioral status is good. Lung is the most common site of metastasis for renal cell carcinoma. Single lung metastasis or metastases located in one lobe of lung, surgical resection may help prolong the survival time of patients. Bone is also a common site of metastasis for renal cell carcinoma, and surgery may be used to remove metastases, or to prevent and treat bone-related events. Patients with resected or resectable primary lesions and only a single bone metastasis should undergo aggressive surgical treatment. Surgical treatment is preferred in patients with weight-bearing bone with risk of fracture, and prophylactic internal fixation should be performed to avoid bone-related events. Patients who have developed pathologic fractures or signs of compression of the spinal cord and who are expected to survive
    

    >3 months, are in good physical condition, and surgery improves quality of life, surgery should also be performed. Metastasectomy should be performed on the basis of effective systemic therapy, with favorable factors including nephrectomy until metastases are found ≥1 year, solitary metastases, complete resection of metastases, pulmonary metastases alone, and age ≤60 years.

    style=”margin-left: 48pt”>
    • Systemic therapy
      
      • Clinical trials: recommended to participate in clinical trials remains advanced renal cell carcinoma
        

  for patients with advanced renal cell carcinoma.

  style=”margin-left: 67pt”>
  • Systematic therapy for clear cell predominant renal cell carcinoma: see Table 14. 1) First-line therapy for clear cell predominant renal cell carcinoma.
    

  1) Pabrolizumab in combination with axitinib: Pabrolizumab is a monoclonal antibody that binds to programmed death protein-1 (PD-1). Axitinib is a next-generation receptor multi-targeted tyrosine kinase inhibitor of VEGFR1 to 3. The randomized, controlled phase III study KEYNOTE426 evaluated the efficacy and safety of pablizumab in combination with axitinib compared to sunitinib in the first-line treatment of metastatic renal clear cell carcinoma. Eighty-one patients were enrolled and randomized to pablizumab.

  Bolizumab (200 mg intravenously once every 3 weeks) in combination with axitinib (5 mg orally twice daily) (432 patients) and sunitinib (50 mg orally once daily for 4 weeks/ 2 weeks off) (429 patients). Pabrolizumab combined with axitinib significantly improved the overall survival time of patients compared with sunitinib (HR=0.53, 95
  CI 0.38 to 0.74, P < 0.0001), median progression-free survival time (15.1 vs. 11.1 months, HR = 0.69, 95
  CI 0.57 to 0.84, P=0.0001) and objective remission rate (59.3% vs. 35.7%, P<0.0001). Good efficacy was observed with pabrolizumab in combination with axitinib in all subgroups, including the IMDC risk group and the programmed death ligand-1

  (programmed death ligand-1, PD-L1)-expressing subgroups. The incidence of treatment-related grade 3 to 5 adverse events was 62.9% in the pablizumab combined with axitinib group and 58.1% in the sunitinib group.

  ②Pabrolizumab combined with lenvatinib: Lenvatinib is a receptor tyrosine kinase inhibitor that inhibits VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3

  (FLT4), fibroblast growth factor receptor (FGFR) 1-4, platelet derived growth factor receptor (PDGFR) α, KIT and RET, which are kinases involved in pathological angiogenesis, tumor growth and progression in addition to normal cellular functions.

  The randomized, controlled, phase III clinical study KEYNOTE581/CLEAR (Study 307) included 1069 patients with untreated advanced renal clear cell carcinoma on a 1:1 basis.

  1:1 ratio randomized to receive lenvatinib (20 mg orally, once daily)

  +pabrolizumab (200 mg intravenously once every 3 weeks) or lenvatinib

  Nib (18 mg orally once daily) + everolimus (5 mg orally once daily)

  style=”margin-left: 47pt”>
  • times) or sunitinib (50mg orally once daily for 4 weeks/stop)
    
  • week). The results showed that the lenvatinib combined with pabrolizumab group significantly prolonged median progression-free survival compared with the sunitinib group (23.9 vs. 9.2 months, HR=0.39, 95
    CI 0.32 to 0.49, P<0.001); regardless of patient PD-L1
    

    expression level, IMDC risk stratification, lenvatinib in combination with pabrolizumab resulted in a significant progression-free survival time benefit. Median overall survival time was not achieved in either group, but prolonged overall survival time in the lenvatinib combined with pabrolizumab group compared with the sunitinib group (HR=0.66, 95
    CI 0.49 to 0.88, P=0.005). There was a higher objective remission rate in the lenvatinib combined with pabrolizumab group (71.0 < span style="font-family:Times New Roman">
    vs.

    36.1 ) and higher rates of complete remission (16.1
    vs. 4.2). The ≥3 grade treatment-related adverse reactions were 71.6 and 58.8 respectively “https://www.kiraspecialist.com/wp-content/uploads/2022/06/062222_1307_2022115.png” alt=””/>.

    ③Navulizumab in combination with cabozantinib: Navulizumab is an anti-PD-1 monoclonal antibody. Cabozantinib is a target for VEGFR, MET, AXL, etc.

  Oral small molecule kinase inhibitors at the VEGFR, MET, and AXL targets. The randomized, open, phase III clinical study Checkmate 9ER evaluated the efficacy and safety of nabritumomab in combination with cabozantinib compared with sunitinib in the first-line treatment of metastatic renal clear cell carcinoma. Sixty-five1 patients were enrolled and randomized to nabritumomab (240 mg, intravenous drip, per

  1 time every 2 weeks) combined with cabozantinib (40 mg orally once daily) group (323

  cases) and sunitinib (50 mg orally once daily for 4 weeks/ 2 weeks off) groups (328 cases). Navritumomab combined with cabozantinib significantly improved the median progression-free survival time of patients compared with sunitinib (17.0 vs. 8.3 months, HR=0.52, 95
  CI 0.43 to 0.64, P < 0.0001), median overall survival time (NR vs. 29.5, HR = 0.66, 95
  CI 0.50 to 0.87, P=0.0034) and objective remission rate (54.8
  vs. 28.4).

  ④Navulizumab in combination with Epilimumab: Epilimumab is a human blocking antibody to Cytotoxic T lymphocyte antigen 4 (CTLA-4). The CheckMate214 study is a multicenter randomized controlled phase III clinical study evaluating nabritumomab in combination with epirimumab versus sunitinib in the first-line treatment of advanced/metastatic intermediate-to-high-risk renal cell carcinoma (1082 cases). The results showed that in the first-line treatment of intermediate-risk advanced renal cell carcinoma in IMDC, the combination therapy group was associated with a higher objective remission rate than the sunitinib group.

  (42
  vs.27 , P<0.001) and median overall survival There were significant benefits in terms of time (not reached vs. 26 months, P<0.001). Based on the results of this study, in April 2018 the US Food and Drug Administration approved nabritumomab in combination with epirimizumab as standard first-line therapy for high-risk advanced renal cell carcinoma in IMDC.

  5 Pezopanib: Pezopanib is a therapy that inhibits VEGFR1, VEGFR2, and

  VEGFR3, PDGFR, FGFR1, FGFR3, KIT, interleukin-2 receptors induce T-cell kinase, leukocyte specific protein tyrosine kinases, and multi-tyrosine kinase inhibitors of membrane-penetrating glycoprotein receptor tyrosine kinases.

  The clinical data for pegaptanib in metastatic renal cell carcinoma from its international multicenter phase III clinical study showed a median progression-free survival of 11.1 months and an objective remission rate of 30%, significantly better than the placebo control group. The ultimate survival analysis showed a median overall survival time of 22.6 months. Another international multicenter phase III clinical study of pegaptanib versus sunitinib for the first-line treatment of metastatic renal cell carcinoma (COMPARZ study), in which several centers in China participated, independently evaluated the median progression-free survival of pegaptanib and sunitinib at 8.4 versus 9.5 months, respectively, with statistically non-inferiority, and secondary study endpoints: objective remission rates of 31% versus 25%, and median overall survival of 22.6 months. The objective remission rates were 31% versus 25%, median survival times were 28.4 versus 29.3 months, and quality of life scores were better for pegaptanib than sunitinib. A total of 367 Asian patients, including Chinese subjects, were included in the study, and subgroup analysis showed that Asian patients with pegaptanib

  The median progression-free survival time in the treatment group was 8.4 months, which was not significantly different from the European and American populations.

  Recommended dose of pegaptanib: 800 mg orally once daily, without food (at least 1 hour before or 2 hours after a meal). Dose adjustment: 200 mg orally once daily at baseline in moderate hepatic impairment. Not recommended for patients with severe liver injury.

  6) Sunitinib: Sunitinib is a multi-target receptor tyrosine kinase inhibitor with VEGFR1-2, PDGFRα, PDGFRβ, and c-KIT as the primary targets.

  and FMS-like tyrosine kinase 3 (FLT3), which has anti-tumor angiogenic and inhibitory effects on tumor cell proliferation.
  The study enrolled 750 patients, 90 of whom were at low to moderate risk for MSKCC, with median progression-free survival times of 11 months and 5 months (HR 0.42.

  95
  CI 0.32 to 0.54, P<0.001), with objective remission rates of 31and

  6(P<0.001), with median survival times of 26.4 months and 21.8 months, respectively

  (P=0.051). This establishes sunitinib as a first-line treatment for renal clear cell carcinoma. Results from a multicenter phase IV clinical study of sunitinib in first-line treatment of Chinese patients with metastatic renal cell carcinoma showed an objective efficiency of 31.1%, with a median progression-free survival time of 14.2 months and a median overall survival time of 30.7 months.

  Based on these clinical data, sunitinib is recommended for the first-line treatment of advanced clear cell renal cell carcinoma, administered as 50 mg orally once daily in a 4/2 regimen (4 weeks on, 2 weeks off). Considering the high incidence of hematologic adverse reactions with the 4/2 dosing regimen of sunitinib, the 2/1 regimen (2 weeks of dosing and 1 week off) could be chosen with improved tolerability and unaffected efficacy.

  (7) Axitinib: In 2013, the Lancet reported a randomized controlled phase III clinical study of 288 patients enrolled 2:1 in first-line treatment of advanced renal clear cell carcinoma with a median progression-free survival time of 10.1 and 6.5 months, respectively, with axitinib versus sorafenib. 10.1 and 6.5 months (HR 0.77, 95
  CI 0.56 to 1.05). Despite a 3.6-month extension in progression-free survival, which was not statistically significantly different due to the small number of cases enrolled, it still demonstrated the effectiveness of axitinib for first-line treatment of renal clear cell carcinoma

  . Based on clinical study data, axitinib is recommended as first-line therapy for patients with advanced renal clear cell carcinoma at 5 mg twice daily.

  8 Cabozantinib: A phase II multicenter randomized study (CABOSUN) compared the efficacy of first-line cabozantinib with sunitinib in patients with intermediate-risk or high-risk (Heng score) renal clear cell carcinoma.157 Patients were randomized in a 1:1 ratio to receive first-line cabozantinib (60 mg once daily) or sunitinib. The results showed that progression-free survival was significantly better in the cabozantinib group than in the sunitinib-treated group, with median progression-free survival of 8.2 versus 5.6 months (P = 0.012), objective remission rates of 46% and 18%, and overall survival of 30.3 versus 21.8 months, respectively.

  Based on data from foreign clinical studies, cabozantinib is recommended as first-line therapy for patients with intermediate-to-high-risk advanced renal clear cell carcinoma at 60 mg once daily.

  Texilomox: Texilomox is an mTOR inhibitor that, in addition to its antitumor effects through inhibition of mTOR signaling, also inhibits angiogenesis, primarily by inhibiting transcription of the hypoxia-inducible factor HIF-1 and reducing the effect on vascular-associated In addition to the anti-tumor effects of mTOR signaling, the inhibitor also has an angiogenic effect, mainly by inhibiting transcription of the hypoxia-inducible factor HIF-1 and reducing stimulation of vascular-related growth factors such as VEGF/PDGF/transforming growth factor, thereby inhibiting tumor angiogenesis.

  Phase III clinical data from the international multicenter randomized controlled phase III clinical study (ARCC study) in patients with a high-risk prognosis score showed that the median overall survival time for tesilomomox monotherapy was 10.5 years. The median overall survival time was 10.9 months and the median progression-free survival time was 5.5 months, which was significantly better than the IFN-α treatment group. A tesylomorphic treatment

  A non-randomized, single-arm, open phase II clinical study in an Asian population enrolling 82 patients with metastatic renal cell carcinoma in China, Japan, and Korea showed The clinical benefit rate was 48%, the objective efficiency rate was 11%, and the median progression-free survival time was

  7.3 months.

  Texilimox is not approved for marketing in China, but based on these clinical data, it is recommended for first-line treatment of patients with advanced clear cell renal cell carcinoma at a high risk of 25 mg once weekly.

  Cytokine therapy: Cytokine therapy has focused on earlier studies, mainly IFN-α and interleukin-2. 2002 JCO reported a retrospective analysis of 463 patients with advanced renal cell carcinoma treated with IFN-α, with a median survival time of 13 days. Survival time 13

  The median time to progression was 4.7 months, with a median survival time of 5, 14, and 30 months for high-, intermediate-, and low-risk patients, respectively. In a retrospective analysis of 173 patients with metastatic renal cell carcinoma treated with interleukin-2-based therapy, the median survival time was 13 months, and the 1-, 3-, and 5-year survival rates were 92, 61 and 41 . Cytokines are not generally used as first-line treatment of choice at this time.

  In the context of our specific situation, it is believed that cytokine therapy can be recommended as an alternative treatment for patients with metastatic renal clear cell carcinoma who cannot receive targeted drug therapy, of which high-dose interleukin-2 can be used for the treatment of metastatic renal clear cell patients with a good general condition and normal cardiopulmonary function, with the usage of 18 million IU/d subcutaneously 5 days a week for 1 week, 9 million IU every 12 hours for days 1 to 2, and 9 million IU once a day for days 3 to 5 for 3 weeks, repeated after a 1-week break. However, with high-dose interleukin-2 therapy, the incidence of serious adverse reactions

  Highly monitored, IFN-α is administered as 9 million IU subcutaneously 3 times/week for 12 weeks.

  2) Follow-up treatment of clear cell-dominant renal cell carcinoma

  1) Axitinib: In 2011, the Lancet reported a randomized controlled phase III clinical study (AXIS study) of second-line treatment of advanced renal cell carcinoma that had failed first-line therapy (overwhelmingly cytokine or sunitinib), with a total of 723 patients

  Median progression-free survival was 6.7 and 4.7 months with 1:1 treatment with axitinib and sorafenib, respectively (HR 0.665, 95
  CI 0.544 to 0.812, P<0.0001), with an efficiency rate of 19 and 9 (P=0.0001), respectively.

  The median progression-free survival time for first-line cytokine therapy was 12.1

  months and 6.5 months (P<0.0001), respectively, and the median progression-free survival for first-line sunitinib

  survival was 4.8 months and 3.4 months, respectively (P=0.01), and median survival

  survival times were 20.1 months and 19.3 months, respectively. A registry clinical study of Asian patients with metastatic renal cell carcinoma treated with axitinib in second line, mostly in China, showed a median progression-free survival time of 6.5 months and an objective efficiency of 23.7% with axitinib. A subgroup analysis showed a median progression-free survival time of 4.7 months for second-line axitinib in patients previously treated with sunitinib. Based on these clinical trial results, axitinib is recommended as second-line therapy for metastatic renal cell carcinoma as axitinib 5 mg twice daily.

  ② Everolimus: Everolimus is an orally administered mTOR inhibitor, and clinical data on its use in metastatic renal cell carcinoma are mainly from an international multicenter randomized controlled phase III clinical study reported in the Lancet in 2008

  (RECORD-1 study). Patients with advanced renal cell carcinoma who progressed after treatment with sunitinib or sorafenib were treated with everolimus and placebo in a 2:1 ratio, respectively.

  The final statistical median progression-free survival time was 4.9 months and 1.9 months, respectively.

  (HR, 0.33; P <0.001), and patients in the placebo group progressed with 80 crossed over to the everolimus group, so there was no significant difference in median survival time between the two groups, which was 14.8

  months and 14.4 months, respectively. Common adverse effects of everolimus were gastritis, rash, and malaise. A multicenter registry clinical study of domestic patients treated with everolimus (study L2101) confirmed the efficacy and safety of everolimus as a second-line targeted therapy after failure of TKI therapy, with a disease control rate of 61%, median progression-free survival time of 6.9 months, clinical benefit rate of 66%, 1-year survival rate of 56%, and 1-year progression-free survival rate of 36%.

  Based on these clinical trial results, everolimus is recommended as a second-line treatment after failure of TKI therapy for metastatic renal cell carcinoma, specifically everolimus 10 mg once daily.

  ③Sorafenib: Sorafenib is the first multi-target receptor tyrosinase inhibitor marketed for metastatic renal cell carcinoma with dual anti-tumor effects: on the one hand, it inhibits the RAF/MEK/ERK signaling pathway, and on the other hand, it acts on the VEGFR, PDGFR, and other components of the metastatic renal cell carcinoma. The inhibitor has a dual anti-tumor effect: it inhibits tumor growth by inhibiting the RAF/MEK/ERK signaling pathway on the one hand and VEGFR, PDGFR, and targets such as c-KIT, FLT-3, and MET on the other.

  In 2009, the Journal of Clinical Oncology reported a phase II clinical study of sorafenib versus TNF-α 1:1 in the first-line treatment of metastatic renal clear cell carcinoma, enrolling 189 patients with sorafenib 400 mg twice daily and TNF-α In the phase II clinical study, 189 patients were enrolled with sorafenib 400 mg twice daily and TNF-α 9 million U 3 times a week, which could be increased to 600 mg twice daily after progression in the sorafenib group, and interference

  The sorafenib group can be crossed over to the sorafenib group after progression. The median progression-free survival times for sorafenib and TNF-α were 5.7 months and 5.6 months, respectively, and the two groups developed tumors

  shrinkage was 68.2and 39.0, the sorafenib group had better quality-of-life scores and was better tolerated. Due to the lack of validated large studies of sorafenib in first-line therapy and the increasing availability of alternatives, the NCCN guidelines do not currently recommend sorafenib for first-line treatment of renal clear cell carcinoma, but mainly for post-treatment. A national multicenter study of 845 patients with advanced renal cell carcinoma in the first line

  A retrospective analysis of survival and prognostic factors after treatment with sorafenib or sunitinib showed that the median progression-free survival time was 11.1 months and 10.0 months in the sorafenib and sunitinib groups, respectively (P = 0.028) There was no difference in median overall survival time between the two groups, both at 24 months. Because sorafenib is well tolerated and has shown high efficiency in Asian populations, sorafenib is still recommended as first-line treatment in some patients with renal cell carcinoma in China.

  In 2009, the Journal of Clinical Oncology reported a phase III randomized controlled clinical study of patients with advanced renal clear cell carcinoma who had failed first-line therapy (overwhelmingly cytokine), had at least 8 months of first-line therapy, and had an ECOG score of 0 to 1. 903 patients received sorafenib and placebo, respectively, with progression-free survival times of 5.5 and 2.8 months and median survival times of 17.8 and 14.3 months in the two groups (HR = 0.78, P = 0.029), respectively.

  4) Sunitinib: Second-line treatment with sunitinib in patients with metastatic renal cell carcinoma that progressed after cytokine therapy also showed some effectiveness. 2006 JCO reported a retrospective study of 63 patients with renal cell carcinoma that progressed after cytokine therapy.

  Patients with metastatic renal cell carcinoma treated with sunitinib in the second line had an efficacy of 40, with a median progression-free survival time of 8.7 months. Similarly, in 2006 JAMA reported a retrospective study of 106 patients with an effective rate of 34 with a median progression-free survival time of 8.3 months.

  5 Cabozantinib: Cabozantinib second-line treatment of advanced renal clear cell carcinoma has a significant survival advantage compared with everolimus, and in 2016 Lancet Oncol reported final results from the METEOR study for renal patients who received first-line VEGFR -TKI therapy, the median survival time was 21.4 months and 16.5 months for patients with renal clear cell carcinoma who progressed after 1:1 cabozantinib versus everolimus treatment (HR 0.66, 95
  CI 0.53 to 0.83, P=0.000 26), and again progression-free survival time was significantly improved, with efficiency rates of 17 and 3, respectively.

  Cabozantinib has not yet been approved for marketing in China, but based on the results of the foreign clinical trials described above, cabozantinib is recommended as a second-line treatment for metastatic renal cell carcinoma after failure of TKI therapy, as indicated by cabozantinib 60 mg once daily.

  Navulizumab: The 2015 CheckMate 025 study showed that in patients with renal clear cell carcinoma that had progressed after 1-2 treatments, median survival was 1:1 with navulizumab and everolimus. times were

  25.0 months and 19.6 months, respectively, with an efficiency of 25 and 5, with median progression-free survival times of 4.6 months and 4.4 months, respectively. 3/4 degree adverse events occurred at 19 and 37, respectively.

  (7) Lenvatinib + everolimus: In 2016 Lancet Onco reported the results of a phase II clinical study of lenvatinib in combination with everolimus for the second-line treatment of renal clear cell carcinoma, with 153 patients randomized to lenvatinib in combination with everolimus The results of the study showed that 153 patients were randomized to receive lenvatinib in combination with everolimus.

  The median progression-free survival time was 14.6 months in the combination group and 5.5 months in the everolimus group, and the median survival time was 5.6 months in the combination group and 5.5 months in the everolimus group, respectively.

  Survival time was 25.5 months and 15.4 months, respectively, and the median survival time in the lenvatinib monotherapy group was 25.5 months and 15.4 months, respectively.

  Survival time was 18.4 months.

  8 Pegaptanib: In the phase III trial of pegaptanib first-line therapy, 202 patients progressed after cytokine therapy, and the median progression-free survival times were 7.4 months and 4.2 months for pegaptanib versus placebo, respectively. Another phase II study of 56 patients showed that pegaptanib treatment was effective in patients who failed after treatment with sunitinib or bevacizumab 27, median progression-free survival time

  was 7.5 months, with a 2-year survival rate of 43.

  9Texilomox: The median progression-free survival time for texilomox as second-line therapy in patients with renal cell carcinoma who failed sunitinib was 4.28 months.

  Median survival time of 12.27 months.

  Xi tivozanib: Tivozanib is a tyrosine kinase inhibitor that inhibits phosphorylation of VEGFR1, VEGFR2, and VEGFR3, as well as other kinases, including c-KIT and PDGFRβ, and the growth of various tumor cells, including human renal cell carcinoma. For adult patients with recurrent or refractory advanced renal cell carcinoma after 2 or more prior systemic therapies. Recommended dose: 1.34 mg once daily on an empty stomach or with meals for 21 days with 7 days off (28-day cycle) until disease progression or unacceptable toxicity occurs. In patients with moderate hepatic insufficiency, the dose should be reduced to 0.89 mg after 21 days of treatment and then discontinued for 7 days (28-day cycle).

  Table 14 Drug treatment strategies for metastatic or unresectable clear cell renal cell carcinoma
  

  (recommended for preferred participation in clinical studies in any of the following situations)
  

  td>

  < td>

  >

  < td style="border-top: none"> 

  Cabotenib

  >

  Treatment Status	Layering	Class I Expert Recommendation	Class II Experts Recommended	Recommended by Level III experts
  First-line treatment	Medium-low risk	Pabrolizumab + Axitinib	Avelumab + axitinib	Axitinib
  <		Pabrolizumab + lenvatinib	Carbolitinib	high-dose interleukin-2
  			Navulizumab + Cabozantinib	Navulizumab + Cabozantinib	Navulizumab + Epirimumab
  			Pezopanib
  	Sunitinib
  	High Risk	Pabrolizumab + axitinib	Avelumab + axitinib	Axitinib
  <		Pabrolizumab + lenvatinib	pezopanib	high-dose interleukin-2
  			Navulizumab + Cabozantinib	Navulizumab + Cabozantinib	Sunitinib	Ticlosporinib Moose
  			Navulizumab + Ipilimumab
  		Cabotenib
  Backline Therapy		Axitinib	Bevacizumab
  	Navulizumab	Lenvatinib + everolimus	Lenvatinib + everolimus	Sorafenib
  			Navulizumab + Epilimumab	Pabrolizumab + Axitinib	High Dose Interleukin-2
  						Everolimus	Tesilimus
  					Pezzopanib
  					Sunitinib
  			Tivozanib
  				Avelumab + axitinib

   

  • Systematic treatment of non-clear cell type renal cell carcinoma: Patients with advanced non-clear cell carcinoma due to small sample size There is a lack of corresponding bulk randomized controlled clinical trials. Expanded clinical studies of sunitinib, sorafenib, and everolimus, as well as phase II studies in small samples, have shown that these targeted agents are effective in the treatment of non-clear cell renal cell carcinoma, but their efficacy is inferior to that of clear cell renal cell carcinoma (Table 15).
    

    Table 15 Drug treatment strategies for metastatic or unresectable non-clear cell renal cell carcinoma
    

    (recommended for preferred clinical study participation in any of the following conditions)
    

   

  < tr style="height: 80px">

  Treatment Status	Stratification	Class I expert recommendation	Class II Expert Recommendation	Recommended by Level III experts
  First-line treatment	Non-collective ductal carcinoma	Clinical studies	Sunitinib (Evidence 2A) Everolimus (Evidence 2A) Tesilimus (Evidence 2A) Cabozantinib (Evidence 2A) Cabozantinib (2A evidence)	Sorafenib pegaptanib axitinib
  	Collecting Ductal Carcinoma	Clinical studies	Clinical study	Gemcitabine + cisplatin   Sorafenib + Gemcitabine + Cisplatin

  >

   

   

   

  • Sunitinib: Studies in non-clear cell renal cell carcinoma are currently mostly phase II clinical studies, with one study involving 31 patients in non-clear cell renal cell carcinoma.
    

    The efficiency of sunitinib in clear cell carcinoma was 36, with a median progression-free survival time

    was 6.4 months; in another study including 53 patients, sunitinib/so

    Rafenib had an efficiency of 23, with a median progression-free survival time of 10.6 months. 108 patients with primary non-clear cell carcinoma in the ASPEN study were randomized to

    The median progression-free survival time for sunitinib and everolimus treatment was 8.3

  months and 5.6 months for the low- and intermediate-risk groups, respectively, and a median progression-free survival time of

  14.0 months versus 5.7 months and 6.5 months versus 4.9 months; everolimus had a slight, but not statistically significant, advantage in the high-risk group (4.0 months versus 6.1 months). In the ESPN study, 68 patients were randomized to receive sunitinib and everolimus

  In first-line treatment, the median progression-free survival time was 6.1 months for the two groups, respectively.

  months and 4.1 months (P=0.6), respectively, and median survival times of 16.2 months and

  14.9 months (P=0.18).

  • Axitinib: The efficacy and safety of axitinib in patients with non-clear cell renal cell carcinoma is unclear and studies are ongoing. 3) Sorafenib: A retrospective phase II clinical study showed that 53 patients with non-clear cell renal cell carcinoma were treated with sorafenib.
    

    Patients with clear cell renal cell carcinoma treated with sunitinib or sorafenib had a 10, with a median progression-free survival time of 8.6 months and a median survival time of 19.6 months.

  • Bevacizumab: A phase II clinical study showed that 41 patients with renal papillary carcinoma were treated with bevacizumab + erlotinib treatment, 19 of whom had received at least one systemic therapy, with an efficiency rate of 60 for hereditary smooth muscle disease and renal cell carcinoma, disseminated papillary carcinoma efficiency 29, median progression-free survival time minutes
    

    24.2 months and 7.4 months, respectively.

    Another phase II clinical study showed that 34 patients with primary non-clear cell carcinoma treated with bevacizumab + everolimus had a median progression-free survival time and overall survival time of 11.0 months and 18.5 months, respectively, with an efficiency rate of 29.

  • Cabozantinib: The efficacy and safety of cabozantinib in patients with non-clear cell renal cell carcinoma is unclear and studies are ongoing. The study is ongoing.
    
  • Erlotinib: A phase II clinical study showed that 41 patients with renal papillary carcinoma treated with bevacizumab + erlotinib, 19 of whom had received at least one systemic therapy, had hereditary smooth muscle tumor disease and renal cell carcinoma with an efficiency
    

    60 , disseminated papillary carcinoma efficiency 29, and median progression-free Survival times were

    24.2 months and 7.4 months, respectively.

  • Evimox: A phase II clinical study showed that 34 patients with primary non-clear cell carcinoma treated with bevacizumab + The median progression-free survival time and overall survival time were 11.0 months and 18.5 months, respectively, in 34 patients with primary non-clear cell carcinoma treated with bevacizumab + everolimus in a phase II clinical study, with
    

    Efficiency 29.

  • Lenvatinib + everolimus: The efficacy and safety of treatment with lenvatinib + everolimus in patients with non-clear cell renal cell carcinoma is currently The efficacy and safety of lenvatinib + everolimus in patients with non-clear cell renal cell carcinoma is unclear and studies are ongoing.
    
  • Navulizumab: The efficacy and safety of navulizumab in patients with non-clear cell renal cell carcinoma is currently unknown. The efficacy and safety are not clear and studies are ongoing.
    
  • Pezopanib: An Italian retrospective study of 37 patients with non-clear cell renal cell carcinoma Patients treated with pegaptanib in the first line had a disease control rate of
    

    81 , effective rate 27, median progression-free survival time and overall survival time were

    15.9 months and 17.3 months, respectively.

  • Texilimox: A retrospective ARCC trial showed that texilimox for non-clear cell carcinoma had a median survival time of 11.6 months, with a Class I recommendation for tesipramox in the MSKCC-rated high-risk group.
    
    style=”margin-left: 64pt”>
    • Chemotherapy: in sarcomatoid and rapidly progressive RCC tumors with gemcitabine
      

  The combination regimen with doxorubicin may be an option, specifically doxorubicin

  (50 mg/m2) and gemcitabine (1500 or 2000 mg/m2) over 30 minutes once every 2 to 3 weeks, with granulocyte colony-stimulating factor support therapy.

  style=”margin-left: 83pt”>
  • Palliative radiotherapy
    

  For patients with local tumor bed recurrence, regional or distant lymph node metastases, skeletal or pulmonary metastases, palliative radiotherapy can achieve pain relief and improve the quality of survival.

  style=”margin-left: 83pt”>
  • Treatment principles for specific site metastases
    

  The common metastatic sites of renal cell carcinoma are lung (45.2 %), bone

  (29.5%), lymph nodes (21.8%), liver (20.3%), adrenal gland (8.9%), brain (8.1%), and retroperitoneum (6.9%). Among them, metastases to the liver, bone, and brain have some specificity in management because of their characteristics such as compression of peripheral nerves or tissues, severe impact on quality of life, and poor prognosis.

  • Bone metastases from renal cell carcinoma: Bone metastases from renal cell carcinoma are mostly found in the spine, pelvis and proximal bones of the limbs, and the main symptoms are The main symptom is progressive pain at the site of the lesion; under X-ray, it mainly shows osteolytic bone destruction, so pathological fractures are likely to occur at the metastatic site, and even compression of the spinal cord may cause paraplegia. This patient should be treated with a combination of targeted drugs, surgery, radiotherapy, and osteoprotective agents.
    

    The vertebral body is a common site of bone metastases from renal cell carcinoma, and according to the NOMS (Neurologic, Oncologic, Mechanical and Systemic) treatment protocol for spinal metastases, SBRT or surgery combined with SBRT is recommended for vertebral metastases that are not sensitive to conventional radiotherapy, including renal cell carcinoma. The treatment modality of SBRT is recommended for vertebral metastases that are not sensitive to conventional radiotherapy, including renal cell carcinoma. The literature reports that SBRT for vertebral metastases from renal cell carcinoma has a 1-year local control rate of 71 span style=”font-family:MS UI Gothic”>∼1 year
    

  90 , with a 1-year pain control rate of 82 , with only 0∼3 degrees or more of serious side effects2.

  Surgical resection of metastases may be considered for isolated or weight-bearing bone metastases; prophylactic internal fixation may be used to avoid bone-related events in patients with weight-bearing bone metastases at risk of fracture. Surgery is recommended for patients with pathologic fractures or compression of the spinal cord who meet the following 3 criteria.

  1) the patient is expected to survive >3 months; 2) the patient is in good physical condition; and 3) the patient’s quality of life is improved after surgery to facilitate further targeted therapy, radiation therapy, and care. Percutaneous vertebroplasty can be used to treat osteolytic destruction of the spine and pathological collapse of the vertebral body, which can improve stiffness and force compression at the metastatic site and relieve local pain. Local palliative low-dose radiation therapy is useful in relieving the pain of bone metastases. In addition, concomitant use of osteoprotective agents drugs, including bisphosphonates and denosumab, radium-223, may reduce the occurrence of bone-related events.

  A subgroup analysis of the METEOR study from the 2016 American Society of Clinical Oncology Annual Meeting showed that 142 of the 658 patients with advanced renal cell carcinoma included in the METEOR study had bone metastases, and 112 of these patients had both bone and visceral metastases. The results showed that the median progression-free survival time for patients with bone metastases was 7.4 months after treatment with cabozantinib compared with 2.7 months in the everolimus group, and for patients with both bone and visceral metastases, the median progression-free survival times were 5.6 months and 1.9 months after treatment with cabozantinib or everolimus, respectively, suggesting that cabozantinib may be appropriate for the treatment of patients with bone metastases from renal cell carcinoma.

  • Brain metastases from renal cell carcinoma: Radiotherapy is more effective than surgical treatment for brain metastases, and radiotherapy can take care of multiple brain metastases with dexamethasone.
    

  and dehydrating agents can significantly shrink the tumor and edema zone and relieve intracranial hypertension symptoms and other neurological symptoms. For patients with good physical condition and simple brain metastases (≤3 brain metastases, maximum diameter of brain metastases ≤3cm), stereotactic radiotherapy (γ-knife, X-knife, 3D conformal radiotherapy, intensity modulated conformal radiotherapy) or brain surgery combined with radiotherapy is preferred; for patients with multiple brain metastases (>3 brain metastases, maximum diameter of brain metastases >3cm), whole cranial radiotherapy can be considered. Then systemic antitumor drug therapy should be administered according to the patient’s tolerance.

  • Liver metastases from renal cell carcinoma: Patients with liver metastases from renal cell carcinoma usually have a poor prognosis and should first consider systemic targeted drug therapy. If systemic therapy is ineffective, the combination of local treatment of liver metastases, such as ablation therapy, transhepatic artery chemoembolization, SBRT and high-intensity focused ultrasound therapy, can be considered as part of the comprehensive treatment to improve local control of liver metastases, and the treatment alone is not significant.
    

    VII. Follow up
    

    Routine follow-up visit includes: ①History inquiry. (2) Physical examination. (3) Laboratory tests, including urine routine, blood routine, urea nitrogen, creatinine, glomerular filtration rate, lactate dehydrogenase, liver function, alkaline phosphatase, and serum calcium. Bone scan is indicated if there is an abnormal elevation of alkaline phosphatase and/or if there are signs of bone metastases such as bone pain. (iv) CT scan of the chest. The patient with a renal tumor with acute neurologic signs or symptoms should have an immediate cross-sectional CT or MRI scan of the head or a spinal cord scan based on the appropriate segmental syndrome.

    (i) Postoperative follow-up.

    Patients with pT1N0/NxM0 stage renal cell carcinoma treated with surgery should be followed up at the time of surgery.

  Abdominal CT or MRI should be performed as a baseline film within 3 to 12 months after surgery, and then once a year for 3 consecutive years for abdominal imaging ultrasound, CT, or MRI, and once a year for 3 consecutive years for chest CT to determine the presence of pulmonary metastases. The time frame for imaging in patients with pT2-4N0/NxM0 renal cell carcinoma treated with surgery was changed to once every 6 months for at least 3 years, and then once a year thereafter.

  (ii) Follow-up of locally treated patients.

  Patients with pT1aN0/NxM0 stage renal cell carcinoma treated locally with cryopreservation and radiofrequency should have an abdominal CT or MRI as a baseline radiograph 3-6 months after surgery and once a year thereafter (including abdominal and chest imaging). (including abdominal and chest imaging); if the original renal lesion is found to be enlarged, newly enhanced, or a new lesion appears during follow-up, a puncture biopsy of the lesion is required.

  (iii) Follow-up of patients with advanced disease.

  For patients with recurrent/metastatic stage IV renal cell carcinoma receiving systemic therapy, CT or MRI imaging of all evaluable lesions (lesions larger than 1 cm in maximum diameter) throughout the body should be performed as a baseline film before systemic therapy if possible, and every 6 to 16 weeks thereafter, depending on the disease and treatment plan. The same imaging should be performed every 6 to 16 weeks to compare the change in lesion size and number to evaluate the efficacy of systemic therapy, depending on the disease and treatment plan.

  Attachments
  

  Renal Cancer Guideline (2022 Edition) Development and Validation Expert Group
  

  (in order of last name stroke)

   

  Team leader: Zhang Xu

  Members: Ma Jianhui, Wang Wo, Wang Xiaoying, Tian Aiping, Xing Nianzeng

  Yuguo Liu, Chuanliang Xu, Fang Li, Xiao Li, Liru He, Yan Song, Wenjie Zhang, Flash Zheng, Cuiling Zheng, Hui Fang, Jian Huang, Xinan Sheng, Sujun Han, Jing Liao