Advanced/metastatic renal cell carcinoma refers to renal cell carcinoma that has broken through the renal fascia, with extra-regional lymph node metastasis or distant metastasis, including TNM stage T4N0~1M0/T1~4N0~1M1, and clinical stage IV.
Systemic drug therapy is the main treatment, supplemented by palliative surgery or radiotherapy for primary foci or metastases. 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.

1. Surgical treatment

Surgery as an adjuvant treatment for metastatic renal cell carcinoma, including reduction 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 for highly selected patients.
(1)

Surgical treatment of the primary renal lesion

: Surgical subtraction should be performed on the basis of effective 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. Currently, subtractive nephrectomy is more appropriate for patients with metastatic renal cell carcinoma who are in good general condition (ECOG score <2, no or mild associated symptoms, low metastatic load, and moderate risk factors for significant reduction of tumor load with surgery, and subtractive nephrectomy is not usually recommended prior to systemic therapy. In addition, palliative nephrectomy or renal artery embolization may be performed in patients with severe hematuria or pain associated with renal tumors to relieve symptoms and improve quality of life.
(2)

Surgical treatment of metastases

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: For isolated metastases, the metastases can be surgically removed if the patient is in good behavioral status. The lung is the most common site of metastasis for renal cell carcinoma, and surgical resection of a solitary lung metastasis or a metastasis located in one lobe of the lung may help prolong the patient’s survival. 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 compression of the spinal cord should also be treated surgically if the patient is expected to survive >3 months, is in good physical condition, and if surgery can improve quality of life. 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.

2. Systemic therapy

(1)

Clinical trials

: Recommendation to participate in clinical trials remains a priority option for patients with advanced renal cell carcinoma.
(2)

Systemic therapy for clear cell-dominant 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. The 861 patients were randomized to pablizumab (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). Compared with sunitinib, pabrolizumab combined with axitinib significantly improved patients’ overall survival time (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 (PD-L1)-expressing subgroup. 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 to 4, platelet-derived These kinases are involved in pathological angiogenesis, tumor growth and progression in addition to their normal cellular functions.
The randomized, controlled, phase III clinical study KEYNOTE581/CLEAR (Study 307) included 1069 untreated patients with advanced renal clear cell carcinoma who were randomly assigned in a 1:1:1 ratio to receive either lenvatinib (20 mg orally once daily) + pabrolizumab (200 mg intravenously once every 3 weeks) or lenvatinib (18 mg orally once daily). oral, 1 time daily) + everolimus (5 mg, oral, 1 time daily) or sunitinib (50 mg, oral, 1 time daily, 4 weeks of dosing/2 weeks off). 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 combined with pabrolizumab resulted in a significant progression survival time benefit. Median overall survival was not achieved, but was prolonged in the lenvatinib combined with pabrolizumab group compared with the sunitinib group (HR=0.66, 95 CI 0.49-0.88, p=0.005). There was a higher objective remission rate (71.0 vs. 36.1) and a higher complete remission rate (16.1 vs. 4.2) in the lenvatinib combined with pabrolizumab group. The ≥3 grade treatment-related adverse reactions were 71.6 and 58.8, respectively.
(iii) Navulizumab in combination with cabozantinib: Navulizumab is an anti-PD-1 monoclonal antibody. Cabozantinib is an oral small molecule kinase inhibitor against VEGFR, MET, AXL and other targets. The randomized, open, phase III clinical study Checkmate 9ER evaluated the efficacy and safety of nabritumomab in combination with cabozantinib compared to sunitinib in the first-line treatment of metastatic renal clear cell carcinoma. The 651 patients enrolled were randomized to nabritumomab (240 mg IV once every 2 weeks) in combination with cabozantinib (40 mg orally once daily) (323 patients) and sunitinib (50 mg orally once daily for 4 weeks/ 2 weeks off) (328 patients). Compared with sunitinib, nabritumomab combined with cabozantinib significantly improved patients’ median progression-free survival (17.0 vs. 8.3 months, HR=0.52, 95 CI 0.43 to 0.64, P<0.0001), median overall survival (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).
The CheckMate214 study is a multicenter randomized controlled phase III clinical study evaluating nabritumomab in combination with ibritumomab versus The CheckMate214 study is a multicenter randomized controlled phase III clinical study evaluating the efficacy of sunitinib in combination with ipilimumab versus sunitinib in the first-line treatment of advanced/metastatic intermediate to high-risk renal cell carcinoma (1082 cases). The results showed a significant benefit in the combination therapy group versus the sunitinib group in terms of objective remission rate (42 vs. 27, P<0.001) and median overall survival time (not reached vs. 26 months, P<0.001) in the first-line treatment of intermediate-risk advanced renal cell carcinoma in IMDC. 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 treatment for high-risk advanced renal cell carcinoma in IMDC.
⑤ Pezopanib: Pezopanib is a multi-tyrosine kinase inhibitor that inhibits VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR1, FGFR3, KIT, interleukin-2 receptor-inducible T-cell kinase, leukocyte-specific protein tyrosine kinase, and membrane-penetrating glycoprotein receptor tyrosine kinase.
Clinical data for pegaptanib in metastatic renal cell carcinoma from its international multicenter phase III 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, with a median overall survival of 22.6 months in the final survival analysis. 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. The study included 367 Asian patients, including Chinese subjects, and subgroup analysis showed a median progression-free survival time of 8.4 months in the pegaptanib-treated group in Asian patients, 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 for moderate hepatic impairment at baseline. Not recommended for patients with severe hepatic impairment.
Sunitinib: Sunitinib is a multi-target receptor tyrosine kinase inhibitor, with the main targets being VEGFR1-2, PDGFRα, PDGFRβ, c-KIT and FMS-like tyrosine kinase 3 (FLT3), which has anti-tumor angiogenesis and inhibits tumor cell proliferation.
In 2007, the New England Journal of Medicine reported a phase III clinical study of sunitinib versus TNF-α 1:1 in the first-line treatment of metastatic renal clear cell carcinoma, enrolling 750 patients, 90 of whom were at low to moderate risk for MSKCC, with median progression-free survival times of 11 and 5 months, respectively (HR 0.42, 95 CI 0.32 to 0.54, P<0.001), objective remission rates of 31 and 6, respectively (P<0.001), and median survival times of 26.4 and 21.8 months, respectively (P=0.051). This established sunitinib as a first-line treatment for renal clear cell carcinoma. The results of 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 as 50 mg administered 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 of discontinuation) could be chosen with improved tolerability and unaffected efficacy.
(7) Axitinib: In 2013, the Lancet reported a randomized controlled phase III clinical study in which 288 patients were enrolled 2:1 for the first-line treatment of advanced renal clear cell carcinoma with median progression-free survival times of 10.1 and 6.5 months (HR 0.77, 95 CI 0.56 to 1.05), respectively, with axitinib versus sorafenib. Despite the 3.6-month extension in progression-free survival, which was not statistically significant due to the small number of cases enrolled, the effectiveness of axitinib in first-line treatment of renal clear cell carcinoma was demonstrated. Based on the clinical study data, axitinib is recommended as first-line therapy for patients with advanced renal clear cell carcinoma at 5 mg twice daily.
A phase II multicenter randomized study (CABOSUN) compared the efficacy of cabozantinib and sunitinib in the first-line treatment of patients with intermediate-risk or high-risk (Heng’s score) renal clear cell carcinoma.157 Patients were randomized 1:1 to first-line cabozantinib (60 mg once daily) or sunitinib (50 mg, 4/2 regimen), and the results showed that the cabozantinib group had a progression-free survival. The median progression-free survival time was 8.2 versus 5.6 months (P = 0.012), the objective remission rate was 46% versus 18%, and the overall survival time was 30.3 versus 21.8 months in the cabozantinib group.
Based on data from foreign clinical studies, cabozantinib is recommended as first-line treatment for patients with intermediate-to-high-risk advanced renal clear cell carcinoma at 60 mg once daily.
Tesilomox: Tesilomox is an mTOR inhibitor, which not only inhibits the anti-tumor effect of mTOR signaling, but also inhibits angiogenesis, mainly by inhibiting the transcription of hypoxia-inducible factor HIF-1 and reducing the stimulation of vascular-related growth factors such as VEGF/PDGF/transforming growth factor, thus inhibiting tumor angiogenesis.
Phase III clinical data from the international multicenter randomized controlled phase III clinical study (ARCC study) of tesilomox first-line treatment of metastatic renal cell carcinoma, enrolling patients with a high-risk prognosis score, showed a median overall survival time of 10.9 months and a median progression-free survival time of 5.5 months for tesilomox monotherapy, which was significantly better than the IFN-α treatment group. A non-randomized, single-arm, open phase II clinical study of tesilomox in an Asian population enrolling 82 patients with metastatic renal cell carcinoma in China, Japan and Korea showed a clinical benefit rate of 48%, an objective efficiency rate of 11% and a median progression-free survival time of 7.3 months.
Based on these clinical data, tesilomox is recommended for first-line treatment of patients with advanced clear cell renal cell carcinoma at 25 mg once weekly.
Cytokine therapy: Cytokine therapy has been focused on earlier studies, mainly on IFN-α and interleukin-2. 2002 JCO reported a retrospective analysis of 463 patients with advanced renal cell carcinoma treated with IFN-α. In 2003, Cancer reported a retrospective analysis of 173 patients with metastatic renal cell carcinoma treated with interleukin-2 based therapy, with a median survival time of 13 months and survival rates of 92, 61 and 41 at 1, 3 and 5 years, respectively. cytokines are generally not used as first-line treatment of choice.
For patients with metastatic renal clear cell carcinoma who cannot be treated with targeted drugs, cytokine therapy can be recommended as an alternative treatment, in which high-dose interleukin-2 can be used for metastatic renal clear cell patients with good general condition and normal cardiopulmonary function. 9 million IU once every 12 hours on days 1 to 2, and 9 million IU once daily on days 3 to 5 for 3 weeks, to be repeated after a 1-week break. IFN-α is administered as a subcutaneous injection of 9 million IU 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 723 patients treated 1:1 with axitinib and sorafenib for advanced renal cell carcinoma who failed first-line therapy (overwhelmingly cytokine or sunitinib), with median progression-free survival times of 6.7 months and 4.7 months, respectively (HR 0.665, 95 CI). HR 0.665, 95 CI 0.544 to 0.812, P<0.0001), with efficiency rates of 19 and 9, respectively (P=0.0001), and median progression-free survival times of 12.1 and 6.5 months for first-line cytokine therapy (P<0.0001) and 4.8 and 3.4 months for first-line sunitinib, respectively (P<0.0001). The median progression-free survival times for first-line sunitinib were 4.8 and 3.4 months, respectively (P=0.01), and the median survival times were 20.1 and 19.3 months, respectively. A registry 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 the results of these clinical trials, axitinib is recommended as second-line treatment for metastatic renal cell carcinoma, and is administered as axitinib 5 mg twice daily.
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 (RECORD-1 study) reported by the Lancet in 2008. 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, with a final statistically significant median progression-free survival time of 4.9 months and 1.9 months, respectively (HR, 0.33; P <0.001), and 80 patients in the placebo group crossed over to the everolimus group after progression, so there was no significant difference in median survival time between the two groups, which were 14.8 months and 14 months, respectively. 14.8 months and 14.4 months, respectively. The common adverse effects of everolimus were gastritis, rash and malaise. A multicenter registry clinical study (Study L2101) of everolimus in domestic patients confirmed the efficacy and safety of everolimus as second-line targeted therapy after TKI treatment failure, 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 the results of the above clinical trials, everolimus is recommended as a second-line treatment for metastatic renal cell carcinoma after failure of TKI therapy, with the specific usage of everolimus 10 mg once daily.
Sorafenib: 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 VEGFR, PDGFR, c-KIT, FLT-3, MET and other targets to inhibit tumor growth.
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. 189 patients were enrolled, with sorafenib 400 mg twice daily and TNF-α 9 million U three times a week. The median progression-free survival time was 5.7 and 5.6 months for sorafenib and TNF-α, respectively, and the proportion of tumor shrinkage was 68.2 and 39.0 for the two groups, respectively, with better quality-of-life scores and better tolerability in the sorafenib group. Due to the lack of large studies of sorafenib in first-line treatment and the increasing number of alternatives, the NCCN guidelines do not recommend sorafenib for first-line treatment of renal clear cell carcinoma, but mainly for second-line treatment. A multicenter study in China retrospectively analyzed the survival and prognostic factors of 845 patients with advanced renal cell carcinoma treated with sorafenib or sunitinib, and 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), and the median overall survival time did not differ between the two groups, both being 24 months. Sorafenib is still recommended as first-line treatment for some patients with renal cell carcinoma in China because of its good tolerability and the high efficiency shown in Asian populations.
In 2009, the Journal of Clinical Oncology reported a phase III randomized controlled clinical study of 903 patients with advanced renal clear cell carcinoma who had failed first-line therapy (overwhelmingly cytokine) for at least 8 months, with an ECOG score of 0 to 1, treated with sorafenib and placebo. The median survival time was 17.8 months and 14.3 months, respectively (HR = 0.78, P = 0.029).
In a retrospective study reported by JCO in 2006, 63 patients with metastatic renal cell carcinoma that had progressed after cytokine therapy were treated with sunitinib in the second line, with an efficiency of 40 and a median progression-free survival time of 8.7 months. Similarly, in 2006, JAMA reported a retrospective study of 106 patients with an efficiency rate of 34 and a median progression-free survival time of 8.3 months.
⑤ Cabozantinib: Cabozantinib has a significant survival advantage over everolimus in the second-line treatment of advanced renal clear cell carcinoma, and in 2016 Lancet Oncol reported the final results of the METEOR study, in which patients with renal clear cell carcinoma that progressed after first-line treatment with VEGFR-TKI received cabozantinib 1:1 versus everolimus, with median survival times of 21.4 months and 16.5 months, respectively. (HR 0.66, 95 CI 0.53-0.83, P=0.000 26), again with a significantly improved progression-free survival time and an efficiency rate of 17 and 3, respectively.
Cabozantinib has not yet been approved for marketing in China, but based on the results of the above foreign clinical trials, cabozantinib is recommended as a second-line treatment for metastatic renal cell carcinoma after failure of TKI therapy, specifically cabozantinib 60 mg once daily.
(6) Nabritumomab: The results of the 2015 CheckMate 025 study showed that for patients with renal clear cell carcinoma that had progressed after 1-2 treatments, median survival times were 25.0 months and 19.6 months for nabritumomab and everolimus in a 1:1 ratio, with efficiency rates of 25 and 5, respectively, and median progression-free survival times of 4.6 months and 4.4 months, respectively. The incidence of grade 3/4 adverse events was 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. 153 patients were randomized to receive lenvatinib in combination with everolimus, lenvatinib monotherapy, and everolimus monotherapy, with median progression-free survival times of 14.6 months and 5.5 months in the combination and everolimus groups, respectively. The median progression-free survival time was 14.6 months and 5.5 months in the combination group and the median survival time was 25.5 months and 15.4 months in the everolimus group, and the median survival time was 18.4 months in the lenvatinib monotherapy group.
(8) Pegaptanib: In a phase III trial of pegaptanib first-line treatment in 202 patients who progressed after cytokine therapy, 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 in patients who failed after treatment with sunitinib or bevacizumab, pegaptanib was 27 effective, with a median progression-free survival time of 7.5 months and a 2-year survival rate of 43.
⑨ Ticlomoxib: Ticlomoxib as second-line treatment for patients with renal cell carcinoma who failed sunitinib treatment had a median progression-free survival time of 4.28 months and a median survival time of 12.27 months.
Tivozanib: Tivozanib is a tyrosine kinase inhibitor that inhibits the phosphorylation of VEGFR1, VEGFR2 and VEGFR3, and inhibits the growth of other kinases, including c-KIT and PDGFRβ, as well as 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 type renal cell carcinoma(3)

: Patients with advanced non-clear cell carcinoma lack corresponding bulk randomized controlled clinical trials due to small sample sizes. 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(1) Sunitinib: Most studies in non-clear cell renal cell carcinoma are currently phase II clinical studies, with one study involving 31 patients in which sunitinib had an efficacy rate of 36 and a median progression-free survival time of 6.4 months in non-clear cell carcinoma and another study including 53 patients in which sunitinib/sorafenib had an efficacy rate of 23 and a median progression-free survival time of 10.6 months. In the ASPEN study, 108 patients with primary non-clear cell carcinoma randomized to sunitinib and everolimus had a median progression-free survival of 8.3 months and 5.6 months, respectively, with a median progression-free survival of 14.0 months versus 5.7 months and 6.5 months versus 4.9 months in the low- and intermediate-risk groups, respectively; everolimus had a slight but not statistically significant advantage in the high-risk group ( 4.0 versus 6.1 months). In the ESPN study, 68 patients were randomized to sunitinib and everolimus, with median progression-free survival of 6.1 months and 4.1 months (P=0.6) and median survival of 16.2 months and 14.9 months (P=0.18), respectively, in the first-line treatment.
(2) Axitinib: The efficacy and safety of axitinib for 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 treated with sunitinib or sorafenib had an efficiency of 10, a median progression-free survival time of 8.6 months, and a median survival time of 19.6 months. 19.6 months.
(4) Bevacizumab: 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 an efficiency of 60 for hereditary smooth muscle disease and renal cell carcinoma and 29 for disseminated papillary carcinoma, with a median progression-free survival time of 24.2 months and 7.4 months, respectively.
In another phase II clinical study, 34 patients with primary non-clear cell carcinoma treated with bevacizumab + everolimus had a median progression-free survival of 11.0 months and an overall survival of 18.5 months, respectively, with an efficiency of 29.
(5) Cabozantinib: The efficacy and safety of cabozantinib for patients with non-clear cell renal cell carcinoma is unclear and studies are ongoing.
(6) Erlotinib: In a phase II clinical study, 41 patients with renal papillary carcinoma were treated with bevacizumab + erlotinib, 19 of whom had received at least one systemic therapy.
(7) Everolimus: A 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 of 29.
(8) Lenvatinib + everolimus: The efficacy and safety of lenvatinib + everolimus in patients with non-clear cell renal cell carcinoma is unclear and studies are ongoing.
(9) Navulizumab: The efficacy and safety of navulizumab in patients with non-clear cell renal cell carcinoma is unclear and studies are ongoing.
In a retrospective study in Italy, 37 patients with non-clear cell renal cell carcinoma received pegaptanib in the first line with a disease control rate of 81 and an effective rate of 27.
The median progression-free survival time and overall survival time were 15.9 months and 17.3 months, respectively.
(11) Tesilomox: A retrospective ARCC trial showed a median survival time of 11.6 months for tesilomox in non-clear cell carcinoma, and tesilomox was recommended as a class I for the MSKCC-rated high-risk group.
(12) Chemotherapy: A combination regimen of gemcitabine and doxorubicin may be an option in sarcomatoid and rapidly progressive RCC, specifically doxorubicin (50 mg/m2) and gemcitabine (1500 or 2000 mg/m2) over 30 minutes every 2 to 3 weeks, given with granulocyte colony-stimulating factor support therapy.