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Keywords:

  • molecular targeted therapy;
  • renal cell carcinoma;
  • sorafenib;
  • sunitinib;
  • temsirolimus

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular targeted therapeutic agents against RCC
  5. Treatment options for metastatic RCC according to various guidelines
  6. Conclusion
  7. References

Advanced renal cell carcinoma (RCC) is resistant to chemotherapy and radiotherapy. Immunotherapy is relatively effective against RCC. However, the response rate is approximately 15–20%. Therefore, new therapeutic approaches are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC are identified, and molecular targeted therapy is developed. Bevacizumab, sorafenib, sunitinib, axitinib, temsirolimus, everolimus are promising molecular targeted therapeutic agents for metastatic RCC, and will be used widely in clinics in the near future. In addition, combination therapy with molecular targeted therapy and other therapies including immunotherapy may also be developed soon.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular targeted therapeutic agents against RCC
  5. Treatment options for metastatic RCC according to various guidelines
  6. Conclusion
  7. References

Surgery including radical nephrectomy and partial nephrectomy is the main treatment for localized renal cell carcinoma (RCC). Immunotherapy including interferon-α (IFN-α) and interleukin-2 (IL-2) was the general therapy against metastatic RCC. However, the response rate of immunotherapy is low.1,2 Therefore, novel treatments against metastatic RCC are needed.

Molecular mechanisms of the growth of RCC were relatively clearly identified recently. Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and others have been demonstrated to be associated with the proliferation of RCC. Molecular targeted therapy against VEGF, PDGF etc. have been developed.3,4 Molecular targeted therapeutic agents including sorafenib and sunitinib are used in the USA and European countries. In Japan, sorafenib and sunitinib have been approved this year. In the present review, recent advances in molecular targeted therapy for metastatic RCC are introduced.

Molecular targeted therapeutic agents against RCC

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular targeted therapeutic agents against RCC
  5. Treatment options for metastatic RCC according to various guidelines
  6. Conclusion
  7. References

Molecular targets of molecular targeted therapeutic agents introduced in this review are listed in Table 1.

Table 1.  Molecular targets of molecular targeted therapeutic agents
Molecular targeted therapeutic agentsMolecular targets
VEGFVEGFRPDGFRmTOR
  1. mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

Bevacizumab   
Sorafenib  
Sunitinib  
Axitinib   
Temsirolimus   
Everolimus   

(1) Bevacizumab

Bevacizumab is the antibody for VEGF.5,6 Bevacizumab binds to VEGF and blocks the action of VEGF, resulting in inhibition of neo-vascularization. A randomized controlled trial (RCT) published in 2003 demonstrated that bevacizumab was more effective for patients with cytokine-refractory metastatic RCC, compared with a placebo.7 Based on these data, a RCT on IFN-α with/without bevacizumab as the first-line treatment for patients with metastatic RCC was planned and reported.8 IFN-α was subcutaneously given at 9 million units three times per week. Bevacizumab was given intravenously at 10 mg/kg per day. Response rates were 31% (complete response: CR: 1%, partial response: PR: 30%) and 13% (CR: 2%, PR: 11%) in the IFN-α with/without bevacizumab-treated groups, respectively. Thus, the antitumor effect of the IFN-α and bevacizumab-treated group was significantly better than that of the IFN-α-treated group. Progression-free survival rate in the IFN-α and bevacizumab-treated group with only low/intermediate risk according to the Memorial Sloan-Kettering prognostic factors model9 was higher than that in the IFN-α-treated group. Adverse events (more than grade 3) including fatigue in the IFN-α and bevacizumab-treated group were often observed, compared with the IFN-α-treated group. Discontinuation due to adverse events in the IFN-α with/without bevacizumab-treated groups occurred in 28% and 12% of patients, respectively. These results suggest that IFN-α plus bevacizumab as the first-line therapy may be useful for patients with low and intermediate risk metastatic RCC. However, adverse events should be taken care of.

(2) Sorafenib

Sorafenib is a multi-kinase inhibitor that blocks raf kinase and tyrosine kinase of VEGF receptor (VEGFR) and PDGF receptor (PDGFR).10,11 RCT on sorafenib (n = 451) versus placebo (n = 452) as salvage therapy for patients with cytokine-refractory metastatic RCC was reported.12 The patients belong to low and intermediate risk according to the Memorial Sloan-Kettering prognostic factors model. Sorafenib was orally given at 400 mg twice per day. Response rates were 10% (CR: < 1%, PR: 10%) and 2% (CR: 0%, PR: 2%) in the sorafenib-treated and placebo-treated groups, respectively. The rates of stable disease (SD) were 74% and 53% in the sorafenib-treated and placebo-treated groups, respectively. Median progression-free survival periods in the sorafenib-treated and placebo-treated groups were 5.5 months and 2.8 months, respectively. In addition, overall survival rates at one year in the sorafenib-treated and placebo-treated groups were 70% and 60%, respectively. Thus, the antitumor effect of sorafenib was superior to that of placebo. Major adverse events were diarrhea (43%) and fatigue (37%) as well as hand-foot syndrome (30%) and hypertension (17%), which were specific to sorafenib. Hypothyroidism was one of the causes of fatigue and was observed in 31% of patients in the sorafenib-treated group.13 Dose reduction due to these adverse events was carried out in 13% of patients and discontinuation due to adverse events was carried out in 10% of patients in the sorafenib-treated group. These results suggest that sorafenib as the second-line therapy may be effective for patients with cytokine-refractory low and intermediate risk metastatic RCC. However, side effects including hand-foot syndrome should be taken care of.

Based on the data above, RCT on sorafenib (n = 97) versus IFN-α (n = 92) as the first-line therapy for patients with metastatic RCC was shown.14 The histological type of RCC was clear cell type. Antitumor response rates were 5% and 9% in the sorafenib-treated and IFN-α-treated groups, respectively. Median progression-free survival periods in the sorafenib-treated and IFN-α-treated groups were 5.7 months and 5.6 months, respectively. There was no significant difference in the antitumor effect between the sorafenib-treated and IFN-α-treated groups. These data suggest that the antitumor effect of sorafenib as the first-line therapy for patients with metastatic RCC may be comparable to that of IFN-α. However, adverse events (grade 1–4) such as hand-foot syndrome (60% vs 4%), diarrhea (55% vs 14%), and hypertension (24% vs 6%) in the sorafenib-treated group were often observed, compared with the IFN-α-treated group.

The expanded study (n = 2502) including both the first-line (n = 1247) and the second-line therapies (n = 1255) with sorafenib for metastatic RCC was carried out.15 Although this study was not a phase III study, the result may be very close to that in a real clinic. The first-line therapy included not only cytokine therapy including IFN-α and IL-2, but also bevacizumab treatment. The histological types of RCC were both clear cell type and non-clear cell types, such as papillary and chromophobe types. The performance status of the patients was less than 3. Brain metastasis was included in this study. The response rate was only 4%. In addition, the response rate in the first-line therapy was similar to that in the second-line therapy. Furthermore, the response in patients with brain metastasis was comparable to that without brain metastasis. Moreover, the antitumor effect against clear cell type RCC was also similar to that against non-clear cell type RCC. Side effects including diarrhea, fatigue, hand-foot syndrome and hypertension were observed as previous studies.

The clinical trial as the second-line therapy with sorafenib against metastatic RCC was carried out in Japan. The total number of patients was 129. The response rate was 12% (PR: 12%), and the median progression-free survival period was 8 months. Adverse events including hand-foot syndrome, diarrhea, fatigue and hypertension were seen as previous reports.

These findings suggest that sorafenib may be a potential molecular targeted therapeutic agent against cytokine-refractory metastatic RCC in the second-line setting. However, side effects specific to sorafenib as well as bevacizumab should be taken care of.

(3) Sunitinib

Sunitinib is a multi-kinase inhibitor that blocks tyrosine kinase of VEGFR, PDGFR etc., and inhibits tumor growth.16,17 RCT on sunitinib (n = 375) versus IFN-α (n = 375) as the first-line therapy for patients with metastatic RCC was reported.18 The histological type of RCC was clear cell type. Sunitinib was given orally at 50 mg per day for 4 weeks, and was stopped for 2 weeks. The term of one course was 6 weeks. IFN-α was given subcutaneously at 3 million units three times per week for 1 week, at 6 million units three times per week for 1 week, and at 9 million units three times per week. The response rates were 37% and 9% in the sunitinib-treated and IFN-α-treated groups, respectively. Only one CR was observed in the sunitinib-treated group. The other response was PR. The rates of SD were 47% and 57% in the sunitinib-treated and IFN-α-treated groups, respectively. Median progression-free survival periods in the sunitinib-treated and IFN-α-treated groups were 11 months and 5 months, respectively. In addition, median overall survival periods in the sunitinib-treated and IFN-α-treated groups were 26 months and 22 months, respectively. Main adverse events (grade 1–4) were diarrhea, nausea and fatigue in the sunitinib-treated group. Grade 3–4 side effects were diarrhea (3%) and fatigue (7%). Hypothyroidism, one of the causes of fatigue, was seen in 85% of patients in the sunitinib-treated group, and 30% of the patients needed hormone replacement.19,20 Hypertension and hand-foot syndrome (grade 1–4) were also observed in approximately 20% of the sunitinib-treated group. Grade 3–4 side effects were hypertension (8%) and hand-hoot syndrome (5%). Neutropenia, anemia and thrombocytopenia (grade 1–4) were observed in approximately 70% of the sunitinib-treated group. Pancytopenia (grade 3–4) were seen in 4–8% of the sunitinib-treated group. Dose reduction due to the adverse events was carried out in 32% of patients and discontinuation due to the adverse events was carried out in 8% of patients in the sunitinib-treated group. These results suggest that sunitinib as the first-line therapy may be effective for patients with metastatic RCC.

It has been reported that the response rate of sunitinib was high (40%) for the patients with cytokine-refractory metastatic RCC.21 Then, the expanded trial (n = 2341) as the second-line therapy with sunitinib for metastatic RCC was carried out.22 The histological types of RCC were both clear cell type and non-clear cell type. The performance status of the patients was less than 3. Patients with brain metastasis were included in this study. The first-line therapy included not only cytokine therapy, but also treatment with molecular targeted therapeutic agents. The response rate was only 9%. The response rate was independent of previous treatments.23 Furthermore, the response in patients with brain metastasis was comparable to that without brain metastasis. In addition, the response rate in patients with performance status less than 2 was similar to that in patients with performance status 2. Moreover, the antitumor effect against clear cell type RCC was also similar to that against non-clear cell type RCC.24 Since many patients were included in this study, the result in the present study may be very close to that in a real clinic. Although the response rate was reported to be high at first, the real response rate may be low. Median progression-free survival period was 8.9 months, as in the previous study. Side effects (grade 1–4) including diarrhea and fatigue were observed in approximately 40% of patients. Dose reduction due to the adverse events was carried out in 38% of patients.

Fatigue, hypertension and hand-foot syndrome are specific adverse events of sunitinib. Cardiac toxicity was also induced by sunitinib.25,26 Death caused by cardiac toxicity was observed in 1% of patients. However, decreased left ventricular ejection fraction was seen in 20% of patients. Hypertension is one of the causes of cardiac toxicity, and was also induced by sunitinib. The other report demonstrated that cardiac infarction was induced in 1% of patients by sorafenib or sunitinib, and abnormality in electrocardiogram was seen in 14% of patients.27 These findings suggest that direct injury of heart by sunitinib may induce cardiac toxicity, and hypertension may also promote cardiac toxicity. Examinations such as electrocardiogram are necessary, especially for patients with a past history of cardiac diseases.

The clinical trial as the first-line and second-line treatments with sunitinib against metastatic RCC was carried out in Japan. The numbers of patients registered in the first-line and second-line therapies were 25 and 26, respectively. The response rate in the first-line therapy was 48% (CR: 4%, PR: 44%), and the response rate in the second-line therapy was 46% (CR: 0%, PR: 46%). Adverse events (grade 3–4) including hand-foot syndrome (14%), fatigue (20%) and pancytopenia (about 50%) were often observed, compared with American reports.

These findings suggest that sunitinib may be a potential molecular targeted therapeutic drug for clear cell type metastatic RCC as the first-line setting. However, side effects specific to sunitinib as well as bevacizumab and sorafenib should be taken care of.

Sequential therapy with sorafenib and sunitinib for meatstatic RCC was reported.28,29 Sablin et al. analyzed 90 patients. The response rate of treatment with sorafenib then sunitinib was 15%, and the response rate of treatment with sunitinib then sorafenib was 9%. Dham and Dudek analyzed 37 patients.29 The median progression-free survival period of treatment with sorafenib then sunitinib was 42 weeks, and median progression-free survival period of treatment with sunitinib then sorafenib was 30.5 weeks. These data suggest that sequential therapy with sorafenib and sunitinib may be effective for metastatic RCC, and the recommended sequence may be sorafenib at first and sunitinib next.

(4) Axitinib

Axitinib is an oral molecular targeted therapeutic agent that blocks tyrosine kinase of VEGFR, and inhibits neo-vascularity.30,31 Phase II study on axitinib (n = 52) as the second-line therapy for patients with cytokine-refractory metastatic RCC was reported.32 Axitinib was orally given at 5 mg twice per day. Response rate was 44% (CR: 4%, PR: 40%). The rate of SD was 42%. SD continued for more than 8 weeks. In addition, 60% of SD continued more than 24 weeks. Median progression-free survival period was 23 months. In addition, median overall survival period was 29.9 months. Major adverse events were diarrhea, hypertension and fatigue. Grade 3–4 side effects were observed in 54% of patients, but were manageable.

Based on the results, a clinical study on axitinib (n = 62) as the second-line therapy for patients with sorafenib-refractory metastatic RCC was reported.33 The response rate was 21%.

These findings suggest that axinitib may be a potential molecular targeted therapeutic agent for cytokine-refractory and sorafenib-refractory metastatic RCC in the second-line setting.

(5) Temsirolimus

Temsirolimus is a molecular targeted therapeutic agent that inhibits mammalian target of rapamycin (mTOR), and suppresses tumor growth.34 RCT on temsirolimus versus IFN-α versus both as the first-line treatment for patients with metastatic RCC was reported.35 The patients belong to poor risk according to the Memorial Sloan-Kettering prognostic factors model. Temsirolimus was given intravenously at 20 mg/m2 per day once per week. IFN-α was given subcutaneously at 3 million units three times per week for one week, at 9 million units three times per week for 1 week, and at 18 million units three times per week. Response rates were 9%, 7% and 11% in the temsirolimus-treated, IFN-α-treated, and both-treated groups, respectively. Thus, the antitumor effect of each group was similar. Progression-free survival rate and overall survival rate in the temsirolimus-treated and both-treated group were higher than those in the IFN-α-treated group. There was no synergistic or additive effect of temsirolimus and IFN-α. Adverse events (more than grade 3) including asthenia (11%), neutropenia (3%) and anemia (20%) in the temsirolimus-treated group were observed. Dose reduction and discontinuation due to the adverse events occurred in 23% and 7% of patients, respectively. These results suggest that temsirolimus as the first-line therapy may be useful for patients with poor risk of metastatic RCC.

(6) Everolimus

Everolimus as well as temsirolimus is an inhibitor of mTOR.36 RCT on everolimus (n = 272) versus placebo (n = 138) as salvage therapy for patients with sorafenib and/or sunitinib-refractory metastatic RCC was reported. Everolimus was orally given at 10 mg once per day. Response rates were 3% (PR: 3%) and 0% in the everolimus-treated and placebo-treated groups, respectively. The rates of SD were 63% and 32% in the everolimus-treated and placebo-treated groups, respectively. Median progression-free survival periods in the everolimus-treated and placebo-treated groups were 4.6 months and 1.8 months, respectively. Thus, the antitumor effect of everolimus was superior to that of placebo. Major adverse events (all grades) were stomatitis (40%), fatigue (37%) and anemia (91%). Discontinuation due to the adverse events occurred in 10% of patients in the everolimus-treated group. These results suggest that everolimus as salvage therapy may be effective for patients with sorafenib/sunitinib-refractory metastatic RCC.

Treatment options for metastatic RCC according to various guidelines

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular targeted therapeutic agents against RCC
  5. Treatment options for metastatic RCC according to various guidelines
  6. Conclusion
  7. References

Previous physician data query (PDQ) of National Cancer Institute (NCI) recommended IL-2 and IFN-α for the treatment of stage IV RCC. However, the present PDQ recommends sorafenib, sunitinib and bevacizumab (Table 2). The National Comprehensive Cancer Network (NCCN) recommended sunitinib, temsirolimus (poor risk) and bevacizumab + IFN-α for the treatment of clear cell type stage IV RCC. NCCN also recommended temsirolimus (poor risk), sorafenib and sunitinib for non-clear cell type stage IV RCC. The European Association of Urology (EAU) recommends sorafenib, sunitinib and temsirolimus for the treatment of metastatic RCC. Clinical guidelines for RCC from the Japanese Urological Association (JUA) also recommend sorafenib, sunitinib, temsirolimus and bevacizumab for the treatment of metastatic RCC. Thus, all guidelines recommend molecular-targeted therapeutic agents such as sorafenib and sunitinib for the treatment of metastatic RCC.

Table 2.  Molecular targeted therapeutic agents recommended in various guidelines for metastatic renal cell carcinoma (RCC)
Various guidelinesRecommended molecular targeted therapeutic agents
  1. EAU, European Association of Urology; JUA, Japanese Urological Association; NCCN, National Comprehensive Cancer Network; PDQ (NCI), Physician Data Query (National Cancer Institute).

EAUSorafenib, Sunitinib, Temsirolimus
NCCNSorafenib, Sunitinib, Temsirolimus Bevacizumab + IFN-α
PDQ (NCI)Sorafenib, Sunitinib, Temsirolimus, Bevacizumab
JUASorafenib, Sunitinib, Temsirolimus, Bevacizumab

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular targeted therapeutic agents against RCC
  5. Treatment options for metastatic RCC according to various guidelines
  6. Conclusion
  7. References

Potential molecular targeted therapeutic drugs such as bevacizumab, sorafenib, sunitinib, axitinib, temsirolimus and everolimus were developed for metastatic RCC. These agents are used mainly in the United States and European countries at present. In spite of the evidence, many urologists in Japan do not abandon immunotherapy, especially IFN-α, now. There is little difference in treatment with immunotherapy between Japan and Western countries. One of the reasons is that IFN-α therapy is familiar to Japanese urologists and has some antitumor effects without severe adverse events.

Table 3 lists the treatment options for metastatic RCC based on phase III studies. Most of the responses are PRs, not CRs. In the near future, useful biomarkers, more effective molecular targeted therapeutic agents and potential combination therapies may be developed.

Table 3.  Treatment options for metastatic renal cell carcinoma (RCC) based on phase III trials
TreatmentPatientAgent
  • Memorial Sloan-Kettering prognostic factors model.9 IFN-α, interferon-α; IL-2, interleukin-2; VEGF, vascular endothelial growth factor.

First-lineLow + intermediate riskSunitinib, High-dose IL-2 Bevacizumab + IFN-α
Poor riskTemsirolimus, Sunitinib
SalvageCytokine-refractorySorafenib
VEGF inhibitors-refractoryEverolimus

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Molecular targeted therapeutic agents against RCC
  5. Treatment options for metastatic RCC according to various guidelines
  6. Conclusion
  7. References
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