Adjuvant therapy in renal-cell carcinoma: Is it prime time yet?
Editorial

Adjuvant therapy in renal-cell carcinoma: Is it prime time yet?

John Dimitriadis, Aristotelis Bamias

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece

Correspondence to: Aristotelis Bamias. Department of Clinical Therapeutics, ALEXANDRA Hospital, 80 Vas. Sofias Ave, Athens 115 28, Greece. Email: abamias@med.uoa.gr.

Provenance: This is an invited Editorial commissioned by Section Editor Hong-Chao He, MD, PhD (Department of Urology, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China).

Comment on: Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016;375:2246-54.


Submitted Jan 15, 2017. Accepted for publication Feb 23, 2017.

doi: 10.21037/tcr.2017.03.28


More than 200,000 people worldwide are diagnosed with renal-cell carcinoma (RCC) each year, and almost one third of them will die from metastatic disease (1). Although 5-year survival rate for metastatic disease has increased from 34% in 1954 to 73% in 2011, it still remains low (8–10%) in metastatic setting (2). Although nephrectomy can be curative for the majority of patients presenting with localized disease, nearly 40% of patients initially diagnosed with stages II and III, will eventually relapse (3). Taking the above into consideration, development of an effective adjuvant treatment for patients in high-risk for relapse following nephrectomy is needed.

RCC is a highly vascular tumor and it represents an excellent target for antiangiogenic treatment due to the dominant role of the vascular endothelial factor (VEGF)/VEGF receptor (VEGFR) pathway in carcinogenesis and tumor expansion (4). This has led to the approval of different agents, targeting VEGF or VEGFR for the management of metastatic disease, such as sorafenib (5), sunitinib (6), pazopanib (7), axitinib (8), bevacizumab (9), cabozantinib (10) and lenvatinib (11). Improvement in progression free survival (PFS) and overall survival (OS) was shown in a series of different trials in patients with metastatic RCC (mRCC). For example, sunitinib (6) prolonged PFS by 6 months compared to interferon alpha (IFN-α) and achieved significantly higher response rates at 30–40%. PFS benefit was also achieved by axitinib over another inhibitor of the tyrosine kinase (TKI) of the VEGFR in the AXIS trial (8) in second line, while more recently cabozantinib prolonged OS compared to everolimus, another agent used in relapsed mRCC (10). In spite of these exciting results reported in metastatic disease, the role of VEGF inhibition in the adjuvant setting after nephrectomy still remains unclear.

The recently published S-TRAC trial (12) investigated the efficacy and safety of sunitinib in preventing disease relapse in high risk patients with resected renal cell carcinoma were accessed. Accrual lasted from September 2007 to April 2011 and 615 patients with locoregional, high-risk clear-cell RCC (T3N0M0 or T4N0M0 or node-positive) were randomized in a 1:1 fashion to receive either sunitinib (50 mg per day) or placebo on a 4-week-on, 2-week-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The study met its primary endpoint: median duration of disease free survival (DFS) was longer in patients receiving sunitinib [6.8 vs. 5.6 years, hazard ratio (HR), 0.76; 95% confidence interval (CI), 0.59 to 0.98; P=0.03]. Toxicity profile of sunitinib was comparable to that reported in trials on metastatic setting. Adverse events grade 3 or more were reported in 63% of patients receiving sunitinib, but the rate of serious adverse events was similar in both arms. Treatment discontinuation due to toxicity was considerable and occurred in 28% of the patients.

S-TRAC results should be reviewed within the current environment of clinical research on adjuvant therapy in RCC. Apart for the S-TRAC, five more trials are addressing this issue (13-17). Only one has been reported yet: the ASSURE trial studied the adjuvant use of sorafenib and sunitinib in RCC (13). This trial showed no benefit in DFS and OS from the use of VEGFR TKIs. The SORCE trial focuses on treatment duration, administering sorafenib for 3 vs. 1 year (14). The PROTECT trial investigates the adjuvant use of pazopanib in clear-cell, >T2, grade 3–4 disease, but high discontinuation rates led to a protocol amendment to allow a lower dose of pazopanib (15). The ATLAS trial treats patients for three years with axitinib (16), while the EVEREST trial exploits the inhibition of a different pathway [the mammalian target of rapamycin (mTOR)], using everolimus in the adjuvant setting (17).

The reasons for the discrepancy between the results of S-TRAC and ASSURE are not clear. S-TRAC aimed at a higher-risk population than ASSURE. It included only patients with T3 and T4 node negative disease, whereas ASSURE also included patients with T2 and T1b Fuhrman Grade 3 and 4 N0M0 patients. Furthermore, ASSURE required negative surgical margins, whereas S-TRAC accepted microscopic (R1) residual disease. Presence of predominant clear cell histology was mandatory in S-TRAC but not in ASSURE. Clear-cell RCCs seem to be more dependent on the VEGF pathway, which may have underpowered the results of ASSURE.

Another factor contributing to the discordance between ASSURE and S-TRAC results may be the difference in the treatment dosage and compliance. ASSURE had a higher drop out due to toxicity (44%) compared to S-TRAC. This is surprising taking into consideration that an amendment in ASSURE clinical protocol allowed initiation with a lower level of sunitinib dosage (37.5 mg daily for 4 weeks on a 6-week cycle) for the first two cycles, which led to only 41% of patients receiving full dose of sunitinib during third cycle. On the other hand, S-TRAC initiated sunitinib in its full dose (50 mg daily for 4 weeks on a 6-week cycle) and 54% achieved to maintain this dose throughout treatment period. This may have increased efficacy, as suggested by previous studies, associating higher exposure to sunitinib with higher response rates (18).

Finally, progression was centrally assessed in S-TRAC but not in ASSURE. This factor may be of importance, since statistical significance difference in DFS between the two arms was observed only through independent assessment of progression in the S-TRAC trial.

The major question following the publication of the results of S-TRAC, is whether they should change the current practice of follow up after nephrectomy for localized RCC, regardless of the risk of relapse. Certain points should be taken into consideration. Whether DFS is the most appropriate endpoint for adjuvant therapy trials in the current treatment paradigm of RCC remains questionable. Many agents used in metastatic disease, sunitinib included, prolong survival. In that sense S-TRAC may be viewed as an early vs. late sunitinib study. For this reason, definitive conclusion about the wide application of this strategy, should be drawn after maturation of OS data. The current median follow up of 5.4 years is not adequate, taking into consideration the natural history of RCC. Furthermore, no information regarding the use of sunitinib at relapse has been made available yet. Another important question is the way adjuvant sunitinib may influence sensitivity to VEGFR TKIs at relapse. Data from metastatic setting suggest reduction of efficacy of subsequent therapies after sunitinib failure. This was noted in both RECORD-1 and CheckMate-025 trial, where prior progression on sunitinib correlated with poorer outcome of second line treatment (19,20).

Finally, the most appropriate method for selection of patients in high-risk for relapse after nephrectomy remain elusive. The results of the Cancer Genome Project suggest that traditional pathological characterization may be further tuned by molecular markers (21).

In conclusion, S-TRAC represents an important study, underscoring the efficacy of VEGFR/VEGFR pathway blockade in the adjuvant setting of renal cell carcinoma. Further research to define the precise role of this strategy is required.


Acknowledgements

None.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.


References

  1. International Agency for Research on Cancer. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. Available online: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx
  2. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol 2001;166:1611-23. [Crossref] [PubMed]
  3. Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol 2011;60:615-21. [Crossref] [PubMed]
  4. Keefe SM, Nathanson KL, Rathmell WK. The molecular biology of renal cell carcinoma. Semin Oncol 2013;40:421-8. [Crossref] [PubMed]
  5. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099-109. [Crossref] [PubMed]
  6. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24. [Crossref] [PubMed]
  7. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061-8. [Crossref] [PubMed]
  8. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931-9. [Crossref] [PubMed]
  9. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370:2103-11. [Crossref] [PubMed]
  10. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:917-27. [Crossref] [PubMed]
  11. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015;16:1473-82. [Crossref] [PubMed]
  12. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016;375:2246-54. [Crossref] [PubMed]
  13. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016;387:2008-16. [Crossref] [PubMed]
  14. Sorafenib in Treating Patients at Risk of Relapse After Undergoing Surgery to Remove Kidney Cancer (SORCE). NCT00492258. Available online: https://clinicaltrials.gov/ct2/show/NCT00492258
  15. A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma (RCC) (PROTECT). NCT01235962. Available online: https://clinicaltrials.gov/ct2/show/NCT01235962
  16. Adjuvant Axitinib Therapy of Renal Cell Cancer in High Risk Patients (ATLAS). NCT01599754. Available online: https://clinicaltrials.gov/ct2/show/NCT01599754
  17. S0931, Everolimus in Treating Patients With Kidney Cancer Who Have Undergone Surgery (S0931). NCT01120249. Available online: https://clinicaltrials.gov/ct2/show/NCT01120249
  18. Houk BE, Bello CL, Poland B, et al. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol 2010;66:357-71. [Crossref] [PubMed]
  19. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 2010;116:4256-65. [Crossref] [PubMed]
  20. Motzer RJ, Padmanee S, McDermott DF, et al. CheckMate 025 phase III trial: Outcomes by key baseline factors and prior therapy for nivolumab (NIVO) versus everolimus (EVE) in advanced renal cell carcinoma (RCC). J Clin Oncol 2016;34:abstr 498.
  21. Ciccarese C, Brunelli M, Montironi R, et al. The prospect of precision therapy for renal cell carcinoma. Cancer Treat Rev 2016;49:37-44. [Crossref] [PubMed]
Cite this article as: Dimitriadis J, Bamias A. Adjuvant therapy in renal-cell carcinoma: Is it prime time yet? Transl Cancer Res 2017;6(Suppl 2):S360-S362. doi: 10.21037/tcr.2017.03.28