Over the past decade, the treatment of metastatic renal cell carcinoma (mRCC) has been an exciting field for researchers and patients alike as new treatments have made their way into clinical practice. VEGF and mTOR inhibitors have become the mainstay of treatment, replacing interferon. This field has grown quickly, and we now have multiple agents available for treating patients. This has led to more questions than we can answer, including what sequence or combination can maximize the benefit to patients. This article highlights some of the emerging trends and challenges facing today’s investigators and clinicians.
In the era of interferon therapy, 2 trials by SWOG and EORTC established an overall survival (OS) benefit for cytoreductive nephrectomy in the setting of mRCC.1,2 Currently, 2 ongoing trials are attempting to further define the role of cytoreductive surgery in the era of targeted therapy: the CARMENA trial, which randomizes patients with mRCC to sunitinib alone versus nephrectomy followed by sunitinib (NCT00930033); and the SURTIME trial, which compares immediate nephrectomy with deferred nephrectomy after 3 cycles of sunitinib (NCT01099423). Retrospective analyses by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) suggest that even when biases for patient referral for surgery are accounted for, in the era of targeted therapy there may still exist a role for cytoreductive surgery based on an observed OS benefit.3 It is important to note that poor-risk patients who were not expected to survive more than 12 months did not benefit from surgery.3
Adjuvant cytokine-based immunotherapy trials did not demonstrate a survival benefit. The role of adjuvant targeted therapy is currently being investigated, and so far the initial reports for sorafenib and sunitinib are not promising.4 Similarly, the role of neoadjuvant targeted therapy is being studied. Until further data are available, the use of targeted therapy (VEGF inhibitors or mTOR inhibitors) is not recommended in either setting outside of a clinical trial.
Metastasectomy is an appropriate surgical intervention for a select group of patients and is associated with improved cancer-specific survival.5 Metastasectomy can be done at the time of nephrectomy to render the patient disease-free, either at the time of recurrence after nephrectomy or after systemic treatment for metastatic disease after nephrectomy. Generally, patients most likely to benefit are those with a good performance status and low volume and number of metastases in a single organ system, such as lung, adrenal, or bone, as well as those patients who can have complete resection.6
There are 2 widely used risk stratification models for kidney cancer: the Memorial Sloan Kettering Cancer Center (MSKCC) model7,8 and the IMDC model, also known as the Heng Criteria.9 The advantage of the Heng Criteria is that it was derived and validated using data from patients who had received VEGF-targeted therapy, and as a result, it may be more applicable in today’s clinical practice. However, there is significant overlap between the 2 models, and most patients will be similarly risk-stratified using either criteria.
While several targeted therapy agents have received US Food and Drug Administration (FDA) approval and are available in the first-line setting, high-dose interleukin-2 (IL-2) still has a significant role in this setting in the treatment of mRCC. This is based on clinical trial data demonstrating durable remission in about 10% of patients,10,11 and increasing evidence that even a minor response to IL-2 is associated with better outcomes.12 Patient selection is important. Ideal candidates for high-dose IL-2 have good performance status, no bone metastases, relatively low-volume disease, and prior nephrectomy.13-15 In addition to these factors, toxicities of high-dose IL-2 are significant and must be balanced against the potential benefits.16
It is also important to recognize that high-dose IL-2 is an inpatient therapy and is only available at centers with highly experienced staff. Therefore, high-dose IL-2 may not be a viable option for many patients. For those patients who are not candidates for or don’t have access to high-dose IL-2 therapy, therapy with one of the multiple agents that target VEGF and/ or mTOR is an option.
For patients with poor-risk disease, temsirolimus is a reasonable option, as is a VEGF inhibitor based on level 1 evidence from a phase III trial.17 Of the 2 available mTOR inhibitors, everolimus does not have a proven role in first-line therapy.18 The choice of VEGF inhibitor in this setting is less clear. Data from the COMPARZ trial19 suggest that although sunitinib and pazopanib are equally effective, pazopanib may have an edge over sunitinib with respect to side effects and quality of life. A phase III trial of axitinib versus sorafenib in the first line did not meet its endpoint but demonstrated safety and activity, and therefore provides some support for the use of axitinib as a frontline agent.20 Patients with a solitary metastasis should be evaluated for metastasectomy. Symptomatic or worrisome bone lesions should be evaluated for stereotactic radiation therapy.21 Brain metastases should be treated surgically or by stereotactic radiosurgery or whole-brain radiation therapy prior to systemic therapy.22-24
For patients who develop progressive disease after immunotherapy with IL-2, or less commonly in recent years with interferon-α (IFN-α) therapy, the same principles as first-line targeted therapy apply. For patients with disease progression on a VEGF-targeting agent, an mTOR inhibitor or another VEGF-targeting agent may be appropriate. Axitinib has the best evidence base as a second-line option,25 with everolimus having level 1 evidence to support its use after failure of 1 or 2 VEGF-targeted agents.
While non–clear cell histologies constitute a minority of cases of RCC, they pose a significant therapeutic challenge. A meta-analysis of targeted therapy clinical trials suggests that VEGF-targeting agents may have activity in patients with non–clear cell or clear cell histologies with sarcomatoid features.26 These tumors do not respond to immunotherapy with IL-2.14 There has been modest response to chemotherapy in tumors with predominant non–clear cell histologies, including the combination of doxorubicin and gemcitabine for sarcomatoid tumors,27 and gemcitabine plus platinum for collecting duct carcinomas.28
Ongoing clinical trials are directed at the adjuvant setting, the role of cytoreductive nephrectomy, and novel targeted therapies and immunotherapies.29 With the advent of active and tolerable immunotherapy in the form of vaccines and inhibitors of immune checkpoint mediators CTLA4, PD-1, and PD-L1, new treatment options are on the horizon.30,31
Based on some early results signaling safety and activity in mRCC, vaccines alone or in combination with other cytokines are being evaluated to define their role in the treatment of RCC.32 Similarly, immune checkpoint agents are actively being studied in various cancer types including mRCC, with some early results showing safety and activity.33 Larger trials are under way, and until results are available, these strategies remain experimental. The Figure provides a diagram of clinical decision making in mRCC, and the Table provides a summary of key clinical trials in this field.
Affiliations: Sarmad Sadeghi, MD, PhD, and David I. Quinn, MD, PhD, are from the University of Southern California Norris Comprehensive Cancer Center, Los Angeles.
Disclosures: Dr Sadeghi has no relevant financial conflicts of interest to disclose. Dr Quinn has served on an advisory board for Pfizer, Bayer, Novartis, Genentech, Bristol-Myers Squibb, Astellas Pharma, Medivation, and Janssen Pharmaceuticals, and has received research support from Genentech, GlaxoSmithKline, and Millennium.
Address correspondence to: Sarmad Sadeghi, MD, PhD, USC Norris Comprehensive Cancer Center, 1441 Eastlake Ave, Suite 3440, Los Angeles, CA 91011. Email: email@example.com.
- Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655-1659.
- Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358(9286):966-970.
- Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 2014;66(4):704-710.
- Haas NB, Manola J, Uzzo RG, et al. Initial results from ASSURE (E2805): adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial. J Clin Oncol. 2015;33(suppl 7; abstr 403).
- Alt AL, Boorjian SA, Lohse CM, et al. Survival after complete surgical resection of multiple metastases from renal cell carcinoma. Cancer. 2011;117(13):2873-2882.
- Meimarakis G, Angele M, Staehler M, et al. Evaluation of a new prognostic score (Munich score) to predict long-term survival after resection of pulmonary renal cell carcinoma metastases. Am J Surg. 2011;202(2):158-167.
- Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17(8):2530-2540.
- Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20(1):289-296.
- Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794-5799.
- Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688-696.
- Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113(2):293-301.
- McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin “select” trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2015;21(3):561-568.
- Atkins MB, Sparano J, Fisher RI, et al. Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J Clin Oncol. 1993;11(4):661-670.
- Upton MP, Parker RA, Youmans A, et al. Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother. 2005;28(5):488-495.
- Figlin R, Gitlitz B, Franklin J, et al. Interleukin-2-based immunotherapy for the treatment of metastatic renal cell carcinoma: an analysis of 203 consecutively treated patients. Cancer J Sci Am. 1997;3(suppl 1):S92-S97.
- Belldegrun A, Webb DE, Austin HA, 3rd, et al. Effects of interleukin-2 on renal function in patients receiving immunotherapy for advanced cancer. Ann Intern Med. 1987;106(6):817-822.
- Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271-2281.
- Motzer RJ, Barrios CH, Kim TM, et al. Record-3: phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2013;31(15 suppl; abstr 4504).
- Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722-731.
- Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013;14(13):1287-1294.
- Nguyen QN, Shiu AS, Rhines LD, et al. Management of spinal metastases from renal cell carcinoma using stereotactic body radiotherapy. Int J Rad Oncol Biol Phys. 2010;76(4):1185-1192.
- Shuch B, La Rochelle JC, Klatte T, et al. Brain metastasis from renal cell carcinoma: presentation, recurrence, and survival. Cancer. 2008;113(7):1641-1648.
- Sahgal A, Aoyama H, Kocher M, et al. Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2015;91(4):710-717.
- Chang EL, Selek U, Hassenbusch SJ, 3rd, et al. Outcome variation among “radioresistant” brain metastases treated with stereotactic radiosurgery. Neurosurgery. 2005;56(5):936-945; discussion 936-945.
- 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(9807):1931-1939.
- Vera-Badillo FE, Templeton AJ, Duran I, et al. Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and meta-analysis. Eur Urol. 2015;67(4):740-749.
- Haas NB, Lin X, Manola J, et al. A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802. Med Oncol. 2012;29(2):761-767.
- Oudard S, Banu E, Vieillefond A, et al. Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d’Etudes des Tumeurs Uro-Genitales) study. J Urol. 2007;177(5):1698-1702.
- Philips GK, Atkins MB. New agents and new targets for renal cell carcinoma. Am Soc Clin Oncol Educ Book. 2014:e222-227. doi: 10.14694/EdBook_AM.2014.34.e222.
- Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33(13):1430-1437.
- McDermott DF, Drake CG, Sznol M, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab [published online March 30, 2015]. J Clin Oncol. 2015. pii: JCO.2014.58.10412015
- Kugler A, Stuhler G, Walden P, et al. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nat Med. 2000;6(3):332-336.
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- Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125-134.
- Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115-124.
- 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(9605):2103-2111.
- Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26(33):5422-5428.
- 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(6):1061-1068.
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- Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: results from a phase III randomized, open-label, multicenter trial. J Clin Oncol. 2012;30(15 suppl; abstr 4501).
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