Renal Cell Carcinoma: The Translation of Biology to Clinical Application

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The year 2006 was a watershed in the translation of biology to clinical application with implications for therapeutic improvement for patients with renal cell carcinoma. At the most recent American Society of Clinical Oncology (ASCO) presentations in Atlanta, GA, two plenary session presentations described the results of targeted therapy in previously untreated patients with metastatic renal cell carcinoma that will change the therapeutic options for patients.¹, ² In this issue of Seminars in Oncology, I have assembled a distinguished panel of scientists and clinicians to review where we are, how we got here, where we are going, and what the next decade will deliver in renal cell carcinoma.

Renal cell carcinoma accounts for 2% of all new cancer cases worldwide. Incidence rates have been rising steadily around the world. In the United States, the rates have been increasing most rapidly in African Americans, whose incidence rate has now surpassed that of white Americans. Cigarette smoking and obesity are the most consistently established causal risk factors, and epidemiologic studies are needed to identify the reasons for this increasing incidence of renal cancer with a particular focus on why the incidence rates for African Americans continues to rise dramatically (see McLaughlin et al). The pathology of renal epithelial neoplasms continues to be at the corner stone of diagnosis, prognosis, and increasingly therapeutic choices. Now more than ever, renal cell pathology dictates the choices in therapy in relationship to selection criteria for prospective clinical trials and the growing belief that this heterogeneous disease called renal cell carcinoma exhibits different light microscopic changes that assist the clinician in the choice of therapy. It has only been in the last several years that disease-specific trials have entered patients based on histologic subtypes for which we have a better understanding of not only the pathology, but also the basic biology leading to those pathologic changes. The expertise of the modern day genitourinary pathologist continues to challenge us to understand the morphologic and antigenic diversity seen in specific types of tumors in order to classify them more precisely, to understand the antigenic diversity in these tumors as they apply to targeted therapy, and to learn to classify these tumors on minimal material, such as needle biopsies and aspirates (see Reuter).

Kidney cancer is not a single disease, but a number of different types of cancer that occur in the kidney, each with a different histologic type, clinical course, responding differently to therapy, and caused by a different genetic abnormality. The biology of sporadic kidney cancer has been elucidated by a better understanding of families with a predisposition to the development of renal neoplasms, including von Hippel Lindau, hereditary papillary renal carcinoma, Bert-Hogg-Dubé, and hereditary leiomyomatosis renal cell carcinoma. Efforts continue to understand the genetic basis of renal cell cancer and how these findings can be transferred to a better therapeutic opportunity (see Sudarshan and Linehan).

The last decade has seen a burgeoning of a better understanding of nephron-sparing surgery in renal cell carcinoma, such that this treatment has entirely replaced the historical radical nephrectomy for the majority of patients with kidney cancer. Localized renal cell carcinoma remains primarily a surgical disease, and the delineation that with appropriately selected tumors nephron-sparing surgery offers equal efficacy and diminishes the risk of renal failure, offering superior quality of life with no significant differences in complications or cost. The role of lymphadenectomy remains an area of research interest and we are now sparing more adrenal glands, as we recognize that adrenalectomy in the context of a radical nephrectomy is no longer necessary for most tumors, except for upper pole lesions. The integration of newer operative procedures, such as cryosurgery and radiofrequency ablation remains to be delineated (see Leibovich and Blute).

Our ability to identify the prognostic factors in patients with both localized and metastatic renal cell carcinoma, facilitates our ability not only to predict prognosis but also to place patients in risk groups that allow for better constructed prospective clinical trials. Prognostic systems such as those developed by the University of California at Los Angeles and Memorial Sloan-Kettering Cancer Center have enabled better clinical trial design both in the adjuvant, as well as the advanced metastatic disease setting. Patient selection for clinical trials is now almost always dependent on prognostic variables that can identify risk and allow better stratification in prospective research. In the advent of tissue microarrays and protein, and gene expression profiles, we are now on the horizon of predicting kidney cancer biology at the level of protein and gene, possibly mitigating against the need for classical light microscopic pathology (see Shuch et al).

Patients with high-risk resected renal cell carcinoma will benefit from effective adjuvant therapies. Approaches to the high-risk resected patient must include the careful delineation of risk, and of therapies that balance risk and benefit in an asymptomatic patient population but with a potentially high likelihood of recurrence. Trials testing these hypotheses using immunotherapy, vaccines, and, more recently, targeted therapy will hopefully over the next 5 years delineate the first true options in the adjuvant setting for high risk resected renal cell carcinoma patients (see Jacobsohn and Wood).

Interleukin-2 (IL-2) has been used since the late 1980s in metastatic renal cell carcinoma because of the seminal work by Steven Rosenberg, MD, at the National Cancer Institute. We now know that IL-2 remains the only curative approach to metastatic renal cell carcinoma, with patients free of their cancer off of all treatment over a decade later. We have made great improvements in our ability to define populations most likely to benefit based on histologic parameters, as well as a growing evidence base suggesting that certain pathways and biomarkers may predict response to IL-2–based immunotherapy. If IL-2 is to remain an active treatment option for patients with renal cell carcinoma, further delineation of patients most likely to benefit must be provided because of the potential morbidity associated with this treatment (see McDermott and Atkins).

Much of the efforts establishing the role of targeted therapy in renal cell carcinoma have arisen from preclinical laboratory-based experiments. With the understanding of the effects of the von Hippel Lindau gene mutation, physician/scientists have helped us to understand how to approach this disease at a molecular level. It is because of these seminal works that we now have additional treatment options targeting pathways that have been identified to be important in sporadic renal cell carcinoma. Future breakthroughs in the treatment of renal cell carcinoma will most certainly come from a better understanding of the molecular biology, the interaction of differing targeted pathways, and the integration of molecular therapeutics to inhibit those pathways that lead to cell growth. Angiogenesis inhibitors now form the backbone of the treatment paradigm for metastatic renal cell carcinoma. In December of 2005, Sorafenib was approved for advanced renal cell cancer, in January 2006 Sunitinib was approved for the treatment of advanced renal cell carcinoma, and with the plenary session presentations at ASCO 2006, we can hope that Temsirolimus will have a favorable review during this calendar year as well. Each of these agents targets pathways in kidney cancer that have been better identified in the laboratory with a translation to the clinic. When given alone these agents produce progression-free survival benefits compared to either interferon or placebo, and most recently a survival benefit in poor risk patients treated with Temsirolimus.² The vascular endothelial growth factor (VEGF) pathway and the mammalian target of rapamycin (mTOR) pathway remain at the cornerstone of treatment for renal cell carcinoma. The translation of molecular biology to the clinic has resulted in multiple drug approvals based on positive trials that have extended progression-free survival and overall survival. In 2006, we are using single-agent targeted therapy to benefit patients with kidney cancer; a challenge going forward will be to combine in a scientifically valid approach combinations of targeted agents against multiple pathways to improve on these results (see Kim and Kaelin, Choueiri et al, and Pantuck et al).

Lastly, renal cell carcinoma remains a disease that can be approached immunotherapeutically. Efforts with vaccines in renal cell carcinoma continue to evolve from the perspectives of antigen identification, vaccine preparation, and equally importantly, an understanding of how to modulate the immunosuppressive environment around the kidney cancer cell. We still hope that durable remissions can be obtained with a better understanding of the immune systems interface with renal cell cancer and the development of appropriate strategic approaches (see Kübler and Vieweg).

In summary, renal cell carcinoma has undergone major scientific advances since last reviewed in the Seminars in Oncology; the laboratory has revealed information that has been rapidly translated into the clinic with new drug approvals for the first time in almost 15 years. Continued vigorous pursuit of the understanding of the different histologic and genetic subtypes of renal cell carcinoma in the laboratory will allow us to tailor therapeutic approaches using targeted therapy and vaccines, allow for the proper selection of patients in prospective clinical trials for those people most likely to benefit from the treatments offered, and allow for the continued optimal management of renal cell cancer to evolve by partnership between the laboratory scientist, the genitourinary surgical oncologist, and the genitourinary medical oncologist. The future remains brighter than ever and full of hope.

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References 

1. Motzer RJ, Hutson TE, Tomczak P, et al. Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa (IFN-α) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2006;24(18S):2s;(abstr LBA3)
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2. Hudes G, Carducci M, Tomczak P, et al. A phase III, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-prognosis patients with advanced renal cell carcinoma. J Clin Oncol. 2006;24(18S):2s;(abstr LBA4)
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