OncoLog

 

From OncoLog, May 2012, Vol. 57, No. 5

Compass: Advanced Renal Cell Carcinoma

By Sunni Hosemann

Introduction

This discussion addresses renal cell carcinoma (RCC) with one or more distant metastases. Rarer renal cancers such as renal sarcoma and Wilms tumor are not considered here.

RCC, which accounts for 85%–90% of renal cancers, has five histologic types. Clear cell histology, often called conventional RCC, is seen in 80%–85% of RCCs. Papillary cell RCC accounts for another 10%–15% of RCCs, and the remainder are chromophobe RCC, collecting duct RCC, or unclassified RCC.

Our discussion includes those RCCs in which the patient presents with a primary kidney tumor and one or more distant metastases and those in which the patient has had a previous nephrectomy and now presents with metastases. In either case, the metastases may occur at one site or be multifocal, and there may or may not be lymph node involvement because renal cancers often spread hematologically to distant sites before involving lymph nodes. The most common sites for distant metastases from RCC are the lungs and mediastinum, bones, liver, lymph nodes, adrenal glands, and brain, but metastases may involve any organ.

RCC is amenable to curative surgery if discovered at an early stage, but unfortunately, a large percentage of patients will require treatment for advanced disease. According to Eric Jonasch, M.D., an associate professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, 25%–33% of RCC patients present with metastatic disease, and 20%–40% of patients who undergo treatment for localized disease will develop metastases later. “In short, this means that approximately half of patients with RCC will require treatment for metastatic disease,” he said.

The high incidence of metastatic disease suggests a need for effective systemic therapies for the initial treatment of patients who have advanced disease and for adjuvant use in those with lower stage disease who are at risk of progression. How ever, until recently, few useful systemic agents had been identified.

Because RCC has proven particularly unresponsive to traditional (cytotoxic) chemotherapy agents, these are not used in the treatment of RCC with one exception: patients whose tumors have sarcomatoid features are treated with gemitabine and doxorubicin or with other agents that have activity against sarcoma. Any of the histologic subtypes of RCC may exhibit a component of sarcomatoid differentiation, which is thought to be a high-grade transformation that portends a more aggressive course of disease.

For most RCC subtypes, few options were available for the treatment of metastatic disease or for patients at high risk of developing metastases until cytokine immunotherapies, notably interleukin-2 (IL-2) and interferon alfa, emerged in the 1990s. High-dose regimens of IL-2 were found to produce complete remissions in 6%–8% of patients with metastatic RCC and a cure in 5%. However, high-dose IL-2 is highly toxic and thus appropriate only for the subset of patients who can tolerate it and are likely to benefit from it: those with clear cell histology, good performance status, and a small metastatic burden. Furthermore, the regimen requires hospitalization and should be administered only in a center with specialized supportive care.

Interferon alfa produces more modest benefits but has a lower toxicity profile and is easier to administer than IL-2. Thus, interferon alfa has been used in more patients and more research protocols than has IL-2. Because interferon alfa has not demonstrated a survival benefit over other agents, it is not currently used as a first-line, single-agent therapy but is used in combination with newer targeted agents.

A new era in the treatment of metastatic RCC commenced around 2005, when targeted agents with activity against RCC began to appear. Since that time, the median survival for patients with metastatic RCC has increased from 10 months to more than 20 months. The development of these agents grew out of an increased understanding of RCC pathogenesis at the molecular level, in particular from the study of the von Hippel–Lindau tumor suppressor gene (VHL). A challenge for using these agents is deciding which one to give to a particular patient and how best to deploy them along with surgical interventions.

Seven targeted agents have been approved by the U.S. Food and Drug Administration for use in metastatic RCC. Sunitinib, sorafenib, pazopanib, axitinib, and bevacizumab are antiangiogenic agents targeting the vascular endothelial growth factor (VEGF) pathway, and temsirolimus and everolimus are mammalian target of rapamycin (mTOR) inhibitors. “Whereas conventional cytotoxic chemotherapy targets the tumor cells, the anti–VEGF agents target the microenvironment—the milieu in which they grow,” said Nizar M. Tannir, M.D., an associate professor in and deputy chair of the Department of Genitourinary Medical Oncology.

The targeted agents are easier to administer (many are oral agents) and have fewer side effects than traditional immunotherapies. According to Surena F. Matin, M.D., an associate professor in the Department of Urology, the advent of these new agents has changed the paradigm for the treatment of advanced kidney cancers. “The old approach was to remove the kidney first, even in patients with metastatic disease,” he said, “but the new classes of medicines available today are changing that, and we have more options.”

Treatment options

The standard treatment options for patients who present with metastatic RCC are nephrectomy and metastasectomy, cytoreductive surgery followed by systemic therapy, or first-line systemic therapy.

The approach for an individual patient is best determined by a multidisciplinary team in which medical and surgical oncologists collaborate to weigh the many factors to be considered.

Surgery

Among the first tasks in weighing a patient’s treatment options are to assess whether the disease is resect able and to determine the patient’s ability to tolerate surgery. Resectability depends largely on the location and distribution of primary and metastatic disease. Dr. Matin said that surgery to excise disease (nephrectomy and metastasectomy) is a reasonable consideration for a patient whose disease is primarily in the kidney with a small metastatic burden—perhaps a solitary metastatic lesion—or for a patient who presents with a solitary metastasis after a previous nephrectomy. Conversely, a patient with a small primary tumor and a larger metastatic burden—perhaps multifocal metastases—is less likely to benefit from surgery.

Additional considerations can help identify patients who will benefit from surgery and spare others from an ineffectual operation. The following risk factors—which were identified in a study led by Christopher Wood, M.D., a professor in and deputy chair of the Department of Urology—indicate that surgery is not likely to help, as survival outcomes are about the same for patients with more than three of these factors regardless of whether the patients do or do not undergo surgery:

  • symptoms from metastases,
  • elevated lactate dehydrogenase (LDH) levels,
  • metastases in the liver,
  • retroperitoneal lymph node involvement,
  • supradiaphragmatic lymph node involvement, or
  • a locally advanced primary tumor.

For some patients, nephrectomy may be indicated to alleviate symptoms, notably pain and hematuria.

Patients with potentially resectable primary tumors and multifocal resectable metastases may benefit from cytoreductive surgery followed by systemic therapy. Cytoreductive surgery became part of the therapeutic regimen for metastatic renal cancers with the advent of immunotherapies in the early 1990s.

According to Dr. Wood, the cytoreductive surgery involves the removal of as much tumor-bearing tissue as possible, including that at the primary site, lymph nodes, and metastases.

Studies of cytoreductive surgery followed by immunotherapy showed that while not all patients benefited, some had a clear survival benefit, and criteria to select candidates for this treatment emerged. These criteria are good performance status; the presence of clear cell histology; the absence of brain, liver, or bone metastases; and the absence of sarcomatoid features.

Postoperative systemic therapy

Despite the advent of targeted agents, high-dose IL-2 therapy (preceded by cytoreductive surgery) remains the only known cure for metastatic RCC. Because of the rigor and toxicity of this treatment course, however, it must be used judiciously in carefully selected patients. Although only a small percentage of patients will be able to receive this treatment, it is important to identify potential candidates before any other agents are administered because studies indicate that the benefit is less and the toxicity may be higher for patients who have received targeted therapies prior to IL-2 than for those who have not. The selection criteria for IL-2 treatment are a good performance status without significant comorbidities, clear cell histology, and adequate risk scores.

The two risk scoring systems most often used by clinicians to direct RCC therapy are the Memorial Sloan-Kettering Cancer Center (MSKCC) and the University of California Los Angeles Survival after Nephrectomy and Immunotherapy scales. The widely used MSKCC risk score takes into account the patient’s performance status, the length of time from initial diagnosis of RCC to initiation of therapy, and serum LDH, hemoglobin, and calcium levels to stratify patients as having favorable, intermediate, or poor risk. In addition to these factors, the patient’s attitude toward risk must be addressed and taken into account when high-dose IL-2 therapy is considered.

For patients who are not candidates for high-dose IL-2 therapy, postoperative systemic therapy options include the newer targeted agents.

Dr. Jonasch said that bevacizumab is used in tandem with interferon alfa, but sunitinib, sorafenib, pazopanib, axitinib, temsirolimus, and everolimus are currently used singly and sequentially rather than in combination. Although the idea of using combinations that target more than one pathway or different parts of a single pathway is logical, early phase I and II trials indicated that the drugs’ toxicities tend to be additive, even when drugs with differing toxicity profiles are used. “Although the ultimate goal of these agents is to be able to target the molecular profile of each individual tumor and thus truly personalize treatment, we are not at that point yet,” Dr. Tannir said. Thus, for now, the choice of which agents to use and how to sequence them is decided on the basis of tumor histology and the prognostic risk scores described above.

In general, the antiangiogenic agents appear to be most helpful for patients in the favorable and intermediate risk groups, and the mTOR inhibitors have been shown to benefit patients in the poor risk category. However, the effectiveness of combining cytoreductive surgery with newer targeted agents in the same manner as IL-2 has yet to be determined in clinical trials.

First-line systemic therapy

Agents recommended for first-line treatment of metastatic RCCs with predominantly clear cell histologies include sunitinib, sorafenib, pazopanib, bevacizumab, and temsirolimus. As clear cell histologies are the most common, more data about them are available from studies than for the rarer non–clear cell types. Although some data support the use of sunitinib, sorafenib, temsirolimus, and erlotinib in the treatment of non–clear cell RCC, patients with these histologies are currently best served in clinical trials of experimental agents.

Systemic therapy is indicated as an initial treatment for patients who do not meet the criteria outlined above for nephrectomy/metastasectomy or cytoreductive surgery followed by systemic therapy. The group not meeting the criteria for surgery includes patients who present with a large metastatic burden or other characteristics that place them in the poor risk group—a category of patients for whom there were no effective therapies prior to the development of targeted agents.

In some patients, initial systemic therapy can shrink a large primary tumor and render it amenable to surgery. Reducing disease burden can also enhance fitness for surgery in some patients.

Other patients considered for first-line systemic treatment at MD Anderson are those who have the risk factors listed above that indicate they would be unlikely to benefit from surgery. “In these instances, systemic therapy can provide a therapeutically rich period of observation,” Dr. Jonasch said.

Dr. Tannir explained that giving targeted therapy before nephrectomy can help determine whether a patient is likely to benefit from surgery. After receiving systemic therapy, as many as 20% of such patients will have progressive disease. These patients would not benefit from surgery and can thus be spared its morbidity. Patients without progressive disease usually undergo cytoreductive nephrectomy at a time determined to be optimal for each patient or, in patients treated in clinical trials, after a fixed number of cycles of a particular agent. “Systemic therapy is a way of letting the disease declare itself,” he said. MD Anderson pioneered this approach, which has an additional benefit: “We can interrogate the tissue eventually removed in surgery to analyze key pathways and targets and compare them to untreated tissue from nephrectomy and metastasectomy specimens,” he said. This information can be used to guide future research and therapy.

Many patients respond to first-line treatment with targeted agents, and their disease stabilizes. But these agents have not proven curative, and most patients treated with them will eventually experience disease progression. “We need to understand more about what determines response and disease progression,” Dr. Tannir said. “What happens in the tumor and its microenvironment that causes the drug to cease being effective?”

Some patients can enjoy years of partial or near-complete remission but over time develop other health issues related to cumulative toxicities of therapy. The most common of these issues are nephrotic syndrome and hypertension. “We need to better understand the mechanisms involved,” Dr. Tannir said, noting that some of the effects are not simply side effects but may actually be markers of response to the drugs. “We need a concerted effort to work with specialists in nephrology, cardiology, pulmonology, and endocrinology to better understand these complications and how to manage them.”

Observation

Although observation (without treatment) is not listed among the standard alternatives for managing RCC, Dr. Tannir said that this is the wisest initial course for a minority of patients because the disease must be assessed in the context of a patient’s overall health, comorbidities, and life expectancy. “This is part of the art of medicine that cannot be listed in templates or guidelines,” he said. For example, patients who present after a previous nephrectomy with small and asymptomatic metastases in the pancreas, lymph nodes, or lungs may have indolent disease, particularly if an extended period has elapsed since initial treatment. For such patients—particularly if they are elderly or have significant comorbidities—the RCC is less likely to shorten life compared with the comorbid illnesses. For these patients, treatment may pose unnecessary risk or negatively impact quality of life and may reasonably be deferred until their disease progresses.

On the horizon

Although recent advances in understanding RCC have resulted in agents that target the disease at the molecular level, it is not yet possible to match specific agents to individual histologies in a truly customized way.

Ongoing studies continue working toward the goal of individualized therapy. One of the most important initiatives at MD Anderson is the Sequential Two-Agent Assessment in Renal Cell Carcinoma Therapy (START) trial. Dr. Tannir is the principal investigator of the study, in which patients with metastatic clear cell RCC and a prior nephrectomy are randomly assigned to receive one of six two-agent sequences of everolimus, bevacizumab, or pazopanib, receiving one of these three agents up front and a different one when disease progression is noted. An important part of this trial is the collection of tissue and blood samples along with functional imaging studies to observe response and disease progression. “We will learn about the characteristics of patients who respond and their profile when the disease progresses,” Dr. Tannir said.

Dr. Tannir pointed out that in the excitement over targeted agents, less attention has been focused on immunotherapies. But two newly identified immune pathways (PD1 and CTLA4) and agents that target them have rekindled interest in immunotherapies.

Finally, although von Hippel–Lindau disease is rare, the study of RCC associated with the hereditary disease will play a pivotal role in determining the best sequence of newer agents. Dr. Jonasch explained that many of the nonhereditary RCCs have a VHL mutation that exists only in the tumor. In patients with von Hippel–Lindau disease, however, the mutation can be seen in other cells, such as white blood cells, which are more amenable to study. Dr. Jonasch said the study of VHL mutations and the agents that act on their pathways could lead to better treatments for all patients and help determine the best sequence of treatment for each individual. Stressing the importance of finding effective first-line treatments, he said, “You don’t have an infinite number of times to intervene with kidney cancer.”

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Eric Jonasch, M.D.
Associate Professor, Genitourinary Medical Oncology

Surena F. Matin, M.D.
Associate Professor, Urology

Nizar M. Tannir, M.D.
Associate Professor and Deputy Depart ment Chair, Genitourinary Medical Oncology

Christopher G. Wood, M.D.
Professor and Deputy Department Chair, Urology

References
Hudes GR, Carducci MA, Choueiri TK, et al. NCCN Task Force report: optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy. J Natl Compr Canc Netw 2011;9(suppl 1):S1–S29.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300.
Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22:454–463.
National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology, Kidney Cancer, V2.2012 [PDF].

For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.

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