Kidney cancer: An Interview with Dr. Kimryn Rathmell

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Julia Draznin Maltzman, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 4 de julio del 2004

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Renal cell carcinoma is a very rare, but lethal disease. It affects roughly 30,000 people each year, 40% of whom will eventually die of their disease. The most prominent risk factor is smoking, although many non-smokers get diagnosed with this disease. Some occupational exposures have been linked to the development of kidney cancer. Such compounds as asbestos, cadmium, and petroleum by-products have been found to be associated with renal cell carcinoma. More recently, obesity has been implicated in the pathogenesis of kidney cancer, although the mechanism is not exactly understood. Certain patients who have diseases such as polycystic kidney disease or chronic kidney failure are at higher risk for developing kidney cancer. Some recent data showed that prolonged use of analgesics, especially those containing aspirin, is associated with the development of this cancer as well. Finally, genetics does play a big role in kidney cancer, especially among those who get diagnosed under the age of 30.

Most often doctors talk about kidney cancer presenting with the "classic triad" of flank pain, bloody urine, and an abdominal mass that may be palpable on physical examination. However, kidney cancer is also dubbed "the internists' disease", in that it has a reputation for presenting in very unusual, atypical, and often seemingly innocuous ways. If kidney cancer is suspected, some sort of imaging study such as an ultrasound, a CT scan, or an MRI is imperative. A biopsy is the only way to confirm the presence of a cancer. The stage of the disease must then be ascertained. Kidney cancer that has spread beyond the kidney carries a worse prognosis than disease that is limited to the kidney itself. When possible, surgery is offered to the patient as it offers the best chance for cure. Surgery can consist of removal of the kidney, and, in some instances, includes removal of any isolated metastasis that may be surgically accessible. Cryoablation and radiofrequency ablation may be offered to patients who cannot tolerate surgery for medical reasons. The role of chemotherapy and immunotherapy have traditionally been frustratingly unsuccessful in the treatment of this tumor. Recently, however, kidney cancer has made the headlines with a New England Journal of Medicine article touting the use of Bevacizumab (Avastin, Genentech) in this disease. The future is looking brighter for this traditionally difficult to treat disease.

OncoLink is honored to obtain the latest insight by a discussion with one of the world's leading experts in this cancer. Dr. Kimryn Rathmell trained at Stanford, University of Chicago, and the University of Pennsylvania. She is now on faculty at University of North Carolina and provides us with her unique expert perspective. She treats exclusively kidney cancer patients and directs her own laboratory that is looking at the pathogenesis of kidney cancer.

OncoLink: What is known about the way renal cell carcinoma (RCCa) develops, grows, and spreads?

Dr. Rathmell: This is a very complex question and touches on the molecular, cellular, and systemic aspects of this disease. However, in answering we can overview many of the difficult issues associated with this cancer. RCCa occurs as a result of a series of genetic changes or mutations in the DNA of cells derived from the kidney. The gene that is most commonly mutated in this cancer is called the von Hippel Lindau (VHL) gene and it is very well studied. This is named for a familial syndrome in which affected family members are at a very high risk for developing RCCa. More sophisticated studies of RCCa's have shown that in addition to mutations in VHL (an average of five) are required for a cancer to develop. Many carcinogens have a link to RCCa including smoking and an occupational exposure to bromine. Two of the more intriguing associations with RCCa are the significant ties with kidney disease / long term hemodialysis use, and suppression of the immune system. RCCa tumors often contain a mixture of cystic and solid tissues. RCCa may develop from benign cysts, although, kidney cysts are fairly common and RCCa is relatively rare. RCCa growth is very hard to characterize and can range from indolent growth (slow tumor doubling time) to an explosive progression of cancer. A given individual will not know the pace of the growth of their disease until some time has passed and objective evaluation (by CT scan or MRI) is possible. Unfortunately, even in a single patient, the growth characteristics can change without warning, so vigilant observation is necessary even for those patients that appear to have very slowly growing disease. Even before the tumor has spread outside of the kidney it can grow into the veins that drain the kidney. This pattern of growth is typically associated with a worse outcome. When RCCa spreads outside of the kidney, the first place it usually goes is the surrounding lymph nodes or the adrenal glands, which are positioned on top of the kidneys. The most common site for distant metastases is the lung, although RCCa can also be found in the liver, bone, or brain. Unlike most other cancers, if the sites of metastatic disease are easily removed with surgery a small number of patients can still be cured.

OncoLink: What is the role for surgery?

Dr. Rathmell: Surgery is still the mainstay of treatment in this disease regardless of the stage. If the tumor is confined to the kidney, surgical resection is a curative treatment in more than half of patients. Even after the disease has spread outside of the kidney, there is a proven benefit to removing the primary kidney tumor in addition to any other appropriate therapy. Furthermore, resection of metastatic sites (such that may occur in the lungs) can also be curative for a selected group of patients that have very limited and accessible metastatic disease. Currently available techniques have made a nephrectomy (surgical excision of the kidney) a much more tolerable and less invasive surgery. There is the growing experience with hand assisted laparoscopic nephrectomy (HALN). This less invasive procedure is associated with decreased blood loss, a shorter recovery time, and a shorter hospitalization and can be considered in most cases of RCCa.

OncoLink: What kind of therapy is available for RCCA?

Dr. Rathmell: The pharmaco-therapeutic approach to RCCa is unique among solid tumors. Because there is no effective cytotoxic therapy, currently available treatments are designed to attempt to boost the body's own immune system to recognize the tumor as a foreign tissue and eliminate it using the immune mechanisms already in place. This approach has potential to work in kidney cancer because RCCa has been anecdotally observed to shrink as a result of naturally occurring changes in the immune system. The only FDA-approved treatment is high dose therapy with a cytokine called IL-2. IL-2 works by activating the most potent killer cells of the immune system. However, this drug is very toxic at the doses required for kidney cancer treatment, and can cause organ failure or even death in a very short period of time. Although these serious effects are not common, because of the severity of this treatment, many patients are excluded from even trying this option due to other medical issues (such as heart disease). Furthermore, many hospitals will not support IL-2 therapy. It must, therefore, be administered only at certain regional centers by experienced physicians and nurses. Despite to the toxic side effect profile, the treatment only offers a 15-20% chance of response by the tumor. However, the small proportion of the patients who do respond can have a response lasting several months or even years. For patients who are not physically fit enough to tolerate high dose IL-2 or those who do not have access to a center which provides this treatment, many practitioners have adopted a low dose long-term treatment plan with either IL-2 or interferon-alpha (another cytokine with similar action to IL-2), or a combination of both agents. Although the treatment is better tolerated, it does have a smaller response rate, and because of the long-term nature of the treatment (6 months or more) many patients find the treatment intolerable. When these drugs fail, sometimes, traditional cytotoxic chemotherapy agents are given, although these drugs usually have an even smaller rate of success in this disease. Treatment with radiation is reserved for treatment of symptomatic metastatic sites. Because of the rather dismal outlook for current treatment modalities for RCCa, this cancer is unique in that it is widely accepted that most patients with metastatic disease should seek out and participate in a clinical trial aimed at advancing the present standard of care.

OncoLink: What do you see for the future of RCCA?

Dr. Rathmell: Although the current therapy for RCCa is not promising, for the first time in decades some real breakthroughs have been made for treatment targeting both the immunologic aspect of the disease as well as the fundamental genetics of RCCa (mutations in VHL). First, significant interest in expanding the role immune mediated tumor response has spawned a number of studies evaluating immunization of patients with a tumor vaccine. The assumption being that a more sustained and more effective immune response will be attained by "training" the immune system to recognize the tumor as a foreign tissue. Second, is the recent explosion in the development of pharmacologic agents that block signaling pathways that are important for the growth of RCCa. The first of these to gain national attention is Bevacizumab, (Avastin, Genentech) an antibody inhibitor of blood vessel growth. This signaling pathway is uniquely important to RCCa because the common mutation of VHL causes a string of events that promotes the cell to "turn on" a large number of genes involved in the cell's response to oxygen deprivation. One part of this response in the normal state is the recruitment of blood vessels to an area of reduced oxygen in order to bring blood and oxygen closer to the affected cells. One of the proteins that recruits blood vessels is called Vascular Endothelial Growth Factor (VEGF). VEGF is "turned on" inappropriately in RCCa cells along with many other genes that assist the cell in a low oxygen environment because of the mutation in VHL. Bevacizumab blocks VEGF from being able to recruit blood vessel growth, which is detrimental to tumor growth and ultimately leads to cancer cell death. Patients given this drug on average had a longer time before their tumors grew, suggesting that blocking this pathway is an important step in treating this cancer. This drug is now undergoing the final stages of investigation in RCCa. Additionally, there are other drugs not yet as mature as bevacizumab, which are showing promise in early clinical trials, and, I believe, are poised to change the way we treat advanced RCCa.

OncoLink: What other research is going on in RCCa?

Dr. Rathmell: A tremendous amount of research is currently ongoing specifically directed at understanding the biology and treatment of RCCa, although this kind of research can be difficult to fund because this cancer type is not as high profile as others. We are constantly learning more about the genetics of RCCa, which has already had an impact on emerging treatments, and will certainly aid in refining and supplementing treatments. With this information, an important step, which has not yet been accomplished, is the development of a reliable animal model of RCCa. This is the primary focus of my research. Others have exploited the newer targeted therapy approaches using small molecules. These are being tested in RCCa and show promise in preliminary studies. However, these trials are not yet mature enough to change clinical practice.



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