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Targeted agents changing treatment of metastatic renal cell carcinoma
Patient selection and timing of cytoreductive nephrectomy are being questioned.
More than 200,000 people around the world were diagnosed with renal cell carcinoma in 2007, and approximately one-third of those presented with metastatic disease. Historically, the prognosis for this group of patients has been poor, and the treatments administered were considered largely palliative. Within the last decade, however, targeted molecular therapies have shown superiority to immunotherapies interferon and interleukin-2 and have increased progression-free survival.
It is in this context that the role of surgery in metastatic clear cell renal cell carcinoma (mRCC) comes into question. For many years, cytoreductive nephrectomy was performed as an upfront treatment without any concrete studies suggesting a survival benefit. In 2001 this changed, with two identically designed studies indicating a benefit with the procedure followed by systemic immunotherapy.
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Photo by Barry Smith |
As data continue to mount on the efficacy of targeted therapies such as sunitinib (Sutent, Pfizer) and temsirolimus (Torisel, Wyeth), researchers have begun to debate the role of cytoreductive nephrectomy. Is it necessary when some agents have shown activity against the primary tumor? Should it still be used as a first-line treatment followed weeks later by initiation of systemic therapy? Could some systemic therapies now be used before nephrectomy, perhaps leading to better selection of candidates for surgery?
These questions and others have yet to be answered conclusively, but there is little doubt that the management of a difficult and devastating disease is undergoing a revolution.
Cytoreductive nephrectomy
Until 2001, no definitive data on the benefits of cytoreductive nephrectomy existed. Then, two studies were conducted by the Southwest Oncology Group and the European Organization for Research and Treatment of Cancer Genito-Urinary Group. The studies utilized the same design, comparing patients who underwent cytoreductive nephrectomy before systemic therapy with interferon-alpha (IFN-alpha) with patients treated with IFN-alpha alone.
A subsequent analysis pooling the two studies, for a total of 331 patients, showed a significant survival benefit with the surgical procedure.Patients who underwent nephrectomy had a median survival duration of 13.6 months vs. 7.8 months for those who did not (P=.002). Despite the high degree of statistical significance, the researchers pointed out that the overall survival advantage was only 5.8 months for the nephrectomy group. “These two randomized trials showed that cytoreductive nephrectomy prior to immunotherapy had a survival advantage, and thus it became the standard of care,” said Sandy Srinivas, MD, an associate professor of medical oncology at the Stanford University Medical Center in Palo Alto, Calif. A review article she co-authored highlighted the relatively low survival benefit, though, and suggested that the use of the newer targeted therapies could substantially improve that number.
The new drugs
“The challenge with mRCC in 2008 is that we’re still not curing people,” said Eric Jonasch, MD, an assistant professor in genitourinary medical oncology at The University of Texas M.D. Anderson Cancer Center in Houston. “We are doing a lot better than we were, and we’re going to see the survival meaningfully prolonged with the newer agents.”
Although cytoreductive nephrectomy represents half of the previous standard-of-care paradigm, immunotherapy in the form of IFN-alpha or high-dose interleukin-2 (IL-2) represents the other half. Those therapies, however, are being replaced by new targeted molecular agents including bevacizumab (Avastin, Genentech), sunitinib, sorafenib (Nexavar, Bayer) and temsirolimus.
Bevacizumab is an antibody that sequesters vascular endothelial growth factor, which is believed to be involved in the tumor growth molecular pathways.
Sunitinib and sorafenib block the VEGF receptors; both appear to promote tumor shrinkage. Temsirolimus inhibits mammalian target of rapamycin (mTOR) and downregulates the hypoxia response pathway involved in tumor formation. Sunitinib was approved in 2006 based on a study that found the drug more than doubled the progression-free survival when compared to IFN-alpha (P<.001); the progression-free survival for sunitinib was 11 months. The partial response rate was 31% compared to 6% with IFN-alpha (P<.001), and some primary tumor shrinkage was seen as well.
Sorafenib, was approved a year earlier based on a study in patients who had previously failed at least one other cytokine-based treatment. In that setting, sorafenib resulted in a prolonged progression-free survival (P<.01) in 903 patients when compared with placebo. Again, the drug showed some tumor shrinkage in more patients receiving sorafenib than in those receiving placebo.
Temsirolimus, meanwhile, was approved for treatment of mRCC in 2007. A study involving 626 patients with poor prognosis compared temsirolimus alone with temsirolimus plus IFN-alpha and IFN-alpha alone. The temsirolimus alone arm of the study showed a significantly prolonged survival compared to the IFN-alpha alone group (P>.008), as well as longer progression free survival (P<.001). There was little difference between the combination arm and the IFN-alpha alone arm.
Bevacizumab has been approved for other cancers, and data from large phase-3 trials will soon be reported with regard to mRCC specifically. For all of these drugs, the overall survival benefit has not been high when compared to immunotherapy. “We are pushing things forward a little bit, but this has not been a sea change,” Jonasch said in an interview. “We are making real progress, but it is incremental progress. The change from those small steps to where we have a cure fraction of 5%, 15% or 30% will require the integration of systemic therapy and surgery.”
Jonasch and a number of other researchers are attempting to find the best way to bring together cytoreductive nephrectomy with the new agents. Many agree that debulking the primary tumor in a patient with advanced metastatic disease does not appear to make sense. “If more than 75% of your tumor burden is in the kidney along with, say, only a few isolated lung lesions, that patient would be a good candidate to have the kidney removed followed by systemic therapy,” Srinivas said. “On the other hand, if a patient has metastases in bad locations such as the liver, bone or multiple lung sites, that patient is in need of systemic therapy first. After three months of therapy the patient can be reassessed regarding the need for removal of the primary tumor.”
Some of the arguments in favor of presurgical systemic therapy are straightforward. Potential cytoreduction provided by the targeted agent — as has been demonstrated in large trials — can make the nephrectomy easier. Also, the ability to harvest and analyze treated tissue can allow a better understanding of the mechanisms involved in response and resistance to the systemic therapy. Finally, more rapid initiation of systemic therapy could possibly decrease cancer-related morbidity prior to operating on the patient.
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“You really want to control the disease with systemic therapy, and then integrate the surgery with the systemic therapy,” Jonasch said. “The use of systemic therapy as a sort of screening strategy to decide which individuals will most benefit from cytoreductive surgery is going to be an evolving concept.”
There are arguments against changing the standard of care as well. One argument is that there is little evidence available suggesting that the standard of care need be changed. “Cytoreductive nephrectomy has been a major part of all the clinical trials that have been done in kidney cancer with the targeted therapies,” said Robert Figlin, MD, a professor of medical oncology and the medical oncology chair and associate director of clinical research at City of Hope Cancer Center in Duarte, Calif. “Although these agents have activity and may cause control of the disease in the primary tumor, I think the standard of practice in 2008 is cytoreductive nephrectomy followed by systemic therapy.”
Figlin said that although neoadjuvant therapy is an interesting and potentially useful concept, until more studies have been done it should not be considered. “I know of no data to support treatment of systemic disease as a way to identify people who are most likely to benefit from surgery,” he told HemOnc Today. “Outside of a clinical trial I would not use that paradigm.” Another argument against up-front systemic therapy points out that if the initial therapy fails to induce a response, the window for performing the nephrectomy may close due to worsening performance status of the patient.
Ongoing and future research
A number of clinical trials are ongoing in attempts to answer these questions. Several randomized prospective trials are moving forward in Europe comparing preoperative to postoperative systemic therapy. The Gruppo Italiano Mammella is conducting one of these, a phase-2 study using sunitinib, and another will most likely begin soon at M.D. Anderson Cancer Center. Jonasch and colleagues have recently finished enrolling patients for a neoadjuvant trial of bevacizumab as well. Srinivas said that one of the most important benefits to these trials will be the ability to study the kidney tissue that is removed and how the targeted therapies affected it preoperatively.
Other studies aim to increase the knowledge base for the newer agents by testing various combinations as well as the use of some drugs as second-line therapy once another of the molecular agents has failed. One example of the combination therapy studies, which is scheduled to begin recruiting shortly, will compare bevacizumab plus temsirolimus to bevacizumab plus IFN-alpha.
“There is a lot of work to be done in terms of developing the targeted therapies and learning how to optimally use them, including in patients with the primary tumor still in place,” said Brian Rini, MD, from the department of solid tumor oncology at the Cleveland Clinic Taussig Cancer Institute and Glickman Urology and Kidney Institute, Ohio. “I think multimodal therapy is certainly going to be the prevailing treatment paradigm. For some patients that may involve systemic therapy up front followed by surgery, and for others debulking nephrectomy initially followed by appropriate systemic therapy may be reasonable.”
Even though a shift in the timing of nephrectomy is clearly still up for debate, most appear to agree that patient selection for the procedure is even more crucial in the era of molecular targeted therapies. “I think in practice, people are not readily jumping to do a cytoreductive nephrectomy on everyone who is diagnosed with kidney cancer with metastatic disease,” Srinivas said. With the new drugs showing activity in the primary tumor as well as for the metastases, patients who are at high risk of having progressive disease during the recovery from surgery may be harmed more than helped by an initial nephrectomy.
Figlin outlined some of the notable risk factors that should influence the decision to perform a nephrectomy. “If a patient has symptoms attributable to the primary tumor, such as bleeding, pain or local symptomatology, or if the plan is for the patient to receive IL-2 therapy, then the paradigm is to take the tumor out and then treat the metastatic disease,” he said. Patients with poor performance status or a small primary tumor but large volume metastatic disease, however, would most likely benefit more from immediate systemic therapy.
“An important point is that there are good data to support debulking nephrectomy in metastatic kidney cancer,” Rini said. “Everyone agrees that we need to appropriately select patients, whether you are a strong believer or a weak believer. If we send inappropriate patients then it is not going to benefit them or the group as a whole.”
The volume of trials further testing the targeted molecular agents as well as those examining their neoadjuvant use underscores the rapidity with which the field of metastatic renal cell carcinoma is changing, although the use of up front cytoreductive nephrectomy in appropriate patients remains the standard of care. “There is no question in my mind that the overall survival of metastatic kidney cancer patients is now significantly better than it was 10 years ago, or even six or seven years ago in the era before these agents emerged,” Rini said. “There are a lot of new questions to ask and answer now that we have more active drugs in our repertoire.” – by Dave Levitan
For more information:
- Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Proc Am Soc Clin Oncol. 2005;23:4510.
- Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004;171:1071-1076.
- Harshman LC, Srinivas S. Current status of cytoreductive nephrectomy in metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2007;7:1749-1761.
- Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281.
- Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2007;57:43-66.
- Jonasch E. Presurgical therapy in metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2007;7:73-78.
- Margulis V, Wood CG. Cytoreductive nephrectomy in the era of targeted molecular agents: Is it time to consider presurgical systemic therapy? Eur Urol. 2008;doi:10.1016/j.euroro.2007.12.041.
- Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib vs. Interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124.
- Rini BI, Campbell SC. The evolving role of surgery for advanced renal cell carcinoma in the era of molecular targeted therapy. J Urol. 2007;177:1978-1984.