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Should new targeted molecular agents be used as neoadjuvant therapy for metastatic renal cell carcinoma?
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Safe to perform cytoreductive nephrectomy after administration of targeted agents
There is a general consensus that the previous therapies, the cytokines interleukin-2 (IL-2) and interferon alfa (IFN), did not significantly shrink the primary tumor in the kidney; thus, it made sense to remove the kidney. The two trials that were published in 2001 and established cytoreductive nephrectomy as the standard of care in the management of metastatic renal cell carcinoma, if the patient is a good surgical candidate, showed significant prolongation of survival in favor of upfront cytoreductive nephrectomy before systemic therapy with IFN. If a patient has symptoms attributable to the primary tumor, such as bleeding or pain, then everybody agrees that a palliative nephrectomy should still be done first to control these symptoms.. However, the ongoing debate is whether upfront cytoreductive nephrectomy is necessary for a patient who has widely disseminated disease and does not have symptoms attributable to the primary tumor. I would argue that it is not necessary to perform the nephrectomy upfront on all patients even if they are surgical candidates for the procedure. It makes sense to treat some these patients upfront with systemic therapy first.
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There are patients who, if they undergo cytoreductive nephrectomy first, would have progressive or even explosive disease and declining performance status within four to six weeks, and thus would no longer be able to receive systemic therapy later. Such patients would actually be harmed by upfront cytoreductive nephrectomy. These patients include those with a number of different risk factors, including anemia, high serum calcium level, high serum lactate dehydrogenase level and multiple organ involvement, especially liver or bone.
Unfortunately, the two trials of cytoreductive nephrectomy did not look at these risk factors to see who developed explosive disease after surgery. Guided by the recently published prognostic models, we now recognize the risk factors that convey a bad outcome for these patients, and, therefore, we are judicious in our recommendation of who should get nephrectomy first.
The other argument that allows us to recommend systemic therapy first is that the novel targeted therapies, unlike immunotherapy, do shrink the primary tumor much better than IFN or IL-2. Thus, the argument that we should do the nephrectomy upfront because the primary tumor in the kidney doesn’t respond to systemic therapy does not hold up anymore.
Some would argue that the data we have on the effectiveness of the newer agents were obtained from studies where more than 90% of the patients had prior nephrectomy, and therefore upfront cytoreductive nephrectomy should remain the paradigm in the management of patients with metastatic RCC. However, those same studies (sunitinib vs IFN; temsirolimus vs IFN vs temsirolimus plus IFN) also showed that patients who did not have prior nephrectomy also benefited from the targeted agents.
I am not suggesting that we should never perform cytoreductive nephrectomy, but the question of timing of nephrectomy is legitimate. We and others are in favor of systemic therapy first followed by delayed nephrectomy. This way, patients who are responding to systemic therapy whose disease is not exploding can then be considered for delayed cytoreductive nephrectomy. Furthermore, we have demonstrated both in patients treated on protocol and in patients treated off protocol, that it is quite safe to perform cytoreductive nephrectomy after the administration of targeted agents.
The activity of the newer agents against the primary tumor and the metastases raises the question whether we will eventually develop highly effective combinations that would obviate the need for cytoreductive nephrectomy completely. That may be years off, but there are patients who actually are now living longer with systemic therapy, without cytoreductive nephrectomy. I can’t say we are curing these patients, but I think we have reset the clock, and we are seeing patients continue to receive and tolerate therapy for many months, maybe even a couple of years, with controlled disease or tumor shrinkage both in the primary tumor as well as metastatic sites.
Nizar Tannir, MD, is an Associate Professor is the Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center.
More data needed on effects of new molecular targeted drugs as upfront therapy
Based on the two studies in 2001 that showed the benefit of surgical removal of the primary tumor in patients who present with metastatic disease, we can still conclude that nephrectomy should be regarded as the standard treatment in selected patients with metastatic kidney cancer who are candidates for immunotherapy.
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But the question is, in this era of molecular targeted agents, should we use the same paradigm in these patients? So far, the data on the response rate in primary tumors is still unclear with regard to the new drugs. We do not know if or how much they benefit from systemic therapy with the new agents.
The phase-3 trials found that the clinical benefit duration from the molecular targeted therapies is limited in patients with metastatic renal cell carcinoma. Progression-free survival with sunitinib was 11 months, and with sorafenib in patients who failed cytokine-based therapy it was closer to six months. So, to which patients should we consider giving the upfront therapies?
Although we may eventually use the new molecular targeted drugs in patients as upfront therapy, we need more data on their effects. I would envision doing this primarily within clinical trials first so we can definitively monitor the effect of the drugs before surgery. Eventually, we would then get a sense of the possible clinical benefit.
Furthermore, shortened up-front treatment may be useful as it could allow us to learn more about the biological activity of the agents by performing biopsies and examining any histological changes brought about by the targeted agents at the time of the nephrectomy.
At this point, though, cytoreductive nephrectomy should still be used initially in properly selected patients with metastatic kidney cancer who are candidates for systemic therapies. Following the surgery patients should receive systemic therapy, either targetd therapy or high-dose IL-2.
In selected patients with metastatic disease, up front systemic therapy may be considered, but we still need to have additional evidence, and well-designed clinical trials will provide that evidence in the near future.
The role of single agent targeted therapies in the neoadjuvant setting is still unclear. These single agents may induce some partial response, but not complete responses.
We really need to have a more potent agent or a systemic combination in order to achieve complete response.
Roberto Pili, MD, is an Associate Professor of Oncology and Urology at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University.