GU Oncology Now met with A. Ari Hakimi, MD, an associate attending surgeon in the Department of Urology at Memorial Sloan Kettering Cancer Center, to discuss how cytoreductive nephrectomy has evolved and is being utilized in today’s metastatic renal cell carcinoma (RCC) treatment paradigm.
What is cytoreductive nephrectomy and how is it used clinically?
Dr. Hakimi: Cytoreductive nephrectomy refers to the removal of the primary tumor and, in the context of metastatic RCC, the kidney. It is a procedure that has been utilized since the 1990s, and it was considered standard of care in the early 2000s after 2 randomized clinical trials demonstrated its benefit. It’s a longstanding operation that has been used primarily for 2 reasons. The first is that kidney tumors were often diagnosed very late, and often patients were symptomatic. In this scenario, there was palliative benefit to removing a primary tumor because doing so could take away the pain and bleeding for patients.
The second reason is that there were very limited systemic therapy options available at the time of its popularity. There was some thought that removing the bulk of the tumor would lead to potential survival advantages for patients. However, in the 2010s, advent of immune checkpoint blockade therapies moved the standard of care away from cytoreduction and toward systemic therapy.
That is the historical context of cytoreductive nephrectomy. Its use today has obviously changed quite a bit due to the evolution of how we treat kidney cancer.
What is the theory or understanding of how or why cytoreduction may benefit a patient? Is it not too late for cytoreduction once the disease has metastasized?
Dr. Hakimi: The belief that cytoreduction could benefit patients started anecdotally. There were cases where the primary tumor was removed, followed by disease regression. The metastasis disappeared altogether.
Kidney cancer is one of the unique cancers that always seemed to have this immunologic response. Even before we had conventional immunotherapies, there were earlier, much cruder methods to induce an immune response that were very toxic. There has always been this notion that it is an immunologically active tumor type, and the early data suggested that if we removed a primary tumor, we could see regression in the metastatic sites.
The prevailing rationale today, with the biological and genomic understanding of the diversity of tumors, is that the primary tumor is much more genetically diverse than we ever knew. The primary tumor has many diverse components to it, so-called “clones” of cancer. One or a few of those will escape to develop metastasis. But if we remove the primary tumor, we are also removing that diversity, which has the potential to make treatment more effective because there’s less ability for the cancer to continue to evolve.
Which patients are considered optimal candidates for cytoreductive nephrectomy today?
Dr. Hakimi: The consensus on optimal candidates is evolving to this day. Before we had the recent data to challenge the appropriateness of cytoreduction, we relied on old trials from the 1990s and 2000s, which highlighted not-so-effective immunotherapies like interferon alpha or interleukin 2. A small series of randomized trials published in the New England Journal of Medicine showed that patients randomized to cytoreduction had an increased survival benefit of a few months compared with those randomized to immunotherapy. The data was largely interpreted to mean that everybody should be considered a potential candidate for cytoreduction.
Years later, as a result of retrospective data, we started to consider only patients with favorable or intermediate risk for cytoreduction. In the data analyses, patients who received systemic therapy did not perform as well as those who underwent cytoreduction. There has always been pushback on these analyses that there is selection bias involved; the argument is that only the patients who are fit enough to have surgery in the first place actually received the surgery. So perhaps those patients lived longer because they were more fit to begin with?
This notion was challenged in 2018 in the French CARMENA trial, which randomized patients to anti-vascular endothelial growth factor (VEGF) therapy, a commonly used treatment for kidney cancer (though no longer considered standard of care). Patients received either anti-VEGF therapy alone or surgery plus anti-VEGF therapy. In short, the results suggested no survival benefit for cytoreduction, and many thought it should only be used for palliative purposes.
CARMENA was problematic for a few reasons. First, it didn’t accrue the initial goal number of patients. Second, the patients were spread out over 70 centers in France, and the median number of nephrectomies done per year was less than 1 in a lot of those centers. Furthermore, patients were not selected based on performance status and other risk criteria. All patients were included, and many of the patients who did not do well were poor-risk patients to begin with. There was never any expectation that they should undergo cytoreduction in the first place.
While CARMENA made a big splash, there was still a ton of pushback. Today, at Memorial Sloan Kettering as well as most major centers in the United States, patients with low-volume metastatic disease and good performance status undergo upfront cytoreduction followed by best standard-of-care treatment.
What role does consolidative cytoreduction have in today’s treatment paradigm?
Dr. Hakimi: With the newer immunotherapies and combinations, we’re seeing such great responses. As a result, we’re recommending that some candidates who are borderline candidates for surgery begin first with treatment, and then they come back for what’s called consolidative cytoreduction. Some patients who are not candidates for upfront surgery get systemic treatment for 3 months or up to 2 years and then come back for removal of the primary tumor.
This is done commonly today for a few reasons, one being that patients are responding well to treatment and the only remaining sign of disease is in the primary tumor. Another reason is they are responding well to treatment, but the primary tumor continues to grow. Lastly, in some patients, the primary tumor is causing symptoms while they are receiving treatment. They may be bleeding a lot, which interferes with their ability to get treatment.
Thus, while it’s becoming more common to integrate cytoreduction into a later part of patient care, it is an important part of treatment and likely will remain so, certainly for the foreseeable future. Of course, the biological justification remains; even patients who are responding well to treatment benefit from removal of the primary tumor because removal eliminates some of the diversity that could potentially evolve over time, leading to future metastases and resistance to therapy.
Are there currently ongoing trials to evaluate this consolidative approach?
Dr. Hakimi: There are a few trials that are looking at an integrated approach of upfront treatment followed by cytoreduction or just upfront treatment alone. One study that comes to mind is PROBE, a phase 3, randomized trial for currently used treatment only or treatment plus cytoreduction. PROBE is likely to be more impactful than CARMENA because better drugs are being given and it is restricted to larger centers in the United States where you would expect to see better outcomes for those patients.
Consolidative trials are difficult to enroll because patients are often not willing to delay anything they believe to be in their best interest. Many patients say, “I want the big part of this out right away” rather than taking their chances with treatment. It requires a lot of integrative discussions with the medical oncologists, the surgeons, and the patients to explain the complexities of why upfront treatment may be a better option in some cases.
What are the noteworthy adverse events or risks associated with cytoreductive nephrectomy? When do the harms outweigh the benefits?
Dr. Hakimi: Just like any other treatment option, it is about selection and choosing the right patient at the right time. There are numerous data sets that suggest that high-volume centers have better outcomes with surgery in general. Cytoreduction is certainly no exception to that trend.
We at Memorial Sloan Kettering like to compare our data with that of other big centers like Mayo Clinic and MD Anderson. Across all of these institutions, cytoreduction is associated with better outcomes in terms of the patients living longer with fewer complications.
We know that surgery itself can induce an immunologic storm in some patients, albeit not many. For this reason, we’ve shied away from operating on very symptomatically ill patients. We know that they won’t do well with surgery and will have a lot of complications afterward. They may end up developing ascites, which can make systemic treatment very complicated. They may also develop blood clots or other debilitating issues, and that can impact their ability to get systemic therapies. We believe that operating on these patients will do more harm than good. They are definitely not the right group for cytoreduction.
Are there any biological or genetic markers that help predict survival benefit after cytoreduction?
Dr. Hakimi: We have noticed that for some patients after surgery, their clinical risk group (IMDC or MSKCC risk group) can change. Some of the blood-based values are dynamic and can improve following surgery, placing the patients in more favorable risk categories. The blood-based values are sort of an overall measurement of your body’s immune response to the tumor. These are all surrogates for immunologic control, so to speak. When they revert back to a better risk group, it implies that equilibrium between the body and the cancer has shifted toward the body’s control.
There are other emerging biomarkers on the horizon. Many of us are interested in circulating tumor DNA (ctDNA), though its role in cytoreduction remains to be seen. For example, if a patient had a certain level of ctDNA, underwent surgery, and then that level drops off to undetectable, will that be continuously beneficial for that patient?
As for mutational biomarkers, there really are not any emerging signals at the moment.
I’ll add that there is belief in a cytoreduction-plus-observation strategy, especially in good-risk patients. There are data to suggest that good-risk disease may be a predictive marker for survival benefit after cytoreduction. These patients can simply be observed, even if they have metastatic disease, typically a single site or very small amounts. Kidney cancer is interesting in that stage 4 disease is conventionally thought of in a binary sense—either you have it, or you don’t—while in fact, there is a whole spectrum of what it means to be stage 4. We have many stage 4 patients we selectively operate on who have very low-volume disease. They get focal treatment (surgery or radiation) followed by surveillance. These patients do quite well, and they have a very different trajectory than the patient who presents with many sites of disease.
I believe there are many emerging clinical as well as blood-based biomarkers that will help us better understand and utilize cytoreductive nephrectomy for the patients who can benefit from it most.