Clearing Up Confusion on Cytoreductive Nephrectomy in mRCC

David D. Thiel, MD

The decision of whether or not to recommend cytoreductive nephrectomy to patients with metastatic renal cell carcinoma (mRCC) is much more nuanced than the topline findings of the phase III CARMENA trial suggest, said David D. Thiel, MD.

The study showed the noninferiority of sunitinib (Sutent) monotherapy to cytoreductive nephrectomy followed by sunitinib in patients with mRCC. Median overall survival (OS) in the VEGF TKI—alone arm was 18.4 months versus 13.9 months in the sunitinib/nephrectomy arm (HR, 0.89; 95% CI, 0.71-1.10). However, the majority of patients had intermediate- or poor-risk disease and have a historically poor prognosis—regardless of therapeutic intervention, cautioned Thiel.

Although the trial did call into the question the population of patients who are best suited for the procedure, it should not dissuade the field from recommending the procedure entirely, he added.

“In some respects, the CARMENA trial has caused a lot of confusion in the urology and hematology/oncology community in that some people who have caught the trial in passing say that, ‘Patients with kidney cancer do not benefit from cytoreductive nephrectomy,’” said Thiel. “That kind of misinterpretation can be dangerous.”

Rather, Thiel emphasized that the decision should be based on surgeon comfort, potential morbidity from surgery, patient preference, and ultimately, resectability.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Thiel, chair of the Department of Urology, Mayo Clinic, provided perspective on the CARMENA findings in mRCC.

OncLive: What is the role of cytoreductive nephrectomy in mRCC following the results of the CARMENA trial?

Thiel: The CARMENA trial is one of the only randomized, controlled trials that we have in mRCC. However, some of the findings from the trial have been misinterpreted by the oncologic community. The results of that study showed the noninferiority of sunitinib monotherapy to cytoreductive nephrectomy plus sunitinib.

The problem is there was a long accrual time, which tells us that many oncologists or urologists sent their patients for nephrectomy as opposed to enrolling them on the trial. Approximately 30 patients in the treatment arm underwent a nephrectomy once their response was suitable. This also tells us that urologists and oncologists believe that cytoreductive nephrectomy confers a long-term cure or better OS.

Ultimately, the patients who were enrolled on CARMENA had intermediate- and poor-risk disease; these patients don't do well regardless of [our efforts]. The good thing about CARMENA is that it calls into question who we should be offering cytoreductive nephrectomy to. We probably should be more selective in whom we offer cytoreductive nephrectomy. With the results of the SWOG 8949 trial and the EORTC trial 30947, it became standard for us to try and remove the kidney of every patient with mRCC who could tolerate it. We know that the surgical morbidity is high in certain patients and some don't benefit from having their kidney removed. It's more beneficial for those patients to receive systemic therapy.

The SURTIME trial had a better design; however, investigators had a hard time accruing patients. The trial showed that patients who received upfront sunitinib followed by nephrectomy had a better OS than patients who received cytoreductive nephrectomy followed by sunitinib. Both trials showed that we need to look closely at who we're going to offer cytoreductive nephrectomy to and when.

Should cytoreductive surgery be offered in the first- and second-line settings?

It's easy to throw the word “surgery” around, but in this setting, we're talking about cytoreductive nephrectomy. However, we also know that patients with mRCC can benefit from having metastatic lesions removed—especially if it renders them free of disease.

For the sake of my discussion, there's no doubt that most patients with a good performance status—an ECOG performance status of 0 or 1—could benefit from cytoreductive nephrectomy if their tumors can be removed. What determines resectability is a question we've wrestled with over the last decade and a half. To me, it's not the size of the tumor that determines resectability, it's the amount of lymphadenopathy around the renal hilum.

For instance, a large amount of lymphadenopathy around the renal artery and renal vein can make surgical resection very difficult. Conversely, we would definitely aim to remove a big tumor with a renal vein thrombus or a vena cava thrombus without a lot of lymphadenopathy and heavy bulky metastatic disease prior to starting systemic therapy.

The good news about CARMENA and SURTIME is that they are the first randomized controlled trials in this space. Another thing that gets overlooked from the CARMENA trial is patient preference. Many patients, especially in the United States, consider not having a nephrectomy as “giving up.” An interesting social media survey asked patients with RCC whether they would still want their kidney removed given the results of the CARMENA trial. The overwhelming response was “yes,” not only for the perceived benefits, but also because they wanted the root of the evil removed.

Have there been any advances in surgical techniques that have made the procedure less morbid?

That answer is two-fold. Our surgical technology is better. Over the last 15 to 20 years, we've developed minimally invasive procedures for radical nephrectomy. Robotic radical nephrectomy and laparoscopic radical nephrectomy have a clear advantage over open surgery in terms of recovery time, incision size, hospital stay, etc.

However, in the setting of metastatic disease, it's common to have big tumors or lymphadenopathy. In that setting, many times, minimally invasive surgery is not possible. Our surgical technique for big, open kidney surgery has probably not improved over the last 15 to 20 years. What has improved is our ability to take care of patients postoperatively. Our surgical quality has improved as far as preventing pneumonias, deep vein thrombosis, and pulmonary embolus. Many of the pioneers in our field developed the techniques that we use today when it comes to removing large kidney tumors with lymphadenopathy, renal vein thrombus, inferior vena cava thrombus, and so on.

How are these data incorporated into a paradigm that is now largely defined by combinations of immunotherapy and VEGF TKIs?

The CARMENA trial has not had much of an impact on our practice at a tertiary destination medical center. However, we’ve had patients come in with completely resectable kidneys with a small amount of metastatic disease, who have been told that there is no benefit to cytoreductive nephrectomy. I don't agree with that, and most [surgeons] would not agree with that.

How could that misinterpretation be clarified?

Most patients with mRCC are seeing urologists or surgeons first. In some ways, we work together now a lot more than we ever have. The decision to proceed with nephrectomy followed by systemic therapy or upfront systemic therapy is a combination of surgeon comfort, potential morbidity from surgery, and patient choice. We also have to ask how qualified the patient is for surgical resection.

For the first time since I've been doing this—and I've been doing this for 18 years—we're really starting to see some dramatic benefits from some of the newer PD-1/PD-L1 inhibitors or receptor antagonists. These are [successes] we have never seen before. Huge tumors and bulky lymphadenopathy dissolve into almost nothing where we can now do laparoscopic nephrectomies, and, in some cases, proceed to partial nephrectomies. One problem with the interferon alpha and interleukin eras is [these agents] did OK with metastatic lesions, but they didn't do anything to the primary tumor. With some of the [checkpoint] inhibitors, we're starting to see dramatic shrinkage on primary tumors that make them resectable.

What is your take-home message to your colleagues working in this space?

We know that patients with mRCC are better off in centers that do [cytoreductive nephrectomies] routinely. Volume matters, and volume can predict patient outcome. Patients with mRCC should seek centers of excellence, places that handle a lot of patient volume not only on the oncology side, but the surgical side as well. They should also ensure that oncologists and neurologists are working closely together to portend the best benefit for patients.

Mèjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal cell carcinoma. N Eng J Med. 2018;379(5):417-427. doi: 10.1056/NEJMoa1803675.