Surgery After Targeted or Immune Therapy Improves Health Outcomes in Some Patients with Metastatic Kidney Cancer

Patients with metastatic renal cell carcinoma (RCC) who were initially treated with targeted drugs or immunotherapies had better outcomes if they later underwent surgical removal of the kidney tumor, an analysis has found.

Cytoreductive nephrectomy is a surgery designed to remove all cancerous cells from the kidney and any involved surrounding organs, such as the spleen, pancreas, intestines or liver. Adding it to treatment extended the length of life for patients in the study, according to Dr. Ziad Bakouny, a postdoctoral genitourinary oncology research fellow at Dana-Farber Cancer Institute in Boston.

That finding should resolve an ongoing controversy about the value of cytoreductive nephrectomy at a time when targeted drugs and immunotherapies are taking center stage in the treatment of stage 4 kidney cancer, Bakouny said in an interview with OncLive®, a sister publication of CURE®.

“With the present database of this very large, retrospective study,” Bakouny explained, “there is currently no evidence to say that cytoreductive nephrectomy no longer has a place in the immune checkpoint inhibitor era, despite the fact that (immunotherapies) are effective.”

Extending Survival

The study included 4,639 patients who received initial diagnoses of metastatic RCC and were treated with either checkpoint-inhibitor immunotherapy or targeted therapy between 2009 and 2019. A total of 4,202 of the patients received a targeted therapy, and 2,631 from that group underwent cytoreductive nephrectomy while 1,571 did not.

Meanwhile, 437 of the patients received treatment with immune checkpoint inhibitors, 245 of whom followed that with cytoreductive nephrectomy while 192 did not.

The analysis was retrospective, looking back at the patients’ cases after treatment had occurred. The data were gathered from the International Metastatic RCC Database Consortium (IMDC), which includes patients from more than 40 centers across the world.

At a median follow-up of 38.5 months, those in the targeted therapy group who received cytoreductive nephrectomy experienced a median overall survival (OS) of 26.5 months versus 10.3 months in those who did not undergo cytoreductive nephrectomy. Those in the immune checkpoint inhibitor cohort with and without a cytoreductive nephrectomy experienced a median OS of 53.6 months versus 21.4 months, respectively.

Testing The Value of Surgery

The researchers embarked on the study because the advent of targeted drugs and immunotherapies has raised questions about whether cytoreductive nephrectomy – which in the past was routine for patients with RCC diagnosed in the metastatic stage – is still necessary, Bakouny said.

Before 2005, the surgery was a standard strategy because there were very few systemic therapies that could be considered as alternatives, Bakouny noted. But after that year, the targeted drugs Sutent (sunitinib) and Nexavar (sorafenib) were found to improve the survival of patients with this disease.

“As more effective systemic therapies (emerged), the question became: ‘Is cytoreductive nephrectomy still relevant?’” he said.

Large studies have generated different answers to that question.

While some retrospective studies established that the surgery was still effective in the era of targeted therapies, a recent, large clinical trial called CARMENA, which treated patients with Sutent either by itself or after cytoreductive nephrectomy, showed that the drug alone did not lead to worse outcomes.

Bakouny pointed out that this outcome could be related to the fact that the trial included patients with higher-risk RCC. On the other hand, his own analysis focused on patients who were younger and had lower-risk disease, although their cancers had some characteristics that indicated aggressiveness.

Armed with evidence that surgery had value in the age of targeted drugs, Bakouny and his colleagues set out to determine whether it was also effective in patients who received immunotherapy.

The investigators used two styles of analysis designed to correct for factors that could skew results. A multivariable analysis controlled for the effects of factors including age and IMDC risk group, and a propensity-based analysis balanced out bias in the selection of study participants.

“We found that the same signal we had seen in the targeted therapy era, we saw again in the immune checkpoint inhibitor era,” Bakouny said.

Applying The Findings

Still, that doesn’t mean that every patient with metastatic RCC will benefit from cytoreductive nephrectomy given in conjunction with targeted treatment or immunotherapy. According to Bakouny, the CARMENA trial found that patients who had one IMDC risk factor (such as low hemoglobin or high calcium levels) benefited from surgery before receiving Sutent, especially if they had only one site of disease spread, while those with two risk factors did not.

“We see the same signal in our data, as well,” Bakouny said. “As we see effective systemic therapies emerge, we’re going to (increasingly use cytoreductive nephrectomy in) more selected populations.”

In fact, he said, that’s already happening in medical practices throughout the world, which are selecting patients with the lowest-risk disease to receive regimens that include both surgery and either a targeted or immune-stimulating drug.

Bakouny said it makes sense that these patients would be most likely to benefit.

“Although factors like normal hemoglobin and normal calcium have been shown to correlate with good prognosis in patients in general,” he said, “these are patients who would not progress and would be perfect for a cytoreductive nephrectomy, at least until we have other evidence to suggest otherwise.”

Looking Ahead

Clinical trials that are in progress will help confirm whether such combination regimens should continue and in which patients, Bakouny said.

The PROBE trial, as well as a separate trial in Europe, is looking at initial treatment with the immunotherapies Opdivo (nivolumab) and Yervoy (ipilimumab) followed by cytoreductive nephrectomy. Meanwhile, the CYTOSHRINK trial is testing initial Opdivo/Yervoy followed not by surgery, but by stereotactic body radiation therapy (SBRT). “Although this is not cytoreductive nephrectomy, the primary lesion is being targeted with SBRT, so it is a similar concept,” Bakouny said.

Many of these trials are looking at deferred surgery, rather than initial surgery followed by drugs. “As such, many of these trials are now looking at very effective regimens, such as (giving Opdivo/Yervoy) or other immune checkpoint inhibitor-based regimens, getting a deep partial response and then just removing the remaining bulky mass and trying to render the patient (to have no evidence of disease), which makes a lot of sense,” Bakouny said.