Since the use of vascular endothelial growth factor (VEGF)-targeted therapy became an option for frontline treatment of metastatic renal cell carcinoma (RCC) in the early 2000s, the role of cytoreductive nephrectomy has become less certain.
Previously, radical nephrectomy was a primary treatment option for patients diagnosed with metastatic disease, as it was the only treatment that could potentially improve survival, according to William Huang, MD, a urologic oncologist at NYU Langone Health in New York City.
"Especially over the last decade there have been significant advances in systemic therapy for the treatment of metastatic RCC," Huang said. "Because of the arrival of targeted therapies, like tyrosine kinase inhibitors (TKIs) and mTOR inhibitors, and the development of novel forms of immunotherapy such as checkpoint inhibitors, there have been dramatic strides taken in terms of treatment options for patients with metastatic disease."
In response to these early advances, there was a need for high-quality data to guide treatment decisions on the role of surgery. The SURTIME and CARMENA trials were developed to evaluate the relevance of cytoreductive nephrectomy in this new treatment era.
was designed to look at timing of surgery and randomly assigned patients with primary metastatic RCC to either immediate cytoreductive nephrectomy followed by sunitinib or sunitinib followed by surgery in the absence of progression after sunitinib. The study closed after 5.7 years, having accrued only 99 of 458 patients. Deferred nephrectomy did not improve 28-week progression-free rate. However, with the deferred approach, more patients received sunitinib and overall survival results were higher.
randomly assigned 450 patients with confirmed clear-cell RCC to undergo nephrectomy and then receive sunitinib or to receive sunitinib alone. At a planned interim analysis, the overall survival results in the sunitinib-alone group were noninferior to those in the nephrectomy and sunitinib group: 18.4 months versus 13.9 months. Huang noted that this patient population had a high number of poor-risk patients, which may have affected interpretation of the results.
Role of Risk
Risk stratification was developed and refined at the same time that more targeted treatments became available.
"Patients are stratified to good-, intermediate-, and poor-risk groups based on clinical variables, and outcomes of these patients seem largely determined by which risk group they fall into," Huang said.
One of the first prognostic models to be more widely used was the Memorial Sloan Kettering Cancer Center (MSKCC) model, which was derived from trials using interferon. Later, was derived from patients treated with VEGF-targeted therapies. This risk model for metastatic RCC uses baseline factors at the start of the current line of systemic therapy.
showed that for patients with two or more IMDC risk factors, overall survival was significantly longer with sunitinib alone compared with nephrectomy plus sunitinib (31.2 vs 17.6 months; P=0.03). In contrast, for patients with only one IMDC risk factor, overall survival was longer after nephrectomy plus sunitinib (31.4 vs 25.2 months; P=0.02).
"For good-risk patients or those who have limited metastatic disease, the decision to undergo surgery is still pretty straightforward," Huang noted. "Most surgeons would agree that patients with large kidney tumors and limited disease such as small pulmonary nodules can benefit from undergoing surgery."
However, Andres F. Correa, MD, a urologic oncologist at Fox Chase Cancer Center in Philadelphia, said that the decision in certain good-risk patients with low volume of disease can be more complicated.
"You ask, 'If I'm doing surgery and the patient is still not able to avoid systemic therapy, then why do it?'" he said. "If the kidney is not having any significant effect on the patient or their quality of life, it makes no sense to put them through the surgery."
Correa noted that with the newer combinations of immunotherapy, there can be significant reductions in disease burden, allowing patients to keep their kidney.
For patients with poor-risk disease, most surgeons would avoid surgery because the patient is unlikely to benefit from it and it could delay treatment.
Another situation in which both Huang and Correa said surgery is still a primary option is for patients who are symptomatic.
"If the patient is bleeding or has significant pain related to tumor burden, then you might choose to remove the kidney first, even in the setting of metastatic disease, to allow the patient better quality of life before undergoing systemic therapy," Correa explained.
For patients with intermediate risk, the discussion of when to use surgery must also be tailored and discussed with the patient and treating physicians.
Metastasectomy
As the role of surgery has evolved, so has that of metastasectomy.
Huang said that the choice to perform metastasectomy is often driven by both the organ and by the patient's response to treatment.
"A good example is pulmonary metastases," he added. "These are well known to be good targets for surgical resection, especially if it is a solitary metastasis to the lung or a solitary recurrence in the retroperitoneum."
Those patients who recur at a longer time interval, perhaps years after nephrectomy, are also felt to be ideal candidates for metastasectomy. Correa noted that data support the use of metastasectomy in these patients with long periods of stable disease.
"Maybe the patient has a liver mass or a lung nodule and there is no growth and no new masses," he said. "You may allow these patients metastasectomy in the hope of allowing them to stop systemic therapy."
supported the use of metastasectomy as part of multimodality treatment for metastatic RCC. The study looked at the effect of metastasectomy on all-cause mortality and overall survival among 431 patients (59 favorable-risk, 274 intermediate-risk, 98 high-risk). Metastasectomy was performed in 37%, 24%, and 16% of these patients, respectively, and was associated with improved all-cause mortality (HR 0.56; P=0.005). Median overall survival was longer with metastasectomy in favorable-risk (P=0.003) and intermediate-risk patients (P=0.038), but not in high-risk patients.
However, Correa noted that in some cases, radiation or another form of ablative energy could also potentially be used.
Continued Evolution
The SURTIME and CARMENA studies were conducted with the available TKIs of the time.
"We haven't gotten to the point where we can't say if the treatment paradigms should necessarily be changed further with the use of combination immunotherapy," Huang said.
Correa agreed, noting that "the decision to do surgery now is much more nuanced than it was in the past. We know that the answer in intermediate or poor risk, that those patients need to go to systemic therapy first. It is the patient with good risk and low volume, or with unconfirmed metastatic disease, where you question what to do."
In the future, Correa said he imagines the role of cytoreductive nephrectomy is going to become smaller as systemic therapy continues to become better.
"The role of cytoreduction in other cancers is also less than it was as they get better treatments," he continued. "As we have now gone through this renaissance of systemic options for kidney cancer, the role of surgery will be more limited and tailored like in the metastasectomy setting."
Disclosures
Correa and Huang had no relevant conflicts of interest.