SURGERY UNDERUSED FOR METASTATIC RENAL CANCER

Cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC) has become underutilized since targeted therapy drugs have come on the market, and that may be contributing to inferior survival, experts say.

In a retrospective review of data from the National Cancer Data Base (NCDB), researchers discovered that CN was being performed in just 3 of 10 patients with mRCC who were being treated with targeted therapies.

They also found discrepancies between those who received the surgery and those who did not, with black patients, uninsured patients, and those being treated at nonacademic centers being less likely to undergo CN.

Further, their study showed that there was a significant advantage in overall survival (OS) for patients who received both CN and targeted therapies compared with those who received targeted therapies alone.

The review, led by Nawar Hanna, MD, from Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston, Massachusetts, is published in the Journal of Clinical Oncology.

A Wake-up Call

These new data "should serve as a wake-up call to both medical oncologists and urologists to seriously consider CN for every patient who presents with mRCC," say experts in an accompanying editorial. The editorialists are Ana M. Molina, MD, and David Nanus, MD, both from the Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City.

The study by Dr Hanna and colleagues "confirms prior reports that with the incorporation of effective VEGF-targeted therapies, CN is underutilized. Moreover, this underutilization appears to directly contribute to inferior survival among patients who present with mRCC," they write.

n an interview with Medscape Medical News, Dr Molina said that in the 1990s, there was considerable debate about the benefit of CN for patients with mRCC.

"Many argued that removal of the primary tumor resulted in better responses in patients who were then treated with cytokine therapies such as interleukin-2 or interferon-alfa, while others argued that the surgical morbidity and mortality, as well as the delay in initiating systemic therapy resulting in disease progression, did more harm than good," she said.

It wasn't until 2001 and 2004, when results of two trials showed a significant improvement in survival of patients with mRCC who received nephrectomy, that CN became the new standard.

"The combined analysis of those two trials showed cytoreductive nephrectomy prolonged survival ― not by much, from 7.8 months up to 13.6 months, but for kidney cancer, that used to be amazing," Dr Molina said.

Shortly after those studies were published, targeted therapies such as sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer), and pazopanib (Votrient, GlaxoSmithKline) came on the market after phase 1 and phase 2 studies showed that they dramatically improved disease-free survival and OS.

Treatment with targeted therapies then became the standard of care and replaced cytokine therapy. But, the thing is, over 90% of the patients in these studies had cytoreductive nephrectomy. So the improvements in disease-free and overall survival observed in these studies were in patients among whom the primary tumors had been removed in the majority of cases, and these were the ones who were deriving benefit from these targeted therapies," Dr Molina said.

Results from the review of NCDB data by Dr Hanna and colleagues show the same thing.

In their study, the researchers identified 15,390 patients with mRCC who were treated with targeted therapies between 2006 and 2013. About a third of these patients (n = 5374) also underwent CN.

OS was significantly better for patients receiving both the surgery and targeted therapy compared with those receiving targeted therapy alone.

With CN, the median OS was 17.1 months (95% confidence interval [CI], 16.3 - 18.0 months); in contrast, without CN, the median OS was 7.7 months (95% CI, 7.4 - 7.9 months).

This finding is "alarming," the editorialists comment.

Older patients (≥60 years) and sicker patients (Charlson comorbidity index [CCI] ≥ 2) were less likely to undergo CN than younger patients (< 50 years) and those with a CCI score of 0 (P < .001 for all).

Black patients were significantly less likely to undergo CN than white patients (P < .001).

Patients without insurance as well as those treated at community, comprehensive community, or integrated network programs were less likely to be treated with CN than patients with Medicare or Medicaid insurance and those treated at academic centers.

The small number of patients who are being treated with CN is "worrisome," Dr Hanna and colleagues comment.

They also say that the contrast in utilization rates between academic centers and community centers is "disconcerting, because it may suggest underuse of CN in the general population. This becomes even more problematic when considering that certain patient and sociodemographic characteristics (eg, race, insurance) unrelated to clinical factors were found to be associated with receipt of CN in the current cohort."

What Should We Be Doing?

Many physicians question the need to perform CN and believe that treatment with targeted therapies is sufficient.

The issue should be answered once and for all by the results of two ongoing major studies in Europe, Dr Molina believes.

The two prospective, randomized trials are the Clinical Trial to Assess the Importance of Nephrectomy (CARMENA; NCT0093033) and the European Organization for Research and Treatment of Cancer's Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients with Metastatic Kidney Cancer (SURTIME; NCT01099423).

The CARMENA study, is being conducted in France and is currently enrolling patients. They patients will be randomly allocated to receive either nephrectomy plus sunitinib or sunitinib alone. The trial should answer the question of whether survival is affected by nephrectomy in patients receiving targeted therapy, Dr Molina said.

The SURTIME study, which has completed accrual, is intended to determine the best time to have surgery for mRCC. In that trial, immediate nephrectomy followed 4 weeks later by sunitinib therapy is being compared with deferred nephrectomy, in which patients first receive sunitinib therapy.

"I think these trials will answer the question about cytoreductive nephrectomy. They will either show a survival benefit or not for CN, and then we will start recommending surgery," Dr Molina said.

In their editorial, Dr Molina and Dr Manus emphasize that until the CARMENA and SURTIME studies are completed and reported, "CN remains the recommendation for patients with mRCC with a good performance status, and should be considered for all patients who present with mRCC," as per guidelines from the National Comprehensive Cancer Network and the European Society for Medical Oncology.

The study was supported in part by the Quebec Urological Association, the Trust family, Loker Pinard, the Michael Brigham Funds for Kidney Cancer Research at Dana-Farber Cancer Institute, the Dana-Farber/Harvard Cancer Center Kidney Cancer Program, and the Dana-Farber/Harvard Cancer Center Kidney Cancer. Dr Hanna reports no relevant financial relationships. Dr Molina receives honoraria from the American Society of Clinical Oncology and consulting or advisory fees from Eisai and Novartis.