Wednesday, August 6, 2014

Cytoreductive Nephrectomy for Metastatic Renal Cancer: Frontiers in Selecting Patients for Surgery

Metastatic renal cancer.
Up to 25% of patients with renal cell carcinoma (RCC) have metastatic disease at the time of diagnosis (1). One treatment option for patients who have multiple metastatic sites, a potentially resectable primary tumor in the kidney, and who are deemed appropriate surgical candidates is surgery [cytoreductive nephrectomy (CN)] followed by systemic medical therapy (2). The rationale for surgically removing the primary tumor includes removing a source of new metastases and reducing the immunosuppressive effects of the tumor itself. While surgery alone likely has a minimal survival benefit compared to no treatment, two randomized controlled trials (RCTs) demonstrated the value of CN plus systemic therapy versus systemic therapy alone (3-5). (Read our blog Classic Manuscripts in Urology: Flanigan, NEJM, 2001 and Mickisch, Lancet, 2001 for more details on these studies) In these studies, patients who underwent CN followed by systemic therapy had improved overall survival and time to disease progression; in fact, a combined analysis of these studies indicated a 31% decrease in the risk of death in the CN group (6).

However, these trials were conducted in the era of cytokine-based systemic therapy. These therapies include interferon-alpha and interleukin-2, medications rarely used now. Since then, we have transitioned to targeted systemic therapy agents that have a different mechanism of action, are more efficacious, and are better tolerated. Additionally, most patients in the trials leading to the approval of these targeted therapy agents had a prior nephrectomy. Therefore, a re-evaluation of the value of CN in the context of targeted systemic therapy is necessary. To this end, there are currently 2 ongoing RCTs being conducted: the CARMENA and SURTIME trials. The CARMENA trial is examining sunitinib (a targeted therapy agent) alone versus sunitinib + CN, while the SURTIME trial is examining the timing of sunitinib therapy with respect to CN (i.e. presurgical versus postsurgical sunitinib)
(7, 8). While the results of these trials are pending, a few retrospective studies have suggested improved survival in patients undergoing CN + targeted therapy (9, 10).

Selecting Patients for Cytoreductive Nephrectomy

In addition to determining the value of CN in the new era of targeted therapy, patient selection criteria for CN in this era also needs to be determined. Evidence from the cytokine therapy era indicated that patients with lung-only metastases, ECOG performance status scores of 0-1, and good prognostic factors were the most likely to benefit from surgery (2). While several studies have sought to further define favorable and unfavorable prognostic factors (such as the presence of liver metastases, low albumin levels, T3/T4 clinical stage, etc.) (11), there is a paucity of dedicated patient selection studies specifically in the targeted therapy era. Understanding which patients would most benefit from surgery in the context of targeted therapy is important because some patients may not be able to receive systemic therapy after undergoing an operation. In fact, a recent retrospective study indicated that approximately 1/3 of patients who undergo CN do not ultimately receive systemic therapy; the most common reasons were rapid disease progression (30%), decision for surveillance by medical oncologist (21%), and perioperative mortality (19%) (12). While all the patients who had rapid disease progression had either high grade tumor or sarcomatoid differentiation, on multivariate analysis, ECOG performance status was the only covariate significantly associated with whether or not a patient received or was eligible to receive systemic therapy after CN (12). While ECOG performance status scores may be helpful in predicting which patients with metastatic disease are good surgical candidates, the metric itself certainly has its limitations, as it is subjective and can be susceptible to considerable inter-rater variability (13). Given the limitations of the ECOG performance metric, an evaluation of alternate metrics to inform pre-operative risk stratification is warranted.

Frailty and Sarcopenia

Frailty is a potential alternate metric that could help to better elucidate patient selection for CN in the targeted therapy era. Frailty is a concept originally conceived and validated in the geriatrics literature. It is a novel domain of risk that captures decreased physiologic reserve and is a construct that is independent of comorbidity and disability (14). Frailty is based on five components defined by the Fried criteria: shrinking, weakness, exhaustion, low physical activity, and slowed walking speed (14). Frailty has been shown to be an independent predictor of post-operative outcomes in the general surgery and transplant populations. For example, in kidney transplant recipients, we have shown that frailty is independently associated with poor outcomes, including early hospital readmissions, delayed graft function, and mortality (15-17). While frailty is not routinely measured in the clinical setting, sarcopenia is a radiographic correlate of frailty that is assessed on CT imaging and is, therefore, more readily available in our surgical patients. Sarcopenia (the degenerative loss of skeletal muscle) is based on core lean muscle size, and, like the Fried index, it has also been shown to be an independent predictor of post-operative outcomes in the general surgery and transplant populations (18, 19).

The psoas muscles (highlighted in blue) are a
common measure of sarcopenia.
Sarcopenia is also beginning to be examined in the urology literature. A recent study indicated that approximately 1/3 of patients with metastatic RCC have sarcopenia and that sarcopenic patients undergoing targeted therapy for metastatic RCC have decreased overall survival and increased susceptibility to the dose-limiting toxicities of targeted therapy (20, 21). Furthermore, in a study of bladder cancer patients, sarcopenia was independently associated with post-cystectomy mortality, after adjusting for ECOG performance scores. In fact, the ECOG performance scores did not differ significantly between patients who were sarcopenic and less sarcopenic (22). Therefore, sarcopenia may very well add granularity to patient selection criteria (beyond ECOG performance scores) to help determine which patients would be the best candidates for CN in the targeted therapy era and which patients are at risk of rapid progression or deterioration after surgery and would, thus, benefit most from immediate systemic therapy. To this end, investigators at the Brady Urological Institute are investigating sarcopenia in metastatic RCC patients in the hopes of improving pre-operative risk stratification by using novel risk metrics.


This blog was written by Natasha Gupta, Medical Student at Johns Hopkins Medical School.  Natasha recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "Metastatic Renal Cell Carcinoma: Cytoreductive Nephrectomy" from which this blog is inspired. Natasha is looking forward to a career in urology.


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