BERKELEY, CA (UroToday.com) - The natural history of patients with renal cell carcinoma (RCC) and metastases at diagnosis (mRCC) is extremely heterogeneous. To date, only 30% of patients undergo cytoreductive nephrectomy (CNT) as primary approach or part of a multimodal therapy 2. In this context, two ongoing phase 3 studies will address the importance of CNT in the targeted therapy era (CARMENA, "Randomized Phase III Trial Evaluating the Importance of Nephrectomy in Patients Presenting With Metastatic Renal Cell Carcinoma Treated With Sunitinib" and EORTC, "Randomized Phase III Trial Comparing Presurgical Sunitinib Followed by Nephrectomy and Sunitinib Versus Nephrectomy Followed by Sunitinib in Patients with Synchronous Metastatic Renal Cell Carcinoma").[3, 4] While preliminary data from those trials are awaited, it is currently clear that the mRCC population cannot be considered a homogeneous cohort of patients due to extremely divergent natural histories among individuals.
In the current paper, the authors aimed to test whether the combination of number of metastatic organs and the pattern of metastases focality affect cancer-specific survival (CSS). Overall, 242 mRCC patients were treated with CNT at a single tertiary academic institution. Data were stratified in 4 tiered groups: patients with presence at diagnosis of 1) one single metastasis and one single organ affected (SM+SO) vs 2) multiple metastases and one single organ affected (MM+SO) vs 3) one single metastasis for each of multiple organs affected (SM+MO) vs 4) multiple metastases for each of the multiple organs affected (MM+MO).
Overall, metastases were diagnosed in lung (n=141 [58.3%]), bone (n=75 [31.0%]), adrenal gland (n=44 [18.1%]), liver (n=38 [15.7%]), brain (n=27 [11.2%]), and other sites (n=40 [16.5%]). Sixty-six (27.3%), 85 (35.1%), 10 (4.1%), and 81 (33.5%) mRCC patients showed SM+SO, MM+SO, SM+MO, and MM+MO, respectively. Patients with a single organ affected (SM+SO or MM+SO) showed similar survival relative to patients with multiple organs affected by a single metastasis (SM+MO). Conversely, patients with multiple organs affected by multifocal metastases (MM+MO) had significantly poorer survival (Figure 1). Specifically, the median survival was 34.7 mo (95% CI, 19.5–49.9) vs 32.3 mo (95% CI, 19.5–45.2) versus 29.6 mo (95% CI, 0.82–54.0) versus 8.5 mo (95% CI, 6.1–10.8) for SM+SO, MM+SO, SM+MO, and MM+MO patients, respectively. Regarding the organ-specific effect of metastases, lung, liver, and bone were predominantly affected by multiple localisations when either single or multiple organs were affected (MM+SM or MM+MO, 85.9% vs 73.3% vs 89.5% in lung vs liver vs bone, respectively). However, lung was the location with the highest rate of a single organ affected by metastases (SM+SO or MM+SO, 50.3% vs 35.1% in other sites; p < 0.001). Considering only patients with a single metastasis (SM+SO), CSS rates at 1, 2, and 5 years were 73.3%, 64.2%, and 36.7% (adrenal) versus 63.8%, 46.8%, and 25.5% (bone) versus 87.5%, 62.5%, and 37.5% (brain) versus 83.3%, 58.3%, and 48.6% (liver) versus 81.1%, 58.5%, and 27.5% (lung) versus 72.7%, 63.6%, and 25.5% (other sites) (log-rank pairwise comparisons: all p>0.3).
The results systematically demonstrated that the number of organs affected is an independent predictor of CSS. Moreover, patients with a single organ affected, regardless of the unifocality vs multifocality of metastases, showed similar survival relative to patients with multiple organs affected by a single metastasis. Conversely, patients with multiple organs affected by multifocal metastases demonstrated significantly poorer survival, likely due to the relative inadequate fraction of cancer debulking. Lung and bone represented the sites at a higher prevalence of metastases from RCC, at least in patients who are candidates for surgical debulking. Interestingly, conversely to bone or liver, multiple metastases frequently affect lungs without any other site affected. At univariable analyses, lung metastases showed slightly better survival rates relative to other metastatic sites. However, after adjustment for the number of organs affected, it seems that the apparent better survival of patients with lung metastases was mainly due to the lower prevalence of multiple organs affected by multifocal metastases relative to other sites. Therefore, the overall better survival rates usually associated with lung metastases is probably due to the lower prevalence of multiple organs affected by multifocal metastases when the lung is one of the metastatic sites.
The findings have several implications for daily clinical practice. Firstly, according to the current results, data coming from the CARMENA trial and the EORTC trial will also be implicitly applicable to patients with brain metastases, exclusive bone metastases, or multiple metastases at one single organ. Those characteristics, excluded from the CARMENA and EORTC trials, affected roughly 57% of mRCC candidates for surgery in the current paper. Secondly, the current findings strongly affect prognosis evaluation and the indication for adjuvant medical therapy. Specifically, patients with a single organ affected, regardless of unifocality vs multifocality of metastases, and patients with multiple organs affected by single metastases showed the same risk of midterm cancer-specific mortality. Conversely, patients with multiple organs affected by multifocal metastases should be considered at a significantly higher risk of early progression. Finally, the location of metastases, except for feasibility aspects, should not be considered a primary reason for endorsing or dismissing adjuvant treatments.
Figure 1: Kaplan Meier depicting cancer-specific survival in 242 mRCC patients according to the number of metastases and the number of organs affected. Patients were stratified in 4-tiered groups: Single Metastasis and Single Organ affected (SM+SO, dark green line) vs Multiple Metastases and Single Organ affected (MM+SO, light green line) vs Single Metastasis for each of the Multiple Organs affected (SM+MO, yellow line) vs Multiple Metastases for each of the Multiple Organs affected (MM+MO, red line).
- Ljungberg B, Cowan NC, Hanbury DC, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010; 58(3): 398-406.
- Jeldres C, Baillargeon-Gagne S, Liberman D, et al. A population-based analysis of the rate of cytoreductive nephrectomy for metastatic renal cell carcinoma in the United States. Urology. 2009; 74(4): 837-41.
- CARMENA. Randomized Phase III Trial Evaluating the Importance of Nephrectomy in Patients Presenting With Metastatic Renal Cell Carcinoma Treated With Sunitinib [online] http://clinicaltrials.gov/ct2/show/NCT00930033?term=renal+cancer&recr=Open&intr=nephrectomy&rank=2. 2009.
- EORTC. Randomized Phase III Trial Comparing Presurgical Sunitinib Followed by Nephrectomy and Sunitinib Versus Nephrectomy Followed by Sunitinib in Patients with Synchronous Metastatic Renal Cell Carcinoma [online], http://www.eortc.be/protoc/Details.asp?Protocol=30073&T=. 2010.
- Pierorazio PM, McKiernan JM, McCann TR, Mohile S, Petrylak D, Benson MC. Outcome after cytoreductive nephrectomy for metastatic renal cell carcinoma is predicted by fractional percentage of tumour volume removed. BJU Int 2007; 100(4): 755-9.
Umberto Capitanio, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Dept. of Urology
San Raffaele Hospital
Via Olgettina 60, 20132, Milan, Italy
Effect of number and location of distant metastases on renal cell carcinoma mortality in candidates for cytoreductive nephrectomy: Implications for multimodal therapy - Abstract
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