Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 95% of renal neoplasms [53]. In the European Union, there were approximately 85 new cases and 35 deaths per 100,000 in 2012 [31]. The figures are similar for the United States with approximately 64,000 new cases in 2014 [125]. Metastatic RCC is present in up to 30% of patients at diagnosis with multiple sites affected in 95% [32, 114]. An additional 40% of those undergoing surgery for localized RCC will develop metastases later. Therefore, approximately 30,000 patients a year have metastatic disease in the European Union alone, of whom an estimated 7,000 demonstrate non-clear cell histology. Data from the Nationwide Inpatient Sample show a preference for certain sites with the lungs involved in 45.2%, followed by skeletal metastases in 29.5%, lymph nodes in 21.8%, liver metastasis in 20.3%, and brain in 8.1% [15]. Other locations have been described but at a lower frequency. Despite the introduction of targeted agents, treatment of metastatic RCC presents a therapeutic challenge. Although objective responses following targeted therapy are observed in 40–30% of patients, complete responses occur in only 1–3% [45, 87, 88]. Moreover, it has become evident that despite the most effective drugs in first-line treatment, median overall survival is only marginally longer than 2 years, which may be extended to 40 months in selected patients with adequate sequential therapy [30]. Therefore, together with the occasional durable responses achieved with high-dose interleukin-2, surgical resection of all lesions, when technically feasible, provides the only potentially curative treatment. However, only a minority of patients with metastatic RCC are candidates for metastasectomy. No reliable data exist on the percentage of patients with metastatic RCC who will be eligible for metastasectomy. A population-based analysis revealed that up to 65% of patients with metastatic RCC have a single disease site but most of them are either not solitary or not accessible for surgery [15]. It has been estimated that only 25% of patients with metachronous metastases are suitable candidates for resection of metastatic disease [2, 29]. Regarding synchronous metastatic disease, this proportion may be much lower. A Scandinavian whole nation study on prevalence and potential resectability identified 154 patients (16.9%) with synchronous lung metastases in whom the proportion of metastasectomy was evaluated [98]. Eventually, only 11 patients had single lesions deemed eligible for metastasectomy which was performed in only one patient. Additionally, proper patient selection for this approach is difficult due to the heterogeneous biology of metastatic RCC. Metastasis may present at diagnosis or within a year after nephrectomy with rapid progression of disease, whereas in other individuals, disease-free intervals of more than 20 years have been observed followed by slow growth pattern of the metastatic lesions. In few cases spontaneous regression of metastases has been documented, which has been ascribed to the presence of effective immune surveillance [78, 147]. In summary, there is considerable uncertainty regarding the best approach to metastasectomy. The major reason is a complete lack of randomized studies in this setting. A recent systematic review addressed the question whether local therapy for RCC metastases is beneficial and what the best options are [19]. Conducted in accordance with Cochrane Review methodology, including all types of comparative studies on local treatment of metastases from RCC in any organ, 2,235 studies were identified, of which 16 studies reporting on a total of 2,350 patients were eligible for inclusion. All studies were retrospective comparative studies with small patient numbers. The results revealed a benefit for complete metastasectomy when compared to either incomplete or no metastasectomy for metastases to various organs in terms of survival and symptom control, such as pain relief in bone metastases. However, the overall extensive risks of bias across all studies resulted in a significant risk of confounding. Due to the relatively poor quality of the few comparative studies, the evidence retrieved in the review was associated with large uncertainty, and no general recommendations were made. Ultimately, proper selection of patients for metastasectomy is of paramount importance. Surgical resection alone or in combination with targeted agents may result in clinical efficacy that is superior to systemic therapy alone. Currently, management of metastatic disease is depending on a number of clinical factors such as performance status, the length of the disease-free interval, the presence of synchronous or metachronous metastases, as well as the number and location of sites involved [73]. One of the most commonly used prognostic models, the Memorial Sloan Kettering Cancer Center (MSKCC) risk-score model, has been established from a database of 670 patients treated with cytokines. A previously validated risk score based on Karnofsky performance status, interval from nephrectomy, and serum hemoglobin, calcium, and lactate dehydrogenase was used to categorize patients as being favorable, intermediate, or poor risk [89]. Metastasectomy is associated with survival and clinical benefit across these various risk groups [28, 29]. A retrospective analysis was performed in 129 patients with localized RCC treated with partial or radical nephrectomy who were subsequently diagnosed with disease recurrence. In the favorable-risk group, metastasectomy improved 5-year survival from 36 to 71%. In the intermediate-risk group, 5-year survival was 38% after metastasectomy as opposed to 0% in the same risk group without metastasectomy or the poor prognosis group. Even after adjusting for risk score in a multivariate analysis, patients who did not undergo metastasectomy had a 2.7-fold increased risk of death. A previous cohort from the same institution included 118 patients who had a median survival time of 21 months from the time of recurrence [29]. Overall survival was strongly associated with risk group category (p < 0.0001). Median survival time and 2-year survival rates for low-risk, intermediate-risk, and high-risk patients were 76, 25, and 6 months and 88% (95% CI, 77 to 99%), 51% (95% CI, 37 to 65%), and 11% (95% CI, 0 to 24%), respectively, suggesting that only patients with favorableor intermediate-risk features are candidates for metastasectomy. Despite the introduction of targeted therapy, the MSKCC risk score remains a valid tool among other similar risk scores to identify potential candidates for metastasectomy [46, 104].

Table 11.1. Clinical factors associated with a favorable outcome after metastasectomy. General and additional reported site-specific factors for the lungs, bone, and brain

__Kidney Cancer_ Principles and Practice-Springer International Publishing (2015) T 11.1

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