Several studies have shown volume modifications of the primary lesion after TT (Table 12.2). After 8 weeks of therapy, Jonasch et al. reported a reduction of the size of primary lesions of between 10% and 30% using RECIST criteria in 23% of patients [44]. It is questionable whether RECIST criteria are suitably accurate for the evaluation of TT results because they consider only the dimensional reduction of the mass and not the increase of its necrotic component and other imaging signs of tissue modifications. Indeed, many lesions greatly increase the content of necrosis after TT, which does not always corre- late with a reduction in volume of the tumor. Conversely, in many cases we observe increases in their volume.

Beyond tissue modifications, a minimal reduction in volume is not useful from a surgical perspective. Frequently, in metastatic RCC, the primary tumor is >10 cm and a reduction of 10% of the volume does not simplify the procedure significantly. Recently, Kroon et al. investigated the correlation between tumor size and downsizing after TT therapy. Median downsizing in tumors of diameter 7–10 cm, 5–7 cm, <5 cm were 14%, 11% and 34%, respectively. Hence, small primary lesions showed increased susceptibility to TT in terms of downsizing [45]. These results are in agreement with the potential application of TT before elective NSS, which aims to simplify the procedure and reduce complications, as suggested by Ficarra et al.

Sometimes, the clinical scenario in metastatic kidney cancer is characterized by minimal metastatic disease associated with retroperitoneal bulky disease due to a large primary tumor with extension to an adjacent organ and/or with an associated confluent nodal mass involving the great vessels [47]. In these cases, which are defined as “surgery-limiting tumor sites (SLTSs)”, effective preoperative therapy can allow complete tumor removal with an acceptable risk of complications. Unfortunately, experiences with SLTSs shows good results at metastatic sites but poor results against primary complex tumors [42].

A total of 4–10% of RCCs have thrombus in the inferior caval vein (IVC) and, in 1% of cases, the thrombus involves the right atrium. Up to 60% of these patients have also concurrent subclinical metastases [48]. Surgical patients N0M0 show a median overall survival of 51.7 months compared with 10.7 months for N+M0 and 6.9 months for N×M+ [49].

The risk of perioperative morbidity and mortality from RN and thrombectomy is related to the level of the thrombus. Whether the level of the thrombus (independent from pathologic stage) has an impact on survival is controversial. It is known, however, that higher-level tumor thrombi tend to be associated with a higher grade and a more advanced T stage.

Neoadjuvant systemic therapy can potentially decrease the burden of the tumor thrombus and thus improve the safety and feasibility of resection. Many case reports have been published stating this viewpoint with positive results. We also have positive experiences with preoperative TT in the presence of IVC thrombi, but large cohorts (>25 cases) are present in few publications. Cost et al. did not report exciting results: 1 patient (4%) had an increase in the thrombus level (level II to level III), 21 (84%) had stable thrombi and, in 3 (12%), the thrombus level was decreased. Hence, there was only 1 case (4%) in which the surgical approach was potentially affected by regression of the tumor thrombus (level IV to level III) [50].

Major and overall complications are not influenced by neaoadjuvant therapy; only surgical wound healing represents a real risk due to preoperative therapy [51]. To evaluate the most appropriate time for therapy discontinuation, we must consider the half-life of the drugs: temsirolimus, 17 h; sorafenib, 24–48 h; sunitinib, 60–110 h; bevacizumab, 14–21 days; and pazopanib, 30.9 h. To be sure, we advocate therapy discontinuation by a time ≥2/3-times the half life of the drug.

Before the conclusion of the SURTIME trial, we do not know whether the best initial therapeutic approach for metastatic RCC is surgery or molecular therapy. However, considering different aspects we can identify certain useful criteria to select patients for cytoreductive nephrectomy or for neoadjuvant therapy.

We consider the ideal candidates for surgery (as the first treatment) those patients with resectable primary tumor (no bulky disease or involvement of adjacent organs), no lung metastases and good performance status, and when surgery can remove >90% of tumor volume [52]. In the other cases, neoadjuvant treatment with TT is probably a more rational approach.

We are in a phase of rapid transition in which NSS is increasing its role over RN as experiences with conservative surgery and the efficacy of hemostatic agents increases and in which minimally invasive approaches such us laparoscopy, robotics and ablative procedures are advancing. In particular, RAPN represents a viable alternative to open NSS with the goal of decreasing postoperative pain and accelerating the return to normal activities. For the open procedure, extreme attention must be paid to limiting the WIT to 20–30 min.

Preoperative systemic therapy seems to be safe and feasible but the potential advantages must be tested rigorously. Until further data become available, caution should be exercised in applying this treatment for potentially curable and resectable disease.