The Impact of Local Intervention Combined with Targeted Therapy on Metastatic Renal Cell Carcinoma

Discussion

Our results reveal that combining a complete resection of metastatic lesions with targeted therapy can prolong overall survival for MRCC patients, whereas the poor MSKCC risk group indicated a poor outcome.

Previously reported series have also supported the use of a metastasectomy, particularly for complete resection. You et al. were the first to compare the role of complete metastasectomy paired with targeted therapy only (10). They discovered that patients experienced better overall survival after complete resection, than those who underwent incomplete resection and targeted therapy only. In our series, the median overall survival rate was not different between the complete resection group and the incomplete local intervention group. A possible explanation for this was patient selection in the incomplete local intervention group. In their series, poor risk patients who were following IMDC criteria accounted for 37.9% of the group, which was far higher than the results in our series (0% poor risk using MSKCC criteria). The selection bias may lead to a poorer outcome in their incomplete resection group, which could cause overall survival differences to appear.

Additionally, the targeted treatment duration was similar between our complete resection and incomplete intervention groups (Table I), with the median estimate overall survival being prolonged for 1.5 years in the complete resection group (Figure 1). We think this additional duration of overall survival was due to the value of complete resection in terms of it providing drug holidays to MRCC patients. The other evidence of this theory came from the detailed analysis of the complete resection group. Among the 26 patients who had complete tumor resection, only 5 of them could achieve a target therapy-free duration longer than 12 months after their metastasectomy (Metastases to spine for 2 patients, lung for 1, adrenal gland for 1 and intra-peritoneal soft tissue for 1; median targeted therapy free survival time 29 months, ranging from 15 to 96 months). Among these 5 patients, 3 remained disease-free and 2 experienced newly metastatic lesions during follow-up. The remaining 21 patients who had complete resection experienced either newly metastatic lesions within one year (16 patients), or local recurrence (5 patients). The median targeted therapy free survival time was 6 months (range=1-10 months). Upon analysis of the subgroup data, we believe there are not only benefits to be had from drug holidays after local interventions, but also that there is an important role systemic targeted therapy plays in order to maintain long-term disease control. This is because of the high relapse rate.

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Figure 1.

Overall survival comparison among the complete focal disease control group, incomplete focal disease control group and targeted therapy-only group.

There have been additional studies which have supported our findings. Karam et al. reported that their small series received a metastasectomy during targeted therapy (8). They found a median disease-free survival time of 43 weeks, and an overall survival benefit of longer than 2 years with a manageable complication rate (18%, Grades 1 and 2). Brehmer et al. also reported a similar experience when implementing pre-surgical targeted therapy followed by focal treatments (9). Both studies showed that a benefit of drug holidays after a metastasectomy is that patients could have a break from the adverse events of targeted therapies.

Outcomes of different metastatic sites have been controversial (12-14). A study from the SEER (Surveillance, Epidemiology, and End Results) database shows that liver, bone, lymph nodes and brain metastases were associated with a poor outcome in the current targeted therapy era (12). Verma et al. retrospectively reviewed their single institute experience and revealed a median overall survival time of 6 months after the diagnosis of brain metastases from renal cell carcinoma (14). However, our results showed no statistical correlation between different metastatic sites and patient's overall survival (Table II). Jakubowski et al. and Kato et al. also reported their excellent experience with solid organ and spinal metastasectomies linked to high cancer specific survival (84% and 69% respectively), which could be achieved in both retrospective series (15, 16). However, both series attempted to control the enrolled cases in order to fit statistical comparison, thereby subsequently compromising the real world varieties of MRCC which showed high local recurrence and new metastases possibilities in our series.

The lungs were the most common site where a metastasectomy was performed in our series. This finding was similar to other series (17, 18). The most common metastasectomy procedure for lungs was a thoracoscopic wedge resection. Rather than undergoing a lung resection, one of our patients received cryotherapy over 10 sessions during a 2-year period. Clinically, detection of lung lesions can only be based upon a CT scan and intra-operative findings. The true complete resection is difficult to achieve.

Our retrospective study still had certain limitations. First, similarly to other studies, the retrospective selection bias may lead to a deviation of the results. In general, patients who received local interventions would have a good performance status as part of their MSKCC risk score. A poor MSKCC-risk group was correlated with a poorer outcome in our series. Second, the small patient numbers decreased the statistical power. Third, the decision of what type of local intervention to implement was not universal. Some patients received surgical resection while others received non-surgical local intervention. Fourth, although the targeted treatment durations were recorded, the true targeted drug dose intensities, along with variation between different regimens were still not identical. Since the targeted therapies were costly treatments, the different insurance reimbursement policy during different time points may also compromise the treatment options of individual patients in real world practice.