The Efficacy of Wide Resection for Musculoskeletal Metastatic Lesions of Renal Cell Carcinoma

Discussion

Historically, metastatic renal cell carcinoma carried an unfavorable prognosis, and in patients with bone metastasis, supportive care such as palliative orthopedic procedures (closed nailing for temporary stabilization), radiotherapy and administration of bisphosphonates to reduce skeletal-related events (pain or pathological fracture) was the main course of treatment (11-12). While persistent treatment of metastatic RCC with nephrectomy and cytokine therapy have been helpful (13), the development of molecularly targeted therapy has made long-term survival possible in these patients (14). Moreover, some reports support the possibility that metastasectomy would not only improve the patient's quality of life but also prolong survival (2, 4-6). Naito et al. reported that, in a series involving a group of 1,463 patients with metastatic RCC, the mean survival time of the patients who underwent metastasectomy was significantly increased compared with patients who did not undergo metastasectomy (44.3 vs. 16.4 months) (4). Focusing on bony metastasis, Fuchs et al. reported that patients who had a surgical procedure had better survival rates (p=0.007) compared patients who had no surgical treatment or simple biopsy of the local lesion, with 5-year survival rates of 36% versus 8% (15). The survival in our study was even more favorable: the mean survival time and 5-year survival after metastasectomy were 52.8 months and 48%, respectively.

From these viewpoints, surgical resection can now be recommended for patients with metastatic lesions from RCC, and some guidelines indeed endorse metastasectomy in certain conditions. National Comprehensive Cancer Network (NCCN) guidelines for kidney cancer recommend that patients with a solitary resectable metastatic site be considered candidates for surgical metastasectomy (16). In addition, in guidelines by the Japanese urological association, surgical resection for metastasis is recommended as grade B (strong recommendation with moderate quality evidence) when the patient has a good performance status and metastatic site is resectable (17). Remarkably, the number of metastatic sites is not mentioned in the latter guidelines, though metastasectomy is limited to solitary metastasis in the former guidelines, and the indications for metastasectomy for multiple metastases remain controversial.

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Figure 1.

(a) A Kaplan–Meier survival rate curve of the 30 patients from the time of metastasectomy. OS, Overall survival; MST, median survival time. (b) OS rate curve of the patients based on surgical method. Survival rate was significantly higher in the wide resection group than intralesional group (p=0.04). (c) Recurrence-free survival rate curve of the patients based on surgical methods. Recurrence rate was significantly lower in the wide resection group than the intralesional group (p=0.001). (d) Metastasis-free survival rate curve of the patients based on surgical methods. There was no significant difference in each group (p=0.71).

Many reports mentioned that the number of metastatic sites is a predictor for survival (18, 19). Lin et al. reported that patients presenting with an apparently solitary bone lesion had a better survival rate than patients with other patterns of metastases (p<0.0001), with 5-year survival rates of 35% (7). For this reason, the suggestion that metastasectomy should be limited when the metastasis site is solitary was supported by several authors and guidelines (16, 20, 21). However, among patients with metastatic disease, only a small percentage will present with a solitary metastasis. Also, some authors suggest that complete resection of all metastatic deposits within an organ was more important than the number of metastatic deposits within the organ (22, 23). Dernevik et al. reported that no significant survival difference existed with respect to the number of lesions excised in the patients with lung metastases (22). Kavolius et al. showed that best survival was achieved in patients with in a solitary metastatic site (p<0.005). However, long-term survival for patients with multiple metastases was possible, with 5-year survival rates of 29% as a result of metastasectomy, provided all metastatic disease could be completely removed (23). In our data, the survival was significantly lower in patients with more than two metastatic sites before metastasectomy than in patients with only one metastatic lesion. However, the mean survival of our subjects (54 months) was better than that reported by Kavolius et al.. In addition, there was no significant difference in survival between patients with or without a single site of metastasis before metastasectomy. From multivariate analysis, the existence of metastases (including multiple metastases) before metastasectomy was not a significant risk factor for survival, whereas surgical technique had a strong association with survival. Hence, we believe that, for patients with an acceptable general condition, metastasectomy of multiple metastases is a reasonable option that may provide relatively long survival.

When we think about surgical intervention for metastatic lesions from RCC, the appropriate extent of surgery, such as whether we treat the tumor like a primary bone tumor or not, often comes into question, though the above guidelines do not mention the type of surgical treatment. Compounding the problem, in osseous metastases from RCC, because the tumors tend to be large, highly destructive, and hypervascular, aggressive metastasectomy may lead to a loss of postoperative function and endanger the patient's health because of long surgical time or large volumes of hemorrhaging. Thus, some groups recommend marginal or intralesional resection for any metastatic disease (15, 21) while others recommend wide excision of metastatic lesions because doing so may prolong survival (23, 24). Kavolius et al. reported that patients who underwent curative resection (n=141) fared better than those who underwent a noncurative resection (n=70) or non-surgical initial management of metastasis (n=67), and the 5-year survival rates were 44%, 14%, and 11%, respectively (23). Fottner et al. reported that the histologic resection margin affected overall survival in 101 patients with RCC bone metastases, and patients with a tumor-free resection margin had a significantly better survival (p=0.028) (24). Conversely, Fuchs et al. reported that there was no survival advantage for patients who had a wide resection of the lesion compared with patients who had intralesional resection or intramedullary stabilization alone. However, the authors also noted that patients with complete resection and reconstruction of the metastatic lesion tended to have fewer complications, like local disease progression, than those receiving intralesional curettage and local stabilization (15). In the present study, the survival rate and recurrence rate were significantly better in the wide resection group by univariate analysis, and intralesional resection was the major independent risk factor for poor survival by multivariate analysis. Because wide resection did not influence the metastasis rate, complete removal of the metastatic lesion was not the only determining factor accounting for increased survival in this patient group. Furthermore, since this was a retrospective study with few patients, clear treatment indications could not always be determined and may not have been applied consistently. Thus, there is the potential for selection bias in the treatment approach chosen. However, we consider it possible that the wide resection can control the local lesion well and relieve the pain from imminent fracture as well as improving patients' impaired activities of daily living, all of which might contribute to prolonged survival.

Furthermore, we regard wide resection as a safe procedure because there were no severe complications related to the surgery except in one patient with a radius metastasis who developed posterior interosseous nerve palsy after the metastasectomy. Baloch et al. also reported that there were seven complications, including prolonged wound healing and problems related to the endoprosthesis, none of which resulted in major morbidity among 25 patients with metastatic RCC. Furthermore, they recommended wide resection and argue that the vascularity of the tumor is not a contraindication, since the surgeon never cuts into the tumor during the procedure. Despite aggressive surgical intervention, they reported a low incidence of complications (20). In our study, though surgical time compared favorably between the two surgical techniques, intraoperative bleeding was significantly lower in wide resection. Thus, wide resection for the bone and soft tissue metastases of RCC is relatively safe and is the recommended option both for control of local disease and because of the prospect of long-term survival in some patients.

Similar to other studies, we found that patients with bone or soft tissue metastases from RCC have a good prognosis for long-term survival. Furthermore, our results suggest that wide resection of bone and soft tissue metastatic lesions of RCC are a favorable option, not only for controlling local metastasis, but also for improving prognosis. This approach can also be used for patients with multiple metastases to improve impaired activity, since patients may achieve a relatively long survival despite these metastases.