Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)
Metastasectomy after biological response modifiers
The concept of pretreating patients with metastatic disease followed by complete surgical resection has been investigated in the 1980s and 1990s in small retrospective series. Between 1988 and 1996, 14 patients underwent initial interleukin-2-based cytokine therapy followed by surgical resection of primary and metastatic RCC lesions . After cytokine therapy, nine patients had an objective response and five patients had stable disease. All patients were then rendered disease-free by surgical excision of residual metastases and the primary tumor. The cancerspecific survival rate at 3 years was 81.5%. The median overall survival was 44 months (range 4–97 months). Two other series of 16 and 17 patients treated with either interleukin-2  or interferon alpha  followed by complete resection of all lesions reported median overall survival of 11 months (range 4–44 months) and 26 months (range 6–34 months), respectively. Another series evaluated this strategy for pulmonary metastasis only and found similar long-term survival . The results of these studies were often used to justify aggressive surgical resection of stable or responding lesions after cytokine therapy, but it has to be acknowledged that these series contained patients with resectable oligometastatic disease that were retrospectively selected because complete resection had been achieved. Only one prospective trial has been performed to investigate if cytokine therapy followed by surgical resection of metastases with curative intent after a period of disease stabilization or response leads to prolonged survival . Within a period of 8 years, 38 patients with responsive or stable potentially resectable metastatic RCC after cytokine treatment were enrolled. Patients subsequently underwent metastasectomy with curative intent and adjuvant systemic therapy. Predictive factors for a favorable long-term outcome included pulmonary disease and surgical complete resection. The median overall survival was 4.7 years (range 3.0–7.8 years) with a median time to progression of 1.8 years (0.8–3.1 years). Twenty-one percent of the patients remained disease-free by the end of the study. Failure to have a surgical complete resection was the strongest negative predictor of prolonged progression-free and overall survival. In addition, metastasectomy of multiple sites if completely resected did not seem to be associated with worse prognosis than of a solitary metastasis. A secondary objective of this small study was to determine the percentage of patients who would achieve complete resection of their metastases considered resectable by radiographic criteria, which was 76%. Though the trial is limited by its small sample size, it appeared that patients with good performance status, oligometastatic disease regardless of organ site, and a period of disease stabilization or response may be the candidates in whom complete metastasectomy is eventually feasible and associated with long-term survival. This finding supports the results of several previously published retrospective studies.
Metastasectomy following targeted therapy
The higher response rate and downsizing after targeted therapy in comparison to cytokine treatment may increase the therapeutic multimodality options in RCC. As a consequence, more patients who were not candidates for complete metastasectomy or cytoreductive surgery are now being offered systemic therapy with the option to reconsider resection following response or substantial downsizing. To date, this investigational approach has not been prospectively studied, but case reports and retrospective series have been published. This concept may follow distinctively different goals (Table 11.3) (Fig. 11.1).
Table 11.3. Rationale for pretreating patients with targeted agents prior to planned metastasectomy
- Turning patients with technically unresectable disease into candidates for metastasectomy after downsizing
- Reconsidering patients with multiple and extensive metastases for complete surgical resection after downstaging to oligometastatic disease
- Selecting patients who do not progress under therapy for metastasectomy
- Improving cancer-related morbidity in patients who may be candidates for metastasectomy but have a reduced performance status
Fig. 11.1. CT scan of a 67-year-old male patient before (a, b) and after (c, d) three cycles of sunitinib for metachronous retroperitoneal lymph node metastases 2 years following nephrectomy of a clear cell RCC. The absence of progression under pretreatment and downsizing may be used to select patients for metastasectomy. In this case it remains disputable if retroperitoneal lymph node dissection was facilitated by pretreatment. Despite viable clear cell lymph node metastasis at pathology, the patient remains disease-free at a follow-up of 12 months
Several cases have been reported with shrinkage of nodal metastases following tyrosine kinase inhibitors. Sunitinib therapy was followed by complete resection of bulky lymphadenopathy with encasement of the great vessels not amenable to initial excision in a number of patients with a primary clear cell RCC and no evidence of distant metastases [102, 112, 124, 139]. In all instances downsizing up to 40% was reported following five to ten cycles. “Second-look” surgery with complete retroperitoneal LND was feasible in all cases. Despite necrosis all had viable clear cell RCC on pathology. Others have observed prolonged disease-free survival after complete resection of pretreated metastatic lesions at sites other than the retroperitoneum. A series reported on three patients with complete resection of liver, lymph node, and vertebral metastases following the absence of further progression under treatment with sorafenib and sunitinib . The patients remained disease-free after 16, 24, and 29 months. There are reports on the discontinuation of targeted therapy after complete resection of metastatic lesions. A series of patients who discontinued targeted therapy after complete response included six patients after complete resection of residual metastases in the lungs, iliac bone, skin, and thyroid following treatment with sunitinib. The patients remained off treatment for 5–19 months [54, 55]. The largest cohort included 22 patients from three institutions who underwent consolidative metastasectomy after at least one cycle of targeted therapy . Metastasectomy sites included the retroperitoneum in 12 patients, lung in 6, adrenal gland in 2, bowel in 2, and mediastinum, bone, brain, and inferior venal caval thrombus in 1 each. A total of six postoperative complications were observed in four patients within 12 weeks after surgery, which resolved with appropriate management. Postoperatively nine patients continued with targeted therapy. In 11 patients recurrence developed a median of 42 weeks after metastasectomy. At a median follow-up of more than 2 years, 21 patients were alive and 1 died of renal cell carcinoma 105 weeks after metastasectomy. In these selected patients with a limited tumor burden after treatment with targeted agents, consolidative metastasectomy proved feasible with acceptable morbidity. Though a significant time off targeted therapy and long-term disease-free status can be gained with this approach, it remains unresolved if this is primarily due to the complete resection of metastatic disease, which has been identified as an independent factor associated with prolonged survival, or the combination of surgery and targeted therapy. This approach may not be disputable in those reported cases with technically unresectable disease who were reconsidered for surgery following downsizing. However, there is little evidence how often pretreatment may result in a meaningful downsizing of metastases allowing resection of an initially inaccessible lesion. In a retrospective study, two to six presurgical cycles of sunitinib were evaluated in patients with synchronous metastatic RCC to downsize surgically complex tumors and reconsider resection . The series of ten patients included four patients with bulky retroperitoneal lymph node metastases and encasement of the major blood vessels. In three patients the lesions had an increase of the longest diameter of 13–46% following sunitinib. Only one patient had a reduction of the longest diameter of 21%, but despite the downsizing, encasement of vital structures remained and surgery was not reconsidered. Though not directly transferable, more data on downsizing are available for primary tumors. Several authors observed a median reduction of longest diameter in 7–12% with only 6% of the patients having a >30% reduction of the primary tumor diameter [1, 109], though there is evidence that metastatic lesions with their generally smaller volume have a higher overall response rate and shrinkage . Data on combining surgery with targeted therapy are emerging from several retrospective and prospective nonrandomized trials and suggest that pretreatment with tyrosine kinase inhibitors which have a generally shorter half life are preferable over antiVEGF monoclonal antibodies . Reports indicate that pretreatment with sunitinib, axitinib [43, 60], and sorafenib as long as 1 or 2 days before surgery is not associated with a higher complication rate [13, 18, 43, 60, 80, 109]. Currently prospective non-randomized trials evaluate the role of metastasectomy following targeted therapy (NCT00918775).
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