The Evolving Role of Metastasectomy for Patients with Metastatic Renal Cell Carcinoma

Surgical metastasectomy continues to be utilized for patients with solitary or low-volume metastatic renal cell carcinoma (mRCC). Although few high-quality data are available to evaluate outcomes, local treatment is recommended when feasible because it may allow a subset of patients to delay or avoid systemic treatments. With the development of improved mRCC therapies, utilization of metastasectomy has increased because most patients have incomplete responses to systemic treatment of their metastases. This review discusses the rationale and history of metastasectomy, trends in utilization, prognostic factors for patient selection, site-specific considerations, alternatives for nonsurgical local treatment, and risk of morbidity associated with metastasectomy.

Key points

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Surgical metastasectomy may enable periods of systemic treatment-free survival in well-selected patients.
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Ideal patients for metastasectomy are not frail and have a small volume of metastatic disease without aggressive pathologic features.
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The risk of morbidity associated with surgery depends on multiple factors and must be balanced with potential benefits from surgery.
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Prior to metastasectomy, patients should have a multidisciplinary evaluation, including surgeons and medical oncologists, to provide the best shared decision making.

Introduction

In 1939, Barney and Churchill reported no recurrence of disease for 5 years after a patient was treated with nephrectomy for adenocarcinoma of the kidney and subsequent lobectomy for a 6-cm lung metastasis that was resistant to radiation therapy. Other historical case reports demonstrate that metastasectomy occasionally resulted in long-term survival for patients with metastatic renal cell carcinoma (mRCC), despite having no effective options for systemic therapy in this era. In 1967, Middleton reported 41 patients who had nephrectomy despite known metastatic disease treated from 1932 to 1965 at New York Hospital. The reported overall survival was significantly better for patients with solitary metastasis, most of whom were treated with metastasectomy. Long-term survivors included a patient, who was alive without recurrence, 31 years after the initial nephrectomy and 14 years after excision of a brain metastasis.

The rare opportunity to provide long-term, disease-free survival for a subset of patients with solitary metastasis provided a rationale for metastasectomy before active systemic treatments became available. More recently, patients with oligometastatic renal cell carcinoma (RCC) have been treated with metastasectomy after partial responses to cytokine therapy or targeted therapies. However, the benefit of surgery as a local treatment for RCC metastases is difficult to measure accurately beacause benefits are confined to a small fraction of patients and no large randomized clinical trials having investigated metastasectomy for typical mRCC patients. Furthermore, surgeons intentionally choose lower-risk patients with slow-growing metastases for metastasectomy, creating an observation bias when comparing outcomes.

Over the past 2 decades, systemic treatments that target angiogenesis or cell growth pathways have demonstrated prolonged survival compared to patients treated with interferon-α in large randomized clinical trials. ^, Although better systemic treatments for mRCC became increasingly available, the utilization of metastasectomy continued to increase from 2006 to 2013. More recently, single-agent or combination therapies that target immunologic checkpoints have emerged as first-line systemic therapies. In 2019, new combination treatments using both targeted therapies and immune checkpoint inhibitors gained approval for mRCC treatment after demonstrating improved survival in clinical trials. ^, Metastasectomy may be less utilized with complete responses, which are more common with newer therapies (9% complete response rate for patients treated with nivolimab plus ipilimumab). Metastasectomy, however, is likely to continue to play a role in the multidisciplinary treatment of mRCC until systemic therapies produce complete and durable responses. The purpose of this review is to examine the currently available data for metastasectomy in mRCC patients, including site-specific data and strategies for patient selection.

Utilization of metastasectomy for metastatic renal cell carcinoma

Studies that estimate how often mRCC patients are treated with metastasectomy were uncommon before the development of large cancer registries. Furthermore, improvements in imaging technology during the past few decades have resulted in earlier detection of smaller asymptomatic metastases, which also may have an impact on the utilization of metastasectomy, which also may vary significantly among institutions. For example, in a single-institution series of 887 mRCC patients from 1976 to 2006, 48% of patients had surgical resection of metastases. Sun and colleagues evaluated population-level data from the National Cancer Database and found 1976/6994 (28%) patients with mRCC were treated with metastasectomy from 2006 to 2013 and that utilization increased from 24.9% in 2006 to 31.4% in 2013. Increased utilization of metastasectomy in recent years has not been limited to kidney cancer. Bartlett and colleagues found that metastasectomy increased from 2000 to 2011 across many cancer types, including colorectal, lung, breast, and melanoma. Increase in utilization was greatest in colorectal cancer, which had the most efficacious systemic therapy during the study period.

Evidence for metastasectomy in metastatic renal cell carcinoma

Multiple reviews and meta-analyses are available to systematically evaluate the evidence for surgery in the treatment of RCC metastases. In 2018, Ouzaid and colleagues systematically reviewed the literature and found that median overall survival for patients treated with metastasectomy (36–142 months) was higher compared with patients treated without metastasectomy (8–27 months). Investigating the concept of complete versus incomplete surgical metastasectomy also provides evidence for the possible impact of surgical treatments. Alt and colleagues evaluated 887 patients with multiple RCC metastases from 1976 to 2006, including 125 who had complete surgical metastasectomy. The median cancer-specific and overall survival rates for patients who underwent complete metastasectomy were 4.8 years and 4.0 years, respectively, compared with 1.3 years and 1.3 years, for patients who did not undergo complete metastasectomy. There was a survival benefit provided by complete metastasectomy compared with incomplete metastasectomy when patients had 2 or more metastases. Patients treated surgically, however, had significant differences in disease burden and performance status compared with the nonsurgically treated patients. In a subsequent article from the same institution, evaluating 586 patients with first occurrence of metastases between 2006 and 2017, 158 patients were treated with complete metastasectomy. After adjusting for age, sex, timing, number, and location of metastases, the investigators found that complete metastasectomy was associated with reduced likelihood of death from RCC (hazard ratio 0.47; 95% CI, 0.34–0.65; P <.001). Collectively, these data suggest improved survival for patients treated with complete metastasectomy was better than incomplete metastasectomy or no local treatment, although this concept should be investigated in multi-institutional cohorts.

Patient selection

Patient selection is critical to achieve optimal outcomes, and metastasectomy for mRCC is one of the best examples of this surgical maxim. Factors associated with improved outcomes after metastasectomy include (1) smaller volume of metastatic disease, (2) slower disease progression, and (3) lack of competing caused for mortality. Prior to metastasectomy, patients should consult with a multidisciplinary team and discuss expectations for outcomes based on individual considerations ( Fig. 1 ).

Overall patient health is important to consider prior to surgery (see Fig. 1 A). Patients with limited life expectancy because of comorbidities are less likely to benefit from surgery. Although metastasectomy is more likely to be utilized in younger patients, actual patient age may be less important than physiologic age, which is associated with treatment outcomes in older patients with cancer. Performance status is a critical factor associated with survival in mRCC and surgeons should consider patients with better performance status for metastasectomy. It is important, however, to consider how surgery may affect short-term and long-term performance status. Occasionally, performance status may improve for patients with symptomatic metastasis, such as patients with pathologic bone fractures or gross hematuria. Furthermore, because major adverse events of systemic therapies also affect performance status, surgery may improve performance status by delaying systemic therapy and potential adverse events in some patients.

Cancer-specific survival in mRCC patients varies significantly, with many known tumor specific prognostic factors (see Fig. 1 B). In general, patients with solitary or low-volume metastatic disease and fewer sites of metastasis have longer expected survival. In addition, patients with initially localized tumors and a longer time from nephrectomy to metastatic diagnosis are more likely to survive longer compared with patients with synchronous metastatic disease. Several validated risk assessment tools estimate overall survival in mRCC ^, and may be useful for patients considering metastasectomy. Observed radiographic growth of metastatic tumors also is important as a prognostic factor for survival, and some patients with slow-growing metastases may be observed safely without systemic treatment. Tumor growth despite systemic treatment is associated with poor survival and these patients are unlikely to benefit from aggressive surgery. Rapid progression also is associated with aggressive pathologic features, such as sarcomatoid de-differentiation, and upfront cytoreductive surgery, generally is not recommended. Similarly, Thomas and colleagues found no benefit for metastasectomy after nephrectomy in a matched-pair analysis of mRCC patients with sarcomatoid de-differentiation.

In addition to the patient-specific and tumor-specific factors, shared decision making before metastasectomy should consider the possible short-term and long-term morbidity associated with surgical treatment (see Fig. 1 C). Morbidity varies with the type of procedure, approach, and anatomic location but may be comparable to other surgeries for primary tumors at those anatomic locations. Surgery may be more complex if scarring is present from prior surgery or tissues are poor quality because of prior radiation therapy. In addition, treatment with targeted therapies for mRCC are associated with wound-healing complications and surgery requires interruption of certain systemic treatments. Other considerations to consider may be the need for medical replacement of hormones after adrenalectomy, thyroidectomy, or pancreatectomy. Informed consent should include a balanced discussion of the risks of surgical as well as the systemic therapies. Given the multiple unique medical and surgical factors to consider before metastasectomy, discussion with a multidisciplinary team of surgeons and medical oncologists is recommended.

Individual metastatic sites

Certain anatomic sites and prognostic factors may be associated with better outcomes in with mRCC metastasectomy sites ( Table 1 ). Some anatomic sites are more surgically more accessible, and procedures may be less morbid. For example, patients treated with a minimally invasive wedge resection of a small lung metastasis are exposed to less risk of surgical morbidity compared with an open resection of large liver metastases. More importantly, some metastatic sites are associated with slower disease progression. For example, pancreatic RCC metastatic tumors frequently are observed to be slow growing and patients with pancreatic metastasis may have longer survival compared with those with metastasis at other sites. Clinical observations from multiple centers have confirmed these observations and demonstrated that metastasectomy is a feasible treatment in patients with pancreatic RCC metastases. Recently, basic science evidence has emerged that may begin to explain the slower natural history of pancreatic metastasis. In 2018, Turajlic and colleagues observed that pancreatic metastasis had the longest time to presentation of all RCC metastases, which was associated with significantly less chromosomal instability and few additional driver mutations despite longer time to clinical detection.

Table 1

Prognostic factors for survival according to anatomic site of metastasectomy

Data from Refs. ^,^,^,^,^,

Site
Lung	• Absence of lymph node involvement • Forced expiratory volume • Longer disease-free interval from initial nephrectomy • Fewer number of metastases • Smaller size of metastases • Unilateral lung involvement
Liver	• Solitary metastasis • No extrahepatic disease • Low tumor grade • No lymph node metastasis at initial diagnosis • Metachronous presentation • Better ECOG performance status
Bone	• Peripheral location of metastases • Solitary metastases • Lower MSKCC risk score • Ability to complete resect tumor
Thyroid	• Solitary metastasis • Younger age • Metachronous presentation • Ability to complete resect tumor
Pancreas	• Asymptomatic presentation • Solitary metastasis • No extrahepatic disease • Absence of vascular invasion • Ability to complete resect tumor
Brain	• No extracranial metastasis • Greater performance status • Solitary metastasis • Age ≤65 years old • Control of primary tumor