Role of surgery in patients with metastatic renal cell carcinoma

INTRODUCTION — Patients who present with metastatic renal cell carcinoma (RCC) or who develop metastases or recurrent disease following prior treatment are generally managed with systemic therapy, primarily using immunotherapy or agents targeting the vascular endothelial growth factor (VEGF) pathways. (See "Systemic therapy of advanced clear cell renal carcinoma".)

However, not all patients with metastatic RCC behave similarly; some data suggest that there may be a subgroup whose tumors will display an indolent growth pattern that may warrant careful surveillance rather than active surgical or medical therapy [1]. Regardless, most patients with metastatic RCC will require treatment, and surgery is sometimes part of the therapeutic plan.

This topic will discuss the role of surgery in patients with metastatic RCC. Other topics relevant to this population are discussed separately. (See "Overview of the treatment of renal cell carcinoma", section on 'Advanced renal cell carcinoma'.)

The role of surgery in the initial management of patients with localized RCC is discussed separately. (See "Definitive surgical management of renal cell carcinoma".)

OVERVIEW OF SURGICAL TREATMENT FOR METASTATIC RENAL CELL CARCINOMA — Surgery continues to play an important role in the management of patients with metastatic renal cell carcinoma (RCC) in one of several ways (algorithm 1):

●Nephrectomy may be performed as part of a combined modality approach either to decrease tumor burden prior to systemic therapy or to resect residual abnormalities in patients exhibiting major responses to systemic therapy. (See 'Cytoreductive nephrectomy' below.)

●Metastasectomy may be performed in patients with one or a very limited number of metastases. (See 'Metastasectomy' below.)

●Palliative nephrectomy may be performed to control severe local and systemic symptoms from the primary tumor. (See 'Palliative nephrectomy' below.)

CYTOREDUCTIVE NEPHRECTOMY — Cytoreductive nephrectomy (sometimes referred to as debulking nephrectomy) is a reasonable treatment option for carefully selected patients with metastatic renal cell carcinoma (RCC).

In general, we offer cytoreductive nephrectomy before systemic therapy to patients with no or one risk factor and good performance status (see 'Patient selection for cytoreductive nephrectomy' below). Patients with more advanced disease (≥2 risk factors) should receive systemic therapy first but may benefit from nephrectomy subsequently if they demonstrate good response to systemic therapy.

The majority of patients will undergo systemic therapy after cytoreductive nephrectomy; only a small group of patients who have indolent disease or no evidence of disease (M1NED) can be observed. If systemic therapy is given first, patients should generally be restaged in 8 to 12 weeks; those who have a major response may be considered for cytoreductive nephrectomy then. However, there is considerable variability in the timing of restaging and the eligibility criteria for cytoreductive nephrectomy after systemic therapy, depending upon both the systemic therapy used and clinician preference.

A multidisciplinary consultation that includes discussion of the patient's prognosis, the radiologic features of the primary and metastatic sites, the proposed systemic treatment options, and the potential need for establishing a histologic diagnosis prior to surgery is recommended to formulate an appropriate plan for each patient.

The possible benefit of retroperitoneal lymphadenectomy in the context of nephrectomy and systemic therapy for patients presenting with stage IV disease has not been well studied (table 1) [2-4], but at least one report suggests that there is no advantage to this approach [2]. Other data suggest that the presence of retroperitoneal nodes is a strong predictor of systemic treatment failure.

Patient selection for cytoreductive nephrectomy — There is no universal approach to selection of the appropriate patient with metastatic RCC who should be offered cytoreductive nephrectomy. For patients who are deemed to be candidates for cytoreductive nephrectomy, clinical trial participation should be encouraged.

In general, the selection of patients should be done with considerable care so that appropriate patients can proceed with systemic therapy. This is best ensured by taking into consideration both the patient's performance status (usually assessed by the Karnofsky performance status [KPS]) and their prognosis. Two very similar models are widely used to predict the patient's prognosis, containing five and six variables, respectively. Each of these variables is called a risk factor, and the total number of risk factors is an important determinant of a patient's eligibility for upfront cytoreductive nephrectomy. (See 'Cytoreductive nephrectomy' above.)

The Memorial Sloan Kettering Cancer Center (MSKCC) model includes five variables [5]. Patients with none, one to two, and three to five of these factors are considered good, intermediate, and poor risk, respectively.

●<1 year from diagnosis to treatment

●KPS <80

●Serum lactate dehydrogenase (LDH) >1.5 times the upper limit of normal

●Corrected serum calcium > upper limit of normal

●Serum hemoglobin < lower limit of normal

Another model from the International Metastatic Database Consortium (IMDC) includes six variables [6]. Patients with none, one to two, and three to six of these factors are considered good, intermediate, and poor risk, respectively.

●<1 year from diagnosis to treatment

●KPS <80 percent

●Corrected serum calcium > upper limit of normal

●Serum hemoglobin < lower limit of normal

●Absolute neutrophil count > upper limit of normal

●Platelet count > upper limit of normal

Further discussion of prognostic factors for patients with metastatic RCC is covered separately. (See "Prognostic factors in patients with renal cell carcinoma", section on 'Prognostic factors in stage IV disease'.)

Evidence for cytoreductive nephrectomy — The role for cytoreductive nephrectomy in metastatic RCC was established in the cytokine era but extrapolated to the current practice in which more effective therapies (eg, vascular endothelial growth factor [VEGF] tyrosine kinase inhibitors [TKIs] and immune checkpoint inhibitors [ICIs]) are favored.

Cytokine therapy — The primary support for cytoreductive nephrectomy comes from two trials conducted in the era of interferon immunotherapy, which is no longer used as a first-line therapy for RCC:

●The Southwest Oncology Group (SWOG) randomly assigned 246 patients presenting with metastatic RCC to treatment with nephrectomy followed by interferon alfa (IFNa) versus IFNa alone [7]. Compared with IFNa alone, nephrectomy before treatment resulted in a statistically significant improvement in overall survival (median 11 versus 8 months). Among those who underwent nephrectomy plus IFNa, patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 survived longer than those with a performance status of 1 (median 17 versus 7 months) (table 2).

●In a second trial sponsored by the European Organization for Research and Treatment of Cancer (EORTC), 83 patients with metastatic RCC were randomly assigned to the same treatment arms as in the SWOG study above [8]. Both time to progression (median five versus three months) and overall survival duration (median 17 versus 7 months) significantly favored cytoreductive nephrectomy prior to IFNa therapy.

Antiangiogenic therapy and immune checkpoint inhibitors — Whether to offer cytoreductive nephrectomy to patients undergoing modern (antiangiogenic or ICI) systemic therapy for metastatic RCC is less straightforward.

Nevertheless, rapid advances in immunotherapy with ICIs have led to this approach being the preferred treatment for metastatic RCC. (See "Overview of the treatment of renal cell carcinoma", section on 'Checkpoint inhibitor immunotherapy'.)

Although upfront cytoreductive nephrectomy was once considered to be an option in such patients with projected survival >12 months and <4 poor prognostic factors, it was not supported by available prospective data:

●In the CARMENA trial, 450 patients were randomly assigned to nephrectomy followed by sunitinib or sunitinib alone [9]. All patients had intermediate- or poor-risk metastatic RCC. With a median follow-up of 51 months and 326 observed deaths, results with sunitinib alone met the predetermined criteria for noninferiority compared with those with nephrectomy followed by sunitinib (median overall survival 18.4 months with sunitinib versus 13.9 months with surgery followed by targeted therapy, hazard ratio for death 0.89, 95% CI 0.71-1.10).

●A second trial, SURTIME, was terminated prematurely due to poor accrual after enrolling just 99 predominantly MSKCC intermediate-risk patients [10]. Compared with upfront nephrectomy, more patients who underwent deferred nephrectomy (after three cycles of sunitinib) received sunitinib, and the overall survival was better after delayed nephrectomy than upfront nephrectomy (32 versus 15 months).

●Largely based on the results of these two trials, the 2018 updated European Association of Urology guidelines recommended against cytoreductive nephrectomy for MSKCC poor-risk patients and against upfront cytoreductive nephrectomy for MSKCC intermediate-risk patients (with two risk factors) requiring systemic therapy with antiangiogenic agents [11]. MSKCC intermediate-risk patients who derive long-term sustained benefit and/or have minimal residual metastatic burden after vascular endothelial growth factor receptor (VEGFR-TKI) therapy may be considered for delayed nephrectomy.

The results of the CARMENA trial are in contrast to retrospective data. Notably, however, retrospective data are limited by the inherent selection bias of which patients were referred for surgery.

●A follow-up analysis of the CARMENA trial showed that cytoreductive nephrectomy might be beneficial for patients with only one IMDC risk factor [12].

●One study included almost 1700 patients from the IMDC, all of whom were treated with antiangiogenic agents [13]. Compared with patients who did not undergo cytoreductive nephrectomy, those who underwent surgery had significantly longer overall survival (median 20.6 versus 9.6 months, respectively).

●One study from the National Cancer Database identified patients with metastatic RCC treated with antiangiogenic agents between 2006 and 2013 [14]. Of the 15,390 patients treated, 5374 (35 percent) underwent cytoreductive nephrectomy. Overall survival was significantly longer in patients managed with cytoreductive nephrectomy compared with those without cytoreductive nephrectomy (median 17.1 versus 7.7 months).

●A retrospective study from IMDC presented in abstract form at the 2020 American Society of Clinical Oncology (ASCO) GU meeting included 4639 patients with metastatic RCC from 40 centers. Cytoreductive nephrectomy was more likely in patients with the following characteristics: <65 years old, no adverse metastases, IMDC risk score of 0 or 1, and no adverse histology (non-clear-cell or sarcomatoid features). By univariate, multivariate, and propensity-score matched analyses, cytoreductive nephrectomy was associated with improved overall survival compared with no cytoreductive nephrectomy. The benefit of cytoreductive nephrectomy did not differ between patients treated with first-line antiangiogenic versus ICI therapy [15].

●A retrospective study from Memorial Sloan Kettering Cancer Center of 245 patients with metastatic RCC found the total IMDC risk factors changed in more than half of the patients at six weeks and six months after cytoreductive nephrectomy; an increase in the number of IMDC risk factors is a negative prognostic factor [16]. Thus, the systemic benefit of cytoreductive nephrectomy, through significant lowering of the disease burden, may manifest in modifying patients' IMDC scores.

The preponderance of data from prospective and retrospective studies suggest that patients with low disease burden and good performance status may still benefit from cytoreductive nephrectomy, regardless of the choice of systemic therapy [17]. Thus, we can offer nephrectomy in patients with one risk factor and good performance status but reserve nephrectomy for others with two or more risk factors and/or poor performance status until after they have demonstrated good response to systemic therapy.

Although there are no prospective data on the role of cytoreductive nephrectomy in the setting of ICI, we suggest following the same guidelines with regard to cytoreductive nephrectomy as with antiangiogenic therapy before initiating systemic therapy.

Three clinical trials, NORDIC-SUN (NCT03977571), CYTOSHRINK (NCT04090710), and PROBE (SWOG, under development), that are underway should help answer the question of which patients in the ICI era will benefit from cytoreductive nephrectomy.

METASTASECTOMY — In selected patients with metastatic renal cell carcinoma (RCC), surgical resection of metastatic foci, known as metastasectomy, is a treatment option that can yield long-term disease-free survival.

Resection of metastatic disease (metastasectomy) has been performed in several situations:

●Patients with stage IV disease at presentation, where metastasectomy is performed with nephrectomy

●Patients who develop metastatic disease following nephrectomy

●Patients who have persistent disease despite systemic therapy

Patient selection for metastasectomy

Metastasectomy before systemic therapy — Patients eligible for metastasectomy prior to systemic therapy must have limited "oligometastatic" disease (ie, one to three metastases). Those who develop metastatic disease following nephrectomy should have a disease-free interval of >1 year. Following complete metastasectomy, these patients are not placed on adjuvant therapy until recurrence outside of clinical trials.

The potential role of surgery is illustrated by the results from a classic series of 278 patients with recurrent RCC in which 51 percent underwent removal of all of their metastatic disease with curative intent, 25 percent underwent partial resection of their metastatic disease, and 24 percent were treated without surgery [18]. Metastases were most frequently resected from the lung, brain, bone, and soft tissue.

The following findings were noted on multivariate analysis:

●The five-year overall survival rate was highest in patients treated with curative-intent metastasectomy (44 versus 14 and 11 percent, respectively). Survival rates after complete resection of a second and third metastasis were not different from those after initial metastasectomy.

●The strongest predictors of prolonged survival were a disease-free interval from nephrectomy to detection of metastases of greater than one year (55 versus 9 percent five-year overall survival); a single site versus multiple sites of metastases (54 versus 29 percent five-year survival), especially if the site was the lung; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (table 2); and the absence of prior cytotoxic chemotherapy or of significant recent weight loss.

A study published in the targeted therapy era also found that the number of metastatic sites (≥2 versus <2) and sarcomatoid features was associated with recurrence after complete metastasectomy [19].

For patients who undergo complete resection of metastatic disease, surveillance is recommended. Outside of a clinical trial, systemic therapy should be reserved for patients with measurable disease recurrence. Two small randomized studies with vascular endothelial growth factor (VEGF)-targeted agents, sorafenib [20] and pazopanib [21], showed no benefit after complete resection of metastatic disease (M1NED). (See "Surveillance for metastatic disease after definitive treatment for renal cell carcinoma" and "Overview of the treatment of renal cell carcinoma".)

Residual disease after systemic therapy — Resection of metastatic disease appears to be effective following systemic therapy in carefully selected patients. The eligibility criteria, however, are not standardized and therefore require multidisciplinary consultation.

In the cytokine era, resection of residual disease after achieving a partial remission from systemic therapy with interleukin-2 (IL-2) frequently resulted in disease-free survival for significant periods [22,23]. This was illustrated in a series of 31 selected patients with RCC who had a partial or complete response to systemic IL-2 and then underwent resection of relapsing or residual disease; the two-year progression-free survival was 37 percent [23]. Subsequent evaluation has confirmed that most of these patients remain disease free, with follow-up beyond 10 years in some cases [24]. Pathology of the resected lesions frequently reveals an active lymphoid infiltrate surrounding the residual tumor or occasionally no evidence of residual tumor. (See "Systemic therapy of advanced clear cell renal carcinoma".)

Data for patients treated initially with antiangiogenic therapy are more limited and of shorter duration, but they also support the role of metastasectomy in appropriately selected patients. In an observational multicenter series of 22 patients, 11 remained disease free at a median of 43 weeks after surgery [25]. At a median follow-up of over two years, 21 patients were alive.

Evidence for metastasectomy

Thoracic metastases — Surgical resection of isolated lung metastases in carefully selected patients has been associated with a 20 to 50 percent five-year survival. Complete resection of lung-only metastases is associated with markedly improved survival as compared with incomplete resection (five-year cancer-specific survival 73.6 versus 19 percent, respectively) [26]. The general criteria, techniques, and results for surgical resection of pulmonary metastases from solid tumors are discussed separately. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Surgical resection of pulmonary metastases: Benefits, indications, preoperative evaluation, and techniques".)

Isolated thoracic lymph node metastases of RCC can be treated with systematic lymph node dissection. In a series of 15 patients, the median disease-free interval was 40 months (range 0 to 171 months) before isolated thoracic lymph node metastases were detected. After surgery, the survival rates at one, three, and five years were 93, 73, and 73 percent, respectively, and 65 percent of the patients were free of local recurrence at five years. Perioperative morbidity and mortality rates were low [27].

Isolated bone metastases — Excision of bone metastases may be considered in carefully selected patients for both pain relief and tumor control [24,28-30]. In one series, 295 consecutive patients with metastatic RCC who had a solitary lesion, intractable pain, or impending fracture underwent resection [29]. Overall, the one- and five-year survival rates were 47 and 11 percent. The best results were seen in patients who had either a solitary bone lesion or multiple bone-only metastases. Stereotactic radiosurgery (SRS) is increasingly being used to treat oligometastatic bony disease and may extend targeted-therapy treatment [31]. (See "Radiation therapy for the management of painful bone metastases".)

Brain metastases — Brain lesions have been traditionally treated with surgical resection, whole-brain irradiation, or SRS. However, regardless of the treatment approach, the prognosis is poor, and median survival in patients with brain metastases is approximately nine months [32]. For these patients, poor prognostic factors for overall survival include [33]:

●Performance status at the start of therapy <80 percent

●Diagnosis to treatment time <12 months

●>3 sites of brain metastases

SRS alone may be an attractive therapeutic option for patients with incidentally identified brain metastases from RCC [34,35]. In one report of 19 patients presenting with incidentally detected, asymptomatic brain metastases, local control was achieved in 95 percent with SRS [34]. At a mean of 450 days, approximately 20 percent remained free from progression in the central nervous system. (See "Overview of the treatment of brain metastases", section on 'Single brain metastasis'.)

A study of the Surveillance, Epidemiology, and End Results (SEER) database found that 12 percent of patients with metastatic RCC had synchronous brain metastasis, and 20 percent of patients with brain metastasis had brain-only metastasis. Compared with those with brain and other metastases, patients with brain-only metastasis were more likely to undergo cytoreductive nephrectomy (40.8 versus 20.4 percent) and had better prognosis after the surgery (median survival 33 versus 11 months) [36].

Liver metastases — Despite the negative impact of liver metastases on survival [37], resections of solitary metachronous liver metastases are possible, although the morbidity may be high [38]. Contemporary reports suggest that with careful patient selection, two-year survival is greater than 50 percent. Factors that may identify appropriate patients for hepatic metastasectomy include those in whom surgery is being performed with curative intent, an interval of more than 24 months from RCC diagnosis to development of liver metastases, tumor size less than 5 cm, and the feasibility of repeat hepatectomy if necessary [39].

Thyroid metastases — RCC commonly metastasizes to the thyroid gland [40]. Fine needle aspiration is essential to make this diagnosis. Limited data suggest that metastasectomy may confer a survival advantage. In one study of 97 patients with thyroid metastases (22 percent from a renal primary), median survival time was 30 and 12 months for those who underwent metastasectomy compared with those who did not [40]. Poor prognostic indicators were patient age >70 years and prior nephrectomy for contralateral renal metastases.

Pancreatic metastases — Patients with pancreatic metastases seem to have a better prognosis, which may be a result of a more indolent biology [41]. In addition, patients who present with pancreatic metastases also respond better to targeted agents [42], although the reason for this is unknown. A systematic literature review of 384 patients with RCC metastases to the pancreas managed with (n = 321) or without (n = 73) metastasectomy revealed five-year overall survivals of 73 and 14 percent, respectively [43]. The postoperative in-hospital mortality associated with pancreatic resection was 2.8 percent. The presence of extrapancreatic RCC metastases was associated with worse disease-free survival, and symptomatic metastases were associated with worse overall survival. Surprisingly, the size of the largest tumor resected, number of pancreatic metastases, type of pancreatic resection, and interval from diagnosis of RCC to pancreatic metastasis were not predictive of survival.

Local recurrence — Although the majority of patients who develop a local soft tissue recurrence die of metastatic disease, the limited data suggest that resection of the recurrence may prolong survival in carefully selected patients [44-46]. As with metastatic disease, patients with a longer time to recurrence following nephrectomy and with small-volume recurrent disease tend to do better.

PALLIATIVE NEPHRECTOMY — Nephrectomy has been used to control severe local symptoms from the primary tumor such as significant pain or bleeding needing blood transfusions [47,48]. In these cases, we recommend proceeding with palliative nephrectomy, although systemic therapy may also be justified.

Alternative approaches to symptom palliation are illustrated by the following examples:

●Pain can be managed with analgesics or angioinfarction. (See "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)" and "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs" and "Interventional therapies for chronic pain".)

●Hematuria due to renal cell carcinoma (RCC) can be managed by renal angioinfarction, which entails femoral artery puncture and the subsegmental injection of polyvinyl alcohol particles into the renal vessels. However, it may be associated with a high complication rate, including the risk for the development of postembolization syndrome (PES), consisting of intractable pain and nausea, fever, and potentially a paralytic ileus. In one retrospective study that included over 100 patients (34 of whom underwent angioinfarction for palliation), 75 patients (66 percent) experienced a complication [49]. The most common complications were PES, leukocytosis, and fever, which were reported in 44, 28, and 13 percent, respectively; there were no reports of a paralytic ileus.

●The consequences of colic due to obstruction with a clot can be minimized with ureteral stents and hydration. (See "Placement and management of indwelling ureteral stents", section on 'Indications for stent placement'.)

●Hypercalcemia, fatigue, fever, and other systemic symptoms are often controlled with nonsteroidal anti-inflammatory drugs, bisphosphonates, hydration, and/or appetite stimulants in addition to effective systemic therapy for the disease. (See "Treatment of hypercalcemia".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cancer of the kidney and ureters".)

SUMMARY AND RECOMMENDATIONS — Patients who present with metastatic renal cell carcinoma (RCC) or who develop metastases or recurrent disease following prior treatment are generally managed with systemic therapy. (See "Systemic therapy of advanced clear cell renal carcinoma" and "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma".)

Surgery retains an important role in the management of carefully selected patients:

●For patients who have favorable (no risk factor) or low-intermediate risk (one risk factor) metastatic RCC at presentation, a good performance status, and a resectable primary tumor with low tumor burden outside the kidney, we suggest upfront debulking (cytoreductive) nephrectomy (Grade 2C). In such patients, cytoreductive nephrectomy should be performed before systemic therapy (either antiangiogenic therapy or immune checkpoint inhibitor therapy). (See 'Cytoreductive nephrectomy' above.)

●For patients with one to three readily resectable metastases at presentation or who relapse following initial surgical treatment (nephrectomy) but have a disease-free interval >1 year, we suggest metastasectomy rather than immediate initiation of systemic therapy (Grade 2C). This approach has been associated with prolonged disease-free survival in selected patients. (See 'Metastasectomy' above.)

Patients who undergo complete resection of metastatic disease should undergo surveillance. Outside of a clinical trial, systemic therapy should be reserved for patients with measurable disease.

●Although palliative nephrectomy has been used to control severe local symptoms from the primary tumor (eg, pain, bleeding), systemic therapy and interventional angioinfarction techniques are also reasonable options. (See 'Palliative nephrectomy' above.)