General
The lungs
The bone
The brain
Solitary or oligometastatic lesions
Metachronous metastasis and long disease-free interval of >2 years
Complete resection
Single organ site
Good performance status (Karnofsky, ECOG, WHO)
MSKCC good- and intermediate-risk
Absence of sarcomatoid features
Absence of lymph node metastases
<7 metastases
Absence of mediastinal lymph node metastases
Metastases <4 cm
Unilateral lung involvement
Appendicular metastases
Wide excision
Clear cell subtype
RPA class I
Karnofsky PS >70 %
Age <65 years
Absence of extracranial metastases
The lungs are the most frequent metastatic site in RCC and complete resection of fewer than seven pulmonary metastases has been associated with a 5-year survival rate of 37–54 %. Unilateral lung involvement, the absence of lymph node metastases, and smaller size are additional site-specific favorable factors.
Liver metastasis has a poor prognosis. However, if complete resection can be achieved for solitary lesions, 5-year survival rates of 62 % have been reported. Hepatic metastasectomy is associated with significant morbidity and mortality and it is unclear if surgery is superior to ablative percutaneous techniques.
Resection of bone metastasis is mainly performed for palliative reasons, but metastasectomy of metachronous and in particular appendicular solitary bone lesions may result in 5-year survival rates of 75 %. Contrary to symptomatic bone metastases where surgery is superior to radiotherapy, the best approach for asymptomatic solitary bone lesions is unclear. If surgery is selected, wide excision with durable fixation or reconstruction is preferable.
Stereotactic radiosurgery for brain metastasis yields median survival of 24 months in patients with RTOG RPA prognostic class I. Craniotomy may be preferable in lesions >2–3 cm, rapid onset of symptoms, and lesions with midline shift. WBRT is only adequate for patients with poor performance.
Since synchronous solitary adrenal metastases are often resected at the time of nephrectomy, little is known about the management of isolated metachronous ipsi- and contralateral adrenal lesions. Cases are often reported in series of local recurrences. Survival of up to 70 months has been reported after metastasectomy and a long metachronous interval.
Isolated lymph node metastases without further systemic disease are rare. However, their removal may be potentially curative. Synchronous regional lymph node metastases are often resected at nephrectomy. Resection of metachronous isolated lymph node metastases is associated with long-term survival.
Complete metastasectomy of solitary lesions in the pancreas, thyroid, and other less frequently involved sites results in 5-year survival rates comparable to those observed after pulmonary metastasectomy. Careful selection should be made according to the general clinical factors associated with a favorable outcome (Table 11.1).
Repeat complete metastasectomy and complete resection of multiple metastatic sites are associated with long-term survival and a 50 % decrease in the risk of death. Careful selection should be made according to the general clinical factors associated with a favorable outcome (Table 11.1).
Integration of targeted therapy with surgery may lead to more candidates for metastasectomy. Multiple case reports and series report benefits and prospective trials are ongoing.
11.1 Introduction
Renal cell carcinoma (RCC) accounts for approximately 3 % of adult malignancies and 95 % of renal neoplasms [53]. In the European Union, there were approximately 85 new cases and 35 deaths per 100,000 in 2012 [31]. The figures are similar for the United States with approximately 64,000 new cases in 2014 [125]. Metastatic RCC is present in up to 30 % of patients at diagnosis with multiple sites affected in 95 % [32, 114]. An additional 40 % of those undergoing surgery for localized RCC will develop metastases later. Therefore, approximately 30,000 patients a year have metastatic disease in the European Union alone, of whom an estimated 7,000 demonstrate non-clear cell histology. Data from the Nationwide Inpatient Sample show a preference for certain sites with the lungs involved in 45.2 %, followed by skeletal metastases in 29.5 %, lymph nodes in 21.8 %, liver metastasis in 20.3 %, and brain in 8.1 % [15]. Other locations have been described but at a lower frequency. Despite the introduction of targeted agents, treatment of metastatic RCC presents a therapeutic challenge. Although objective responses following targeted therapy are observed in 40–30 % of patients, complete responses occur in only 1–3 % [45, 87, 88]. Moreover, it has become evident that despite the most effective drugs in first-line treatment, median overall survival is only marginally longer than 2 years, which may be extended to 40 months in selected patients with adequate sequential therapy [30]. Therefore, together with the occasional durable responses achieved with high-dose interleukin-2, surgical resection of all lesions, when technically feasible, provides the only potentially curative treatment. However, only a minority of patients with metastatic RCC are candidates for metastasectomy. No reliable data exist on the percentage of patients with metastatic RCC who will be eligible for metastasectomy. A population-based analysis revealed that up to 65 % of patients with metastatic RCC have a single disease site but most of them are either not solitary or not accessible for surgery [15]. It has been estimated that only 25 % of patients with metachronous metastases are suitable candidates for resection of metastatic disease [2, 29]. Regarding synchronous metastatic disease, this proportion may be much lower. A Scandinavian whole nation study on prevalence and potential resectability identified 154 patients (16.9 %) with synchronous lung metastases in whom the proportion of metastasectomy was evaluated [98]. Eventually, only 11 patients had single lesions deemed eligible for metastasectomy which was performed in only one patient. Additionally, proper patient selection for this approach is difficult due to the heterogeneous biology of metastatic RCC. Metastasis may present at diagnosis or within a year after nephrectomy with rapid progression of disease, whereas in other individuals, disease-free intervals of more than 20 years have been observed followed by slow growth pattern of the metastatic lesions. In few cases spontaneous regression of metastases has been documented, which has been ascribed to the presence of effective immune surveillance [78, 147]. In summary, there is considerable uncertainty regarding the best approach to metastasectomy. The major reason is a complete lack of randomized studies in this setting. A recent systematic review addressed the question whether local therapy for RCC metastases is beneficial and what the best options are [19]. Conducted in accordance with Cochrane Review methodology, including all types of comparative studies on local treatment of metastases from RCC in any organ, 2,235 studies were identified, of which 16 studies reporting on a total of 2,350 patients were eligible for inclusion. All studies were retrospective comparative studies with small patient numbers. The results revealed a benefit for complete metastasectomy when compared to either incomplete or no metastasectomy for metastases to various organs in terms of survival and symptom control, such as pain relief in bone metastases. However, the overall extensive risks of bias across all studies resulted in a significant risk of confounding. Due to the relatively poor quality of the few comparative studies, the evidence retrieved in the review was associated with large uncertainty, and no general recommendations were made. Ultimately, proper selection of patients for metastasectomy is of paramount importance. Surgical resection alone or in combination with targeted agents may result in clinical efficacy that is superior to systemic therapy alone. Currently, management of metastatic disease is depending on a number of clinical factors such as performance status, the length of the disease-free interval, the presence of synchronous or metachronous metastases, as well as the number and location of sites involved [73]. One of the most commonly used prognostic models, the Memorial Sloan Kettering Cancer Center (MSKCC) risk-score model, has been established from a database of 670 patients treated with cytokines. A previously validated risk score based on Karnofsky performance status, interval from nephrectomy, and serum hemoglobin, calcium, and lactate dehydrogenase was used to categorize patients as being favorable, intermediate, or poor risk [89]. Metastasectomy is associated with survival and clinical benefit across these various risk groups [28, 29]. A retrospective analysis was performed in 129 patients with localized RCC treated with partial or radical nephrectomy who were subsequently diagnosed with disease recurrence. In the favorable-risk group, metastasectomy improved 5-year survival from 36 to 71 %. In the intermediate-risk group, 5-year survival was 38 % after metastasectomy as opposed to 0 % in the same risk group without metastasectomy or the poor prognosis group. Even after adjusting for risk score in a multivariate analysis, patients who did not undergo metastasectomy had a 2.7-fold increased risk of death. A previous cohort from the same institution included 118 patients who had a median survival time of 21 months from the time of recurrence [29]. Overall survival was strongly associated with risk group category (p < 0.0001). Median survival time and 2-year survival rates for low-risk, intermediate-risk, and high-risk patients were 76, 25, and 6 months and 88 % (95 % CI, 77 to 99 %), 51 % (95 % CI, 37 to 65 %), and 11 % (95 % CI, 0 to 24 %), respectively, suggesting that only patients with favorable- or intermediate-risk features are candidates for metastasectomy. Despite the introduction of targeted therapy, the MSKCC risk score remains a valid tool among other similar risk scores to identify potential candidates for metastasectomy [46, 104].
11.2 History of Metastasectomy and Evolvement of General Prognostic Factors
Before the advent of effective systemic therapy, patients with untreated metastatic RCC had a median overall survival of 10 months, with a 5-year survival rate of less than 10 %. After the introduction of cytokine therapy, overall survival rates were only marginally improved. Surgery was the only chance for cure. Therefore, most of the literature on metastasectomy dates back to the 1960s and 1970s of the last century, when it became evident that patients with a solitary resectable metastasis or multiple metastases restricted to one resectable organ site may have a survival benefit. In 1939 a report was published on a patient who survived 23 years following the resection of pulmonary metastases [11]. One of the first series describing metastasectomy in 41 patients with solitary lesions in the lungs, pleura, central nervous system, and abdomen dates from 1978, an era devoid of effective systemic therapy. In patients in whom complete surgical resection was possible, the median disease-specific survival was 27 months with 59 % of the patients alive at 3 years [23]. Several authors reported a 3-year and 5-year survival after resection of a solitary lesion of 45 % and 29–34 %, respectively [85, 127, 140]. Others observed a significant difference in survival in patients with metachronous and synchronous metastases [97, 110, 141]. In 179 patients the 5-year survival rate after resection of solitary lesions at various sites was 22 % for synchronous versus 39 % for metachronous metastases [133]. In addition, multiple clinical trials involving cytokine therapy revealed a strong association between clinical outcome and metastatic sites [41, 136]. These findings were supported by a series including 101 patients who underwent resection of a total of 152 metastatic lesions at different organ sites [145]. The median survival was 28 months for the entire series. Survival was improved after resection of lung metastases compared to other tumor locations (p = 0.0006) and for patients that were clinically tumor-free after metastasectomy (p = 0.0230). Additional immuno- or radiotherapy did not independently influence survival. Again, time interval between primary tumor resection and metastasectomy correlated positively with survival: a tumor-free interval of more than 2 years between primary tumor and metastasis was accompanied by a longer disease-specific survival after metastasectomy. Patients with bone and liver metastasis had a worse outcome than those with pulmonary lesions [41, 145]. Five-year survival rates for solitary metastases were 56 % for lungs, 28 % skin, 20 % visceral organ, 18 % peripheral bone, 13 % brain, and 9 % axial bone metastases [133]. In an attempt to define selection criteria for patients with solitary metastases, 278 patients with recurrent RCC were retrospectively analyzed [64]. The 5-year overall survival rate for 141 patients who underwent complete metastasectomy for their first recurrence, 70 patients who underwent incomplete metastasectomy, and 67 patients who were treated nonsurgically was 44 %, 14.5 %, and 11 %, respectively. Five-year overall survival rate was 55 % with a disease-free interval greater than 12 months versus 9 % with 12 months or less (p < 0.0001), 54 % for solitary versus 29 % for multiple sites of metastases (p < 0.001), and 49 % for age younger than 60 years versus 35 % if older (p < 0.05). Among 94 patients with a solitary metastasis, the 5-year overall survival rate was 54 % for the lungs. Factors associated with a favorable outcome by multivariate analysis included a solitary site and single metastasis, complete resection of first metastasis, a long disease-free interval, and a metachronous presentation with recurrence. Since then, multiple retrospective series have been published that support these favorable factors [5, 41, 115] (Table 11.1). In particular complete metastasectomy is a cross-cultural favorable prognostic factor. In a series of patients from Japan who had nephrectomy and metastasectomy, survival was approximately twice as long as that of previous studies without metastasectomy [94]. In a recent large multicenter analysis from Japan, incomplete resection, elevated C-reactive protein, brain metastases, and high nuclear grade were confirmed as poor prognostic factors [93]. A caveat of the retrospective series remains the inherent bias of comparing patients with solitary and oligometastatic disease and a prolonged metachronous interval to those who did not undergo resection due to extensive metastatic burden, rapid disease progression, and reduced performance. The most important determinant of outcome may be the biological behavior of the tumor [64]. In one series the only adverse factor for survival was having an aggressive tumor grade [66]. In an attempt to develop a metastasectomy-specific prognostic model, the Leuven-Udine group identified primary tumor T stage ≥3, primary tumor Fuhrman grade ≥3, the presence of nonpulmonary metastases, a disease-free interval ≤12 months, and multiorgan metastases as independent pretreatment prognostic factors for survival after metastasectomy in a multivariable analysis [142]. In contrast to the general MSKCC and Heng prognostic models, the results have not yet been externally validated. Currently, evidence stems almost exclusively from retrospective studies and no prospective randomized trials on metastasectomy for RCC have been performed to guide decision making. Though the factors related to prognosis seem to be generally applicable to metastasectomy at any site, some sites may demand specific management strategies, especially when a solitary site if disease or oligometastases are present, and will be discussed in detail.
11.2.1 Other Focal Therapeutic Strategies
Historically, surgical resection has been the preferred approach to metastasectomy, but recent data on stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) suggest that this treatment modality is a valid noninvasive alternative [21]. Apparently, the ceramide pathway is activated when high doses of radiotherapy are given per fraction, which lends the stereotactic approach a biological rationale. In addition, an indirect abscopal effect caused by immunological processes induced by a combination of targeted therapy and SBRT is observed. Contrary to surgical metastasectomy, SRS, SBRT, or ablative techniques have been for the most part applied to certain metastatic sites [27]. Although therapy of RCC metastases with SRS is gaining ground and is likely to be expanded to multiple anatomical regions, most of the experience has been gained with treatment of brain and bone metastases and will be discussed under the respective sites. While ablative techniques are minimally invasive, they can still cause bleeding and thermal damage. Cranial and extracranial SRS can induce adverse events such as cough, fatigue, skin rash, and local pain. Side effects are generally frequent, but mild (grades I–II in 96 %) [132].
11.3 Site Specific Metastasectomy
11.3.1 Resection of Pulmonary Metastases
The lungs are the most frequently affected metastatic site with a prevalence rate of 74 % in autopsy studies [116]. Metastasis may be hematogenous or through direct lymphatic drainage of RCC into the thoracic duct which subsequently drains into the subclavian vein and pulmonary artery [8]. There is a wealth of retrospective non-randomized studies on the resection of pulmonary metastases. Most of these series published until the last decade of the last century were small, with no more than 50 patients [24, 33, 37, 63, 64, 136]. Collectively, in recent series with larger patient cohorts, a 5-year survival rate of 37–54 % was observed in patients with complete resection of solitary or oligometastatic pulmonary metastases [2, 6, 17, 35, 58, 64, 83, 86, 106, 108, 149]. Consistently, several prognostic factors were repeatedly identified in multivariate analyses (Table 11.1). Conversely, incomplete resection was associated with a poorer 5-year survival of 0–22 % [2, 48, 58, 64, 106, 108, 149]. The number of pulmonary metastases removed was associated with survival [2, 17, 35, 48, 64, 106]. In several series, median 5-year survival after complete resection of solitary metastases was 45.6–49 months versus 19–27 months after complete resection of multiple metastases [17, 35, 48]. In the largest reported series, a cutoff was determined with a significantly longer median 5-year survival observed for patients with fewer than seven pulmonary metastases compared with patients with more than seven metastases (46.8 % vs 14.5 %) [106]. Moreover, the presence of lymph node metastases has been associated with shorter survival [6, 106, 108, 149]. In case of simultaneous lymph node metastases, despite complete pulmonary metastasectomy, median survival decreased from 102 to 19 months [149] and the median 5-year survival rate from 42.1 to 24.4 % [106]. A short disease-free interval after nephrectomy or the presence of synchronous metastases was a consistent factor portending a worse outcome [35, 48, 58, 64, 106, 108]. A disease-free interval of > or <48 months was associated with a median 5-year survival rate of 46 % versus 26 % [35] and a 23-month interval with 47 % versus 24.7 %, respectively [106]. The presence of synchronous pulmonary metastases was a particularly bad feature, with a median 5-year survival rate after complete pulmonary metastasectomy of 0 % versus 43 % for patients with metachronous disease [48]. A further factor is the size of pulmonary metastases [6, 92, 108]. Complete resection of pulmonary metastases of 5 mm was associated with a median 5-year survival rate of 70 % versus 35 % for those with metastases of approximately 45 mm [92]. The type of resection was not associated with survival [17, 86] and ablation techniques may be an alternative to surgical resection in select patients [122]. In 2011 a lung-specific prognostic score was published, developed from 200 consecutive patients with pulmonary metastases [84]. Again, complete resection, size >3 cm, positive nodal status of the primary tumor, synchronous metastases, pleural invasion, and mediastinal lymph node metastases were independent prognostic factors on multivariate analysis. Three risk groups were discriminated with median OS of 90, 31, and 14 months for low, intermediate, and high risks, respectively. This score is not yet externally validated.
11.3.2 Resection of Liver Metastases
Liver metastases occur in 8–30 % of patients with RCC [89]. In an autopsy study hepatic metastases from RCC were observed in 41 % [116], though only in 5 % as solitary metachronous lesion [131]. The main reason for the paucity of reports on liver metastasectomy either by surgery or ablative techniques is the presence of multiple organ metastases generally making further surgical options futile [36]. Moreover, in contrast to solitary pulmonary metastases, it has been consistently demonstrated that liver metastasis carries a poor prognosis [41, 133, 145]. Currently only small retrospective series exist with 13–68 patients which in part suggests that surgical resection may be beneficial in terms of survival [4, 71, 130, 131, 138]. In earlier series median survival following resection of a solitary liver metastasis was 16–48 months with reported 5-year survival rates between 8 and 38.9 % [4, 71, 131, 138]. As has been shown for other metastatic sites, identified prognostic factors include a disease free interval longer than 6–24 months, performance status and completeness of resection. The largest series retrospectively analyzed the outcome of 88 patients with liver metastasis as the only site [130]. Sixty-eight patients underwent resection and were compared to 20 who refused. The median 5-year overall survival rate after resection was 62.2 % versus 29.3 % in the control. In both cohorts 79 % received systemic therapy. This study may indicate that surgical resection of hepatic metastasis is a valuable treatment strategy for carefully selected patients. Patients with high-grade RCC and those with synchronous metastases did not benefit from this approach. Moreover, hepatic metastasectomy was associated with significant morbidity of 20.1 % [130] and one series reported a mortality rate of 31 % [131]. In addition, recurrence frequently occurs after liver resection [4]. These caveats have to be balanced against a potential benefit when selecting patients. It is unclear whether surgery is superior to ablative techniques in this setting [39].
11.3.3 Surgery for Bone Metastases
Skeletal metastases are observed in 16–26 % of patients with metastatic RCC and are frequently symptomatic [89]. The true prevalence of solitary bone metastases is not known. In a series of 94 patients with a solitary RCC metastasis, single bone lesions were observed in 5 patients (5.3 %) [64], and others were observed at a rate of 2.5 % [140]. Although prolonged disease-free survival has been reported after surgical resection of single and even multiple lesions, for most patients the goal of treatment will be palliative because of pain, nerve root compression, and pathological fractures. In many of these instances, radiotherapy may be equally effective but no randomized data exist specifically for RCC. Outcome of patients treated with surgical resection of skeletal solitary or oligometastatic disease has only been reported in retrospective series. Early reports demonstrated that patients with solitary bone lesions had a better survival when resected [134]. In a series of 38 cases with bone metastases from RCC, 13 evaluable patients had solitary lesions, and these patients had a survival that was longer than the 5-year survival rate of 55 % for the entire cohort [3]. Five-year overall survival rate of five and nine patients with resected solitary bone lesions in other series was 40 % [64] and 54 %, respectively [26]. Conversely, a series including 25 patients with wide resection of a solitary bone metastasis reported a 5-year survival rate of only 13 % [10]. A recent series reported on 125 patients after resection of multiple metastases including 11 with bone as single site (8.8 %) and 4 (3.2 %) with the bone and lung involved [2]. The majority (75.2 %) had more than three metastases removed. For those patients with sites outside the lungs, the 5-year survival rate was 32.5 % compared with 12.4 % among a matched cohort without complete resection. One of the largest series on surgical resection of bone lesions from RCC included a literature review. Taken together the data revealed 5-year survival rates between 35.8 and 55 % comparable to that observed after resection of lung lesions [3]. In addition, patients with peripheral skeletal location of their metastases had a 75 % 5-year survival rate. Collectively, metachronous disease with a long disease-free interval, appendicular skeletal location with wide excision, and solitary metastases were correlated with longer survival [3]. Up to 15-year survival has been described after wide excision of bone lesions [62]. Others added the presence of a clear cell histological subtype and reported that the additional presence of pulmonary metastases did not predict early death with some patients surviving for years after both completely resected pulmonary and bone disease [2, 45]. Similar predictive factors and survival rates were reported in a number of smaller retrospective series [10, 26, 57, 67]. Due to the retrospective nature of these studies and their size and selection bias, the curative effect of resection of RCC bone lesions remains controversial. Conversely, the surgical resection of bone lesions to effectively palliate pain and symptoms from spinal cord compression is undisputed. Randomized studies do not exist for RCC, but a randomized prospective trial in patients with bone metastasis from various malignancies demonstrated that direct decompressive surgery plus postoperative radiotherapy was superior to treatment with radiotherapy alone for patients with spinal cord compression caused by metastatic cancer [103]. Only a minority had RCC bone lesions. In addition, a prospective non-randomized observation study demonstrated that spinal surgery was effective in improving quality of life in patients with extradural spinal bone metastases from various cancers by providing better pain control, enabling patients to regain or maintain mobility, and offering improved sphincter control [50]. Surgery proved feasible with acceptably low mortality and morbidity rates.
From a surgical perspective RCC bone metastases are highly destructive vascular lesions. They pose surgical challenges due to the risk of life-threatening hemorrhage. The largest series reporting on surgical approach and outcome included a total of 368 bone metastases of RCC to the extremities and pelvis [45]. The majority of surgical procedures involved curettage with cementing and/or internal fixation or en bloc resection with closed nailing or amputation in a few. The overall survival rates at one and 5 years were 47 and 11 %, respectively. Fifteen patients (5 %) died within 4 weeks after surgery due to acute pulmonary or multiorgan failure in the majority of cases.
After resection of painful RCC bone metastases, pain was significantly relieved in 91 % of patients, while 89 % achieved a good to excellent functional outcome, and 94 % with metastatic lesions of the pelvic girdle and lower extremities were ambulatory [67]. In addition, wider resection lessened the risk of recurrence at the same location and the need for reintervention [74]. This was a general observation made in bone metastasis from a variety of cancers where wide excision resulted in better survival and functional outcome than laminectomy [50]. Therefore, surgery for bone lesions should aim at lasting control at the treated site with a durable fixation or reconstruction to prevent reintervention. As the only randomized trial included radiotherapy in both arms, postoperative radiotherapy should be considered [103]. The literature analyzed in the systematic review suggests prolonged disease-free survival after SBRT or metastasectomy of single and even multiple bone metastases [19]. However, no recommendations can be made as to the best treatment modality. A non-comparative study of 48 RCC patients with 55 spinal lesions suggested the effectiveness of SRS [95]. In this study, the 1-year absence of progression rate in the spine was 82.1 %. A 23 % pain-free rate increased to 44 % 1 month and to 52 % 12 months after SRS. Ablative approaches may be an alternative to surgery in selected cases with bulky bone lesions extending to extraosseous regions [47, 143].
11.3.4 Metastasectomy of Brain Metastases
Metastases to the brain occur between 2 and 17 % of patients with RCC and are symptomatic in more than 80 % of cases [75, 77, 117]. If left untreated, median survival was reported to be 3.2 months [22]. After the introduction of noninvasive radiosurgical techniques, craniotomy has lost its preference except for lesions greater than 2–3 cm, rapid onset of symptoms, and cases of large lesions with midline shift [90, 91, 123]. Generally, factors paramount for selecting patients for therapy of brain metastases regardless of the primary tumor site include performance status, extracranial tumor load, and the course of disease summarized in the Radiation Therapy Oncology Group (RTOG) recursive partition analysis (RPA) [38]. Between 70 and 80 % of RCC patients with brain metastases belong to RPA class II (Karnofsky score (KS) >70 %, further extracranial metastases) who have a reported median survival of 4.2 months [16, 91]. In another study including 4,295 patients, the significant prognostic factors for RCC brain metastasis were KS performance status and the number of brain metastases [128]. Those with a KS of 90–100 % and a single brain lesion had a median survival of 14.8 months versus 3.3 months for those with a KS <70 % and >3 metastases. This was observed and confirmed in 138 RCC patients with brain metastases [123]. In a retrospective series of whole brain radiation therapy (WBRT) survival of RCC patients with a single brain metastasis proved to be only 4.4 months, which suggested that aggressive surgical treatment may be superior [152]. A prospective randomized trial of surgery and WBRT versus WBRT alone in 63 patients with brain metastases from various primaries confirmed the superiority of the combination [96, 146]. For patients with extracranial progressive disease, WBRT seemed sufficient. Currently, WBRT is regarded adequate for patients with a poor performance and multiple lesions in whom palliative control of symptoms is warranted. Craniotomy with resection of brain metastases in 50 patients with RCC proved superior to WBRT with a median overall survival of 12.6 months [151]. The addition of postoperative WBRT did not result in a survival difference. However, stereotactic radiosurgery (SRS) can provide effective local control comparable to surgery even for multiple lesions and recurrent metastases [82]. In one series, 85 RCC patients with 376 brain metastases underwent SRS [91]. The median tumor volume was 1.2 cm (range: 0.1–14.2 cm) although 65 % had multiple brain lesions. Median overall survival was 11.1 months after radiosurgery with a local tumor control rate of 94 %. Most patients (78 %) died because of systemic progression. RTOG RPA classes I, II, and III survived for 24.2 months, 9.2 months, and 7.5 months, respectively. In another 69 patient series, the median survival after SRS was 13 months in patients without and 5 months in those with active extracranial disease [120]. It has been argued that survival rates after SRS are inferior to craniotomy, but the size of the retrospective series involving RCC patients with brain metastases and the fact that more patients with a long metachronous interval and fewer brain metastases were candidates for craniotomy [9, 151] do not allow a direct comparison.
11.3.5 Metastasectomy of Adrenal Metastases
Incidence of adrenal involvement has been observed between 3.1 and 5.7 % in nephrectomy series [105, 126, 144] but in up to 23 % of patients with simultaneous metastasis at other sites. Generally, adrenal metastases portend a poor prognosis despite the fact that solitary ipsilateral metastases are often completely resected at the time of nephrectomy. It is unknown whether this is directly correlated to adrenal metastasis or the fact that most patients with adrenal metastases have advanced tumor stages. In 347 patients with advanced stage disease (T3-4N0-1M0-1), adrenal metastases occurred in 8.1 % [144]. Among 56 patients with adrenal metastases, 82 % had pT3 tumors [126]. On multivariate analysis, only the presence of distant metastases, vascular invasion within the primary tumor, and multifocal growth of RCC within the tumor-bearing kidney were identified as independent predictors of the presence of intra-adrenal metastases [69]. While it is beyond the scope of this chapter to discuss the indication for adrenalectomy at the time of nephrectomy for local disease, it is probably true to conclude that the majority of radiographically or clinically apparent ipsilateral lesions are resected at the time of nephrectomy. As a consequence, little is known about the management of isolated, synchronous contralateral and metachronous ipsilateral or contralateral adrenal metastases. Some series on the management of local recurrences included metachronous ipsilateral adrenal metastases [52, 81, 118]. Generally, survival with locally recurrent RCC is poor with a 28 % 5-year survival rate [52]. However, patients who underwent surgical resection had an improved 5-year survival rate of 51 % compared to 18 % treated with adjuvant medical therapy and 13 % with observation alone. Contralateral adrenal involvement, either synchronous or metachronous, seems to be a rare event. In one autopsy series of patients who underwent nephrectomy for RCC, it was observed in 0.7 % [116]. A small series reported the outcome of 11 patients who had surgery for metastatic RCC to the contralateral adrenal gland. Synchronous contralateral adrenal metastasis occurred in two patients. The mean (median, range) time to contralateral adrenal metastasis after primary nephrectomy for the remaining nine patients was 5.2 (6.1, 0.8–9.2) years. All patients were treated with adrenalectomy. Most patients died from RCC at a median of 3.7 (range 0.2–10) years after adrenalectomy for contralateral adrenal metastasis [72]. Two series described another five patients each [65, 99] and collectively some 60 cases are described in the literature [25]. Survival ranged from 8 to 70 months. The factors that affect outcome are uncertain but seem to be correlated to a metachronous interval of >18 months [65]. Based on these data adrenalectomy for isolated metachronous ipsi- and contralateral adrenal metastasis should be recommended because it is associated with long-term survival in individual patients. As for other metastatic sites, ablative percutaneous techniques may be a valid alternative to open or laparoscopic adrenalectomy [148].
11.3.6 Metastasectomy of Lymph Node Metastases
Though not regarded as distant metastatic disease in the TNM classification, lymph node metastases do occur frequently and are associated with a poor outcome that resembles that of systemic disease. In a retrospective series, survival of patients with regional lymph node involvement was identical to that of patients with distant metastatic disease (Pantuck et al.) [100]. In the literature locoregional and distant, mostly mediastinal, lymph node metastases are differentiated and there is evidence that resection of isolated nodes may be beneficial in terms of survival.
Between 58 and 95 % of patients with lymph node involvement have associated hematogenous metastases [34, 107], which is why lymph node metastases are regarded as a significant indicator of systemic disease and adverse prognosis. Patients with pN0 have a 5-year survival of 75 %, versus 20 % for patients with pN+ [100, 101]. However, there is evidence from the literature that patients with a single lymph node metastasis and no metastatic disease can potentially be cured by lymph node dissection (LND) [100]. The incidence of regional lymph node metastases in patients with renal cell carcinoma ranges from 13 % to over 30 %. However, the true incidence of solitary lymph node metastasis without distant metastatic disease is unknown and seems to be significantly correlated to tumor size. In nephrectomy and autopsy studies, single lymph node metastases were observed in smaller tumors in 3–4.5 % [44, 100, 101]. At autopsy records, a broad variation of the anatomical localization of lymph node metastases was observed [116]. Ipsilateral renal hilar lymph node metastases were found in 7 %, while pulmonary hilar lymph node metastases were found in 66.2 %, retroperitoneal in 36 %, para-aortic in 26.8 %, and supraclavicular in 20.7 % [116]. Single metastases in mediastinal, axillary, supraclavicular, and iliac lymph nodes without any further metastasis were described [49, 56].
In node positive cases, lymph node dissection was associated with improved survival and a trend toward an improved response to immunotherapy [100] (however, patients with regional nodes and distant metastases had significantly inferior survival to those with either condition alone). Lymph node status was a strong predictor of the failure to achieve either an objective immunotherapy response or an improvement in survival when immunotherapy was given after cytoreductive nephrectomy. However, in multivariate analysis, including both clinical and pathologic variables, lymph node status was found to have less of an impact on survival than primary tumor stage, grade, and performance status [100]. The current consensus is that suspicious lymph nodes either at imaging or palpation should be removed during nephrectomy because it was observed that in patients with positive lymph nodes, lymph node dissection (LND) is associated with improved survival when it is performed in carefully selected patients undergoing cytoreductive nephrectomy and postoperative immunotherapy [100]. Even if a survival benefit is doubtful, locoregional LND at the time of nephrectomy may avoid symptomatic local recurrences. There are no data on management of metachronous regional lymph node metastases other than from series reporting on local recurrences [81] but there is a tendency to choose an investigational approach and pretreat these lesions prior to surgical removal (Sect. 11.5.2).
Isolated mediastinal lymph node metastases are more frequently observed in RCC compared to primary tumors from other organs [79, 113, 150]. Lymphatic vessels were found to always connect to the origin of the thoracic duct, some directly without traversing any retroperitoneal lymph nodes [8]. This feature may play an important role in the frequently observed pulmonary and mediastinal metastatic spread in RCC [7].
Cases of patients with resection of isolated mediastinal and intrapulmonary lymph node metastases have been described with disease-free survival of up to 5 years [7, 59]. As these lymph nodes are usually not resected at the time of nephrectomy, these series contain mostly metachronous lymph node metastases. A retrospective analysis of 101 patients who underwent resection of pulmonary metastases specifically evaluated the prognostic value of concurrent hilar and mediastinal lymph node metastases [149]. These data also provide some information on the potential prevalence of lymph node metastases in patients with pulmonary metastatic disease, which was 35 % in this series. Patients with involved lymph nodes had a worse prognosis. Others found lymph node metastases during pulmonary metastasectomy in 20 % and a similar association with poor outcome [6, 106] (see Sect. 11.3.1). With a median survival of less than 2 years, patients with pulmonary metastases and mediastinal lymph nodes may not be candidates for surgical resection, though match paired analysis showed a trend toward improved survival after LND [149]. Despite poorer survival outcome when mediastinal lymph nodes are involved, two recent retrospective series over periods of 11 and 18 years, respectively, support that better long-term survival can be achieved by systematic resection [70, 111].
11.3.7 Metastasectomy of Other Less Frequent Sites
RCC can metastasize to virtually any anatomical location and these have been described in multiple case reports. Most of these locations are rare, but some are more frequently observed and have resulted in additional information that may guide treatment decisions.
Since 1952, surgery for pancreatic metastases of RCC has been described in 411 patients in 170 publications [137]. A systematic literature search including patients from the authors’ institution evaluated the clinical outcome of RCC patients with pancreatic metastases [137]. Evaluable data were retrieved and analyzed for 321 surgically and 73 nonsurgically treated patients. In the resected group, 65.3 % of the metastases were solitary and symptomatic in 57.4 %. After resection the 2-year and 5-year disease-free survival rates were 76 and 57 %, respectively. Two- and 5-year overall survival rates were 80.6 and 72.6 %. After multivariable analysis, the only significant risk factor for disease-free survival was extrapancreatic disease (p = 0.001). This however had no impact on overall survival in the group of resected patients, which was only adversely affected by symptomatic metastatic disease (p = 0.031). Interestingly, the interval from primary RCC to pancreatic metastasis and the number of pancreatic lesions were not associated with a worse outcome. Patients with unresected pancreatic disease had significantly shorter 2- and 5-year overall survival rates of 41 and 14 %, respectively. Collectively, these data suggest there is an indication for resection in patients in whom the pancreas is the only metastatic site and who are fit enough to undergo pancreatic surgery. The observed in hospital mortality rate after pancreatic surgery for metastatic RCC was 2.8 % and a significant number of patients underwent extensive surgery with pancreaticoduodenectomy in 108 patients (35.8 %) and total pancreatectomy in 60 (19.9 %). Given the retrospective analysis of various external data and the probability of significant surgical morbidity, it is therefore preferable to start systemic therapy in patients with a short disease-free interval between nephrectomy and pancreatic metastasis. In accordance with the strategy outlined in Sect. 11.5.2, surgery may be reconsidered after a number of pretreatment cycles in those with disease stabilization or shrinkage.
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