Site specific metastasectomy

Kidney cancer. Principles and practice. Second edition. Primo N. Lara, Jr. Eric Jonasch (Editors). Springer International Publishing (2015)

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 nonrandomized 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.

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].

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 nonrandomized 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].

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.

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 ipsiand 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].

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%, paraaortic 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].

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.

Another uncommon site involves the thyroid gland. Early cases have been described in the 1940s [76]. The largest retrospective series reports on 45 patients undergoing resection of solitary thyroid metastases at 15 different centers, though some patients had resection of other metastatic sites earlier in the course of disease [51]. The 5-year overall survival rate was 51%. Fourteen patients (31%) died of disease progression and nine developed a recurrence in the thyroid remnant. In a multivariate analysis, prognosis was significantly worse in patients older than 70 years. The authors described a significant coincidence of thyroid and pancreatic metastases in their series. Of the 45 patients with thyroid disease, 14 (31%) developed pancreatic metastases. A French group reported on seven patients with solitary RCC metastases in the thyroid, six of whom metachronous after resection of other metastases. The median overall survival after thyroidectomy was 38.1 months [12]. In a clinicopathological study of 36 cases, 23 patients had documented previous evidence of RCC (64%) as remotely as 21.8 years before the thyroid metastases (mean, 9.4 years). The metastasis to the thyroid gland was the initial manifestation of RCC in 13 patients. Twenty-three patients (64%) died of disease progression (mean, 4.9 years), but 13 patients (36%) were alive or had died without evidence of disease (mean, 9.1 years) [42].

Generally, there is little information on how to treat those rare sites. In these circumstances factors associated with a favorable outcome after metastasectomy should be considered for treatment selection (Table 11.1). Individual decisions have to be taken for each case.

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