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THE FUTURE OF KIDNEY CANCER QUO VADIS: Edited by Vitaly Margulis and Manuela Schmidinger

Role of metastasectomy in metastatic renal cell carcinoma

Thomas, Arun Z.; Adibi, Mehrad; Borregales, Leonardo D.; Wood, Christopher G.; Karam, Jose A.

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doi: 10.1097/MOU.0000000000000196
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Abstract

INTRODUCTION

Renal cell carcinoma (RCC) continues to remain an important cause of mortality in the USA, with an estimated 61 560 patients diagnosed with renal tumors in 2015, and 14 080 expected deaths [1]. This represents a 9.8% increase in new diagnoses since 2010 [2]. Of these, 20–30% new cases will have metastatic disease at presentation (synchronous) and up to 40% will develop metachronous metastases after nephrectomy for clinically localized disease [3,4].

Over the last 2 decades, systemic management of metastatic RCC has significantly changed with increased understanding of the molecular biology of RCC. Agents that specifically target relevant biological pathways, such as vascular endothelial growth factor and mammalian target of rapamycin, have revolutionized the treatment of advanced RCC and replaced immunotherapy as first-line therapy [5]. In comparison to immunotherapy, the objective response in the primary tumor and its associated metastatic deposits with targeted therapy correlate with more modest reductions in tumor size of 20–30%, as well as improved progression-free survival and overall survival (OS) [6,7]. Complete disease resolution is, however, still extremely rare with these agents alone [8,9]. Hence, surgical resection of the primary tumor and metastatic deposits continue to remain the primary therapeutic intervention for achieving long-term cure in selected patients, even in the targeted therapy era. In this review, we summarize the role of surgical metastasectomy and review surgical considerations for common sites of metastases including lung, bone, liver, retroperitoneum and brain.

Box 1
Box 1:
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METASTASECTOMY

Complete versus incomplete/no metastasectomy

To date, no randomized controlled trials have compared metastasectomy to medical therapy for patients with metastatic renal cell carcinoma (mRCC). Despite the lack of level 1 evidence, retrospective data suggest that metastasectomy renders cure when performed in selected patients with mRCC. Furthermore, incomplete metastasectomy, although not curative, plays a palliative role in managing patients with mRCC, and still has potential for prolonging survival in some patients.

Early studies within the cytokine/immunotherapy era emphasized the role of metastasectomy in patients with mRCC. In a large observational study of 1463 Japanese patients with mRCC, 28% of patients underwent metastasectomy. Improved survival was significantly increased in patients undergoing metastasectomy compared with nonsurgical patients (median 44.3 versus 16.4 months, respectively) [10]. Kavolius et al. examined 278 patients with mRCC of whom 148 underwent a curative metastectomy for their first recurrence, 70 patients underwent noncurative surgery and 67 patients were treated nonsurgically. Five-year OS rates were 44, 14 and 11%, respectively. Among 94 patients with a solitary metastasis, patients with lung metastasis had the most favorable outcomes. Survival rates after curative resection of second and third metastases did not differ from initial metastasectomy. On multivariate analysis, favorable predictors of survival included a single site of first recurrence, curative resection of first metastasis, a long disease-free interval, a solitary site of first metastasis and a metachronous presentation with recurrence [11].

More recently, Alt et al.[12] reported the survival of patients who underwent complete metastasectomy for multiple RCC metastases in patients undergoing nephrectomy for RCC who developed multiple metastatic lesions. The authors analyzed 887 patients with mRCC, of whom 125 (14%) underwent complete surgical resection of all metastases. After controlling for timing of metastasectomy, location and number of metastases and patient performance status, complete metastasectomy was associated with a significant improvement of median cancer-specific survival (CSS) compared with patients with incomplete or no metastasectomy (4.8 versus 1.3 years, respectively). Patients who had lung-only metastases had a higher 5-year CSS of 73% with complete resection versus 19% without complete resection. A survival advantage from complete metastasectomy was also observed among patients with multiple, nonlung-only metastases, who had a 5-year CSS rate of 32% with complete resection compared with only 12% without complete resection. Complete resection remained predictive of higher CSS for patients who had greater than three metastatic lesions and for patients who had synchronous as well as asynchronous multiple metastases. On multivariate analysis, the absence of complete metastasectomy was associated with a 2.9-fold increased risk of death from RCC [12].

A recent analysis from the only systematic review on this topic identified eight studies that assessed metastases from various organs examining complete metastasectomy versus no or incomplete metastasectomy. The majority reported a significantly longer CSS and OS with complete metastasectomy compared with no metastasectomy or incomplete metastasectomy (median of 40.8 versus 14.8 months, respectively). A summary of survival outcome using forest plot hazard ratios for CSS and OS regardless of organ site unequivocally favored complete metastasectomy in all eight studies [13▪▪].

Integration of systemic therapy and metastasectomy

To date, very little evidence exists to assess the role of targeted therapy in conjunction with metastasectomy. This is due to the fact that the majority of studies exist and/or overlap with the immunotherapy era, in which heterogeneity of timing and the type of agents used are difficult to isolate and analyze [12,13▪▪].

In the immunotherapy era, Daliani et al. evaluated 38 patients who underwent metastasectomy after at least 4 months of immunotherapy including IL-2 and INF-α. All patients underwent metastasectomy with curative intent and 90% of patients went on to receive consolidative adjuvant systemic therapy. Almost 80% of patients had stable disease after initial systemic therapy and 21% had a partial or complete response. After surgery 76% of patients had no evidence of disease. Significant predictors of death after metastasectomy were lack of NED and the presence of pulmonary metastases. The median OS for those who had NED was 5.6 years versus 1.4 years for those who did not [14].

Rini et al.[15] described two patients who achieved tumor burden reduction with sunitinib therapy and underwent subsequent metastasectomy with a long-term response. Another study by Thomas et al. examined 19 patients who underwent surgical resection after targeted therapy. Of these, six patients had resection of local recurrence and three patients had distant metastasectomies. They found that this approach was feasible and relatively well tolerated. Major complications occurred in three patients, including death in one because of disseminated intravascular coagulation. Two minor complications were also noted in patients who did not receive postoperative targeted therapy, including a wound seroma and a ventral hernia. At the time of the study, 16 patients were alive at a median follow-up of 8 months, including eight with disease progression. Of the three patients who underwent resection of distant metastases, two were alive at 13 and 16 months [16].

The largest series to date by Karam et al. evaluated the role of metastasectomy in 22 patients with mRCC who received at least one cycle of targeted therapy (pseudo-neoadjuvant therapy) prior to metastasectomy. All patients had surgical resection of all visible disease. Six postoperative complications were observed in four patients including chylous ascities, ileus and atrial fibrillation which all resolved with appropriate management and occurred in patients with retroperitoneal recurrence. At a median follow-up of 109 weeks, 50% of patients were disease free and a further 11 (50%) did not require postoperative targeted therapy. Nine patients required postoperative systemic therapy in which the median time to initiate targeted therapy after metastasectomy was 55 weeks. This study emphasized that treatment with targeted agents followed by consolidative metastasectomy is well tolerated in highly selected patients, resulting in significant time off targeted therapy and long-term tumor-free status [17]. Currently, the role of pseudo-adjuvant therapy is being investigated in 3 randomized prospective clinical trials (using sorafenib, sunitinib, or pazopanib versus placebo) after complete resection of metastatic disease (clinicaltrials.gov NCT01444807, NCT01216371, and NCT01575548, respectively).

Risk stratification

At the time of disease progression (local and or systemic), deciding between observation, medical and or surgical therapy can pose a significant dilemma for clinicians because of the significant heterogeneity that exists within the literature. As already highlighted, no level 1 evidence exists and significant bias can be attributed to the majority of published retrospective series on metastasectomy in RCC. Furthermore, future prospects of successfully completing a prospective randomized trial within this particular patient population are highly unlikely. Despite such challenges, it is clear from the literature that there are a proportion of patients that benefit from aggressive surgical resection of metastatic deposits not only for palliation, but also those who achieve long-term remission or cure.

Traditionally, the most widely used model in metastatic RCC is the Memorial Sloan Kettering Cancer Center (MSKCC) risk grouping. This model utilizes LDH, corrected calcium, serum hemoglobin, Karnofsky performance status and time from diagnosis to start of therapy to risk stratify patients for survival [18]. Even though the MSKCC risk groups were formulated to stratify survival in patients with mRCC who would most benefit from cytoreductive nephrectomy, these same predictors have been applied in patients undergoing metastasectomy after prior nephrectomy [19]. Eggener et al. evaluated 129 patients disease recurrence following surgery for RCC. Using the MSKCC risk grouping, a five-point prognostic scoring system for patients with advanced RCC was applied classifying patients into favorable, intermediate and poor risk categories. Median, 2 and 5-year survival rates were shown to strongly correlate with risk category (favorable: 73 months, 81%, 57%; intermediate: 28 months, 54%, 16%; poor: 6 months, 11%, 0%, respectively). Patients designated as favorable risk were more likely to undergo metastasectomy highlighting the variability of patient selection. On multivariate analysis, those not undergoing metastasectomy and of higher risk category were both independently associated with decreased survival [20].

In the targeted therapy era, Heng et al. retrospectively reviewed 645 patients with metastatic RCC treated with targeted therapy. They identified six predictors of survival similar to the MSKCC criteria including hemoglobin below lower limit of normal (LLN), calcium above upper limit of normal (ULN), Karnofsky score 80% or less and systemic disease within 1 year of diagnosis as independent predictors of decreased survival. Absolute neutrophil count greater than ULN and platelets greater than ULN were also independent adverse prognostic factors. Based on these six prognostic factors, patients were risk stratified to favorable (zero adverse factors: 75% 2-year survival), intermediate (one to two adverse factors: 53% 2-year survival) or poor (three to six adverse factors: 7% survival) [21]. Both the MSKCC and Heng criteria (also known as IMDC, International Metastatic RCC Database Consortium) are potentially useful to risk stratify patient being considered for metastasectomy, in addition to their use for choice of first-line systemic therapy.

METASTASECTOMY BY LOCATION/ORGAN SITE

Lung metastasis

Table 1 lists the most common metastatic sites from RCC. The lung is the most common site of metastatic spread of advanced RCC with an incidence ranging from 45 to 75% [22]. The resection of solitary lung metastasis dates as far back as 1939 suggesting the potential for long-term cure in select patients [23]. Since then, surgery with wedge resection, segmentectomy, lobectomy or pneumonectomy continues to remain the only effective treatment for patients with isolated lung metastases with 5-year survival rates ranging from 36 to 50% [24].

Table 1
Table 1:
Favorable metastasectomy features based on organ site in metastatic renal cell carcinoma

A large study by Pfannschmidt and colleagues identified 149 out of 191 patients who had complete resection after surgical excision for pulmonary metastases. Similar to preceding studies, the 5-year survival rate after complete metastasectomy versus incomplete resection was 41.5 and 22.1%, respectively. Multivariate analyses showed that the number of pulmonary metastases (<7), the involvement of lymph node metastases and the length of the disease-free interval were all predictors of survival after complete resection [25]. More recent series also show that lymph node involvement with pulmonary metastasis portends significantly poorer survival. An analysis of 110 patients by Winter et al. showed that on multivariate analysis positive infiltrated mediastinal lymph nodes were an independent prognostic factor for patient survival.

Match-paired analysis also showed that after lymph node dissection patients showed a trend toward improved survival. This study further highlighted that computed tomography imaging was highly sensitive (84%) and specific (97%) in predicting lymph node metastasis [26].

Prognostic scoring systems are available to help predict survival in patients with pulmonary mRCC. In 1997, the International Registry of Lung Metastases grouped patients based on three prognostic parameters including resectability of pulmonary metastasis, disease-free interval and number of metastases [27]. A subsequent study by Hofmann et al.[28] used this stratification to divide patients with pulmonary mRCC into four prognostic groups with 5-year survival rates of 53, 48, 22 and 0%, respectively. Meimarakis et al. set up a new score on the basis of significant prognostic factors as determined by multivariate analysis referenced as the Munich Score. The authors included pleural infiltration, synchronous manifestation of primary RCC and pulmonary metastases, nodal status of the primary tumor, metastasis size greater than 3 cm, histologically proven mediastinal and/or hilar lymph node metastases and the completeness of metastasectomy [29]. This new validated scoring system staged patients into more discernable low, intermediate and high-risk groups and may assist in referring patients for additional therapies and or trials.

Bone metastasis

Bone metastases are the second most common distant site of mRCC with an incidence of 15–34% [22,30▪▪]. Compared to other sites, bone metastases tend to be associated with worse survival. The overall 5-year survival after osseous metastasectomy is approximately 15–20% and 35% in patients treated for solitary bone metastasectomy [31,32]. Bone metastases may also cause significant morbidity including bone pain, spinal cord compression with neurological deficit, pathological fractures and/or hypercalcemia. Even with the advent of targeted therapy, the presence of bone metastases continues to have a negative impact on survival. In the largest series to date looking at 2000 patients treated with targeted therapy, bone metastases independently predicted worse survival in low, intermediate and high-risk categories. Possible explanations include limited distributions of targeted agents to bone, or those patients with bone metastases are often excluded from clinical trials because of difficulty in measuring disease response or their poor performance status [30▪▪].

A study by Lin and colleagues reviewed 295 consecutive patients with 368 bone metastases of the extremities and pelvis who were surgically managed. The surgical procedures included curettage with cementing and/or internal fixation, en-bloc resection and closed nailing. The most common sites of bone metastases were the femur, humerus and pelvis. OS at 1 and 5 years were 47 and 11%, respectively, with metastatic pattern having a significant effect on the survival rate. Patients with solitary bone metastases had the most favorable OS rate. It is noteworthy that 5% of patients experienced intraoperative blood loss of over 5 liters and 15 patients (5%) died within 4 weeks after surgery. The authors did not notice any difference in survival in patients undergoing resection versus curettage or those who received postoperative radiotherapy to the site of bone metastases [32].

In summary, in addition to palliative pain relief and preventing imminent pathological fracture or spinal cord compression, surgery for bone metastases in mRCC should be also considered in patients with solitary bone metastases in whom superior survival rates of over 12 months are potentially achievable in a small proportion of patients.

Liver metastasis

Liver metastasis occurs in approximately 20% of patients with mRCC with an OS of approximately 14 months [30▪▪]. The presence of liver metastasis is often ominous of concurrent or pending widespread disease and hence there is paucity in the literature regarding liver resection in RCC patients. Even if lesions are amenable to surgical resection, 5-year survival rates tend to be poor ranging from 18 to 43% [33,34].

A Dutch population study by Rhys et al. evaluated outcomes of surgical treatment in 33 patients with hepatic metastases from 14 centers in The Netherlands. Over an 18-year period these patients comprised 1% of all patients diagnosed with liver mRCC. The OS at 1, 3 and 5 years was 79, 47 and 43%, respectively. Metachronous metastases and radical resection were statistically significant prognosticators of OS. Size less than 0.5 cm, solitary metastases or presence of extrahepatic metastases did not significantly impact survival [34].

Recent studies, however, report better survivals in selected patients. Steahler et al. reported outcomes in 88 patients with mRCC involving the liver amenable to surgery. Of these, 20 patients refused surgery and were used as a control group. The authors reported significant survival differences between those who underwent resection compared with those who declined surgery (62 versus 29%, respectively). Those who most benefited from metastasectomy had better performance status (ECOG 0), node negative disease at nephrectomy (N0), lower histological tumor grade and metachronous metastasis at diagnosis. Patients with synchronous metastasis did not benefit from surgery [35]. Another study reviewing outcomes in 43 patients posthepatic metastasectomy for RCC similarly showed improved 3-year survival (62%) in patients with metachronous metastasis occurring a year after RN, solitary liver lesions and no evidence of extra-hepatic disease. When these patients were matched to patients undergoing liver metastasectomy for colorectal cancer, overall median survival was similar in both groups [36].

Retroperitoneal recurrence

Retroperitoneal recurrence (RPR) is a rare event that may occur in up to 3% of patients after radical nephrectomy [37]. RPR has been generally defined as pathologically proven RCC in the soft tissue/ipsilateral psoas muscle, ipsilateral lymph nodes and or the ipsilateral adrenal gland [38,39]. To date, literature on the natural history and outcomes of RPR recurrence has been limited with no standardized management strategy.

The largest series of patients undergoing RPR resection in the absence of distant metastases at the time of surgery included 102 patients. Of these, 49 patients had RPR in the soft tissue renal bed, 41 patients in the ipsilateral lymph nodes and 12 patients in the ipsilateral adrenal gland. All patients had isolated RPR recurrence and were all rendered clinically NED after surgical resection. Median RFS and CSS after RPR surgery were 23 and 66 months, respectively. After RPR surgery, 42 (41.2%) patients had NED up to the time of last follow-up. Overall metastatic progression was observed in 60 patients after RPR surgery and 1, 3 and 5-year CSS was 92, 71 and 52%, respectively [40▪▪]. On multivariate analysis, pathological nodal stage at original nephrectomy and maximum diameter of RPR tumor were identified as independent risk factors for cancer-specific death. Interestingly, no significant differences in CSS after RPR resection were identified after stratifying the location of recurrent tumor (renal fossa/soft tissue, lymph node or adrenal gland). Despite the lack of level 1 evidence, aggressive surgical resection of RPR resection appears to be feasible in selected patients and potentially curative.

Brain metastasis

Brain metastasis from RCC occurs with an incidence as high as 17% and tends to occur in advanced mRCC with synchronous noncranial metastasis [41,42]. The outcome for patients with RCC who develop brain metastasis is typically poor, with median survival of only 4–11 months after diagnosis and 5-year survival of 12% [43]. Management is challenging and often palliative in nature. Furthermore, even though small central nervous system lesions may be asymptomatic, almost all become symptomatic with time as they impinge on centers of function or cause cerebral edema resulting in headaches, seizures and or motor/sensory deficits.

Treatment options for brain metastasis include whole-brain radiotherapy/conventional radiotherapy, stereotactic radiosurgery (STRS) or surgical resection of metastatic deposits. Even though overall outcome is poor, studies highlight that surgical resection and/or radiosurgery contribute to prolonged survival in select patients [44,45]. In a systematic review, only two studies were identified that compared different radiotherapy modalities and/or surgery for brain metastases in mRCC; hence, recommendation of a specific treatment modality is not possible [13▪▪].

A study by Ikushima et al. study compared brain metastasectomy followed by conventional radiotherapy, STRS and conventional radiotherapy alone. Median survival was 25 months for the STRS group, 18 months for the metastasectomy followed by conventional radiotherapy and 4 months for the conventional radiotherapy-only group. Significant prognostic factors associated with better survival were age less than 60 years and good performance status. STRS seemed to offer better tumor control and prolonged survival over the surgery plus conventional radiotherapy or conventional radiotherapy groups, suggesting that STRS should be considered primary treatment for brain metastases from RCC [45].

Another study by Shuch et al. identified 138 patients with brain metastases from a cohort of 1855 patients with mRCC. Only 5% had isolated brain lesions at the time of diagnosis. Sixty-seven percent of patients had CNS symptoms of whom the lesions tended to be larger and more frequently treated with craniotomy. The median OS after a diagnosis of brain metastasis was 10.7 months, with 1, 2 and 5-year survival rates or 48, 30 and 12%, respectively. The initial number of tumors was found to be an independent predictor of CNS recurrence, in which patients with one and more than one lesion had a median CNS recurrence-free survival of 13 and 4 months, respectively. Type of treatment for brain metastasis did not appear to influence RFS or CSS. Even though post-treatment systemic therapy appeared to have a beneficial effect on survival on univariate analysis, ECOG status (0 versus ≥1) was the only variable to independently improve survival in this study [46].

Marko et al.[44] compared survival outcomes in 80 patients undergoing treatment for mRCC brain lesions. Within this group, 19 patients with asymptomatic incidentally identified brain metastasis and good performance scores treated with STRS monotherapy. Median survival for these patients was 12 months and was not statistically different from survival in similar patients treated with other therapeutic modalities including surgery with or without whole brain conventional radiotherapy. Even though, local control was achieved in 95% of patients, distant central nervous system progression occurred in 79% of patients [44]. Such findings suggest that SRS alone is an attractive therapeutic option for patients with incidentally identified brain metastases from RCC as other options even though equivocal in outcomes may have worse side-effects. For example, a European Organization for Research and Treatment of Cancer Phase III Trial showed that adjuvant whole-brain conventional radiotherapy after surgery or radiosurgery negatively impacts some aspects of patient quality of life in which observation in certain cases may be more appropriate [47].

Last, the influence of TKIs on the development, progression or remission of brain metastasis has not yet been clearly established in which up to recently only case reports have been published describing brain metastasis responding to treatment [48]. A more recent study by Verma et al. retrospectively examined 338 patients with mRCC who developed brain metastasis. Of these, 46% were treated with a targeted agent before brain metastasis, and 54% of patients were not. Median OS was longer in the targeted therapy group (25 months versus 12.1 months) and independently associated with improved survival. Patients who progressed to develop brain metastasis, targeted therapy did not, however, have a significant survival benefit [49]. Such poor responses may be partly attributable to the inability of targeted agents crossing to blood–brain barrier [50]. The appearance of brain metastasis from RCC still portends poor survival despite several options for local treatment. It remains unclear whether TKI agents in combination with local treatments such as surgery or radiotherapy could improve local control or OS for patients and further investigation is needed to characterize the integration of targeted therapy in this cohort of patients.

Pancreas and thyroid

Metastasis from RCC may be found in unusual sites including endocrine organs such as the pancreas and thyroid. Pancreatic metastasectomy for RCC is described mostly in case reports, with very few cohorts from high-volume centers. A meta-analysis of 321 patients reported a 5-year survival rate of 72% in patients who underwent pancreatic resection. Predictors of good outcome included absence of extra-pancreatic disease and absence of symptomatic metastases at the time of resection [51]. It is important to note that pancreatic RCC metastases are often metachronous, and solitary in the majority of patients [51]. Therefore, the true contribution of surgery to survival in patients with pancreatic metastasis likely favors a highly selected cohort of patients. One could argue that patients with less aggressive variants of RCC are more likely to have greater RFS from original nephrectromy and/or isolated pancreatic lesions making them more attractive surgical candidates.

Similarly, metastases of solid tumors to the thyroid are uncommon in which RCC is by far the most frequent source of metastasis in clinical series. Patients with RCC and pancreatic metastases share similar features and survival rates. Patients with RCC thyroid metastases also tend to have lower clinical stage and good differentiation of the primary tumor [52] in which prolonged survival is often reported following resection of solitary thyroid metastases. In a multi-institutional analysis of 45 patients who underwent surgery for thyroid RCC metastases, the overall 5-year survival was 51%. Independent poor prognostic factors included older patients (>70 years) and metastatic disease to the contralateral kidney. There was no statistically significant difference regarding the OS between patients undergoing curative or palliative surgery; hence, surgery may be reserved for symptomatic patients. Interestingly, there was a high rate of coincidence of thyroid and pancreatic metastases in 31% of patients, suggesting that patients with thyroid metastases should be investigated for pancreatic metastases and vice versa.

CONCLUSION

Metastasectomy in patients with mRCC continues to play an important role in the modern era of urological practice. Even with the advent of multiple targeted medical therapies that have revolutionized management in advanced disease, aggressive surgical resection of metastasis appears to improve survival and renders carefully selected patients clinically free of disease, which would not be achievable with medical therapy alone. Careful patient selection will continue to challenge clinicians to optimize care for patients on an individual level. Patients with isolated surgically resectable disease, with long intervals between disease recurrence and those with better performance status are likely to benefit the most from metastasectomy.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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Keywords:

metastasectomy; metastases; renal cell carcinoma

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