Review

Correspondence *Department of Urology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805, USA

Email john.a.libertino@lahey.org

Introduction

Renal cell carcinoma (RCC) is the third most common genitourinary malignancy after bladder and prostate cancer, and accounts for approximately 3% of all adult malignancies in the US.¹ Annually, it is estimated that greater than 200,000 patients are diagnosed with RCC, with a preponderance of males, the elderly, African-Americans, obese patients, smokers, and those with underlying renal abnormalities such as horseshoe kidney, acquired renal cystic disease, and end-stage renal disease.² It is estimated that familial forms of RCC such as hereditary von Hippel–Lindau (VHL) disease and hereditary papillary RCC account for approximately 4% of all cases of RCC. Among the urothelial cancers, RCC is associated with the highest (>40%) mortality rate, in comparison with the estimated 20% mortality rate associated with bladder and prostate cancer. The incidence of RCC has been rising at a rate of 2.3–4.3% annually over the past 30 years.^{2, 3} This trend has, in part, been attributed to a general increase in median lifetime survival and to earlier detection of tumors from the widespread use of abdominal imaging modalities such as ultrasound, CT and MRI.^{2, 4}

In addition to an increase in asymptomatic localized tumors, there has also been an upward trend in advanced tumors per unit population and in disease mortality.² Many of these 'advanced' tumors tend to be of a significant size (>7 cm) and pose surgical dilemmas to most community and inexperienced urologists. These trends in the epidemiology of RCC have resulted in speculation regarding altered tumor biology due to novel exogenous carcinogens that have yet to be identified, possibly causing a more dramatic increase in mortality despite the trend for earlier detection of renal tumors.

Clinical staging of RCC involves radiologic evaluation of tumor size, extension beyond Gerota's fascia and potential local invasion, the degree of venous involvement, and evaluation for nodal and metastatic disease. RCC is currently staged with the 2002 TNM Classification (Box 1 and Table 1). The 5-year cancer-specific survival of patients with these tumors is approximately 73–96%, 63–95%, 38–70% and 11–32% for stage I–IV respectively (Table 2).^{5, 6, 7, 8, 9}

Table 1 AJCC/UICC RCC tumor staging.

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Table 2 Survival data from several contemporary studies.

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Surgical excision of RCC remains the gold standard treatment for non-metastatic disease. This Review will, therefore, focus on surgical management. With the upward shift in tumor size cutoff for T2 tumors from 4 cm to 7 cm in the 2002 TMN staging, we elected to classify 'large tumors' as those greater than 7 cm or having tumor thrombus. In particular, we will address techniques in both open and laparoscopic radical nephrectomy, partial nephrectomy, and approaches for renal vein and caval involvement, along with the utility of preoperative renal artery embolization and cytoreductive surgery. We also discuss the potential use of neoadjuvant treatment with molecular targeted therapies.

Preoperative evaluation

Cost-effective imaging techniques have led to renal lesions being detected incidentally during evaluations for abdominal pain in the emergency room. Series estimate that 15–48% of RCC cases are discovered incidentally.¹⁰ This incidental discovery has led to an improved prognosis due to early-stage detection. RCC has often been described as the 'internist's tumor' because of the abundant number of paraneoplastic manifestations, whereby the diagnosis can be delayed or attributed to multiple other medical conditions, ultimately leading to non-localized disease. Incidentolomas are increasing in number; however, 20–30% of patients still present with metastatic disease. Many of these patients in the latter population have significant tumor size and a 5-year survival of less than 10%.⁴

Imaging

The overall goal of preoperative imaging is to determine the malignant potential of the lesion, assess tumor size and location, determine capsular invasion, and identify regional lymphadenopathy or metastases. In addition, the renal vein and inferior vena cava (IVC) need to be assessed for tumor thrombus, as 4–10% of RCCs will present with venous tumor involvement. One percent of the latter group may also have extension to the level of the right atrium.¹¹ All patients with evidence of tumor thrombus should have an echocardiogram as well.

Computed tomography

CT scans remain the primary mode of imaging to detect and differentiate renal lesions. RCC may display hypodense, isodense, and hyperdense characteristics on native CT scans. The sensitivity and specificity in differentiating RCC from other renal tumor subtypes was 74% and 100%, respectively, for corticomedullary phase, and 84% and 91%, respectively, for excretory phases.¹² The reconstructive capability and anatomical details of CT scans have led to improved surgical decision making (Figure 1).

Figure 1 Right renal mass with associated tumor thrombus at the infrahepatic level in a 50-year-old male patient with no pertinent past medical history.

The CT scan was obtained for microscopic hematuria. The patient subsequently underwent renal artery embolization.

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Magnetic resonance imaging

MRI has great promise in the evaluation of renal masses, tumor multifocality and tumor staging, along with the assessment of vessel and collecting system involvement. Huang et al. correctly staged 29 of 30 patients with RCC using three-dimensional (3D)-MRI.¹³ MRI has been shown to be equal to CT in the detection of renal masses, with MRI showing advantages when discerning complicated cysts from hypodense or avascular tumors. MRI is well suited for individuals with renal impairment, contrast allergies and for evaluating the vena cava. At our institution we choose to evaluate venous tumor thrombus extension with 3D CT reconstructions and magnetic resonance venography (MRV).¹⁴

Angiography

The routine use of arterial and venous direct imaging has fallen out of favor with the introduction of CT and MRI. Arteriography can determine the extent of arterialization of tumors and provide a means for preoperative embolization. Classic findings in RCC include neovascularization, arteriovenous fistula, contrast media pooling, and capsular vessel accentuation. One must also consider coronary angiography when managing patients with larger tumors that might require cardiac bypass to facilitate possible simultaneous repair.

Positron emission tomography

PET imaging supplies information regarding the metabolic activity of tissue by tagging radioisotopes to natural molecules of the human body. PET is a functional technique and can be synchronously combined with CT scanning to obtain anatomic detail. The most frequently used radionuclide in PET scanning is 2-fluoro-2-deoxy-D-glucose (¹⁸F-FDG). Regarding RCC, ¹⁸F-FDG PET may be challenging to interpret, because this radiotracer is renally excreted without significant tubular reabsorption. This mode of excretion results in collecting system accumulation and makes the identification of parenchymal lesions more difficult. Most primary renal tumors have moderate but variable uptake of ¹⁸F-FDG when compared with metastatic lesions.¹⁵ Subsequently, sensitivity for detecting primary tumors ranges from 60% to 90%.¹⁶ PET, however, shows promise in staging and restaging RCC. Compared with the limited abilities of traditional modalities in staging, PET offers sensitivities of 60–100% and is particular adept in detecting metastatic disease.¹⁶ Similar sensitivities of 80–100% have been reported in detecting recurrent RCC.¹⁶ As PET imaging is a relatively novel modality, new techniques such as the use of different radiotracers might further expand the role of PET in RCC.

Preoperative embolization

Renal artery embolization (RAE) was initially used as a palliative procedure (Figure 2). Over the past 30 years, however, it has been used as a preoperative adjunct to resection of locally advanced renal tumors. Opinions on the role of preoperative RAE are controversial, and no consensus exists among urologists, because there are few prospective trials to elucidate its potential validity. However, one retrospective trial did show a survival benefit associated with preoperative RAE compared with case-matched control groups receiving nephrectomy alone.¹⁷ Proponents suggest that RAE facilitates dissection secondary to the resultant tissue plane edema, and diminishes blood loss during mobilization of the inferior and superior surgical margins. In addition, preoperative RAE may decrease the extent of tumor thrombus.

Figure 2 Angiograms from the patient in figure 1 (50-year-old male).

(A) Pre-embolization and (B) Postembolization angiogram. The patient successfully underwent radical nephrectomy and inferior vena cava thrombectomy.

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Arterial embolization also allows the surgeon to ligate the renal vein before the artery, which is particularly useful when treating hilar tumors and in patients with significant adenopathy. Note that it is important to first assess the completeness of preoperative embolization—by intraoperatively examining the extent of renal venous return—before commencing venous ligation, prior to arterial control to avoid unnecessary blood loss. An additional benefit to RAE might be immunomodulation, where post-RAE tumor necrosis induces a tumor-specific response by natural killer cells in addition to a lymphoproliferative response.^{18, 19} The procedure is well tolerated with complication rates of around 5%.²⁰ The most common complication is post-infarction syndrome, characterized by mild pain, fever, nausea and vomiting.

Surgical considerations

Larger renal masses can be difficult to manage surgically. In the absence of nodal disease or metastatic deposits, negative surgical margins indicate a good prognosis. The natural biology of RCC involves venous tumor thrombus in 4–10% of patients, with 1% of these patients having a thrombus extending into the right atrium.¹¹ RCC has been established as resistant to non-surgical therapy (radiation, chemotherapy and hormonal), leaving surgical resection as the gold standard of treatment as first described by Robson et al. in 1969.²¹

Open surgical approaches (anterior and flank/thoracoabdominal) are determined by tumor location, body habitus and prior surgical history. A flank approach in obese patients can provide optimal exposure and minimize morbidity associated with a larger midline incision. A flank approach can also avoid adhesions in patients with prior abdominal surgery. Anterior incisions (midline, paramedian and subcostal) provide transperitoneal and intraperitoneal exposure. By entering the posterior peritoneum via a midline incision the renal pedicles are easily accessed and controlled. Vascular control is a priority in dealing with larger renal tumors.

Surgical anatomy

Radical nephrectomy involves the en bloc removal of the affected kidney, adrenal gland, perirenal fat, proximal ureter and Gerota's fascia. Vascular anomalies are actually the rule rather that the exception, especially in large hypervascular tumors with venous collaterals (Figure 3). Preoperative imaging evaluation is paramount in these complex cases to maximize exposure and limit operative times. Traditional teaching places the kidneys obliquely in the retroperitoneal space with the right lower than the left because of the downward displacement by the liver during development. Posterior to the kidneys are the psoas and quadratus lumborum muscles, which are encased by ribs 11 and 12. Identification of these ribs is important for planning thoracoabdominal incisions. Both kidneys are surrounded by a renal capsule, further embedded in perirenal fat contained within a second enveloping lining known as Gerota's fascia. The Gerota's fascia also encompasses the ipsilateral adrenal gland and has an intimate relationship with the posterior peritoneum. The right kidney is in close apposition to the liver superiorly and adjacent to the hepatic flexure of the colon and duodenum. The left kidney contacts the tail of the pancreas, the splenic flexure of the colon and the spleen.

Figure 3 Renal venous collecting system demonstrating extensive collateral drainage that might occur with renal vein obstruction.

Abbreviation: IVC, inferior vena cava. © The Lahey Clinic. Reproduced with permission.

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The typical vasculature consists of two renal arteries from the aorta lying dorsal to the renal vein with the left longer than the right, the latter with a retrocaval course. Multiple renal arteries occur unilaterally and bilaterally in 23% and 10%, respectively, of the population at large. The left renal vein is longer than the right and receives drainage from the adrenal, phrenic, gonadal and lumbar veins (Figure 4), while the shorter right renal vein receives no tributaries before joining the IVC. The renal lymphatic vessels follow the arterial system and coalesce in the renal sinus before draining into the regional lymph nodes.²²

Figure 4 Removal of infrahepatic vena cava tumor thrombus.

(A) The IVC is palpated to estimate the proximal and distal extent of the tumor, and a DeWeese clip and vessel loops are passed and secured. (B) The contralateral renal vein is also isolated. (C) A cavatomy is made and the thrombus delivered before (D) closing the IVC with a running 4-0 polypropylene suture. Abbreviation: IVC, inferior vena cava. © The Lahey Clinic. Reproduced with permission.

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Tumor thrombus

Aggressive surgical intervention remains the mainstay of treating large renal tumors, with additional studies demonstrating a therapeutic effect of immunotherapy. Numerous contemporary studies have demonstrated that tumor thrombus has a limited prognostic role in the absence of nodal and/or metastatic disease. In fact, an estimated 45–70% of patients with RCC and IVC thrombus can be cured with surgical extirpation.^{29, 30} Staging of IVC thrombus levels remains an area of controversy with respect to cephalad extension and survival outcomes. Our results suggest that patients with tumor thrombus restricted to the renal vein have significantly improved survival outcomes versus those patients with thrombus into the IVC.³¹ Contemporary studies at large institutions have both supported and contradicted our findings, suggesting that continued attention be focused to addressing the staging of these complex tumors.^{32, 33}

With respect to larger tumors with associated tumor thrombus we use a midline transperitoneal incision providing generous access to the IVC. Bilateral subcostal approaches have also been used for equivalent exposure. The importance of thrombus control cannot be stressed enough when confronted with complex renal masses. Preoperative imaging has streamlined surgical approaches; however, a brief review of surgical approaches with respect to thrombus level is warranted. Additional clinical findings to suggest thrombus involvement include lower-extremity edema, right-sided varicocele, dilated abdominal veins (caput medusae), pulmonary emboli, proteinuria, right atrial masses and non-functioning renal units.

Blute et al. have reviewed the largest case series to date reflecting management of RCC with venous tumor thrombus, and their techniques parallel our surgical approaches.³⁴ Traditional urologists are able to perform a radical nephrectomy with little difficulty; however, we recommend tertiary referrals for larger tumors requiring multicomponent surgeries—IVC isolation, liver mobilization (i.e. the Pringle technique), venovenous bypass and atrial cannulation. Often cardiothoracic, vascular and hepatobiliary surgeons are called upon for intraoperative advice. Higher-volume centers are also more adept at managing complications associated with IVC thrombectomy, which occurs in 11–36% of patients.³⁴

For tumor thrombus confined to the renal vein, one might choose an anterior subcostal over an anterior midline approach. Before venous dissection, the renal artery and ureter are ligated and the kidney mobilized outside of Gerota's fascia. The renal vein and IVC should incur limited trauma during mobilization to minimize risk of emboli. Moves to maximize IVC exposure include ligation of hepatic caudate lobe veins. Renal vein tumors are often milked back into the vein and a Satinsky clamp is placed at the renal vein ostium, which is eventually oversewn after the tumor is removed (Figure 4).

As the level of tumor thrombus migrates cephalad, surgical exposure becomes vital to assure minimal blood loss and prevention of tumor emboli. Distal control of the IVC might require ligation of the larger collateral lumbar veins. Tumors below the confluence of the hepatic veins can be removed without the need for bypass, which will be discussed later. The vena cava also needs to be evaluated and removed in the presence of tumor invasion. Aggressive resection with IVC reconstruction (synthetic grafts and pericardial patches) has been reported to provide survival benefit.³⁵ In cases of chronic venous obstruction, complete ligation can be performed because of abundant collateral vessels when faced with a hostile retroperitoneum.

At our institution, RCC with tumor thrombus at or above the level of the hepatic veins is managed with bypass, and outcomes have been comparable to several contemporary series. Intraoperative transesophageal echocardiograms are implemented in all cases to assess tumor extension and monitor for emboli. We advocate the use of circulatory bypass, despite its inherent risks, to minimize against massive blood loss and provide optimal exposure. Venovenous bypass is initiated after the vena cava is isolated, and a region distal to the thrombus is cannulated with inflow at the level of the right atrium or cephalic vein. Techniques for circulatory arrest and profound hypothermia have been described elsewhere and have been modified at our institution to limit morbidity, operative times and complications. The implementation of a minimal access versus a thoracic approach avoids the traditional midline sternotomy and has been paramount in reducing surgical morbidity (Figure 5).³⁶

Figure 5 Minimally invasive approach for circulatory arrest in the management of suprahepatic venous tumor thrombus.

(A) The right subclavian artery was cannulated and a small Gore-Tex^® (WL Gore & Associates, Newark, DE) graft sewn into place for arterial return. (B) A 2-staged venous cannula was inserted into the right atrium and directed up into the SVC via a purse string suture for venous return. Abbreviation: SVC, superior vena cava. Adapted with permission from The Lahey Clinic © 1999 and Blackwell Publishing © 2006 Wotkowicz C et al. BJU Int 98: 289–297.³⁶

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There have been smaller series exploring additional surgical options that avoid the risks associated with bypass surgery, such as platelet dysfunction and coagulopathy, and neurologic sequlae. Ciancio and colleagues have been successful in using liver transplantation techniques (piggyback mobilization) to treat tumors at or beyond the hepatic vein confluence via a milking technique after arterial ligation.³⁷ In their review of 66 patients with venous tumor thrombus (renal 13, infrahepatic 7, retrohepatic 38 and atrial 8) the 36 month actuarial survival in patients was 66%.

In some instances, locally advanced disease requires resection of liver and colon (Figure 6). Colorectal and hepatobiliary consultation can assist in many of these cases and should be obtained preoperatively to facilitate operative management. Likewise, cardiothoracic surgeons need to be involved before surgery to minimize surgical time.

Figure 6 Intraoperative image of locally invasive renal cell carcinoma into the liver.

 

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Laparoscopic radical nephrectomy

With the increasing popularity of minimally invasive surgery, laparoscopic radical nephrectomy (LRN) has become a well-established treatment modality in patients with tumors of less than 7 cm in diameter who are not candidates for nephron-sparing surgical approaches. Multiple studies of patients with stage T1 RCC have demonstrated similar oncologic outcomes with favorable morbidity indexes when compared with open radical nephrectomy (ORN).^{38, 39, 40, 41} In recent years, several groups have extended their inclusion criteria for LRN to include T2 tumors. Recent investigations have demonstrated that LRN seems to be comparable to ORN in relation to short-term oncologic outcomes and perioperative complication rates in disease of stage T2 or above.^{42, 43, 44} The traditional benefits of laparoscopic surgery, such as decreased analgesic requirements, shorter hospital stay and convalescence time, also applied to the patients in these studies.^{42, 43, 44} As LRN has only been applied to large renal tumors relatively recently, there is a paucity of information regarding long-term oncologic outcomes in patients undergoing this procedure.

Whether LRN is performed by an intraperitoneal or an extraperitoneal approach, the surgeon must maintain the principles of ORN by removing the kidney surrounded by the perinephric fat and Gerota's fascia, with or without concomitant adrenalectomy. The intraperitoneal approach is generally preferred for large renal tumors for several reasons. Foremost, the intraperitoneal cavity offers a larger working space compared with a retroperitoneal space. This is paramount in large tumors as a small working space puts adjacent organs at a higher risk for iatrogenic injury and certainly makes maintaining orientation challenging. Furthermore, a larger working space offers the surgeon flexibility in placing additional port sites for supplemental retractors if necessary. It should also be noted that intentional peritonotomy to create extra working space might be required during an initial retroperitoneal approach if space is limited. Avoiding the peritoneal cavity via the retroperitoneal approach mitigates potential intra-abdominal complications such as inadvertent enterotomies, and this technique is often preferred when attempting LRN in patients with significant prior abdominal surgeries. The renal pedicle, however, is less accessible via the retroperitoneal approach than with the intraperitoneal laparoscopic approach. In either technique, special care must be taken to identify the parasitic vessels that regularly supply large renal tumors.

No consensus exists for the best way to approach specimen removal, although it is essential to remove the specimen intact for pathologic examination. The surgeon might prefer to remove the specimen via a flank incision connecting the port sites, or may choose to remove the specimen via a Gibson or Pfannenstiel incision.

Vena cava involvement, bulky perinephric adenopathy and local tumor invasion are all contraindications to a laparoscopic approach. Furthermore, only experienced laparoscopic surgeons should attempt a minimally invasive approach when tackling large renal tumors.

Partial nephrectomy

Radical nephrectomy has been the standard of treatment for localized RCC for decades. With a rise in incidentally found small tumors and improved surgical techniques, nephron-sparing surgery (NSS) has become increasingly used, especially for lesions smaller than 4 cm. Benefits of NSS include a decreased incidence of postoperative renal insufficiency and an overall improved quality of life.^{45, 46} Furthermore, multiple studies have shown similar costs, morbidity, mortality and complications when comparing NSS and radical nephrectomy. Published reports, in addition, have documented comparable rates of local recurrence and 5-year disease free survival.^{45, 47} However, most of these studies include tumors of less than 4 cm in size. More recently, several groups, both laparoscopic and open, have extended their criteria to tumors between 4 cm and 7 cm with encouraging initial results.^{48, 49, 50}

At our institution, we advocate NSS in stage T2 or greater tumors only in extenuating circumstances. Examples of such would include patients with a functional or anatomic solitary kidney, and patients with bilateral synchronous renal tumors. Partial nephrectomy should be avoided in patients in whom there is a suspicion of venous involvement or in those whose imaging studies indicate that there might be local invasion. Special care should be taken in tumors with central and hilar involvement, and tumors with pelvicaliceal invasion. If NSS is not technically feasible, then radical nephrectomy should be performed.

Surgical complications

The complication rates for the surgical removal of larger tumors vary greatly, and for the most part are dependent on the complexity of the tumor, patient comorbidities and the experience of the surgeon. Bowel injuries are uncommon in most procedures unless there is a significant inflammatory reaction. Patients with such inflammation can present with postoperative ileus and might require parenteral nutrition until resolution. Left-sided tumors often require mobilization of the pancreas, which can lead to pancreatitis and the need for parenteral nutrition support with serial laboratory monitoring of amylase and lipase levels. The incidence of pneumothorax ranges from 1% to 25%, and is best managed with placement of a chest tube. Splenic injuries with left-sided tumors are often managed conservatively; however, intraoperative splenectomy must be considered in patients with uncontrollable hemorrhage.⁵¹

The incidence of complications varies widely in patients undergoing radical nephrectomy with tumor thrombus. Boorjian et al. performed an extensive review of their experience with over 400 patients.³⁵ The incidence of both early (<30 days postoperatively) and late (30 days to 1 year after the operation) complications correlated with level of thrombus. Operative times and requirements for blood transfusions correlate with the level of venous tumor thrombus, as expected. Our own personal experience with circulatory arrest has shown that minimally invasive techniques provide improved perioperative outcomes. When reviewing retrospective data, one must be reminded that significant improvements have been made in surgical equipment, anesthesia and perioperative nursing that have contributed to improved outcomes.

Postoperative management

A good postoperative outcome begins with a comprehensive preoperative evaluation and the proper clearance from cardiac, pulmonary and hematological services. All patients undergoing radical nephrectomy should have intraoperative arterial monitoring and central venous lines in place. Any patient with a moderate cardiac dysfunction (cardiac ischemia or congestive heart failure) should have a Swan–Ganz catheter to monitor cardiac output and systemic venous oxygenation. Pain associated with larger thoracoabdominal incisions is best managed with preoperative epidural placement. Entry into the pleural cavity is best managed with formal chest tube placement at the time of operation and daily chest X-rays.

Patients with completely resected stage T1–T3 disease should have an abdominal and chest CT performed 4–6 months following the procedure to check for tumor recurrence, and thereafter at the discretion of the surgeon.⁵² Relapse will occur in 20–30% of patients with localized tumors, with pulmonary lesions being the most common, found in 50–60% of patients with relapse. Studies have indicated that the adjuvant use of two kinase inhibitors (sunitinib [Sutent^®; Pharmacia & Upjohn Ltd, North Peapack, NJ] and sorafenib [Nexavar^®; Bayer AG, Leverkusen, Germany) might be beneficial in reducing recurrence rates; however, clinical trials are still in progress. In addition to imaging studies, monitoring of renal function (blood urea nitrogen and serum creatinine) should be performed periodically, although there is no consensus as to how often this monitoring should be done and it is influenced by patients' comorbid conditions. Patients at high risk for chronic nephropathy (hypertension and diabetes) need increased interval surveillance. Patients with stage IV disease should have immediate interaction with the oncology staff.

Metastectomy and cytoreductive surgery

The incidence of advanced and metastatic kidney cancer is increasing with the aging of the 'baby boomer' population in the US. Patients with metastatic RCC face poor survival outcomes, with estimated median survival of 8 months and 2-year survival rates of 10–20%.⁵³ Surgery is an option for patients with only a partial regression of metastases or with prolonged stabilization following systemic therapy.²⁴ Radical nephrectomy (debulking) can be performed in patients with evidence of metastatic disease—intractable edema, ascites, cardiac dysfunction, associated pain and hematuria—for symptomatic relief. Solitary metastatic deposits have been resected with accompanying 5-year survival rates of 29–35%.²⁴

The motivation for debulking nephrectomy has been spurred on by positive results from targeted molecular therapy trials (cytoreductive therapy followed by systemic therapy). Two randomized trials (Southwest Oncology Group [SWOG]-8949 and EORTC-30947) demonstrated an overall survival advantage (13.6 months versus 7.8 months) for patients treated with nephrectomy and interferon versus interferon alone.⁵⁴ Subgroup analysis revealed performance status to be a significant factor in determining survival. Besides performance status, candidates also need to have primary tumors representing the majority of tumor burden without a rapidly progressive non-renal component, and limited medical comorbidities. Two hypotheses to explain the benefits of debulking nephrectomy center around impaired immune surveillance and angiogenesis in patients with RCC. Data have indicated that RCC impairs recruitment of an immune response, which might allow tumor cells to divide more easily. RCC patients have also been shown to express higher levels of vascular endothelial growth factor (VEGF) supporting the role of VEGF inhibitors in the treatment of RCC.

Adjuvant and neoadjuvant therapy

The advent of VEGF and platelet-derived growth factor (PDGF) targeted systemic therapy has changed the treatment paradigm for non-localized RCC. Traditional immunotherapy for metastatic RCC offered patients response rates of 15–20% and rarely resulted in substantial response of the primary tumor.⁵⁵ In several clinical trials, the VEGF and PDGF modulators sorafenib and sunitinib had exciting results with 40% response rates, 70% rate of tumor shrinkage and significant improvements in progression-free survival.^{56, 57, 58, 59}

Multiple potential applications of these therapeutics exist in the treatment of advanced RCC. Sorafenib and sunitinib are being investigated as agents in adjuvant therapy in the SORCE trial and the Eastern Cooperative Oncology Group (ECOG)-led intergroup trial E2805, with the hope that these agents will decrease recurrence rates and improve disease-free survival in patients with RCC. The use of the VEGF and PDGF modulators as neoadjuvant therapy has also been discussed. As a primary tumor response with molecular targeted therapy has been observed, neoadjuvant therapy might allow the complete surgical removal of gross disease in patients who were deemed to have unresectable disease before neoadjuvant therapy. It might also help to minimize perioperative morbidity in patients with locally advanced but resectable tumors. This approach is most likely to be of benefit in the absence of metastatic disease.⁶⁰

Patients with locally advanced or unresectable disease and distant metastases are likely to benefit most from initial systemic therapy followed by monitoring to assess response to therapy and disease progression. Patients who fail to respond to systemic therapy and have continued disease progression might not benefit from debulking nephrectomy because of the aggressive nature of their disease. Although the theoretical applications of VEGF and PDGF modulators are appealing, numerous clinical trials must be completed to elucidate their optimal applications.

Conclusions

Management of large renal tumors can be quite complicated due to the locally invasive nature of the disease and tumor thrombus biology. The close proximity of the kidney to the spleen, liver and colon in the retroperitoneal space makes dissection difficult at times. We advocate the use of generous incisions to manage large complex tumors, recognizing that retroperitoneal bleeding can be life threatening, especially when one considers the hypervascular nature of RCC and the involvement of collateral veins that occurs with tumor thrombus.

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