Renal Cell Carcinoma Treatment & Management

The therapeutic approach to renal cell carcinoma (RCC) is guided by the probability of cure, which is related directly to the stage or degree of tumor dissemination.^{[1, 2, 3]} More than 50% of patients with early stage renal cell carcinoma are cured, but the outcome for stage IV disease is poor. Thus, the approach is curative for early stage disease.

The 2009 AUA guideline recommends reviewing all available treatment options and the associated benefits and risks, including oncologic issues, renal functional issues, and potential complications, with the patient.^[14]

The treatment options for renal cell cancer are surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or combinations of these. Selected patients with metastatic disease respond to immunotherapy, but many patients with advanced disease can be offered only palliative therapy.

Options for chemotherapy and endocrine-based approaches are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care. Objective response rates with chemotherapy, either single-agent or combination, are usually lower than 15%. Therefore, various biologic therapies have been evaluated.

Renal cell carcinoma is an immunogenic tumor, and spontaneous regressions have been documented. Many immune modulators have been tried, including interferon (IFN), interleukin (IL)-2 (aldesleukin [Proleukin]), bacillus Calmette-Guérin (BCG) vaccination, lymphokine-activated killer (LAK) cells plus IL-2, tumor-infiltrating lymphocytes, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation.

Surgical resection remains the only known effective treatment for localized renal cell carcinoma, and it also is used for palliation in metastatic disease. About 25-30% of patients have metastatic disease at diagnosis, and fewer than 5% have solitary metastasis. Surgical resection is recommended in selected patients with metastatic renal carcinoma. This procedure may not be curative in all patients but may produce some long-term survivors. The possibility of disease-free survival increases after resection of primary tumor and isolated metastasis excision.

Metastasectomy of a solitary metastasis is recommended in selected patients with good performance status. A large retrospective analysis from a single institution revealed improved cancer-specific survival advantage, even with metastasectomy of more than one lesion. The study also revealed increased risk of death due to renal cell carcinoma in patients who did not undergo surgical resection of metastasis.^[17]

Selected patients older than 70 years who have asymptomatic renal masses and slow growth documented on serial imaging may be observed. A retrospective, single institution review of 51 patients showed no metastatic spread with a median follow-up of almost 6 years; only 2 patients required surgical intervention for local progression or symptoms.^[18]

A study by Alt et al found that complete resection of multiple renal cell carcinoma metastases may be associated with long-term survival.^[19]

A study by Zagoria et al found that radiofrequency ablation can result in durable oncological control in patients with renal cell carcinomas that are smaller than 4 cm who are poor surgical candidates.^[20]

Go to Clear Cell Renal Cell Carcinoma and Sarcomatoid and Rhabdoid Renal Cell Carcinoma for complete information on these topics.

For early stage renal cell carcinoma (RCC), an emerging treatment strategy is to utilize molecular approaches earlier in the adjuvant setting in order to improve overall survival rates. Indeed, a randomized phase 3 trial of sunitinib versus sorafenib versus placebo as adjuvant therapy in patients with resected renal cell carcinoma is currently ongoing.^[21]

Targeted therapy in metastatic renal cell carcinoma

The optimal sequence or combination of active agents in advanced renal cell carcinoma is not yet defined. Based on decisions derived from level 1 evidence, the following may be considered as reasonable targeted therapy choices in patients with metastatic renal cell carcinoma who are not eligible for high-dose interleukin (IL)-2 therapy. The 2011 NCCN guideline gives several of these targeted therapy agents category 1 recommendations for this group of patients.^[15]

• For previously untreated patients with predominantly clear cell renal cell cancer of low or intermediate risk, consider sunitinib (NCCN category 1 recommendation) or the combination (NCCN category 1 recommendation) of bevacizumab and interferon (IFN) alfa.
• For patients with previously untreated predominantly clear cell renal cell cancer with poor prognostic (high-risk) characteristics, consider temsirolimus (NCCN category 1 recommendation.)
• For patients with previously treated predominantly clear cell renal cell cancer, consider sorafenib; if standard doses fail, an increase in dose may produce responses. For patients in whom sorafenib is failing, they may be treated with sunitinib if this drug had not been previously used.
• The 2011 NCCN guideline gives pazopanib, an angiogenesis inhibitor, a category 1 recommendation for first-line treatment of patients with relapsed or unresectable predominantly clear cell cancer with poor prognostic characteristics.

The treatment of metastatic renal cell carcinoma is problematic, and, whenever possible, patients should be directed to approved and controlled clinical trials. This applies as well in the adjuvant treatment of surgically resected renal cell carcinoma, for which no therapy has yet been found to offer survival benefit.

• The 2011 NCCN kidney cancer guideline discusses the efficacy of targeted molecular approaches to treating metastatic renal cell carcinoma (mRCC). In separate randomized Phase III trials, each of the following treatments has been shown to be more effective than interferon (IFN) alpha as first-line therapy for mRCC: sunitinib, bevacizumab plus interferon (IFN) alpha, and temsirolimus in prolonging progression-free survival or overall survival times, or both. These targeted agents were shown to provide better results than that of previously recommended cytokines or placebo plus BSC (best supportive care), and are generally better tolerated than cytokines.^[14]

IL-2 immunotherapy

High-dose IL-2 must be considered for robust patients with excellent cardiopulmonary reserve, as this remains the only treatment known to induce complete and durable remissions, albeit in a minority of patients. Prospective studies are under way to identify patients who are more likely to respond to IL-2 immunotherapy based on carbonic anhydrase IX expression in the primary tumor and other assessments of immune function and regulation. This study may help to resolve the sequence and selection of available agents for individual patients with metastatic disease.

Future therapeutic strategies

Future treatment strategies for advanced renal cell carcinoma will likely incorporate a combination of molecular approaches, using multidrug regimens consisting of small-molecule kinase inhibitors with biologic therapies, immunomodulatory therapies, or both.

Sorafenib (Nexavar)

Sorafenib, a small-molecule Raf kinase and vascular endothelial growth factor (VEGF) multireceptor kinase inhibitor, is approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma (RCC). This indication was based on the demonstration of improved progression-free survival in a large, multinational, randomized, double-blind, placebo-controlled phase 3 study (details provided below) and a supportive phase 2 study.

Sorafenib targets serine/threonine and receptor tyrosine kinases, including those of RAF; vascular endothelial growth factor receptor (VEGFR)-2,3; platelet-derived growth factor receptor (PDGFR)-beta; stem cell factor receptor (KIT); Fmslike tyrosine kinase-3 (FLT-3); and the glial cell-line–derived neurotrophic factor receptor (RET).

A study by Verma et al concluded that the use of tyrosine kinase inhibitors reduces the incidence of brain metastasis among patients with metastatic renal cell carcinoma.^[22]

The recommended sorafenib dose is 400 mg (two 200-mg tab) twice daily taken either 1 hour before or 2 hours after meals. Adverse events were accommodated by temporary dose interruptions or reductions to 400 mg once daily or 400 mg every other day.

Sorafenib phase 3 trial

The sorafenib phase 3 study final results established the efficacy and safety of sorafenib in advanced renal cell carcinoma.^[23] The trial was conducted in patients with advanced (unresectable or metastatic) renal cell carcinoma who had received one previous systemic treatment.^[24] Study endpoints included overall survival, progression-free survival, and response rate.

Among 769 patients randomized, the median age was 59 years and 70% were male.^[24] Of patients who had undergone previous therapies, 93% had previous nephrectomies; 99% had received previous systemic therapies, including interleukin (IL)-2 (44%) and an interferon (IFN) (68%).

The median progression-free survival was 167 days in the sorafenib group versus 84 days in the placebo control group.^[24] Time-to-progression was similarly improved. Tumor response was determined by independent radiologic review according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Overall, of 672 patients who were able to be evaluated for response, 7 (2%) patients in the sorafenib group and 0 (0%) patients who received placebo had confirmed partial responses.^[24]

Once improved progression-free survival with sorafenib had been demonstrated, patients assigned to placebo were offered sorafenib. Although an analysis that included patients who crossed over to sorafenib showed no overall survival benefit with sorafenib, a secondary analysis that did not include these patients showed significantly improved overall benefit (17.8 vs 14.3 mo).^[23]

Sorafenib adverse effects

Hypertension is a common side effect of sorafenib treatment, and may be high grade.^[25] Physicians should be aware of the importance of frequent blood pressure monitoring and management, especially during the first 6 weeks after starting sorafenib.

Sorafenib toxicities (based on an updated phase 3 study database of 902 patients) included reversible skin rashes in 40% and hand-foot skin reaction in 30%. Diarrhea was reported in 43%, treatment-emergent hypertension in 17%, and sensory neuropathic changes in 13%. Alopecia, oral mucositis, and hemorrhage were also reported more commonly in the sorafenib arm. The incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib group (2.9%) compared with the placebo group (0.4%).

Hypothyroidism is another potential toxicity of sorafenib.^[26]

Grade 3 and 4 adverse events were unusual; only hand-foot skin reaction occurred at 5% or greater frequency in the sorafenib arm. Laboratory findings included asymptomatic hypophosphatemia in 45% versus 12% and serum lipase elevations in 41% versus 30% of sorafenib versus placebo patients, respectively. Grade 4 pancreatitis was reported in 2 sorafenib patients, although both patients subsequently resumed sorafenib, one at full dose.

The safety and efficacy of sorafenib were also demonstrated in a nonrandomized, open-label expanded access program in which 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Patients included those with no previous therapy, nonclear cell renal cell carcinoma, brain metastases, and previous bevacizumab treatment; and elderly patients. Median overall survival was 50 weeks.^[27]

Sunitinib (Sutent)

Sunitinib is another multikinase inhibitor approved by the FDA for the treatment of metastatic kidney cancer that has progressed after a trial of immunotherapy. The approval was based on the high response rate (40% partial responses), a median time to progression of 8.7 months, and an overall survival of 16.4 months. The receptor tyrosine kinases inhibited by sunitinib include VEGFR 1-3 and PDGFR-alpha and -beta.^[28]

The recommended dose of sunitinib for advanced renal cell carcinoma is one 50 mg oral dose taken once daily, with or without food, on a schedule of 4 weeks on treatment, followed by 2 weeks off treatment.^[29]

In a phase 3 study in 750 patients with previously untreated metastatic renal-cell carcinoma, progression-free survival was longer and response rates were higher in patients who received sunitinib than in those receiving interferon (IFN)-alfa.^[30] In final survival analyses, the median overall survival (26.4 mo) and the objective response rate (47%) was greater in the sunitinib group than in the IFN-alfa group (21.8 mo and 12%, respectively).^[31] An onset of hypothyroidism in patients treated with the kinase inhibitors sunitinib and sorafenib may portend better response.^[26]

An expanded-access trial that provided sunitinib on a compassionate-use basis to 4564 trial-ineligible patients with renal cell carcinoma from countries where regulatory approval had not been granted suggested that the safety of sunitinib in these patients was manageable and its efficacy was encouraging, particularly in subgroups associated with poor prognosis (eg, those with brain metastases, low performance status, non–clear cell disease, and elderly patients).^[32] Median progression-free survival was 10.9 months and overall survival was 18.4 months (17.4-19.2 mo).

Major toxicities (grade II or higher) of sunitinib include fatigue (38%), hypothyroidism (in as many as 30%), diarrhea (24%), nausea (19%), dyspepsia (16%), stomatitis (19%), and decline in cardiac ejection fraction (11%). Dermatitis occurred in 8%, and hypertension occurred in 5% of patients. Hypertension induced by sunitinib may correlate with a significantly higher probability of response and better disease-free and overall survival.^[33]

Temsirolimus (Torisel)

Temsirolimus inhibits mammalian target of rapamycin (mTOR), which is a serine/threonine kinase important in the regulation of cell growth and division. Genes involved with the response to hypoxia (hypoxia-inducible factor [HIF] pathway) are also upregulated by mTOR and are believed to be central to the pathogenesis of kidney cancers.

The FDA has approved temsirolimus for the treatment of advanced renal cell carcinoma at an intravenous (IV) dose of 25 mg weekly until progression.

Temsirolimus has been tested alone and in conjunction with interferon in patients with poor prognosis, advanced renal cell carcinoma. Temsirolimus monotherapy at an IV dose of 25 mg weekly resulted in longer overall and progression-free survival (median survival, 10.9 mo) compared with interferon (median survival, 7.3 mo).^[34] There was no significant additive effect of interferon combined with temsirolimus. A second study combining temsirolimus and interferon over a range of dose levels showed overall survival of 18.8 months and progression-free survival of 9.1 months for the combination.^[35] Partial response was observed in 8% and stable disease in 36% of patients.

Common toxicities of temsirolimus include asthenia, rash, anemia, hypophosphatemia, and hyperlipidemia.

Everolimus (Afinitor)

Everolimus is a serine-threonine kinase inhibitor of mTOR, an important regulatory protein in cell signaling. This agent was approved by the FDA in March 2009 for advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

The recommended everolimus dose for treatment of advanced renal cell carcinoma is 10 mg, to be taken once daily at the same time every day, with or without food.^[36] However, the tablets should be swallowed whole, not be chewed or crushed, with a glass of water.

In a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial in patients with metastatic renal cell carcinoma that had progressed during sunitinib and/or sorafenib treatment, analysis showed significantly longer median progression-free survival with everolimus than with placebo.^{[37, 38]} The median overall survival with everolimus was 14.8 months compared with 14.4 months for placebo; 80% of patients in the placebo arm crossed over to everolimus.^[37]

The most common toxicities associated with everolimus are stomatitis, infections, asthenia, fatigue, cough, and diarrhea.^[36]

Bevacizumab (Avastin)

The novel combination of bevacizumab (a neutralizing monoclonal antibody to VEGF) and interferon has been shown to have activity against metastatic renal cell carcinoma.^[40] Completion of this phase 3 trial by Escudier et al found bevacizumab plus interferon alfa-2a was effective as first-line treatment in patients with metastatic renal cell carcinoma.^[41] In July 2009, the FDA granted approval for the use of bevacizumab (Avastin) in combination with interferon alfa for the treatment of patients with metastatic renal cell carcinoma.^[42]

Axitinib (Inlyta)

Axitinib inhibits tyrosine kinase receptors including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3. The FDA approved axitinib in January 2012 for treatment of advanced RCC after failure of 1 prior systemic therapy.

The approval was based on a single efficacy study, (AXIS trial), of 723 patients with advanced RCC who had failed 1 previous therapy. The trial was a randomized, controlled, open-label, multicenter phase 3 trial that compared axitinib with sorafenib as second-line systemic therapy. Patients were randomized to receive either axitinib 5 mg or sorafenib 400 mg, and the primary efficacy end point was progression-free survival.

The results showed that axitinib extended progression-free survival by 2 months more than sorafenib. The objective response rate for axitinib was also superior to sorafenib (19.4% vs 9.4%).^[51]

Experimental multikinase inhibitors for renal cell carcinoma therapy

Lapatinib is an epidermal growth factor receptor (EGFR) and ErbB-2 dual tyrosine kinase inhibitor that appears to have efficacy in the treatment of tumors that overexpress EGFR, including renal cell carcinoma. A phase 3 study in patients with advanced renal cell carcinoma whose disease had failed previous therapy found that lapatinib was well tolerated and had overall efficacy equivalent to that of hormonal therapy.^[39]

The novel combination of bevacizumab (a neutralizing monoclonal antibody to VEGF) and interferon has been shown to have activity against metastatic renal cell carcinoma.^[40] Completion of this phase 3 trial by Escudier et al found bevacizumab plus interferon alfa-2a was effective as first-line treatment in patients with metastatic renal cell carcinoma.^[41] In July 2009, the FDA granted approval for the use of bevacizumab (Avastin) in combination with interferon alfa for the treatment of patients with metastatic renal cell carcinoma.^[42]

A phase 2 trial of weekly intravenous (IV) gemcitabine (600 mg/m² on days 1, 8, and 15) with continuous infusion fluorouracil (150 mg/m²/d for 21 d in 28-d cycle) in patients with metastatic renal cell cancer (RCC) produced a partial response rate of 17%.^[43] No complete responses were noted. Eighty percent of patients had multiple metastases, and 83% had received previous treatment. The mean progression-free survival duration of 28.7 weeks was significantly longer than that of historic controls.^[43]

Floxuridine (5-fluoro 2'-deoxyuridine [FUDR]), 5-fluorouracil (5-FU), and vinblastine, paclitaxel (Taxol), carboplatin, ifosfamide, gemcitabine, and anthracycline (doxorubicin) all have been used in advanced renal cell carcinoma. Floxuridine infusion has a mean response rate of 12%, whereas vinblastine infusion yielded an overall response rate of 7%. 5-FU alone has a response rate of 10%, but when used in combination with interferon, it had a 19% response rate in some studies.

Renal cell carcinoma is refractory to most chemotherapeutic agents because of multidrug resistance mediated by p -glycoprotein. Normal renal proximal tubules and renal cell carcinoma both express high levels of p -glycoprotein. Calcium channel blockers or other drugs that interfere with the function of p -glycoprotein can diminish resistance to vinblastine and anthracycline in human renal cell carcinoma cell lines.

Interferons and interleukin (IL)–2 are briefly discussed in this section.

The interferons

The interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. These agents have a direct antiproliferative effect on renal tumor cells in vitro, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules. Interferon alfa, which is derived from leukocytes, has an objective response rate of approximately 15% (range, 0-29%).

Preclinical studies have shown synergy between interferons and cytotoxic drugs. In several prospective randomized trials, combinations do not appear to provide major advantages over single-agent therapy. Many different types and preparations of interferons have been used without any difference in efficacy.

Interleukin 2

IL-2 is a T-cell growth factor and activator of T cells and natural killer (NK) cells. IL-2 affects tumor growth by activating lymphoid cells in vivo without affecting tumor proliferation directly.

In the initial study by the National Cancer Institute (NCI), bolus intravenous (IV) infusions of high-dose IL-2 combined with lymphokine-activated killer (LAK) cells produced objective response rates of 33%. In subsequent multicenter trials, not only was the response rate 16%, but it was also shown that LAK cells add no definite therapeutic benefit and can be eliminated from the treatment.^[44] A high-dose regimen (600,000-720,000 IU/kg q8h for a maximum of 14 doses) resulted in a 19% response rate with 5% complete responses. The majority of responses to IL-2 were durable, with median response duration of 20 months; 80% of patients who had a complete response to IL-2 therapy were alive at 10 years.

IL-2 dosing

Most patients had a clinical response after the first cycle, and those who did not show a response after the second cycle did not have a response to any further treatment. Therefore, the current recommendation is to continue treatment with high-dose IL-2 to the best response (up to 6 cycles) or until toxic effects become intolerable. Treatment should be discontinued after 2 cycles if the patient has had no regression. Combinations of IL-2 and interferon or other chemotherapeutic agents such as 5-fluorouracil (5-FU) have not been shown to be more effective than high-dose IL-2 alone.

IL-2 toxicities

Toxic effects associated with high-dose IL-2 are related to increased vascular permeability and secondary cytokine secretion (eg, IL-1, interferon gamma, tumor necrosis factor, nitric oxide). The management of high-dose IL-2 toxicities requires inpatient monitoring, often in an intensive care unit.

The major toxic effect of high-dose IL-2 is a sepsislike syndrome, which includes a progressive decrease in systemic vascular resistance and an associated decrease in intravascular volume due to capillary leak. Other toxic effects are fever, chills, fatigue, infection, and hypotension.

High-dose IL-2 has been associated with a 1-4% incidence of treatment-related death and should be offered only to patients with no cardiac ischemia or significant impairment of renal or pulmonary functions. Management includes judicious use of fluids and vasopressor support to maintain blood pressure and intravascular volume and at the same time to avoid pulmonary toxicity due to noncardiogenic pulmonary edema from the capillary leak. This syndrome is normally reversible.

Other experimental approaches for treatment of renal cell carcinoma (RCC) include immunomodulatory drugs, vaccines, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation.

Lenalidomide

The immunomodulator lenalidomide (Revlimid), a derivative of thalidomide, inhibits vascular endothelial growth factor (VEGF), stimulates T and natural killer (NK) cells, and inhibits inflammatory cytokines. This agent has been evaluated extensively in hematologic malignancies. In phase 2 studies of metastatic renal cell carcinoma, lenalidomide demonstrated an antitumor effect in some cases, with disease stabilization or durable partial response.^{[45, 46]}

Vaccines

Vaccine trials are in early stages of development. Few antigens have been identified that induce T-cell responses from renal cell carcinoma. One example of vaccine strategy is to induce the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) into autologous cultured renal cell cancer lines by retroviral transduction. Patients are then immunized with irradiated tumor cells secreting large amounts of GM-CSF and are evaluated for immune responses and clinical tumor regression. Other approaches to vaccination include tumor lysates and dendritic cells.

Autologous vaccine therapy is now being tried in combination with cytokine therapy. A pilot study of vaccinating with the corresponding mutant von Hippel-Lindau peptides demonstrated safety and proved efficacy in generating a specific immune response in patients with advanced renal cell carcinoma.^[47]

Nonmyeloablative allogeneic stem cell transplantation

Nonmyeloablative allogeneic stem cell transplantation can induce sustained regression of metastatic renal cell carcinoma in patients who have had no response to conventional immunotherapy. In one trial, 19 patients with refractory metastatic renal cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of peripheral blood stem cells from a human leukocyte antigen (HLA)-identical sibling or a sibling with a mismatch of a single HLA antigen.^[48] Patients with no response received as many as 3 infusions of donor lymphocytes. Two patients died of transplantation-related causes, and 8 died from progressive disease. In 10 patients (53%), metastatic disease regressed; 3 patients had a complete response, and 7 had a partial response.^[48] The durations of these responses continue to be assessed. Further trials are needed to confirm these findings and to evaluate long-term benefits.

Megestrol and antiestrogens

Multiple studies have been conducted using megestrol (Megace) in the treatment of renal cell carcinoma. No benefit has been shown except for appetite stimulation, so megestrol is currently not recommended. Antiestrogens such as tamoxifen (100 mg/m²/d or more) and toremifene (300 mg/d) have also been tried, with a response rate as low as that of most chemotherapeutic agents.

For a T1a renal mass, the 2011 NCCN guideline recommends partial nephrectomy, stating that radical nephrectomy should not be used when nephron-sparing procedures are possible. For clinical T1b tumors, the NCCN guideline states that the standard of care is either radical nephrectomy or partial nephrectomy (when possible).^[15]

According to the 2009 AUA management guideline, in patients with a T1 renal mass, complete surgical excision by partial nephrectomy is a standard of care and a strong option. The guideline recommends discussing the potential advantages of nephron-sparing surgery with the patient, such as avoidance of dialysis and reduced risk of chronic kidney disease. If partial nephrectomy is not technically feasible as determined by a urologic surgeon, then a radical nephrectomy should be considered as an alternate standard of care.^[14]

For patients with a clinical T1a renal mass and comorbidities who are at increased surgical risk, the 2009 AUA guideline recommends that clinicians discuss complete renal excision via partial nephrectomy. Thermal ablation is a less invasive treatment option that may be preferable in the patient at high surgical risk, but it is associated with a higher risk of local tumor recurrence compared with surgical excision. Biopsy is recommended for all patients undergoing thermal ablation. The AUA guideline panel cautions that larger tumors (> 3.5 cm) and those with uneven shape or infiltrative appearance may be linked with increased risk of recurrence when managed with thermal ablation. Active surveillance may be an acceptable approach to delay or avoid further intervention in the patient at high surgical risk.^[14]

Radical nephrectomy, which remains the most commonly performed standard surgical procedure today for treatment of localized renal cell carcinoma (RCC), involves complete removal of the Gerota fascia and its contents, including a resection of kidney, perirenal fat, and ipsilateral adrenal gland, with or without ipsilateral lymph node dissection. Radical nephrectomy provides a better surgical margin than simple removal of the kidney, because perinephric fat may be involved in some patients. Approximately 20-30% of patients with clinically localized disease develop metastatic disease after nephrectomy.

Some surgeons believe that the adrenal gland should not be removed because of the low probability of ipsilateral adrenal metastasis and the morbidity associated with adrenalectomy. The 2011 NCCN guideline recommends considering ipsilateral adrenal gland resection if adrenal glands appear abnormal on CT or in patients with large upper-pole kidney tumors. Otherwise, adrenalectomy is not indicated.^[15]

In the absence of distant metastatic disease with locally extensive and invasive tumors, adjacent structures such as bowel, spleen, or psoas muscle may be excised en bloc during radical nephrectomy.

At least 3 common approaches exist for removal of kidney cancer: the transperitoneal approach, the flank approach, and the thoracoabdominal approach. Which approach is used depends on the tumor location and size as well as the body habitus of the patient. The thoracoabdominal approach offers the advantage of palpation of the ipsilateral lung cavity and mediastinum, as well as the ability to resect solitary pulmonary metastases.

Lymph node involvement

Lymph nodes may be involved in 10-25% of patients. The 5-year survival rate in patients with regional node involvement is substantially lower than in patients with stage I or II disease. Regional lymphadenectomy adds little in terms of operative time or risk and should be included in conjunction with radical nephrectomy.

The 2011 NCCN guideline states that patients with enlarged lymph nodes (palpable or detected by CT) should undergo lymph node dissection. To obtain needed staging information, lymph node dissection may also be performed on patients whose lymph nodes appear normal. Lymph node dissection is described as prognostic rather than therapeutic in the NCCN guideline, which cites a 2009 randomized phase 3 trial in which adding lymph node dissection to radical nephrectomy made no significant difference in time to progression, progression-free survival, or overall survival.^[15]

Inferior vena cava involvement

Approximately 5% of patients with renal cell carcinoma have inferior vena caval involvement. In these cases, the NCCN guideline states that radical nephrectomy is preferred, and for stage II and III renal tumors, it is the standard of care.^[15] Tumor invasion of the renal vein and inferior vena cava usually occurs as a well-vascularized thrombus covered with its own intimal surface. In patients with renal vein involvement without metastases, radical nephrectomy is performed with early ligation of the renal artery but no manipulation of the renal vein. If the inferior vena cava is involved, then vascular control of the inferior vena cava is obtained both above and below the tumor thrombus, and the thrombus is resected intact, with subsequent closure of the vena cava. Patients with actual invasion of the inferior vena caval wall have poor prognoses, despite aggressive surgical approaches.

Laparoscopic nephrectomy is a less invasive procedure than radical nephrectomy, incurs less morbidity, and is associated with shorter recovery time and less blood loss. Although the need for pain medications is reduced, operating room time and costs are higher. Disadvantages include concerns about spillage and technical difficulties in defining surgical margins. Laparoscopic partial nephrectomy can be considered at centers with experience in this procedure for early stage renal cell cancer.

Palliative nephrectomy should be considered in patients with metastatic disease for alleviation of symptoms such as pain, hemorrhage, malaise, hypercalcemia, erythrocytosis, or hypertension. Several randomized studies have shown improved overall survival in patients presenting with metastatic kidney cancer who have nephrectomy, followed by either interferon or interleukin-2 therapy. If the patient has good physiologic status, then nephrectomy should be performed before immunotherapy. Reports have documented regression of metastatic renal cell carcinoma after removal of the primary tumor. Adjuvant nephrectomy is not recommended for inducing spontaneous regression; rather, it is performed to decrease symptoms or to decrease tumor burden for subsequent therapy in carefully controlled environments.

Radiation therapy may be considered as the primary therapy for palliation in patients whose clinical condition precludes surgery, because of either extensive disease or poor overall condition.

A dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy. Preoperative radiation therapy yields no survival advantage.

Controversies exist concerning postoperative radiation therapy, but it may be considered in patients with perinephric fat extension, adrenal invasion, or involved margins. A dose of 4500 cGy is delivered, with consideration of a boost.

Palliative radiation therapy is often used for local or symptomatic metastatic disease, such as painful osseous lesions or brain metastasis, to halt potential neurologic progression. Surgery should also be considered for solitary brain or spine lesions, followed by postoperative radiotherapy.

About 11% of patients develop brain metastasis during the course of their disease. Renal cell carcinoma is a radioresistant tumor, but radiation treatment of brain metastasis improves quality of life, local control, and overall survival duration. Patients with untreated brain metastasis have a median survival time of 1 month, which can be improved with glucocorticoid therapy and brain irradiation. Stereotactic radiosurgery is more effective than surgical extirpation for local control and can be performed on multiple lesions.

Renal artery embolization with ethanol and gelatin sponge pledgets has been found effective for palliative treatment in patients who are not candidates for surgery, or who refuse surgery. A retrospective study in 8 patients with stage IV disease found that ethanol ablation controlled hematuria and flank pain.^[49]

It is recommended that patients avoid causative factors such as smoking, obesity, and other factors as described in Etiology.

Careful surveillance of patients with end-stage renal disease or von Hippel-Lindau disease, those who have undergone renal transplantation, and other high-risk groups by ultrasonography and computed tomography scanning is recommended.

Consultations with a urologist and oncologist as well as a specialist in radiation oncology are recommended.

According to the 2009 AUA management guideline, active surveillance is a reasonable choice for the management of localized renal masses. The AUA guideline recommends active surveillance as an option for all patients. For patients with decreased life expectancy or numerous comorbidities that would make them high risk for intervention, active surveillance is recommended as first choice. For those who are candidates for intervention, counseling about active surveillance should include a frank discussion of the small but real risk of cancer progression, the lack of curative therapies if metastases develop, the possible loss of a chance for nephron-sparing surgery, and the limited data on active surveillance. Larger tumors (>3-4 cm) and those with an aggressive appearance (eg, infiltrative growth pattern) may be linked to increased risk and should be managed in a proactive manner if possible.^[14]

For stage I and II renal cell disease, a complete history, physical examination, chest radiographs, liver function tests, blood urea nitrogen (BUN) and creatinine levels, and calcium levels are recommended every 6 months for 2 years, then annually for 5 years. Abdominal computed tomography (CT) scanning is recommended once at 4-6 months and then as indicated.

For stage III renal cell carcinoma (RCC), physical examination, chest radiographs, liver function tests, BUN and creatinine levels, and calcium levels are recommended every 4 months for 2 years, every 6 months for 3 years, and then annually for 5 years. Abdominal CT scanning should be performed at 4-6 months, then annually or as indicated.

Spontaneous regression has been reported anecdotally in renal cell carcinoma. As many as 10% of patients with metastatic disease show no progression for more than 12 months. All systemic therapies are associated with treatment-related toxicity and low response; therefore, close observation is an option for asymptomatic metastatic disease. Once evidence of progression or symptoms appears, appropriate therapy should be initiated.

Careful surveillance of patients with end-stage renal disease by ultrasonography and CT scanning is recommended.