The Washington Manual of Oncology, 3 Ed.

Kidney Cancer

Daniel Morgensztern • Bruce Roth

 I. PRESENTATION

1. Subjective. Symptoms from renal cell carcinoma (RCC) can be caused by local tumor growth, paraneoplastic syndromes, or distant metastases. The classic triad of flank pain, gross hematuria, and palpable abdominal mass is present in less than 10% of patients and indicates locally advanced disease. Paraneoplastic syndromes occur in approximately 20% of patients at presentation and up to 40% during the course of their disease. Hypercalcemia, the most common paraneoplastic manifestation of RCC, occurs in approximately 15% of patients and may be due to bone metastases or production of parathyroid hormone-related protein (PTHrP). Nonmetastatic hepatic dysfunction, also known as Stauffer’s syndrome, is characterized by elevated alkaline phosphatase, elevated prothrombin time, and hypoalbuminemia, with some patients also having elevated bilirubin and liver transaminases. Most patients have associated fever, weight loss, neutropenia, and thrombocytopenia. Symptoms improve or resolve in the majority of patients undergoing nephrectomy. Although erythrocytosis occurs in up to 5% of patients owing to increased production of erythropoietin, anemia is a far more common manifestation, usually with parameters of anemia of chronic disease. Hypertension may occur in up to 40% of patients with RCC and is usually caused by either renin secretion by the tumor or secondary to compression of the renal artery and parenchyma. Constitutional symptoms including fever, weight loss, and fatigue occur in approximately one-third of the patients at presentation. The most common sites of metastases are the lungs, bone, and liver. More recent patient series have shown an increased percentage of asymptomatic patients with incidental diagnosis during radiological investigation of unrelated problems.
2. Objective. Hematuria and flank mass are the most common objective findings in RCC. Scrotal varicoceles are usually left-sided or bilateral owing to higher pressure in the left renal vein, and decompress in the supine position. The presence of unilateral right-sided varicoceles or the lack of reduction in the supine position is suspicious for inferior vena cava (IVC) thrombus, which may be caused by RCC.
3. EVALUATION OF A RENAL MASS. Patients with unexplained hematuria, flank pain, or mass suggesting RCC should be evaluated with a radiographic study, preferably computed tomography (CT) scan. Magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) may be used for further evaluation of the collecting system or IVC involvement. Because of the increased background activity of healthy renal tissue and fluorodeoxyglucose (FDG) excretion in the urine, positron emission tomography (PET) scan has limited value in the RCC diagnosis. With the presumptive diagnosis of RCC by the characteristic radiographic appearance, most patients without metastases undergo resection, which provides both diagnosis and treatment. In patients that are unfit for surgery, renal biopsy of small masses may be performed with minimal risk of tumor spreading, and such patients may be offered cryoablation.

 III. PATHOLOGY. RCC is not a single disease but rather a heterogeneous group of cancers originating in the renal tubular epithelium, with distinct morphology, biology, and response to therapy. Clear cell is the most common subtype, representing approximately 75% of the cases. These tumors arise in the proximal tubule and frequently have loss of 3p25, which is the locus of the von Hippel–Lindau (VHL) gene. These tumors have a vascular stroma with frequent development of hemorrhagic areas. Papillary carcinomas represent approximately 15% of RCCs, also arise in the proximal tubule, are more commonly bilateral and multifocal compared with other subtypes, and may be subdivided into type 1 and type 2, which may be associated with mutations in c-met or fumarate hydratase, respectively. Chromophobe tumors represent approximately 5% of the RCC cases, arise in the distal nephron, may be associated with a higher incidence of liver metastases compared with other histologies, and have an overall better prognosis compared with clear cell carcinomas. Collecting duct carcinomas account for approximately 1% of the cases and usually behave aggressively, with metastases at presentation. Renal medullary carcinomas are aggressive tumors associated almost exclusively with sickle cell trait. Renal oncocytomas are benign tumors (Semin Cancer Biol 2013;23:3).

 IV. WORKUP AND STAGING. The initial workup for patients with a suspicious renal mass incudes history and physical examination, complete blood count, metabolic panel, urinalysis, and chest imaging. MRI of the abdomen may be performed to rule out IVC involvement. If a central mass is present suggesting urothelial carcinoma, patients should have urine cytology performed. Since most metastases to the bones or brain are symptomatic at presentation, bone scan and brain MRI are performed only when clinically indicated.

 The current staging for RCC divides the T stage into T1 (tumor ≤7 cm limited to the kidney; T1a ≤4 cm, T1b >4 to 7 cm), T2 (tumor >7 cm limited to the kidney), T3 (tumor extending into major veins or perinephric tissues), and T4 (tumor invades beyond the Gerota’s fascia including the ipsilateral adrenal gland). N stage is divided into N0 (no regional lymph node metastases) and N1 (metastasis in regional lymph nodes), whereas M stage is divided into M0 or M1 on the basis of the absence or presence of distant metastases. Stages I and II are defined by the presence of T1 and T2, respectively, without lymph node or distant metastases. The presence of T3 or N1 defines stage III, whereas stage IV is defined by T4 or M1.

1. TREATMENT
2. Localized disease (stage I). The standard therapy for localized disease is surgical resection, with either a radical nephrectomy or nephron-sparing surgery. Radical nephrectomy involves the complete removal of the Gerota’s fascia and its contents including the kidney perirenal fat, regional lymph nodes, and ipsilateral adrenal gland. More recently, adrenalectomy has been indicated predominantly for patients with large upper pole lesions or abnormal gland by CT imaging, in an attempt to avoid the complications from adrenal insufficiency (J Urol 2009;181:2009). Regional lymphadenectomy provides prognostic information but does not have an established therapeutic role. The main complication from radical nephrectomy is the development of chronic kidney disease, which increases the risk of cardiovascular events and overall mortality. With the use of modern imaging techniques, there has been a stage migration, with most patients being currently diagnosed with stage T1a. Nephron-sparing surgery, or partial nephrectomy, is indicated for patients with T1a disease and selected cases of T1b. This approach, however, is not indicated for patients with stage II or III disease. Both radical and nephron-sparing nephrectomies can be performed through a laparoscopic approach, depending on the size of the primary tumor. Patients with stage T1a disease that are not candidates for even nephron-sparing surgery may be treated with ablative therapy, including either cryoablation or radio frequency ablation (RFA), which should be preceded by a biopsy to establish the histological diagnosis for future therapies, if needed. Patients with T1a disease and decreased life expectancy or high surgical risk may be offered surveillance based on the fact that for such small tumors, the probability of benign tumor is 20%, only 20% to 30% of the tumors within this size range are potentially aggressive variants, and the risk of development of metastasis is overall low (J Urol2009;182:1271).
3. Locally advanced disease (stages II, III, and T4). Patients with stage II and III RCC should be treated with radical nephrectomy. Following complete surgical resection, for patients with locally advanced RCC, the estimated risk for relapse at 5 years ranges from 11% in T2N0 to 66% in T4N1. Randomized clinical trials comparing immunotherapy, using either interferon alpha (IFN-α) or interleukin-2 (IL-2), failed to improve the disease-free survival (DFS) or overall survival (OS) compared with observation. A new generation of adjuvant trials using vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) inhibitors is currently accruing patients, with DFS as the primary end point (Oncologist 2014;19:1). At this time, however, there is no established role for adjuvant therapy in patients with resected RCC. Surveillance in these patients should include history, physical examination, metabolic panel, and imaging every 6 months for the first 2 years, and annually starting in the third year.
4. Metastatic disease. The standard approach for patients with metastatic disease is systemic therapy, although surgery may have a role in selected cases.
5. Resection of solitary metastases. Patients with oligometastatic disease may still be cured with surgery, particularly those with single site and metachronous presentation. In a retrospective series of 278 patients with recurrent RCC between 1980 and 1993, the 5-year OS for the 141 patients undergoing curative resection for their first metastasis was 44%. Furthermore, resections of subsequent second and third metastases after the initial curative intent resection had an OS of 45%, which was similar to those undergoing the initial resection (J Clin Oncol 1998;16:2261).
6. Cytoreductive nephrectomy. The removal of the primary cancer followed by INF-α has been associated with a significant improvement in the median OS compared with INF-α alone in two identical large randomized trials including a total of 331 patients (13.6 vs. 7.8 months, p = 0.002) (J Urol 2004;171:1071). Patients considered for cytoreductive nephrectomy should have resectable primary tumor, good performance status, and adequate organ function. Although the role for cytoreductive nephrectomy is established for patients treated with subsequent immunotherapy, its use in patients treated with VEGF-targeted therapy has not been prospective established. Optimal candidates for this approach would include patients with small volume metastatic disease, an easily resectable primary tumor, no significant comorbidities that would place them at an increased risk of surgery/general anesthesia, or whose dominant symptoms are from the primary lesion, either bleeding or pain.
7. Systemic therapy. The main options for systemic therapy in patients with metastatic RCC are immunotherapy and targeted therapy with VEGF and mTOR inhibitors.

 Immunotherapy with cytokines has been used for several years with IL-2 and IFN-α as the main drugs. High-dose IL-2 is usually administered as 600,000 to 720,000 IU/kg intravenously over 15 minutes every 8 hours for up to 14 doses over 5 days as tolerated, with a second cycle starting after 5 to 9 days of rest, with responding patients restarting the therapy in 6 to 12 weeks. In a retrospective evaluation of 255 patients treated in seven phase II trials, the overall response rate (RR) was 14%, with 12 (5%) patients achieving complete response (CR). Toxicities were mostly related to capillary leak syndrome, including hypotension in 96% of patients and arrhythmias (J Clin Oncol l995;13:688). In an updated analysis of 259 patients treated with high-dose IL-2 at the National Cancer Institute between 1986 and 2006, 23 patients (9%) achieved CR and 30 patients (12%) achieved partial response (PR). Although all patients with PR eventually developed disease recurrence with a median of 15 months, only 4 of the 23 CR patients developed recurrence by the time of the last follow-up, with the median OS not reached (Cancer 2008;113:293). Administration of high-dose IL-2 should be restricted to a small subset of metastatic patients, including those with nonvisceral metastatic disease, good performance status, optimal end-organ function, and those with dominant clear cell histology. It should be administered by oncologists and staff with extensive experience in the management of side effects of this therapy in high-volume centers. Treatment with IFN-α is associated with fewer response rates and rare durable benefit. Therefore, IFN-α is not currently indicated as single-agent therapy for patients with metastatic RCC. In a retrospective evaluation of 463 patients from six clinical trials treated with first-line IFN-α, five factors were used to create a risk model, known as the Memorial Sloan Kettering Cancer Center (MSKCC) model: Karnofsky performance status (KPS) <80%, Lactate dehydrogenase (LDH)>1.5 times the upper limit of normal (ULN), serum hemoglobin lower than the lower limit of normal (LLN), serum calcium >10 mg/dl, and time from initial diagnosis to treatment of less than 1 year. The median and 3-year OS for patients with good risk (0 factors), intermediate risk (1–2 factors), and high risk (3–5 factors) were 30 months and 45%, 14 months and 17%, and 5 months and 2%, respectively. The median PFS for low-, intermediate-, and high-risk groups was 8.3, 5.1, and 2.5 months, respectively (J Clin Oncol2001;20:289).

 More recent studies have shown promising activity from targeting the programmed death 1 (PD1) and its ligand (PDL1) in patients with RCC. In a phase I study, 9 out of 33 patients (27%) responded to treatment with the anti-PD1 monoclonal antibody nivolumab (BMS936558). Among the 8 responding patients with at least 1 year of follow-up, 5 had continued response lasting more than 1 year. Furthermore, 9 patients (27%) had stable disease (SD) lasting 24 weeks or more (N Engl J Med 2012;366:2443).

4. Targeted therapy. Several drugs have been approved for the treatment of metastatic RCC including the VEGF monoclonal antibody bevacizumab, multitarget tyrosine kinase inhibitors, and mTOR inhibitors.

 Bevacizumab is a monoclonal antibody that binds circulating VEGF, preventing its interaction with the VEGF receptor. Two large randomized clinical trials initially showed a significant benefit from the combination of bevacizumab and IFN-α compared with IFN-α alone. Nevertheless, the updated results from the CALGB 90206 trial showed no significant benefit from the combination arm (18.3 months vs. 17.4 months) (J Clin Oncol 2010;28:2137). The approved VEGF tyrosine kinase inhibitors include sunitinib, sorafenib, pazopanib, and axitinib. The two mTOR inhibitors approved for the treatment of metastatic RCC are the intravenous temsirolimus and the oral everolimus.

 In a retrospective analysis of 645 patients with metastatic RCC treated with sunitinib, sorafenib, or the combination of bevacizumab plus IFN-α between 2004 and 2008, six prognostic factors were used to group patients into three risk categories. The prognostic factors were hemoglobin less than LLN, serum-corrected calcium higher than ULN, KPS <80%, time from diagnosis to initiation of therapy less than 1 year, absolute neutrophil count higher than ULN, and platelets higher than ULN. The median and 2-year OS for patients within the favorable (0 factors), intermediate (1–2 factors), or poor (3–6 factors) categories were not reached and were 75%, 27 months and 53%, and 8.8 months and 7%, respectively (J Clin Oncol 2009;27:5794). Another prognostic score was used in an ARCC trial, which randomized patients to temsirolimus, IFN-α or both. The inclusion criteria specified that patients were previously untreated and had three or more unfavorable risk factors (KPS 60–70, hemoglobin 10 mg/dl, LDD >1.5 times ULN, less than 1 year from diagnosis, and metastases to more than one organ site). The study showed improved median OS for temsirolimus alone compared with IFN-α and increased toxicity without survival benefit from the combination (N Engl J Med2007;356:2271).

5. Treatment of nonclear RCC. Both immunotherapy and VEGF-targeted therapies may be less effective in patients with non-clear cell RCC and those with any histology associated with sarcomatoid variant, with the latter being an aggressive form with poor prognosis. There is far less data on the use of these agents with nonclear cell histology, since such patients were generally excluded from the randomized trials cited above that resulted in the approval of these agents. Although chemotherapy has a limited role in patients with metastatic RCC, gemcitabine, doxorubicin, and capecitabine may have a limited role in those with sarcomatoid variant. A meta-analysis of 7,771 patients with RCC enrolled into 49 studies included 1,244 patients (16%) with non-clear histology, having a significantly lower RR, median PFS, and OS compared with the clear cell histology (Eur Urol 2014, in press).

 The initial therapy for patients with metastatic RCC depends on the histology and risk category. Temsirolimus is indicated mainly for poor-prognosis patients according to the ARCC trial, and high-dose IL-2 may be used in selected patients. Subsequent therapy after first-line therapy includes everolimus and axitinib. Following cytokine therapy, the main options for clear cell RCC include sunitinib, sorafenib, axitinib, and pazopanib. For patients with nonclear RCC, there are no clear recommendations, with essentially all approved drugs being acceptable.

 VI. BACKGROUND

1. Epidemiology. Approximately 65,000 cases of RCC occur in the United States each year, resulting in 14,000 deaths (Ca Cancer J Clin 2014;64:9). The median age at diagnosis is 64 years, and the male-to-female ratio is approximately 1.5 to 1. The incidence of RCC is higher in Europe and North America compared with Asia and South America.
2. Risk factors. There are several established and suspected risk factors for the development of RCC (Hematol Oncol Clin North Am 2011;25:651). Cigarette smoking is an established risk factor for the development of RCC, with a strong dose dependence and decreased risk after smoking cessation. Obesity increases the risk for RCC in both men and women, with the increase in obesity rates providing a possible explanation for the steady increase in the incidence of RCC. Hypertension is another established risk factor for RCC, independent from obesity. There are several familial syndromes associated with increased risk for developing RCC, including VHL (associated with clear cell carcinoma), hereditary papillary cell carcinoma (associated with papillary type I RCC), hereditary leiomyomatosis RCC (caused by abnormalities in the fumarate hydratase and associated with papillary type II RCC, cutaneous and uterine leiomyomas), Birt–Hoggs–Dubé syndrome (associated most commonly with chromophobe tumors or oncocytomas, fibrofolliculomas, and pulmonary cysts), and tuberous sclerosis complex (associated with bilateral renal angiomyolipomas and less frequently clear cell carcinomas).

SUGGESTED READINGS

Cho E, Adami H-O, Lindblad P. Epidemiology of renal cell carcinoma. Hematol Oncol Clin North Am 2011;25:651–665.

Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004;171:1071–1076.

Heng DY, Xie W, Regan NM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor targeted agents: results from a large multicenter study. J Clin Oncol 2009;27:5794–5799.

Moch H. An overview of renal cell cancer: pathology and genetics. Semin Cancer Biol 2013;23:3–9.

Topalian SL, Hodi FS, Brahmer JR. Safety, activity and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443–2454.

Vera-Badillo FE, Templeton AJ, Duran I, et al. Systemic therapy for non-clear cell carcinomas: a systematic review and meta-analysis. Eur Urol 2014 (in press).