Christopher G. Wood Eric Jonasch Michael B. Atkins
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Renal Cell Carcinoma 1350 |
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Epidemiology 1350 |
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Pathology and Cytogenetics 1351 |
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Molecular Biology and Hereditary Disorders 1352 |
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Clinical and Laboratory Features 1353 |
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Radiologic Diagnosis 1355 |
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Staging and Prognosis 1357 |
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Surgical Management 1358 |
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Radiation Therapy 1361 |
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Systemic Therapy 1361 |
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Renal Pelvic Tumors 1367 |
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Presenting Features and Diagnostic Evaluation 1368 |
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Staging and Grading of Renal Pelvic Tumors 1368 |
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Other Kidney Tumors 1368 |
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Renal Sarcomas 1368 |
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Wilms Tumor 1368 |
Malignant neoplasms involving the renal parenchyma and renal pelvis may be primary or secondary in origin. Although meta-static lesions statistically outnumber primary lesions, the former are usually asymptomatic and are either discovered only at post-mortem examination or are of little clinical consequence.
Renal cell carcinomas (RCCs) arise within the renal cortex and account for about 80% to 85% of all primary renal neoplasms. Transitional carcinomas arising from the renal pelvis are the next most common, accounting for 7% to 8% of primary renal neoplasms. Other parenchymal epithelial tumors, such as oncocytomas, collecting duct tumors, and renal sarcomas, are uncommon but are becoming more frequently recognized pathologically. Nephroblastoma (Wilms tumor) is common in children and accounts for 5% to 6% of all primary renal tumors. This chapter focuses on the epidemiology, pathology, genetics, clinical and radiographic presentation, staging methods, and surgical and systemic management of renal cell carcinoma. A brief description of the biology and management of the less common tumors is also presented.
RENAL CELL CARCINOMA
Epidemiology
In 2006, it was estimated that renal cell and renal pelvic cancer would develop in 39,000 people in the United States and that almost 13,000 people would die of the disease. [1] [2] Renal cell carcinoma represents 2% of all cancers and 2% of all cancer deaths. Worldwide, the mortality from renal cell carcinoma was estimated to exceed 100,000 per year.[3]
The incidence varies widely from country to country, with the highest rates in Northern Europe and North America.[4] Although the incidence is reported to be lower in individuals living in African countries[4] the incidence is equivalent among whites and blacks living in the United States.[5] Historically, renal cell carcinoma was twice as common in men as in women, but more recent data suggest this gap is beginning to narrow. Renal cell carcinoma occurs predominantly in the sixth to eighth decade and is uncommon in patients younger than 40 years of age and rare in children. [6] [7] [8] A 40-year-old man's lifetime risk of renal cell carcinoma is 1.27%, and the risk of death is 0.51%.[9]
The incidence of renal cell carcinoma steadily increased over time. Between 1975 and 1995 in the United States the incidence rates per 100,000 person-years increased by 2.3, 3.1, 3.9, and 4.3% annually for white men, white women, black men, and black women, respectively.[5] The incidence has risen at a rate that is threefold higher than the mortality rate. Since 1950, there has been a 126% increase in the incidence accompanied by a 37% increase in annual mortality. [2] [10] The 5-year survival rate of patients diagnosed with kidney cancer has improved from 34% for those diagnosed in 1954 to 62% for those diagnosed in 1996.[10] This improved case-fatality rate is probably a consequence of the increasingly common use of abdominal imaging leading to the diagnosis of disease at earlier stages that are more amenable to surgical cure. Incidental discovery of RCC increased from approximately 10% in the 1970s to 60% in 1998.[10] In addition, at one major institution, the percentage of organ-confined tumors increased from 47% in 1989 to 78% in 1998.[11]
Numerous environmental and clinical factors have been implicated in the etiology of renal cell carcinoma.[12] These include tobacco use, occupational exposure to toxic compounds such as cadmium, asbestos, and petroleum byproducts, obesity, acquired polycystic disease of the kidney (typically associated with dialysis), and analgesic abuse nephropathy. Cigarette smoking doubles the likelihood of renal cell carcinoma and contributes to as many as one third of all cases. [13] [14] [15] The relative risk associated with occupational exposure to cadmium, asbestos, and gasoline are 2.0, 1.4, and 1.6, respectively.[12] Cadmium workers who smoke have been reported to have a particularly high incidence of renal cell cancer. [14] [16] Exposure to such carcinogens may be associated with mutations in genes associated with the pathogenesis of renal cell carcinoma, such as the von Hippel-Lindau (VHL) tumor suppressor gene. For example, renal cancers developing in individuals with exposure to trichloroethylene, a petroleum byproduct used in the dry cleaning industry, exhibited a high incidence of a specific point mutation in the VHL gene not seen in renal cancers in patients without this exposure.[17] Obesity appears to be a risk factor both in men and women, where there appears to be a linear relationship between increasing body weight and the risk of renal cancer. [14] [18] The risk of developing renal cancer in patients with acquired polycystic disease of the kidney has been estimated to be 30 times greater than in the general population.[19] In particular, it is estimated that acquired cystic disease develops in 20% to 90% of patients receiving long-term dialysis, depending on the duration of dialysis,[20] and that renal cell carcinoma develops in between 3.8% and 4.2% of these patients.[21] Men and patients with large cysts appear to be at increased risk for malignant transformation. The carcinomas are multiple and bilateral in approximately one half the cases, a finding that is consistent with the diffuse nature of the underlying disease.[22] Although many of these cancers are clinically insignificant, some can have an aggressive course; consequently, careful surveillance of patients with end-stage renal disease, particularly those receiving long-term dialysis, with ultrasonography and computed tomography (CT) has been recommended. The prolonged ingestion of analgesic combinations, particularly compounds containing phenacetin and aspirin can lead to chronic renal failure. Such patients are at increased risk of renal pelvic tumors and possibly renal cancer, although the latter association remains controversial. [23] [24] [25] Additional clinical factors that have been variably associated with the development of renal cancer include hypertension,[18] unopposed estrogen therapy,[26] and prior radiation therapy.[27] Finally, the use of cytotoxic chemotherapy in childhood for malignancies, autoimmune disorders, or bone marrow transplant conditioning, has been associated with the subsequent development of a rare type of renal cancer called translocation renal cell cancer.[28]
An enhanced risk of renal cell carcinoma has been observed in patients with certain inherited disorders, thereby implicating various genetic abnormalities in its etiology. These disorders include von Hippel-Lindau disease, hereditary papillary renal cancer, the hereditary leiomyoma renal cancer syndrome, and the Birt-Hogg-Dube syndrome. In addition, patients with tuberous sclerosis and hereditary polycystic disease, although not having a dramatically increased incidence of renal cancer can have cancers with unique features.
The renal cancers that occur in patients with hereditary polycystic kidney disease are more often bilateral at presentation (12% versus 1% to 4% in the general population), multicentric (28% versus 6%), and sarcomatoid in type (33% versus 1% to 5%).[29]
Although most renal cell carcinomas are sporadic, factors suggesting a hereditary cause include first-degree relatives with the disease, [30] [31] [32] [33] onset before the age of 40, and bilateral or multifocal disease.[34] Several kindreds with familial clear cell carcinoma have been identified that have consistent abnormalities on the short arm of chromosome 3. [35] [36] [37] [38] Other kindred with papillary tumors have been identified with different genetic abnormalities,[39] suggesting that these tumors represent distinct disease entities. A more detailed discussion of the molecular biology of renal cell carcinoma is provided in a later section.
Pathology and Cytogenetics
Renal cell carcinoma was first reported by Konig in 1826. In 1883, Grawitz hypothesized on histologic grounds that renal cell carcinomas arose from rests of adrenal tissue within the kidney.[40] Although immunohistologic and ultrastructural analyses currently point toward the proximal renal tubule as the true cell of origin,[41] the term “hypernephroma” continues to be incorrectly applied to these cancers.
Renal cell tumors occur with equal frequency in the right and left kidney and are distributed equally throughout the kidney.[42] The average diameter is about 7 cm, but tumors have ranged from less than 2 cm to greater than 25 cm in diameter. Previously, renal lesions less than 2 to 3 cm in size were considered to be benign adenomas. Such distinctions between benign and malignant tumors are no longer made on the basis of size but rather on basic histologic criteria. Even small tumors have been determined to frequently represent renal carcinomas. Therefore, from a practical standpoint, all solid renal masses require biopsy or resection for accurate histologic diagnosis.
Renal cell carcinomas have historically been classified according to cell type (clear, granular, spindle, or oncocytic) and growth pattern (acinar, papillary, or sarcomatoid).[42] This classification has undergone a transformation to more accurately reflect the morphologic, histochemical, and molecular basis of differing types of adenocarcinomas ( Table 38-1 ). [43] [44] [45] Based on these studies, five distinct subtypes have been identified. These include clear cell (conventional), chromophilic (papillary), chromophobic, oncocytic, and collecting duct (Bellini duct) tumors. Each of these tumors has a unique growth pattern, cell of origin, and cytogenetic characteristics. Table 38-1summarizes this information and more accurately reflects the increased knowledge of the molecular and genetic abnormalities of these lesions.
TABLE 38-1 -- Pathologic Classification of Renal Cell Carcinoma
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Carcinoma Type |
Growth Pattern |
Cell of Origin |
Cytogenetic Characteristics |
Incidence (%) |
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Major |
Minor |
||||
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Clear cell |
Acinar or sarcomatoid |
Proximal tubule |
- 3p |
+5, +7, +12, -6q, -8p -9, -14q, - Y |
75–85 |
|
Chromophilic[*] |
Papillary or sarcomatoid |
Proximal tubule |
+7, +17, -Y |
+12, +16, +20, - 14 |
12–14 |
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Chromophobic |
Solid, tubular, or sarcomatoid |
Intercalated cell of cortical collecting duct |
Hypodiploidy |
— |
4–6 |
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Oncocytic |
Typified by tumor nests |
Intercalated cell of cortical collecting duct |
Undetermined[†] |
— |
2–4 |
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Collecting duct |
Papillary or sarcomatoid |
Medullary collecting duct |
Undetermined[†] |
— |
1 |
|
* |
These tumors were previously classified as papillary tumors. |
|
† |
This classification is based on the work of Storkel and van den Berg.[44] |
Clear cell or conventional renal cell carcinomas make up 75% to 85% of tumors and are characterized by a deletion or functional inactivation in one or both copies of chromosome 3p.[46] A higher nuclear grade (Fuhrman classification) or the presence of a sarcomatoid pattern correlates with a poorer prognosis. [47] [48]
Chromophilic or papillary carcinomas make up 10% to 15% of renal cancers. In the hereditary setting papillary carcinomas are multifocal and bilateral, and commonly present as small tumors.[49] These tumors also appear to arise from the proximal tubule but are both morphologically and genetically distinct from clear cell carcinomas. These tumors have been reported to have multiple genetic abnormalities, including monosomy Y, trisomy 7, and trisomy 17,[50] but no abnormalities in 3p.[51] Although these tumors often have a low stage at presentation and are thus attributed a more favorable prognosis, [49] [52] in advanced stages, they can be as aggressive as clear cell lesions.[53]
Chromophobe carcinomas make up about 4% of all renal cell carcinomas. Histologically, they are composed of sheets of cells that are uniformly darker cells than those of the usual clear cell carcinoma, with a peripheral eosinophilic granularity. These cells lack the abundant lipid and glycogen, characteristic of the usual renal cell carcinoma, and are believed to arise from the intercalated cells of the renal collecting ducts. [54] [55] [56] They have a hypodiploid number of chromosomes, but also no 3p loss. [57] [58] [59] These tumors are usually well circumscribed, and patients with these tumors generally have an excellent prognosis. Once metastatic, chromophobe carcinomas are highly refractory to therapy and have a prognosis equivalent to that seen in clear cell carcinomas.[53]
Collecting duct (Bellini duct) tumors are also rare and are frequently very aggressive in behavior.[60] These tumors are located in the renal medulla and pelvis and thus usually present with gross hematuria. In contrast to clear cell carcinomas, these tumors produce mucin and react with antibodies to both high and low-molecular weight keratins.[61] Sarcomatoid variants have also been noted. Neither oncocytomas nor collecting duct tumors have been associated with a consistent pattern of genetic abnormalities.
Medullary renal cell carcinoma is a rare aggressive variant usually seen in individuals with sickle cell trait.[62] This entity was designated by Davis and co-workers as the “seventh sickle cell nephropathy”.[62] Histologically, a variety of growth patterns have been described, including reticular, solid, tubular, trabecular, cribriform, sarcomatoid, and micropapillary.[63] Other findings may include stromal desmoplasia and a mixed inflammatory infiltrate.[64]Little is known about the cytogenetics of this tumor. One investigation reported monosomy of chromosome 11,[65] and another reported the presence of a bcr/abl translocation.[66] Another report showed upregulation of the abl gene in three of three cases but did not find a bcr/abl translocation.[67]
The Xp11.2 translocation carcinoma was first described in 1991 by Tomlinson and colleagues.[68] This translocation results in the fusion of a novel gene, designated RCC17, at chromosome 17q25, to the transcription factor TFE3 located on the Xp11 chromosomal region.[69] These tumors usually occur in children and young adults. Tumor cells are described as having voluminous clear cytoplasm and bulging distinct cell borders, reminiscent of soap bubbles. The architecture is predominantly solid, tubular, acinar, or alveolar, with areas with a pseudo-papillary appearance.[70] Although relatively indolent, they are refractory to systemic therapy.
Renal oncocytomas are infrequent, but increasingly recognized, tumors. [71] [72] [73] Oncocytomas are composed of a pure population of oncocytes, large, well-differentiated neoplastic cells with intensely eosinophilic granular cytoplasm. The cytoplasm of these cells is packed with mitochondria, leading to their histologic appearance. Immunohistochemical studies suggest that oncocytomas probably also arise from the intercalated cells of the distal collecting tubules.[72] The pathologic differentiation of a typical renal oncocytoma from an oncocytic renal cell carcinoma can be difficult. Some series suggest that 3% to 7% of solid renocortical tumors, previously classified as renal cell carcinomas, are in fact oncocytomas.[71] Grossly, oncocytomas are generally well encapsulated and are only rarely invasive. Larger oncocytomas frequently have a stellate, central fibrous scar, which is often visible on preoperative radiologic studies. Renal oncocytomas almost invariably have a benign clinical behavior and are rarely associated with metastases, even when the primary tumor is very large. Although nephrectomy is usually the treatment of choice for large renal masses, the possibility of oncocytoma should be considered with incidentally discovered small renal masses or tumors in a solitary kidney, and thought should be given to performing a nephron-sparing partial, rather than a radical, nephrectomy.
Molecular Biology and Hereditary Disorders
Much of the recent success in developing therapies for RCC has arisen out of an improved understanding of the molecular biology of clear cell RCC and its highly prevalent VHL mutation. Cloning of the VHL gene in 1993[74] and the subsequent functional and structural characterization of the gene product[75] have contributed greatly to our understanding of the genetics of this disease and of renal cell carcinoma in general. Although antiangiogenic therapy (discussed later) is not curative, and the molecular biology of RCC is more complicated than a single gene mutation, it is encouraging that drug development based on molecular insight has resulted in significant improvements in therapy for this difficult to treat disease.
Von Hippel-Lindau disease is transmitted in an autosomal dominant fashion and is characterized by a predisposition to various neoplasms, including renal cell carcinoma (with clear cell histology) and renal cysts, retinal angiomas, spinocerebellar hemangioblastomas, pheochromocytomas, and pancreatic carcinomas and cysts.[76] Renal cysts are frequently multiple and bilateral.
Renal cell carcinoma develops in about one third of all patients with VHL and is a major cause of death. Tumor development in this setting is linked to somatic inactivation of the remaining wild-type allele. Moreover, biallelic VHL inactivation due to somatic mutations or hypermethylation (or both) is observed in >50% of sporadic clear cell carcinoma. Restoration of VHL function in VHL (-/-) renal cell carcinoma cell lines suppresses their ability to form tumors in nude mice xenograft assays, in keeping with the notion that VHL is a renal cancer tumor suppressor gene.[77]
Von Hippel-Lindau-associated tumors are typically hypervascular and occasionally lead to the overproduction of red blood cells (polycythemia).[78] This is due to overproduction of vascular endothelial growth factor (VEGF) and erythropoietin, respectively. Based on the knowledge that these two genes are hypoxia-inducible, several groups went on to show that cells lacking pVHL are unable to suppress the accumulation of hypoxia-inducible genes, including VEGF, under well-oxygenated conditions. [79] [80] [81] In short, whereas normal cells produce hypoxia-inducible mRNAs only under hypoxic conditions, cells lacking pVHL produce these mRNAs constitutively.
The HIF family of transcription factors is at the center of maintaining oxygen homeostasis and regulates a variety of hypoxia-inducible genes. HIF is a heterodimer composed of HIFa and HIFb subunits.[82] Whereas the HIFb subunit is constitutively expressed, HIFa is normally degraded in the presence of oxygen and only accumulates under hypoxic conditions. [83] [84] A 200 amino acid oxygen-dependent degradation domain described by Huang and co-workers lies within the central region of HIF1a. [85] [86] This region is sufficient to target HIF for degradation by the ubiquitin-proteasome pathway in the presence of oxygen. [86] [87] pVHL recognizes an approximately 20 amino acid residue peptidic determinant, corresponding to HIF1a residues 556-575, within the oxygen-dependent degradation domain. The interaction of pVHL with this peptide is governed by an oxygen-dependent post-translational modification involving hydroxylation of HIF1a proline residue 564 or HIF2a proline residue 531. [83] [85] [86] [87] Thus, in the presence of oxygen this residue becomes hydroxylated and HIF is recognized and polyubiquitinated by pVHL. In the absence of oxygen the modification does not take place and pVHL does not bind to HIF. At present, several dozen HIF target genes have been identified including vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and erythropoietin. Their protein products play critical roles in cellular and systemic physiologic responses to hypoxia including glycolysis, erythropoiesis, angiogenesis, and vascular remodeling.[82]Another HIF target, TGFa, has been shown to be a powerful renal epithelial cell mitogen and probably contributes to the development of renal cell carcinoma. [88] [89] [90] Overproduction of both TGFa and its receptor, EGFR, are common in renal cell carcinoma.
Papillary renal cell carcinoma (PRC) possesses unique genetic features. In hereditary cases, PRC is characterized by the formation of multiple bilateral tumors with trisomy of chromosomes 7 and 17.[91] The hereditary PRC gene was identified on chromosome 7q31.1-34 and germ line missense mutations in the tyrosine kinase domain of the c-Met proto-oncogene were detected in several hereditary PRC families.[92] PRC mutations of the c-Met proto-oncogene have been detected in 13% of PRC patients with no family history of kidney cancers.[93] These mutations are oncogenic and create a constitutively active, ligand-independent autophosphorylation of c-Met. These data may underestimate the significance of alterations in c-Met because other mutations, chromosomal duplications (e.g., trisomy 7), and epigenetic events likely increase the frequency of c-Met activation.
The ligand for c-Met is hepatocyte growth factor (HGF) also referred to as scatter factor (SF).[94] HGF-Met signaling has been shown to trigger a variety of cellular responses that vary based on the cellular context. In vivo HGF/c-Met signaling likely plays a role in growth, invasion, tumor metastasis, angiogenesis, wound healing, and tissue regeneration. [95] [96] A key biological function has been cell scattering. The process of cell scattering can be divided into three phases, namely cell spreading, cell-cell dissociation, and cell migration.[97] HGF-c-Met axis also entails increased cell motility, and invasion and metastasis. c-Met stimulation promotes cell movement, causes epithelial cells to disperse (“scatter”) and endothelial cells to migrate, and promote chemotaxis.
The disorder that results from autosomal dominant mutations in the fumarate hydratase (FH) gene is known as multiple cutaneous and uterine leiomyomas (MCUL or MCL: OMIM 150800). Overlapping with this syndrome is another autosomal dominant condition, hereditary leiomyomatosis, and renal cell cancer syndrome (HLRCC; OMIM 605839). This syndrome also results from mutations in the FH gene. Autosomal recessive FH gene mutations also underlie the disorder, fumarate deficiency (OMIM 136850, 605839). This condition is associated with progressive encephalopathy, cerebral atrophy, seizures, hypotonia, and renal developmental delay. Carriers of FH deficiency occasionally (but only rarely) exhibit leiomyomas.[98] HLRCC is characterized by cutaneous leiomyomas, uterine fibroids, and renal carcinomas, which are predominantly single, although multiple and bilateral tumors have been reported. [99] [100] The renal tumors are aggressive, and they may metastasize and lead to death in patients in their thirties. Although originally classified as hereditary papillary RCC type 2, the unique cytomorphologic features of the renal tumors, as well as the finding of mutations in the fumarate hydratase (FH) gene in affected families suggest that it is a distinct entity. [101] [102] The FH gene product is an essential component of the Krebs cycle and the FH enzyme catalyzes the conversion of fumarate to malate in the mitochondrial matrix. It also exists in a cytosolic form thought to be involved in amino acid metabolism.[98] It is not known why this mutation results in the development of renal cell carcinoma, and no clear genotype-phenotype correlation has been found between the various FH gene mutations and the likelihood of developing renal cell carcinoma.
The Birt-Hogg-Dube (BHD) syndrome is characterized by prominent cutaneous manifestations, the development of spontaneous pneumothorax in association with lung cysts, and a predisposition to kidney neoplasms that may be chromophobe renal cancers, oncocytomas, or have features of both (termed mixed oncocytic). [103] [104] [105] The characteristic skin lesions, fibrofolliculomas (hamartomas of the hair follicle), consist of multiple painless dome-shaped papules, 2 mm to 3 mm in diameter, which develop on the skin of the head and neck after age 30. The affected gene, folliculin, was described in 2002.[106] The identification of loss-of-function mutations in the folliculin gene (localized to chromosome 17p) suggests that it functions as a tumor suppressor gene.[106] Its function is currently unknown. A high frequency of somatic mutations have been detected in renal tumors from patients with BHD germline mutations suggesting that malignancy results from the inactivation of both copies of the gene.[106a]
Tuberous sclerosis is an autosomal dominant condition associated with mutations in the tuberous sclerosis complex genes (TSC1 or TSC2). [108] [109] Affected individuals typically manifest facial angiofibromas, cognitive impairment, and develop renal angiomyolipomas.[109] Although the incidence or renal cancer is only slightly increased, such cancers have been associated with bi-allellic loss of the TSC2 gene implicating this pathway in the pathogenesis renal cancer.
The molecular biology of medullary carcinoma is poorly understood. The gene expression profiles of two medullary renal cell carcinomas were analyzed using microarrays containing 21,632 cyclic DNA (cDNA) clones and compared them with the gene expression profiles of 64 renal tumors. Based on global gene clustering with 3583 selected cDNAs, the authors found a distinct molecular signature of renal medullary carcinoma, which clustered closely with urothelial (transitional cell) carcinoma of the renal pelvis.[110] Further work is needed to determine if unique genetic lesions exist in this disease.
The development of renal cell carcinomas may also involve alterations in genes whose products control cell division. These include genes in the ras family and the p53 tumor suppressor gene. Although mutations in the p53 gene are infrequent in renal cell carcinomas, the p53 protein is overexpressed in about 50% of all renal cell carcinomas and may be associated with a more aggressive tumor. [112] [113] Such p53 mutations have been implicated in interleukin-6 (IL-6) overexpression in other tumors,[113] and such overexpression could contribute to many of the protean clinical manifestations, such as fever, anemia, and liver function test abnormalities, which are often seen with high-grade or advanced renal carcinomas (see later). The fact that IL-6 expression has also been implicated in reduced responsiveness to immunotherapy[114] gives this potential connection additional clinical relevance. Nonetheless, the exact significance of these various genetic abnormalities and their true relationship to the pathogenesis and clinical biology of renal cell carcinoma remain to be fully elucidated.
Clinical and Laboratory Features
The clinical presentation of renal cell carcinoma can be extremely variable. Many tumors are clinically occult for much of their course, thus delaying diagnosis. Indeed, 25% of individuals have distant metastases or locally advanced disease at the time of presentation.[45] By contrast, other patients harboring renal cell carcinoma experience a wide array of symptoms or have a variety of laboratory abnormalities, even in the absence of metastatic disease. This propensity of renal cell carcinoma to present itself as a panoply of diverse and often obscure signs and symptoms has led to its being labeled the “internist's tumor.” The increasing incidental discovery of renal cancer on abdominal imaging, mentioned previously, has led to the re-characterization of the disease as the “radiologists tumor.”
Table 38-2 lists the most common presenting symptoms of patients with renal cancer. In early reports of patients undergoing nephrectomy for renal cell carcinoma, [116] [117] the most common presenting symptom was hematuria (which occurred in up to 59% of patients), followed by abdominal mass, pain, and weight loss. In contemporary series these symptoms are less common at presentation and up to 60% of patients are asymptomatic.
TABLE 38-2 -- Presenting Symptoms and Signs in Patients with Renal Cell Carcinoma in Two Series
|
Symptom or Sign |
In 309 Patients[*] (%) |
In 110 Patients[†] (%) |
|
Hematuria |
59 |
37 |
|
Abdominal or flank mass |
45 |
21 |
|
Pain |
41 |
21 |
|
Weight loss |
28 |
30 |
|
Symptoms from metastases |
10 |
|
|
Classic triad |
9 |
|
|
Acute varicocele |
2 |
From Richie JP, Garnick MB: Primary renal and ureteral cancer. In Rieselbach RE, Garnick MB (eds): Cancer and the Kidney. Philadelphia, Lea & Febiger, 1982, p 662.
|
* |
Data from Skinner and colleagues.[115] |
|
† |
Data from Gibbons and colleagues.[116] |
The classic triad of flank pain, hematuria, and palpable abdominal renal mass occurs in at most 9% of patients and when present it strongly suggests advanced disease.[115] Hematuria, gross or microscopic, is usually observed only if the tumor has invaded the collecting system. Gibbons and associates[116] reported the absence of gross or microscopic hematuria in 63% of their patients with proven renal cell carcinoma. An abdominal or flank mass is more commonly palpated in thin adults and with tumors involving the lower pole of the kidney. The mass is generally firm, homogeneous, and nontender and moves with respirations. Occasionally, hemorrhage into the tumor may cause exquisite pain and tenderness on palpation. Substantial bleeding may lead to clot formation and “clot colic.” Scrotal varicocele was reported in up to 11% of patients.[117] Most varicoceles are left sided and typically fail to empty in the recumbent position. Varicoceles typically result from obstruction of the gonadal vein at its entry point into the left renal vein by tumor thrombus. Varicocele development in an adult should always raise the possibility of an associated neoplasm within the kidney. In addition, inferior vena cava involvement by tumor thrombus can produce a variety of clinical manifestations including ascites, hepatic dysfunction, possibly related to Budd-Chiari syndrome, and pulmonary emboli.
Often, symptoms or signs related to metastases prompt medical evaluation.[34] Most (75%) patients presenting with metastatic disease have lung involvement. Other common sites include lymph nodes, bone, and liver. Patients may present with pathologic fractures, cough, hemoptysis, dyspnea related to pleural effusions, or palpable nodal masses. Clear cell pathology in the metastatic lesion or the finding of a renal mass on staging CT scan (or both) usually leads to the proper diagnosis.
A number of patients with renal cell carcinoma experience systemic symptoms or paraneoplastic syndromes. [119] [120] [121] The various syndromes listed in approximate order of frequency are displayed in Table 38-3 .
TABLE 38-3 -- Paraneoplastic Syndromes Associated with Renal Cell Cancer
|
Syndrome |
Incidence (%) |
|
Anemia |
20–40 |
|
Cachexia, fatigue, weight loss |
33 |
|
Fever |
30 |
|
Hypertension |
24 |
|
Hypercalcemia |
10–15 |
|
Hepatic dysfunction (Stauffer syndrome) |
3–6 |
|
Amyloidosis |
3–5 |
|
Erythrocytosis |
3–4 |
|
Enteropathy |
3 |
|
Neuromyopathy |
3 |
From McDougal WS, Garnick MB: Clinical signs and symptoms of kidney cancer. In Vogelzang NJ, Scardino PT, Shipley WU, et al (eds): Comprehensive Textbook of Genitourinary Oncology. Baltimore, Williams & Wilkins, 1996.
Fever is one of the more common manifestations of renal cell carcinoma, occurring in up to 20% of patients.[121] It is usually intermittent and is often accompanied by night sweats, anorexia, weight loss, and fatigue. Secondary amyloidosis has been reported in as many as 3% to 5% of patients.[118] Anemia is also common in patients with renal cell carcinoma [118] [121] [123] and frequently precedes the diagnosis by several months. Although hematuria, hemolysis, or bone marrow replacement by tumor may be contributing factors, the anemia is often out of proportion to these factors. It can be either normocytic or microcytic and is frequently associated with both low serum iron titer and low iron-binding capacity that is typical of the anemia of chronic disease. Hepatic dysfunction in the absence of metastatic disease is noted and labeled “Stauffer's syndrome”.[123] This syndrome, manifested by abnormal liver function results (particularly elevated alkaline phosphatase, α2-globulin, and transaminases) and prolonged prothrombin time, has been reported to occur in up to 7% of patients with renal cell carcinoma.[123] Hepatic dysfunction frequently occurs in association with fever, weight loss, and fatigue. The syndrome likely results from the overproduction of cytokines, such as granulocyte-macrophage colony-stimulating factor or possibly IL-6, by the tumor. [125] [126] Even though the laboratory abnormalities and other symptoms often revert to normal after nephrectomy, this syndrome is felt to portend a poor prognosis, with few patients surviving 5 years without recurrence. A syndrome resembling polymyalgia rheumatica has also been reported to occur in association with renal cell carcinoma. In contrast to the idiopathic disease, the symptoms do not respond to corticosteroids, but are often corrected by nephrectomy.[126] Plasma fibrinogen is frequently elevated in patients with renal cell carcinoma and may correlate with tumor stage and disease activity.[127] Acquired dysfibrinogenemia has been associated with renal cell carcinoma and can be a sensitive plasma marker for the disease and for tumor progression.[128]
Hormones produced by renal cell carcinomas include parathyroid-like hormone, gonadotropins, placentolactogen, adrenocorticotropic hormone-like substance, renin, erythropoietin, glucagon, and insulin.[129] Several of these have been associated with specific paraneoplastic phenomena. Erythrocytosis, defined as a hematocrit value greater than 55 mL/dL, occurs in 1% to 5% of patients with renal cell carcinoma and appears to be due to constitutive erythropoietin production by renal cancer cells.[1] Because VHL gene products have been shown to be involved in the regulation of hypoxia-induced proteins,[130] it is likely that the erythrocytosis seen in many patients with VHL and some patients with renal cell carcinoma is directly related to the inactivation of this gene.
Hypercalcemia occurs in up to 15% of all patients with renal cell carcinoma. The presence of hypercalcemia has been defined as an independent negative prognostic factor in patients with metastatic renal cell carcinoma.[131]Although usually associated with lytic bone metastases, hypercalcemia can occur in the absence of osseous metastases. Ectopic production of parathyroid hormone related peptide by the primary tumor has been documented in these cases.[132] Concurrent production of IL-6 may enhance the action of parathyroid hormone related protein, accentuating the hypercalcemia.[133] In other patients, elevated prostaglandin levels have been implicated in the development of hypercalcemia, which may respond to indomethacin.[134] Long-acting bisphosphonates such as pamidronate or zoledronic acid are the treatment of choice in RCC patients with metastatic disease and hypercalcemia.[135] These agents may be especially beneficial in patients with lytic bone metastases, where such therapy might also reduce the incidence of pathologic fractures.[136]
Radiologic Diagnosis
Many reports have suggested that the incidence of renal tumors is increasing. In addition to a real increase in the number of patients that develop renal tumors, this is, in part, due to increased detection.[5] The widespread use of ultrasonography and CT for other indications has led to the increased detection of renal cell carcinoma as an incidental finding.[137] Incidental detection of renal carcinoma may make up as much as 40% of all diagnoses in well-served medical communities. As discussed in the subsequent section, the prognosis for patients whose tumors were diagnosed incidentally is more favorable than for those that present with symptoms because the former group consists of patients with smaller tumors that tend to be confined to the kidney.[138]
For patients with symptoms suggestive of renal cell carcinoma, numerous radiologic approaches are available for the evaluation of the kidney. With the advent of CT, magnetic resonance imaging, and sophisticated ultrasonography, many of the more invasive procedures of the past are largely of historical interest and rarely used in clinical practice. Although intravenous pyelography remains useful in the evaluation of hematuria, CT and ultrasonography are the mainstays of evaluation of a suspected renal mass. As seen on CT, the typical renal cell carcinoma is generally greater than 4 cm in diameter, has a heterogeneous density, and enhances with contrast ( Fig. 38-1 ). [140] [141]Ultrasonography, although less sensitive than CT in picking up renal masses,[141] is particularly useful in differentiating between a simple benign cyst and a more complex cyst or a solid tumor ( Fig. 38-2 ). The advent of real-time and gray-scale ultrasonography has improved the ability of sonar techniques to delineate homogeneous (sonolucent) from heterogeneous lesions with internal echoes.[142] Smith and Bennett[143] found that ultrasonography alone had a sensitivity of 97%, a specificity of 97%, and a false-negative rate of only 1% in differentiating a benign cyst from a potentially malignant tumor. As a consequence, renal cysts rarely require biopsy to rule out malignancy. Selective renal arteriography was a mainstay of diagnosis in the past. The typical renal cell carcinoma usually appears on a renal arteriogram as a well-vascularized lesion that exhibits tumor vessels, venous lakes within the tumor, puddling of contrast medium in vascular spaces, or necrotic areas of the tumor and shunting of contrast medium rapidly into the renal vein ( Fig. 38-3 ). Renal arteriography is rarely employed in current practice, having been supplanted by magnetic resonance angiography and computed tomography with three-dimensional reconstruction to delineate vascular anatomy and assist in surgical planning.[144] Magnetic resonance imaging with gadolinium is superior to CT for evaluating the inferior vena cava if tumor extension into this vessel is suspected.[145] Magnetic resonance imaging is also a useful adjunct to ultrasonography in the evaluation of renal masses if radiographic contrast CT scans cannot be administered because of allergy or inadequate renal function.
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FIGURE 38-1 A, CT scan reveals massive renal cell carcinoma arising from the right kidney (arrow) and pushing the kidney anteriorly. Note the distortion of the collecting system. B, CT scan of the same patient demonstrates tumor thrombus (arrow) in the center of the inferior vena cava. This section was taken at the upper pole of the left kidney and craniad to the right kidney. (From Richie JP, Garnick MB: Primary renal and ureteral cancer. In Rieselbach RE, Garnick MB [eds]: Cancer and the Kidney. Philadelphia, Lea &Febiger, 1982, p 662.) |
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FIGURE 38-2 Ultrasound scan reveals large, poorly marginated mass (large arrows) with internal echoes distorting the upper pole of the kidney (parasagittal posterior view). Note normal echoes (small arrows) from the collecting system in normal-appearing lower pole (curved arrow). (Reprinted with permission from D'Orsi CJ, Kaplan WD: The radiologic and radionuclide evaluation of the kidney. In Rieselbach RE, Garnick MB [eds]: Cancer and the Kidney. Philadelphia, Lea &Febiger, 1982, pp 56-102.) |
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FIGURE 38-3 Selective right renal arteriogram demonstrates typical tumor hypervascularity with puddling in a patient with renal cell carcinoma. |
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Although most solid renal masses are renal cell carcinomas, some benign lesions complicate the diagnosis. The most common of these rare tumors are angiomyolipomas (renal hamartomas). Unless very small, angiomyolipomas are readily distinguishable from renal cell carcinoma by the finding of a distinctive fat density on CT.[146] However, given that several reports have shown that macroscopic fat can be detected within renal cell carcinomas, it may no longer be possible to dismiss all fat-containing lesions as benign.[147] Fat poor angiomyolipomas have also been described that are very difficult to distinguish from renal cell carcinomas on preoperative imaging and thus frequently must be resected to rule out a malignant neoplasm.[148] As mentioned previously, renal oncocytomas have been described to present on CT as a central stellate scar within a homogeneous, well-circumscribed solid mass.[71] This finding, however, is nonspecific and does not exclude the diagnosis of renal cell carcinoma.
The role of radionucleotide bone scan in the initial diagnosis and preoperative staging of renal cell carcinoma is unclear. Although bone scan demonstrates high sensitivity in the detection of osteoblastic metastases, renal cell carcinoma usually produces osteolytic lesions that may be missed by bone scan. Atlas and colleagues[149] suggested that a combination of bone pain on presentation plus an elevated serum alkaline phosphatase level were comparable to bone scan in evaluating patients with renal cell carcinoma. Others have questioned the sensitivity and usefulness of alkaline phosphatase as a stand-alone test. [151] [152] Koga and co-workers[152] demonstrated bone scan to have a sensitivity of 94% and specificity of 86%, with low yield in patients with earlier stage primary tumors. They recommended omitting bone scan in patients with T1-T3a tumors and no bone pain. Others found that bone scan provided little additional information in patients, even in those with a high pretest probability of having metastatic disease. [154] [155]
A number of studies have been published evaluating the role of PET scans for the detection and management of renal cell carcinoma primary and metastatic lesions. [156] [157] [158] [159] [160] [161] [162] [163] For detection of primary lesions, Bachor and colleagues[160] reported the correct preoperative identification of 20 of 26 pathologically proven renal cell carcinoma primaries using PET; in addition three benign lesions were inappropriately PET positive. Goldberg and associates correctly identified 9 of 10 malignant primaries and 7 of 8 benign cysts prior to pathological confirmation.[162] Most recently, of 17 patients with known or suspected primary tumors, Ramdave and colleagues demonstrated pathologically confirmed true-positive findings in 15 cases, true negative findings in 1 case, and false negative findings in 1.[155] Taken together, these reports suggest a fairly high degree of sensitivity and specificity in providing accurate biological information on renal lesions, and can provide data complementary to that obtained with CT and MRI scans. Nevertheless, due to its expense, lack of general availability and limited, if any, advantages over CT, PET is unlikely to be used as a stand-alone study in the evaluation of a patient with a solid renal mass.
In the restaging and follow-up of renal cell carcinoma, PET scan provides information that is complementary to conventional imaging, and can alter management decisions. [156] [158] [159] Once again, PET scanning has not been prospectively validated as a stand-alone study, but it may provide valuable biological insights on lesions of uncertain significance.
Although morphological or functional imaging modalities such as CT, MRI or PET, have been used to evaluate renal masses, Doppler ultrasonography with contrast agent injection has been shown to provide both morphological and functional information regarding renal lesions. The size of tumors can be accurately measured and the percentage of contrast uptake, an approximation of tumor vascularity, can be evaluated with this technique. In the era of new ani-angiogenic treatment modalities, assessment of tumor neovascularization is of major importance. Lamuraglia and colleagues have shown that contrast Doppler US allowed detection of microvascularization and confirmation of absence of resi-dual microvessels in renal tumors after treatment with Sorafenib.[162a]
Staging and Prognosis
After the presumptive diagnosis of renal carcinoma has been made, attention must be turned to the delineation of the extent of involvement of regional and distant metastatic sites. Renal carcinomas can grow locally into very large masses and invade through surrounding fascia into adjacent organs. The most common sites of metastases are the regional lymphatics, lungs, bone, liver, brain, ipsilateral adrenal gland, and contralateral kidney. The frequency of metastases to these sites is listed in Table 38-4 . [106] [108] [165] [166] Metastases to unusual sites, such as the thyroid gland, pancreas, mucosal surfaces, skin, and soft tissue, are not uncommon in this disease. CT of the abdomen is the principal radiologic tool for defining the local/regional extent of a renal cell carcinoma. Although this technique has recognized difficulty in determining the nature of minimally enlarged regional lymph nodes and the cephalad extent of disease within the renal vein, its accuracy in staging renal cell carcinoma is close to 90%.[139] Staging evaluation should also include CT of the chest and a bone scan if appropriate; 2% of patients present with bilateral tumors, and 25% to 30% of patients have overt metastases at initial presentation. [108] [166] If metastatic disease is suspected on the basis of staging studies, pathologic confirmation is usually required before therapy is contemplated. It is often easier and is frequently more useful to perform a biopsy of a metastatic site rather than the primary tumor. CT or ultrasound-guided percutaneous needle biopsy of a suspected lung, liver, lymph node, adrenal, or sometimes even skeletal metastasis frequently yields diagnostic material. Mediastinoscopy, bronchoscopy, and thoracoscopy are also frequently useful techniques.
TABLE 38-4 -- Sites and Frequencies of Metastases in Renal Cell Carcinoma
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Site |
Incidence (%) |
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Lung |
50–60 |
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Lymph node |
30–40 |
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Liver |
30–40 |
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Bone |
30–40 |
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Adrenal |
20 |
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Opposite kidney |
10 |
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Brain |
5 |
From McDougal WS, Garnick MB: Clinical signs and symptoms of kidney cancer. In Vogelzang NJ, Scardino PT, Shipley WU, et al (eds): Comprehensive Textbook of Genitourinary Oncology. Baltimore, Williams & Wilkins, 1996.
The TNM staging system for renal cell carcinoma (displayed in Table 38-5 ) has largely supplanted the previously used system of Robson. The current staging system as modified in 2002 by the American Joint Committee on Cancer (AJCC) has advantages over the Robson system in that it more clearly separates the various components of locally invasive tumor and quantifies the extent of lymph node and vascular involvement, thereby more explicitly defining the anatomic extent of disease. This system was last modified in 2002 with the division of T1 tumors into T1a for tumors equal to or less than 4 cm in diameter and into T1b for tumors greater than 4 cm. It also included renal sinus invasion in the T3a classification and renal vein invasion in the T3b subset.[164a] Pathologic stage remains the most consistent single prognostic variable that influences survival. Survival based on stage is displayed in Table 38-6 .
TABLE 38-5 -- TNM Staging for Renal Cell Carcinoma
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Primary Tumor (T) |
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TX |
Primary tumor cannot be assessed |
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T0 |
No evidence of primary tumor |
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T1a |
Tumor 4 cm or less in greatest dimension, limited to the kidney |
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T1b |
Tumor more than 4 cm, but 7 cm or less in greatest dimension, limited to the kidney |
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T2 |
Tumor more than 7 cm in greatest dimension, limited to the kidney |
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T3 |
Tumor extends into major veins or invades adrenal gland or perinephric tissues, but not beyond Gerota's fascia |
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T3a |
Tumor invades adrenal gland or perinephric tissues, but not beyond Gerota's fascia |
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T3b |
Tumor grossly extends into renal vein(s) or vena cava below diaphragm |
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T3c |
Tumor grossly extends into vena cava above diaphragm |
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T4 |
Tumor invades beyond Gerota's fascia |
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Regional Lymph Nodes (N)[*] |
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NX |
Regional lymph nodes cannot be assessed |
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N0 |
No regional lymph node metastasis |
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N1 |
Metastasis in a single regional lymph node |
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N2 |
Metastasis in more than one regional lymph node |
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Distant Metastasis (M) |
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MX |
Distant metastasis cannot be assessed |
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M0 |
No distant metastasis |
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M1 |
Distant metastasis |
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* |
Laterality does not affect the N classification. |
TABLE 38-6 -- Correlation of Stage Grouping with Survival in Patients with Renal Cell Carcinoma
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Stage Grouping |
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5-Year Survival |
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I |
T1 |
N0 |
M0 |
90–95 |
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II |
T2 |
N0 |
M0 |
70–85 |
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III |
T3a |
N0 |
M0 |
50–65 |
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T3b |
N0 |
M0 |
50–65 |
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T3c |
N0 |
M0 |
45–50 |
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T1 |
N1 |
M0 |
25–30 |
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T2 |
N1 |
M0 |
25–30 |
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T3 |
N1 |
M0 |
15–20 |
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IV |
T4 |
Any N |
M0 |
10 |
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Any T |
N2 |
M0 |
10 |
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Any T |
Any N |
M1 |
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M, distant metastasis; N, nodes; T, tumor. |
Recent identification of novel clinico-pathologic prognosticators in RCC have resulted in gradual transition from the use of solely clinical factors, such as TNM staging system, to the introduction of systems that integrate multiple validated prognostic factors. Investigators at UCLA have developed the UCLA Integrated Staging System (UISS), a novel staging system based on TNM stage, Fuhrman grade, and Eastern Cooperative Oncology Group (ECOG) performance status (PS).[10] Patients are stratified into three risk groups according to the probability of tumor recurrence and survival, and risk group specific surveillance guidelines are offered. Based on a large sample of patients, investigators from the Mayo Clinic devised a risk system (SSIGN) in which patients with clear cell RCC were assigned a SSIGN score based on tumor stage, tumor size, nuclear grade, and the presence of necrosis.[165] Using a SSIGN score, cancer-specific survival at 1 to 10 years post-treatment can be estimated for an individual patient. Investigators from Memorial Sloan Kettering Cancer Center combined tumor stage, tumor size, histologic subtype, and symptoms at presentation, into a nomogram, predicting probability of freedom from recurrence at 5 years after treatment. This nomogram has recently been updated for clear cell variant of RCC and includes tumor stage, tumor size, nuclear grade, necrosis, vascular invasion, and symptoms at presentation as prognostic factors.[166] For clear cell carcinomas, clinical factors that influence survival include performance status and the presence of paraneoplastic signs or symptoms such as anemia, hypercalcemia, hepatopathy, fever, or weight loss. [170] [171] [172] Various microscopic features, such as Fuhrman nuclear grade, sarcomatoid histology, or granular cytoplasm, and biologic features, such as IL-6 or VEGF production, also may be useful in predicting survival. [32] [112] [113] [114] [171] UCLA investigators determined the following clinical features at time of presentation to be independent of stage and associated with poor survival: an ECOG performance status of 2 or more, weight loss of more than 10% within the past 6 months, erythrocyte sedimentation rate (ESR) > 50 mm/h, and hemoglobin < 10.[169a] In addition, Motzer and colleagues examined features predictive of survival in 670 patients with stage IV disease enrolled in clinical trials at Memorial Sloan-Kettering Cancer Center. Significant factors predictive of poor outcome in a multivariate analysis included: Karnofsky performance status < 80%, hemoglobin < 10 mg/dL, serum lactate dehydrogenase (LDH) > 1.5 times the upper limit of normal, corrected serum calcium > 10 mg/dL, and lack of prior nephrectomy. A risk model was created using these five factors to assign patients to one of three groups: those with zero risk factors (favorable risk), those with one to two risk factors (intermediate risk), and those with three or more risk factors (poor risk). Median survival for the group as a whole was 10 months, but ranged from 15 months for patients with favorable risk down to 4 months for patients with poor risk ( Fig. 38-4 ). Although survival was also superior in patients who were treated more recently and in those who had received interferon alpha and/or IL-2-based therapy, it was uncertain whether these two observations were causally related. In a subsequent analysis examining 463 patients who had received IFN-based therapy, similar prognostic factors were identified, and the median overall survival 13 months ranging from 30 months for patients with favorable risk down to 5 months for those in the poor-risk group.[169b]
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FIGURE 38-4 Survival rates in a series of 86 patients with metastatic renal cell carcinoma treated by various modalities are compared with the survival of patients treated with adjunctive nephrectomy. (From DeKernion JB, Ramming KP, Smith RB: Natural history of metastatic renal cell carcinoma: Computer analysis. J Urol 120:148, 1978.) |
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Surgical Management
Nephrectomy
The mainstay of treatment of primary renal cell carcinoma is surgical excision or nephrectomy. Nephrectomy represents the only proven curative modality. Radical nephrectomy, which involves the early ligation of the renal artery and renal vein and excision en bloc of the kidney with surrounding Gerota fascia and ipsilateral adrenal gland, became the procedure of choice in the 1960s. Robson reported a 5-year survival rate of 66% with this procedure, comparing favorably to the previously reported surgical survival rate of 48% for simple nephrectomy. Various surgical approaches are available for the effective performance of this procedure. [123] [124] [125] [175] The thoracoabdominal approach described by Chute and associates [123] [124] [125] offers the distinct advantage of palpation of the ipsilateral lung cavity and mediastinum and the opportunity to resect a solitary pulmonary metastasis. Alternative approaches include an extrapleural supracostal incision or an anterior transabdominal incision. Regardless of which approach is utilized, the principle of early ligation of the vascular pedicle is important to prevent dissemination of tumor at the time of surgery.
With better understanding of tumor biology and changing patterns of presentation, the value of radical nephrectomy is being reassessed. Involvement of the ipsilateral adrenal gland occurs only 4% of the time, and in most instances, it is associated with direct extension from a large upper pole lesion or the presence of nodal or distant metastases. [176] [177] [178] Therefore, adjunctive ipsilateral adrenalectomy rarely contributes significantly to the value of surgery. Furthermore, adjunctive adrenal resection may limit the options for effectively treating contralateral adrenal metastases should they arise. As a consequence, adrenalectomy is often reserved for patients with large upper pole lesions or those with solitary ipsilateral adrenal metastases identified on preoperative staging studies. Paul and colleagues[174] demonstrated that tumor size and M stage were the best preoperative predictors of adrenal involvement, and suggested that adrenalectomy not be performed if the primary tumor is less than 8 cm in size, and staging studies were negative.
The benefit of performing a regional lymph node dissection in conjunction with the radical nephrectomy is controversial. With improved preoperative CT staging, the incidence of unsuspected nodal metastases is low. Furthermore, in patients without clinically evident distant metastases, nodal involvement is found at surgery in only 10% to 20% of patients. [180] [181] [182] Furthermore, several investigators have concluded that there is no clinical benefit in terms of overall outcome in undertaking regional lymph node dissection in the absence of enlarged nodes detected before or during surgery.[178] Although the 5-year survival rate of patients with microscopic nodal involvement (N1M0 disease) can be as high as 50%, less than 25% of patients with N2 or N3 disease without distant metastases are disease free at 2 years.[179] In addition investigators from UCLA have shown that lymph node status is a strong predictor of the failure to achieve either an objective immuno-therapy response or an improvement in survival when immunotherapy is given as an adjunctive treatment after cytoreductive nephrectomy.[180] Having said that, several institutional series have suggested a therapeutic benefit for extended lymphadenectomy in patients with clinically evident lymphadenopathy in whom few other options exist for aggressive, potentially curative therapy.[181]
Nephron-Sparing Surgery
The generally accepted criteria for consideration of nephron-sparing or partial nephrectomy are listed in Table 38-7 . These include patients presenting with bilateral tumors, tumor in a solitary kidney, or compromised renal function.[187] [188] The rate of recurrence in the partially resected kidney ranges from 4% to 10% in older series [187] [188] [189] [190] [191] [192] [193] and reflects the fact that many patients treated in this manner had large or multifocal tumors. Overall survival was similar to that of patients with comparable-stage disease who underwent radical nephrectomy. [9] [194] [195]
TABLE 38-7 -- Indications for Nephron-Sparing Surgery
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Complications of nephron-sparing surgery include, in decreasing frequency of occurrence: urinary fistulae (7.4%), acute tubular necrosis (6.3%), the need for temporary or permanent dialysis (4.9%), and bleeding (1.9%).[191] Two small studies suggest that a 1 cm to 2 cm margin is not necessary to ensure local control in smaller tumors, and that even a 1 mm margin is sufficient. [197] [198] More extensive prospective data is needed to validate this concept, but it suggests that at least in sporadic renal cell carcinoma, no infiltrative component exists that requires wider excision. A retrospective cost analysis of partial versus radical nephrectomy in 120 cases performed between 1991 and 1997 did not demonstrate any significant difference.
Because of the favorable results seen in nephron-sparing surgery, and the increasing number of smaller incidentally discovered tumors, nephron-sparing surgery has been increasingly used to treat patients with small (<4 cm), polar tumors and a normal contralateral kidney. The primary concern with this approach is that a multicentric tumor would go unrecognized and result in recurrent disease in the salvaged kidney. With highly sensitive preoperative staging, increasingly using three-dimensional reconstruction of CT images and the use of intraoperative ultrasound, such an occurrence should be relatively rare.[194] Furthermore, patients with multicentric tumors in one kidney are more likely to also have disease in the contralateral kidney, supporting a nephron-sparing approach. In patients with small, solitary tumors, the proportion of local recurrences is 0% to 7%[191] with a number of series reporting no local recurrences, [188] [190] [195] [200] [201] [202] [203] [204] [205] further supporting the use of this procedure in appropriately selected patients. Several retrospective series [11] [206] [207] [208] [209] and one prospective study [203] [210] have been published comparing survival after radical versus nephron-sparing surgery in patients with localized renal cell carcinoma, demonstrating equivalent survival for patients who undergo partial versus radical nephrectomy. Most urologists recommend completion nephrectomy in patients documented to have sarcomatoid histology on frozen section or evidence of renal vein invasion.[141] European investigators are conducting a trial in which patients with primary tumors that are less than 5 cm are randomly assigned to undergo either partial or radical nephrectomy. This study should definitively address the concerns regarding local recurrence and its impact on overall survival.
The role of partial nephrectomy utilizing techniques such as “bench dissection” in patients with larger tumors or centrally located tumors still remains controversial. [211] [212] Partial nephrectomy for this population should be restricted to patients participating in clinical studies.
Laparoscopic Nephrectomy
In 1991, Clayman and colleagues published the first case report of a laparoscopic nephrectomy in an 85-year-old woman with renal cell carcinoma.[208] Since then, a number of groups have presented increasingly large series of patients who underwent this procedure. [214] [215] [216] [217]
In 1998, a five-institution retrospective review of 157 patients who underwent laparoscopic nephrectomy demonstrated no port site or renal fossa recurrence, with a mean follow-up of 19.2 months (range 1-72; 51 patients with equal or greater than 2 years follow-up).[213] Longer follow-up and comparison to patients undergoing radical nephrectomy was reported in 2002,[214] with 64 patients who underwent laparoscopic nephrectomy compared to 69 treated with open radical nephrectomy. Median follow-up was 54 months for laparoscopic and 69 months for open procedures. Tumors removed via open techniques were on the average larger (6.2 cm versus 4.3,P< 0.001) than those removed via laparoscopic techniques. Overall survival and disease-free survival were not different between groups, even when both groups were stratified by TNM stage. Meraney and colleagues[215] reported a financial analysis and operative times of 18 open nephrectomies in comparison to 20 early and 15 more recent laparoscopic radical nephrectomies. Over time, with increased experience, the total intra- and postoperative costs associated with laparoscopic nephrectomy were progressively reduced primarily as a consequence of decreased post-operative hospital stays and became less than those associated with open nephrectomy. Although no randomized study has been performed, the data to date strongly suggests that laparoscopic radical nephrectomy is a viable alternative to an open procedure, with equivalent surgical efficacy and safety, and substantially reduced postoperative recovery time.
Most recently, laparoscopic techniques are being applied in the nephron-sparing setting. [141] [221] [222] Hemostasis and caliceal repair have been the major theoretical concerns, and so far, nephron-sparing laparoscopic surgery has been reserved for patients with small, peripheral or exophytic tumors. As surgical experience increases, the use of this approach will likely become more prevalent.
Energy Based Tissue Ablation
Over the past decade, cryoablation and radiofrequency ablation (RFA) have emerged as treatment alternatives for a select group of patients with localized renal tumors. Although long-term follow-up has not been achieved, intermediate oncologic effectiveness is comparable to the current “gold standard” treatment modalities.[218] Loss of radiographic contrast enhancement was used as a surrogate marker for efficacy. Whether this actually correlates with lack of viable cancer remains a subject of much debate. Six of 9 treated tumors demonstrated freedom from enhancement with a mean 10 months follow-up. Subsequent series from other centers [106] [224] demonstrated similar efficacy and no examples of tumor dissemination or progression. However, Rendon and colleagues reported on 10 patients treated with RFA before surgical removal of small (mean diameter, 2.4 cm) renal lesions[220]; four in the perioperative period and six one week before surgery. Although safe, pathological analysis of tumor viability demonstrated between 90% to 100% tumor destruction, with small foci of viable tumor in several cases. The clinical relevance of these small foci is unclear, but demonstrate that careful patient selection and post-procedure follow-up, as well as possible improvement in technology are all needed for RFA of renal tumors.
Surveillance
Surveillance has also been considered for patients with multiple or bilateral tumors (or both), such as those seen in patients with VHL. Some have advocated waiting until the largest lesion is greater than 3 cm before performing a partial nephrectomy.[195] In the past, others have suggested bilateral nephrectomies with transplantation for this population.[190] At the present time, active surveillance of small renal masses, with delayed therapy for patients whose disease progresses, is an experimental approach that can be considered for the elderly or patients with significant comorbidity. As improvements occur in nephron sparing surgery and in minimally-invasive ablation, surveillance will likely become less common, and more aggressive approaches such as bilateral nephrectomy less necessary.
Vena Caval Involvement
Inferior vena caval involvement with tumor thrombus is found in about 5% of patients undergoing radical nephrectomy.[221] It occurs more frequently with right-sided tumors and is commonly associated with metastases. Venal caval obstruction may produce various clinical manifestations. These include abdominal distention with ascites, hepatic dysfunction—possibly related to Budd-Chiari syndrome, nephrotic syndrome, caput medusa, varicocele, malabsorption, and pulmonary emboli.[222] The anatomic location of the tumor thrombus is important prognostically. Although survival in patients with subdiaphragmatic lesions approaches 50%, patients with supradiaphragmatic thrombi do considerably less well. [228] [229] A team of specialists is usually required in the surgical management of these patients, particularly if resection of the intracardiac tumor thrombus is contemplated. Even in experienced centers, the operative mortality may be as high as 5% to 10%. [230] [231] A minimally invasive technique for extracting supradiaphragmatic thrombus was described by Libertino and colleagues,[221] which if generally applicable may significantly reduce the perioperative morbidity and mortality associated with this type of surgery and shorten the recovery time. Five-year survival in patients with co-existing nodal or systemic metastases is extremely low,[222] and, consequently, thrombectomy in this situation should only be considered in the context of a potentially active systemic therapy trial, if at all.
Angioinfarction
Angioinfarction is used with or without nephrectomy in the treatment of patients with metastatic or locally advanced renal cell carcinoma.[227] This approach has been used to reduce vascularity and consequent risk of hemorrhage during nephrectomy in patients with large, marginally resectable primaries and to control symptoms such as bleeding or pain in patients with unresectable tumors or distant metastases.[228] Several techniques have been developed for embolizing the renal artery including gelatin sponge pads (Gelfoam), alcohol, and Silastic spheres.[229] Most patients experience pain, fever, and nausea after the procedure that may last several days. Although some investigators have reported regression of distant metastases following sequential angioinfarction and nephrectomy, a survival benefit has not been documented relative to patients undergoing nephrectomy alone. [235] [236]
Cytoreductive (Debulking) Nephrectomy
Renal cell carcinoma patients who present with metastatic disease have typically been felt to have a poor prognosis, with no 5-year survivors reported in some series.[232] Regression of distant metastases after removal of the primary tumor is an infrequent event, occurring in only 4 of 474 patients (0.8%) in a 1977 database compiled from nine series of patients who underwent debulking nephrectomy.[233] Contemporaneous data on patients undergoing cytoreductive nephrectomy did not show a survival advantage relative to the whole group of patients presenting with metastatic disease.[234]
Responses to immunotherapy are uncommon in patients with primary tumors in place, [240] [241] [242] [243] possibly related to immunosuppressive effects of the primary tumor. Consequently, many groups have advocated that patients presenting with metastatic disease undergo debulking nephrectomy before immunotherapy commences. Two randomized studies have been published demonstrating a significant survival advantage in patients with metastatic disease who underwent nephrectomy prior to embarking on a course of interferon therapy. [98] [244] Important caveats to these papers are nephrectomy did not improve response to immunotherapy per se, and the margin of survival improvement was substantial only in patients with a performance status of 0 or 1. UCLA investigators reported a median survival of 16.7 months and a 19.6% 5-year survival rate in patients treated with interleukin 2 (IL-2) containing therapy following debulking nephrectomy.[240] In addition, the Cytokine Working Group reported a 21% to 24% response rate in patients who received either low-dose IL-2 and interferon or high dose IL-2 following recent nephrectomy.[241] These two analyses suggested that IL-2–based therapy should be administered after nephrectomy in patients presenting with metastatic renal cancer.
Several other reports indicated that anywhere from 13% to 77% of patients treated in this way never make it to immunotherapy because of complications of treatment or rapid, symptomatic disease progression, [247] [248] [249] [250]further emphasizing the need for patient selection if debulking nephrectomy is to be entertained. Recognizing this, Fallick and associates[246] developed strict criteria for determining which patients should be subjected to debulking nephrectomy before receiving systemic IL-2 therapy. Criteria used are displayed in Table 38-8 .
TABLE 38-8 -- Criteria for Nephrectomy before IL-2-Based Immunotherapy
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Greater than 75% debulking of total tumor burden technically feasible |
|
No central nervous system, bone, or liver metastases |
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Adequate pulmonary and cardiac function |
|
No active infection or significant co-morbid condition |
|
ECOG performance status 0 or 1 |
|
Predominantly clear cell histology[*] |
Adapted with permission from Fallick ML, McDermott DF, LaRock D, et al: Nephrectomy prior to interleukin-2 therapy for patients with metastatic renal cell carcinoma. J Urol 158:1691–1695, 1997.
|
* |
Not required prior to surgery; however, patients in whom pretreatment biopsies reveal a predominant non-clear cell histology are excluded. |
Currently no data exists on the role of cytoreductive nephrectomy in patients slated to receive newer anti-angiogenic or targeted therapies. Consequently, decisions regarding cytoreductive nephrectomy in patients presenting metastatic disease should also take into account the proposed systemic treatment approach.
Palliative Nephrectomy
Although severe local symptoms, such as bleeding and pain, systemic symptoms, such as fatigue or fever, and laboratory abnormalities such as hypercalcemia, have been frequent justification for nephrectomy in the past, such “palliative nephrectomies” are rarely necessary now.[247] Pain and bleeding can often be controlled with systemic pain medicines or angioinfarction, clot colic can be minimized with ureteral stents and hydration, and hypercalcemia, fatigue, fever, and other systemic symptoms can often be controlled with nonsteroidal anti-inflammatory drugs, bisphospho-nates, hydration, and appetite stimulants such as medroxyprogesterone.[248]
Resection of Metastatic Disease
Surgical resection of metastatic disease has been actively pursued in certain clinical situations. Patients who present with a solitary metastasis have decreased survival relative to patients who develop metastasis after the primary tumor is removed.[234] Nonetheless, it is common to resect solitary or oligometastases, often in the ipsilateral lung or adrenal gland, in conjunction with nephrectomy, with the occasional patient remaining disease free long term.[254] [255] On the other hand, 5-year survival rates as high as 50% have been reported for patients undergoing resection of isolated metachronous metastases. [241] [256] [257]
Another situation in which resection of metastases has been considered is following effective systemic therapy. Salvage surgery of residual disease after response to systemic IL-2–based immunotherapy has been effective. Most of the patients who underwent resection while still in response remain disease free long term. [258] [259] [260] [261] Pathology frequently shows an active lymphoidal infiltrate surrounding the residual tumor ( Fig. 38-5 ) or at times shows no evidence of residual tumor.
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|
|
|
|
|
FIGURE 38-5 Progression-free survival of patients with newly diagnosed clear cell renal cell carcinoma randomized between sunitinib malate 50 mg daily for 28 days with a 14-day break versus interferon alfa 9 million units subcutaneously three times a week. (From Motzer RJ, Hutson TE, Tomczak P, et al: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124, 2007. Copyright © 2007 Massachusetts Medical Society. All rights reserved.) |
|
Radiation Therapy
Adjuvant to Nephrectomy
Studies looking at the possible benefit of adjuvant radiation therapy are few and inconclusive. Only one nonrandomized trial[118] suggested some benefit, whereas two additional studies found no benefit from postoperative irradiation. All of these studies used relatively primitive irradiation techniques and schedules that also resulted in a high incidence of complications, including severe liver and other toxicities. A mortality rate of up to 19% was noted.[257] Preoperative radiation therapy approaches have produced similarly disappointing results, but trial designs were equally flawed.[258] There remains no well-designed clinical trial of either preoperative or postoperative irradiation in appropriately staged patients with renal cell carcinoma. In the absence of such data, adjuvant radiation therapy should be considered unproved and should be used only in an investigational setting.
Radiation Therapy for Metastatic Disease
The major sites of systemic metastases include lung, bone, and brain. Radiation treatment of disease in these areas can provide palliation of bone pain, prevention of cord compression or fracture, regression of central nervous system metastases, or control of hemoptysis or airway obstruction. Objective responses occur in about 50% of patients with symptomatic skeletal metastases. [264] [265] Symptomatic improvement is often achieved even in the absence of radiologically documented tumor regression. Radiation therapy is also highly effective in controlling hemorrhage from bronchial mucosal lesions. Palliation of large renal bed recurrences by external-beam irradiation has been unsatisfactory. Some relief of pain has been achieved in about 50% of patients, but it is usually of short duration. In patients with brain metastases, whole-brain radiation therapy alone has not demonstrated significant efficacy.[261]Stereotactic radiation surgery has been reported to be effective therapy for selected patients with small (<3 cm) central nervous system metastases from renal cell carcinoma. [267] [268] [269] The presence of more than one brain lesion indicated a higher likelihood of developing subsequent new brain metastases.[263] Mori and colleagues[262] reported that whole brain radiation did not decrease the risk of subsequent development of new brain tumors, suggesting that whole brain radiation treatment may even be omitted in patients who undergo stereotactic radiosurgery.
Systemic Therapy
Although surgical resection of localized disease can be curative, many patients later experience recurrence, and 25% of patients present with either regional or metastatic disease. The prognosis for recurrent or metastatic renal cell carcinoma is poor with a median survival of 10 to 12 months.[131]
Patient selection may greatly influence the response rate and survival, and this factor must be kept in mind in evaluating any phase II or III study. Treatment options over the years have included hormonal therapy, chemotherapy, and immunotherapy; however, more recently, attention has been given to anti-angiogenic and targeted therapy approaches.
Hormonal Therapy
Numerous trials have explored the role of hormonal therapy in the treatment of patients with metastatic renal cell carcinoma. These studies were prompted by preclinical studies of estrogen-induced renal cell carcinoma in the Syrian hamster in which progesterone was shown to be effective in inhibiting both tumor development and tumor growth.[265] Progestins have been the most actively studied clinically as well and have produced response rates ranging from 0% to 20%. Other hormonal agents, such as androgens (or antiestrogens) and combinations of hormones and chemotherapy, have also produced responses in less than 10% of patients.[266] Subsequent studies using more strictly defined tumor-response criteria have consistently produced response rates of only 1% to 2%.[267] In reviewing the data on medroxyprogesterone,[268] it was concluded that irrespective of dose or schedule, human renal cell carcinoma is neither hormone dependent nor hormone responsive. Nonetheless, patients with severe anorexia and weight loss may occasionally derive significant symptomatic relief from the administration of medroxyprogesterone, even in the absence of any direct antitumor effect.
Chemotherapy
Many studies of single-agent chemotherapy have been performed, with most agents showing minimal or no activity ( Table 38-9 ).[266] In a review of the chemotherapy literature, Yagoda and co-workers[269] reported a 4% overall response rate in 3635 patients treated with various chemotherapy approaches. Most responses were of poor quality and were rarely associated with a survival advantage, even for the responding patients. The most active drug has been vinblastine, which was reported to produce response rates of approximately 8% to 25%. In a large-scale Scandinavian trial comparing vinblastine with vinblastine plus interferon alfa, however, the vinblastine arm produced tumor responses in only 2.5% of the 81 patients studied.[270] More recently, gemcitabine chemotherapy has been studied in RCC. As a single agent, response rate between 6% to 30% are reported. [276] [277] [278]
TABLE 38-9 -- Single-Agent Activity in Renal Cell Carcinoma
|
Agent |
Patients (No.) |
Response No. |
% Range |
|
Vinblastine |
296 |
47 |
16 (8–25) |
|
5-Fluorouracil |
201 |
10 |
5 (0–8) |
|
6-Mercaptopurine |
73 |
5 |
7 (0–17) |
|
Hydroxyurea |
140 |
16 |
11 (5–20) |
|
Cyclophosphamide |
132 |
12 |
9 (0–21) |
|
Doxorubicin |
65 |
0 |
0 |
|
Nitrogen mustard |
45 |
2 |
4 (4–10) |
|
CCNU |
59 |
4 |
7 |
|
BCNU |
11 |
0 |
0 |
|
Streptozocin |
15 |
0 |
0 |
|
Methyl GAG |
54 |
4 |
7 (0–16) |
|
Cisplatin |
60 |
0 |
0 |
|
Chlorambucil |
37 |
6 |
16 (14–17) |
|
Actinomycin D |
37 |
1 |
3 (0–11) |
|
Mitomycin C |
28 |
4 |
14 (11–50) |
Modified from Richie JP, Garnick MB: Primary renal and ureteral cancer. In Rieselbach RE, Garnick MB (eds): Cancer and the Kidney. Philadelphia, Lea & Febiger, 1982, p 662.
|
CCNU, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (lomustine); BCNU, 1,3-bis-(2-chloroethyl)-1-nitrosourea (carmustine); Methyl GAG, methylglyoxal-bis-guanylhydrazone. |
The combination of gemcitabine and 5FU demonstrated a response rate of 17% in 41 patients with metastatic RCC.[274] Median progression-free survival in this pretreated group of patients was 28.7 weeks. Follow-up studies using gemcitabine and capecitabine, the oral prodrug form of 5FU, demonstrated response rates of 11% and overall survival of 14 months.[275] In addition, major responses have been reported with carboplatin and taxane, or cisplatin and gemcitabine-based therapy in patients with collecting duct tumors.[276] A case series of patients with sarcomatoid renal cell carcinoma and other aggressive renal cell carcinomas treated with doxorubicin (50 mg/m2) and gemcitabine (1500 or 2000 mg/m2) every 2 to 3 weeks with granulocyte-colony-stimulating factor support was reported in 2004. Two patients had a complete response, five had a partial response, three had a mixed response, and one had stable disease. The median duration of response was 5 months (range, 2–21+ months).[277] A prospective intergroup clinical trial aimed at validating this observation is currently underway.
Analyses of surface protein expression by kidney cells have revealed a potential mechanism for the profound chemotherapy resistance exhibited by renal cell carcinomas. The proximal tubule cells of the renal kidney, the purported source of renal cell carcinomas, have been shown to contain markedly elevated messenger RNA levels for the multidrug resistance protein (P-glycoprotein/P-170),[278] and the corresponding multidrug resistance gene appears to be overexpressed in most renal cell carcinomas.[278] Duensing and colleagues[279] correlated P-glycoprotein expression in primary renal cell carcinomas with poor overall prognosis, suggesting a role for this protein in tumor biology and progression. Other mechanisms for multidrug resistance have also been identified in renal carcinoma cell lines.[280] Efforts to overcome these multidrug resistance mechanisms by co-administration of agents that block the multidrug resistance pathway, such as cyclosporine or its derivative PSC 833, have been disappointing. [286] [287]
Immunotherapy
Immunotherapeutic strategies for renal cell carcinoma have included nonspecific stimulators of the immune system, specific antitumor immunotherapy, adoptive immunotherapy, and partially purified or recombinant cytokines. These have been extensively reviewed elsewhere. [288] [289] Many of these approaches have shown some antitumor activity in this disease. Several of these therapies involve laboriously prepared crude preparations in which the active moieties remain uncertain; consequently, most have been abandoned in favor of the use of purified cytokine-based strategies. Although a number of cytokines have shown antitumor activity in patients with renal cell cancer, the most consistent results have been reported with interferon alpha and IL-2. Although the mechanism of action of these cytokines is incompletely understood, the induction of antitumor responses in mice by IFN alpha and IL-2 has been linked to both the direct killing of tumor cells by activated T cells and natural killer (NK) cells as well as to antiangiogenic effects of these agents.
Interferons
Interferon alpha has undergone extensive clinical evaluation over the past two decades in metastatic renal cell carcinoma. Results of these investigations are thoroughly described in several reviews. [290] [291] Despite the use of a variety of preparations, doses, and schedules, most studies have shown antitumor activity, with the overall response rate being approximately 15%. Responses were often delayed in onset, with median time to response being approximately 4 months. Most responses were partial and short-lived (median response duration, 6 to 7 months). About 2% of patients have had complete responses, with only an occasional patient having a response persist in excess of 1 year after therapy.[286] Although no clear dose-response relationship exists, daily doses in the 5- to 10-MU range appear to have the highest therapeutic index.[286] Toxicity of interferon includes flu-like symptoms such as fever, chills, myalgias, and fatigue, as well as weight loss, altered taste, depression, anemia, leukopenia, and elevated liver function tests. Most side effects, especially the flu-like symptoms, tend to diminish with time during chronic therapy.
Two phase III studies using single agent interferon showed a modest impact on survival in patients with advanced renal cancer. For example, a phase III trial comparing interferon alpha 2a plus vinblastine chemotherapy to vinblastine alone reported a median survival of 67.6 weeks for interferon plus vinblastine arm compared to 37.8 weeks for patients receiving vinblastine alone (p = 0.0049).[270] In another trial that randomized patients with advanced disease to either interferon or Megace, there was a 28% reduction in the risk of death in the IFN group (p = 0.017) and an improvement median survival of 2.5 months.[287]
Efforts to improve upon the clinical activity of interferon alfa have included combinations with 5FU, cis retinoic acid, interferon gamma, thalidomide, and IL-2. For the most part these have met with limited success, with occasionally promising phase II data [293] [294] failing to be confirmed in phase III trials. A recent report showed a benefit of temsirolimus over interferon alfa on overall survival, whereas the addition of temsirolimus to interferon did not improve survival.[289a]
Responses have been reported with interferon gamma as well, although the antitumor activity has, in general, been inferior to that seen with interferon alfa. Phase I and 2 studies of recombinant human interferon gamma-lb, administered at a variety of doses and schedules, produced an average overall response rate of 11.5%. [296] [297] [298] [299] [300] [301] These studies primarily employed escalating or maximal tolerated doses of interferon gamma. Of interest, one study by Aulitzky and associates[296] used 100 mg of interferon gamma once weekly, a dose that produced no side effects and optimal up-regulation of neopterin, a biologic marker for macrophage activation, and showed six responses (two complete and four partial) in 20 evaluable patients (response rate, 30%; 95% confidence limits, 12% to 54%). These encouraging results led to a large-scale, randomized, double-blind phase III trial comparing placebo with interferon gamma (60 mg/m2) administered subcutaneously once weekly. Unfortunately this Canadian Urologic Oncology Group Trial failed to show any benefit for interferon gamma relative to placebo either in terms or response rate, time to disease progression, or overall survival.[297] In summary, despite some promising early clinical results and the potential identification of surrogate markers of immune activation, single-agent interferon gamma therapy appears to have little or no activity in this disease.
Interleukin-2 Therapy
Clinical investigation of IL-2 in renal cell carcinoma began in the mid 1980s. Initial studies were performed with high-dose bolus IL-2 and lymphokine-activated killer (LAK) cells because animal studies had shown a steep dose-response curve for IL-2 and benefit for the addition of LAK cells.[298] Dramatic and durable responses were reported in a small subset of patients. [242] [305] Subsequent clinical studies have shown that high-dose bolus IL-2 possesses antitumor activity that is essentially equivalent to the combination of IL-2 and lymphokine-activated killer cells. [306] [307] [308]
High-Dose Interleukin-2 Investigations
In 1992, high-dose bolus IL-2 received United States Food and Drug Administration approval for metastatic renal cell carcinoma based on data from 255 patients treated in seven clinical trials at 21 institutions. In these studies, recombinant IL-2 (Proleukin, Chiron Corporation, Emeryville, CA) (600,000 to 720,000IU/kg) was administered by 15-minute intravenous infusion every 8 hours on days 1 to 5 and 15 to 19 (maximum, 28 doses). Treatment was repeated at approximately 12-week intervals in responding patients for a maximum of three cycles. Because of considerable toxicity associated with this regimen (hypotension, capillary leak), treatment had to be administered in a setting capable of providing intensive care unit level care and was restricted to carefully selected patients with excellent organ function, treated at experienced treatment centers.
Data presented to the Food and Drug Administration showed objective responses in 36 of the 255 patients (response rate, 14%).[228] There were 12 (5%) complete responses and 24 (9%) partial responses. At that time, the median duration of response was 23.2 months for all responders (18.8 months for partial responders; the median was not reached for complete responders). Fourteen of the responding patients (38%) began therapy with tumor burdens of greater than 50 cm2on pretreatment scans, and 60% of partial responders had greater than 90% regression of all measurable disease. The quality and durability of these responses were what prompted Food and Drug Administration approval, in spite of the relatively low response rate and high level of toxicity.
Alternative IL-2-Based Regimens
Several investigators have evaluated regimens involving IL-2 administered by alternative routes or in lower doses in an attempt to reduce toxicity. Although encouraging initial response rates have been reported by some investigators, follow-up data and information on response durations have been lacking. Continuous intravenous infusion IL-2 and lymphokine-activated killer cell regimens appeared to produce tumor response rates similar to those seen with high-dose bolus intravenous IL-2. [309] [310] [311] Although more convenient to administer, continuous-infusion regimens, on a milligram per milligram of IL-2 basis, were actually more toxic than high-dose bolus IL-2. Even with an approximate fivefold reduction in the amount of IL-2 administered per day, the toxicity of continuous-infusion IL-2 was roughly equivalent to that of high-dose bolus IL-2.[304] Furthermore, omitting the lymphokine-activated killer cells or reducing the dose of IL-2 further to enable prolonged administration (or both), while producing enhanced immune activation, appeared to limit antitumor activity. [312] [313]
The National Cancer Institute published a study comparing high-dose IL-2, low-dose inpatient bolus IL-2, and outpatient SC IL-2.[308] Patients with measurable metastatic RCC and a good performance status were randomized to receive either 720,000U/kg (high-dose [HD]) or 72,000U/kg (low-dose [LD]), both given by intravenous (IV) bolus every 8 hours. After randomly assigning 117 patients, a third arm of low-dose daily SC IL-2 was added. A total of 156 patients were randomly assigned to HD IV IL-2, and 150 patients to LD IV IL-2. There were no IL-2–related deaths in any arm. There was a higher response proportion with HD IV IL-2 (21%) versus LD IV IL-2 (13%;P= .048) but no overall survival difference. The response rate of subcutaneous IL-2 was 10%. Response durability and survival in completely responding patients was superior with HD IV compared with LD IV therapy (P= .04).[308]
Toxicity-Reduction Strategies
Interleukin-2 is a potent inducer of proinflammatory cytokines, such as IL-1, tumor necrosis factor-α (TNF-α), and interferon gamma. [315] [316] [317] These substances and others, including nitric oxide,[312] likely play a major role in IL-2 toxicity. Tumor responses, on the other hand, are thought to be mediated through cellular immune mechanisms, raising the possibility of dissociating the toxicity of IL-2 from its antitumor effect by combining IL-2 with various inhibitors of secondary cytokine function. The addition of dexamethasone was shown to prevent the usual induction of TNF-α by IL-2 and significantly reduced treatment-related toxicity. However, potential interference with antitumor efficacy limited this approach. [319] [320] The use of more selective inhibitors of secondary cytokine function (e.g., CT1501R, CNI-1493, or soluble TNF-α or IL-1 receptors), despite promise in animal models, have not been able to significantly block IL-2 toxicity clinically. [321] [322] [323] [324] Future exploration of this approach will likely require combinations of cytokine antagonists or the use of novel antagonists of secondary cytokines with more pluripotent inhibitory effects.
Interleukin-2 and Interferon-Alpha Combinations
Attempts to improve efficacy have included the addition of interferon alpha and then 5-FU to IL-2. In addition to its modest single-agent antitumor activity in patients with renal cell carcinoma, interferon alpha up-regulates expression of HLA class I and tumor-associated antigens, potentially making the tumor cells more immunogenic and possibly more susceptible to IL-2–mediated lysis. Several animal experiments have shown that the combination of IL-2 and type I interferons enhances effector cell mechanisms and produces superior antitumor activity to that of maximum tolerated doses of the single agents in the same tumor models. [296] [325] Table 38-10 shows the results of several studies involving combinations of IL-2 and interferon-a. Studies are separated according to route of IL-2 administration: high-dose intravenous bolus injection, continuous intravenous infusion, subcutaneous injection, or in combination with 5-FU. [243] [326] [327] Although the initial phase I study of high-dose intravenous IL-2 and interferon-α produced a 31% (11 of 35) response rate in patients with renal cell carcinoma,[320] subsequent high-dose IL-2 and interferon-α studies produced response rates that were not clearly better than that of high-dose IL-2 alone. [243] [328] [329] [330] [331] Many regimens using combinations of interferon with lower doses of IL-2 administered by different routes, either alone or with 5-FU, were suitable for administration in an outpatient setting. Response rates for these approaches ranged from 22% to 39%. [327] [332] [333] [334] [335] [336] [337] [338] [339] [340] [341] [342] [343] [344] [345]
TABLE 38-10 -- IL-2 and IFN-α Therapy
|
Authors (Ref) |
IL-2 Regimen |
N |
CR/PR |
% |
|
Rosenberg[320] |
HD Bolus |
35 |
4/7 |
31 |
|
Atkins[238] |
HD Bolus |
28 |
0/3 |
11 |
|
Sznol[322] |
HD Bolus |
14 |
1/2 |
21 |
|
Spencer[324] |
HD Bolus |
12 |
0/1 |
8 |
|
Budd[325] |
HD Bolus |
21 |
0/2 |
10 |
|
Bergman[340] |
HD Bolus |
36 |
2/7 |
25 |
|
Figlin[329] |
CIV |
30 |
0/9 |
26 |
|
Lipton[327] |
CIV |
39 |
6/7 |
33 |
|
Dillman[328] |
CIV |
3 |
0/6 |
7 |
|
Figlin[326] |
CIV |
22 |
0/7 |
32 |
|
Besana[330] |
CIV |
23 |
1/5 |
26 |
|
Negrier[331] |
CIV |
140 |
2/6 |
19 |
|
Atzpodien[332] |
SC |
34 |
4/6 |
29 |
|
Palmer[333] |
SC |
200 |
7/30 |
19 |
|
Atzpodien[341] |
SC |
152 |
9/29 |
25 |
|
Vogelzang[335] |
SC |
42 |
1/4 |
12 |
|
Lummen[336] |
SC |
30 |
3/4 |
23 |
|
Dutcher[321] |
SC |
47 |
2/6 |
17 |
|
Atzpodien[337] |
5FU/IL2 |
120 |
13/34 |
39 |
|
Sella[338] |
5FU/IL2 |
19 |
3/6 |
47 |
|
Hofmockel[339] |
5FU/IL2 |
25 |
3/10 |
38 |
|
Dutcher[321] |
5FU/IL2 |
50 |
1/7 |
16 |
Atzpodien and colleagues[341] evaluated the combination of IL-2 and interferon-α both administered subcutaneously at doses suitable for an outpatient setting. Responses were noted in 25% of patients.
Subsequently, they developed a regimen that alternated 4 weeks of subcutaneously administered IL-2 and interferon-α with 4 weeks of combined 5-FU and interferon-α and reported a response rate of 39% in 120 patients.[337]Response durations and numbers of durable complete responses were not fully reported; however, median response duration was approximately 12 months for each regimen. Follow-up trials within the Cytokine Working Group failed to confirm the promising results reported by Atzpodien and co-workers. [327] [347]
A more recent study suggested that the antitumor effect of outpatient single agent and combination immunotherapy and is quite limited in patients with intermediate prognosis disease. A French Immunotherapy Group Phase III trial comparing interferon to both IL-2 and IL-2 plus IFN, reported a response rate of only 7.5% for the interferon arm with a 1-year event-free survival rate of only 12%.[342] In the PERCY Quattro trial, untreated patients with more than one metastatic site and Karnofsky score ≥80 were randomized to medroxyprogesterone, interferon-α, subcutaneous IL-2, or the combination of interferon and subcutaneous IL2.[343] Overall survival was no different for either the interferon or IL-2 containing arms compared to the non-interferon on non-IL-2 containing arms.
The Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient IL-2 and interferon α-2β compared to high-dose high dose IL-2 in patients with metastatic renal cell carcinoma.[241] Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5MIU/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/week for 4 weeks) and interferon (5MIU/m(2) subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks. One hundred ninety-two patients were enrolled. One death was reported in each arm. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (9 of 91 patients) for the IL-2 and interferon combination (P= .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and interferon (P= .082). The median response durations were 24 and 15 months (P= .18) and median survivals were 17.5 and 13 months (P= .24). For patients with bone or liver metastases (P= .001) or a primary tumor in place (P= .040), survival was superior with HD IL-2, a surprising finding because liver and bone lesions were generally considered to be relatively refractory to immunotherapy. The overall survival for patients with liver or bone metastases who received HD IL-2 was 14.7 months, versus 8.0 months for the patients who received subcutaneous therapy (P= 0.001).
Predictors of Response and Survival
Many groups have attempted to define reliable predictors of response and survival for patients with metastatic renal cell carcinoma who were receiving immunotherapy. Factors that have been variably associated with response are detailed in Table 38-11 and include performance status,[301] number of organs with metastases (one versus two or more[331]), absence of bone metastases,[238] prior nephrectomy,[237] degree of treatment-related thrombocytopenia, absence of prior interferon therapy,[344] thyroid dysfunction,[345] rebound lymphocytosis,[346] erythropoietin production,[347] and post-treatment elevations of blood TNF-α and IL-1 levels. Negrier and associates[331] also identified independent predictors of rapid disease progression, defined as progression within 10 weeks of initiation of therapy. These included greater than one metastatic site, disease-free interval of less than 1 year, and presence of liver metastases or mediastinal nodes as well as type of immunotherapy used. Patients with liver metastases, more than one site of disease, and disease-free interval of less than 1 year had a lower response rate and a median survival of only 6 months, even while receiving combination IL-2 and interferon-α therapy. Figlin and colleagues[348] identified prior nephrectomy and time from nephrectomy to relapse as important predictors of survival in patients receiving IL-2–based therapy. In their series, patients who received systemic immunotherapy for metastatic disease more than 6 months after nephrectomy had the best median survival and had a 3-year survival rate of 46%. In contrast, recent data from the Cytokine Working Group phase III trial, mentioned earlier, suggested that disease site factors such as primary in place or hepatic or bone metastases, may predict the highest relative response to high dose IL-2 when compared low dose IL-2 and IFN regimens. These data call into question the prior studies and suggest that additional predictors of response to IL-2–based therapy are necessary. Whether any of these predictors of outcome are applicable to patients receiving targeted therapy is another unanswered question.
TABLE 38-11 -- Factors Associated with Response to IL-2-Based Therapy
|
Factor |
Author (Reference) |
|
Performance status |
Fyfe et al[301] |
|
Number of metastatic sites |
Negrier et al[331] |
|
Prior nephrectomy |
Fisher et al[237] |
|
Absence of bone metastases |
Atkins et al[238] |
|
Thyroid dysfunction |
Atkins et al[345] |
|
Rebound lymphocytosis |
West et al[346] |
|
Erythropoietin production |
Janik et al[347] |
|
Treatment-related thrombocytopenia |
Royal et al[344] |
|
Low pretreatment IL-6 levels |
Blay et al[114] |
|
No prior IFN therapy |
Royal et al[344] |
Influence of Subtype
Responses most commonly occur in patients with clear cell-type cancer. Occasional responses have been observed in sarcomatoid and granular variants, but these are usually partial and of shorter duration. Upton and colleagues recently performed a blinded large-scale re-analysis of pathology specimens from patients who received IL-2–based therapy.[348a] They determined that response to IL-2 was significantly associated with clear cell histology with alveolar features and the absence of papillary or > 50% granular features. Patients with these features in their kidney tumor specimens had a 25% response rate; those patients who also had renal vein involvement, had a response rate of over 40%. The results in the kidney tumor specimens were confirmed in a separate analysis of metastatic lesions. In the metastatic setting responses were limited to patients with clear cell tumors with the favorable histologic patterns described in the primary tumor specimens. This data strongly suggests that patients with non-clear cell or indeterminate histology, or clear cell histology with papillary and > 50% granular features and no alveolar features should be considered for non-IL-2–based therapy. Carbonic IX is HIF dependent protein whose expression is enhanced by either hypoxia or the loss of VHL function as seen in the majority of patients with clear cell renal cancer. High level tumor expression of carbonic anhydrase IX was shown by two independent groups to predict for response to IL-2 therapy.[241] Furthermore, although responses were seen in some patients with low carbon anhydrase IX expressing tumors, durable responses were confined to patients with high carbonic anhydrase IX expressing tumors. A two component model combining histologic features described earlier and carbonic anhydrase IX expression was able to correctly assign 26 of 27 responding patients.[241] A prospective evaluation of this model is currently ongoing; however, the MN 75 carbonic anhydrase IX antibody used for this testing has yet to be made available for clinical use.
Adjuvant Therapy
The ECOG completed a trial comparing adjuvant interferon alfa with observation in patients with high-risk resected renal cell carcinoma. Eligible patients were to be T3b-c, T4, and/or N1-N3. Patients were randomly assigned to receive either a year of interferon-α or routine observation. With a minimum follow-up of 36 months and a mean of 68 months overall, no statistically significant difference in disease-free survival was observed between the treatment arms.[349] A smaller study performed by the EORTC, also showed no benefit for the adjuvant administration of interferon alpha. Although the results of these studies were disappointing, they did provide useful information on the natural history of stage III renal cell carcinoma. Specifically, it identified a high-risk group, those with T3c, T4, and/or N2-N3 disease, which had only a 20% to 25% chance of remaining disease free at 2 years.[253] This population was believed to be at sufficient risk of relapse to justify exploration of more aggressive therapy, such as high-dose IL-2, in an effort to prevent or delay relapse. Consequently, the Cytokine Working Group performed a trial randomly assigning patients who satisfy these high-risk staging criteria to either a single cycle of high-dose IL-2 or observation. Unfortunately, this trial shows no survival benefit for the patients receiving HD IL-2 in the adjuvant setting.[350]Thus at the moment, there is no evidence to support the use of either interferon or IL-2 in the adjuvant setting in patients with high-risk renal cancer.
Other Cytokines
Clinical trials with other cytokines, such as IL-4 and IL-6, produced only occasional minor responses. [358] [359] A few durable responses have been observed in phase I trials of recombinant human IL-12 (rhIL-12) administered either intravenously[255] or subcutaneously[353]; however, in general, antitumor activity in these studies has been less than predicted by preclinical models. Subsequent clinical investigations have been delayed by the discovery of a peculiar schedule dependency for rhIL-12 whereby a single “test dose” of rhIL-12 has been shown to increase patients' tolerance to subsequent therapy[354] and possibly reduce antitumor effects. Novel schedules of IL-12[355] and combinations of rhIL-12 with IL-2 have been explored in an effort to sustain the biologic activity of rhIL-12.[355a] The results of these clinical trials have been mixed, with considerably more research likely to be required before significant clinical activity for rhIL-12 can be established.
Vaccines
Vaccination with fusions of autologous tumor cells and allogeneic dendritic cells has been shown to induce disease regression in 7 of 17 patients with metastatic renal cancer.[356] Responses were also seen in 3 of 27 patients treated with a vaccine created from tumor lysate-pulsed autologous dendritic cells.[357] Unfortunately only limited clinical activity was seen with vaccination of fusion cells established from autologous tumor and autologous dendritic cells.[358] Avigan and colleagues showed in a recent study that immunological response and disease stabilization occurred in patients with metastatic renal cell carcinoma treated with autologous dendritic cell vaccination.[358a] Further investigation of this dendritic cell vaccination approach is ongoing with future efforts likely to include the addition of cytokines such as IL-12 as vaccine adjuvants. (Two other recent publications should be mentioned: one combined with breast cancer patients and another looking at allogeneic DCs as fusion partners, both with David Avigan as first author.)
Targeted Agents
Given the frequency of biallelic loss of the VHL gene and associated dysregulation of hypoxia-inducible genes including pro-angiogenic growth factors VEGF and PDGF, renal cell carcinoma may be a particularly promising target for antiangiogenic therapy. Among the most promising agents are those that specifically target proangiogenic pathways. Several of these agents have been tested in patients with advanced renal cancer and have shown remarkable single agent activity.
Bevacizumab
Phase I studies using bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody demonstrated several responses in patients with renal cell carcinoma. A 116 patient phase II study was then performed randomizing patients with metastatic renal cell carcinoma who had failed or were not eligible for cytokine therapy between low-dose bevacizumab (3 mg/kg), high-dose bevacizumab (10 m/kg), or placebo treatment. The study was discontinued prematurely because of a significant delay in disease progression associated with high-dose bevacizumab compared with placebo.[359] Progression-free survival for patients on the high-dose arm was 4.8 months versus 2.4 months for the patients on placebo (P< 0.001). Two large-scale randomized Phase III trials comparing front-line administration of bevacizumab plus subcutaneous interferon alpha to either interferon alone or with placebo have completed accrual and should be analyzed shortly. Studies looking at the role of erlotinib, in combination with bevacizumab were completed. [369] [370] A 63-patient phase 2 study, in which 43 patients were previously untreated, demonstrated an encouraging 11-month progression-free survival for the combination.[360] The role of erlotinib was subsequently discounted in a 100-patient placebo controlled randomized phase II study bevacizumab with or without erlotinib.[361] The progression-free survival for bevacizumab arm was 8.5 months, versus 9.9 months for the combination arm (P= 0.58) and there was no difference in either response rates or overall survival.
Sorafenib
Sorafenib is a bis-aryl urea originally developed as a potent inhibitor of both wild-type and mutant (V599E) B-Raf and c-Raf Kinase isoforms. It was also found to possess inhibitory activity against VEGFR, PDGFR c-KIT, and FLT-3. A Phase II randomized discontinuation study accrued 502 patients of which 202 had metastatic renal cell carcinoma.[362] All patients in this study received 12 weeks of sorafenib. Those who had more than 25% tumor shrinkage continued therapy and those with more than 25% tumor discontinued therapy. The remaining individuals with stable disease were randomly assigned to either continue sorafenib or to take a placebo. In this randomized group, progression-free survival for patients receiving sorafenib was 24 weeks versus 6 weeks in the placebo group (P= 0.0087).
A large-scale phase III trial was subsequently performed in which patients with metastatic RCC who had failed one prior therapy were randomized between sorafenib and placebo. Median progression-free survival was 5.5 months in the treatment arm and 2.8 months in the placebo arm, and these results were highly statistically significant (P= 0.000001). A subsequent survival analysis showed a difference in survival favoring the sorafenib arm (P= 0.018), which did not reach the predetermined threshold of 0.0005 required for early study termination. Tumor responses, all partial, were reported in 10% of the sorafenib-treated patients, although over 70% of sorafenib-treated patients exhibited some degree of tumor shrinkage. Based largely on this data, sorafenib received approval by the Food and Drug Administration in late 2005 for use in patients with advanced renal cell carcinoma. A subsequent interim survival analysis, confounded by substantial patient crossover, showed survival of the placebo arm to be 15.9 months versus 19.3 months in the sorafenib arm (P= 0.015), approaching the predetermined significance boundary of 0.0094.
Sunitinib
Sunitinib is a small molecule inhibitor of VEGFR, PDGFR c-KIT, and FLT-3. Two phase II studies in cytokine refractory patients with metastatic renal cancer were recently performed. The first trial enrolled 63 patients, the majority of whom had tumors with clear cell histology and had undergone prior nephrectomy. The response rate was 40% with no complete responders, and the median progression-free survival was 8.1 months.[3] A subsequent 106 patient study, in which all individuals had clear cell carcinoma, prior nephrectomy, and had failed cytokine therapy, showed a 25% response rate after independent review. Based on these phase II data, sunitinib was approved for use in patients with advanced renal cancer in early 2006. A subsequent large-scale frontline phase III trial randomizing patients between sunitinib and interferon-α showed a response rate of 31% and a median progression-free survival for sunitinib-treated patients of 11 months versus 6% response rate and 5 months median progression-free survival for patients treated with interferon (both P= 0.000001). Although analysis was still early, no significant difference in overall survival was observed.
Temsirolimus (CCI-779)
Temsirolium is a rapamycin analog that inhibits mammalian Target or Rapamycin (mTOR) downstream of AKT and results in cell cycle arrest. Atkins and colleagues[363] reported results of a randomized double-blind phase II trial examining three dose levels of CCI-779 in renal cancer patients who were either refractory to or felt to be poor candidates for cytokine-based therapy.[363] Twenty-nine of the 110 patients enrolled (26%) experienced a partial or minor response. The median time to progression and median survival for all patients were 6 months and 15 months, respectively. The response rate, time to progression and survival were felt to be encouraging for this population of patients, most of whom had poor prognostic features. No obvious dose effect was evident with results appearing equivalent for doses ranging from 25 mg to 250 mg. A re-analysis of the trial in which patients were segregated into prognostic groups based on the criteria established by Motzer and colleagues[364] for patients receiving interferon was recently reported.[365] Of note, patients with intermediate and poor prognostic features appeared to benefit most, exhibiting median survival of 19.3 and 8.2 months, respectively, compared to median survivals of 13.8 and 4.9 months reported in the Motzer database. A phase III study randomizing patients with renal cancer and poor prognostic features between 25 mg IV weekly of temsirolimus, 9MU three times per week interferon-α, and 15 mg IV weekly temsirolimus plus 6MU units three times per week interferon-α showed that the overall survival of patients receiving termsirolimus alone was significantly longer than those receiving interferon (10.9 months versus 7.1 months,P= 0.0069). The survival of patients receiving both agents was 8.4 months, and was not significantly different from the temsirolimus only arm. Although this study established a survival benefit for temsirolimus in patients with renal cell carcinoma and poor prognostic features as defined by Motzer and co-workers, its value in patients with better prognostic features remains to be established.
Thalidomide
Thalidomide has a somewhat unclear mechanism of action but is believed to somewhat alter the expression of angiogenic growth factors, including VEGF and fibroblast growth factor (FGF) in tissues. Although early anecdotal reports suggested objective responses in patients with advance renal cell carcinoma most reports of even high doses of thalidomide (800+mg/day) suggest that the agent, at best, results in disease stabilization. [53] [375] [376] [377]Toxicity includes somnolence, constipation, fatigue, and with prolonged exposure, peripheral neuropathy.[367] A large, multicenter phase III was reported in 2004, which randomized untreated patients between interferon-α and interferon plus thalidomide.[369] The study enrolled 353 patients of whom 342 were eligible. Fatigue, myelosuppression, and thrombotic events (12 versus 4) were greater in interferon plus thalidomide arm. There was no difference in response rates or overall survival. Progression-free survival was statistically significantly longer in the interferon plus thalidomide arm. Quality of life and fatigue scores were worse on the combination arm. At this point in time, thalidomide therapy is generally not recommended for the treatment of patients with RCC.
Epidermal Growth Factor Receptor Blocking Agents
The epidermal growth factor (EGF) receptor antagonists, despite the presence of compelling preclinical data, have not yet lived up to their promise. A high rate of EGF receptor expression on renal cell tumors, coupled with loss of VHL resulting in increased expression of TGFa, supports the presence of an autocrine loop in many renal cell carcinomas. Inhibition of this autocrine loop by either blocking the cell surface receptor (EGFR) or the ligand would be expected to result in growth inhibition and clinical response. However, several Phase II studies demonstrated little response to single agent therapy targeted against EGFR. [379] [380] Furthermore, as mentioned previously, the combination of erlotinib with bevacizumab failed to show a significant progression free survival or overall survival advantage over bevacizumab therapy alone.[361]
Current Status of Antiangiogenic and Targeted Therapies
The recent Food and Drug Administration approval of sorafenib and sunitinib has greatly expanded the treatment options for patients with advanced renal cancer. In addition, the promising activity of temsirolimus and bevacizuamab may ultimately lead to their approved use in renal cancer patients. Several of these agents have shown significant clinical activity in both cytokine refractory patients and relative to interferon in the frontline setting; however tumor responses have been at best partial and un-maintained off of therapy. Consequently, the optimal timing, sequence, and patient population to receive such agents, particularly relative to high dose IL-2, remains to be firmly established. In addi-tion, the appropriate treatment for patients whose disease has become resistant to these agents remains unknown. Current studies exploring these agents in combination either with each other or with cytokines and in the adjuvant setting should shed light on some of these unanswered questions.
Non-Myeloablative Allogeneic Transplantation
Since its inception as a therapy, allogeneic bone marrow transplantation has evolved from a means to achieve chemotherapy dose escalation to a form of adoptive immunotherapy.[372]
Preliminary experiences with non-myeloablative allogeneic transplantation in patients with renal cell carcinoma have been reported by a number of centers. [280] [382] [383] [384] [385] In all studies, the provision existed for post-transplant donor lymphocyte infusion if complete donor chimerism was not achieved. The largest series, reported by Childs and colleagues,[373] demonstrated response in 10 of 19 patients, following a conditioning regimen of cyclophosphamide and fludarabine. Complete donor chimerism appeared to be a prerequisite for response, as was some degree of graft-versus-host disease. More recently, Bregni and co-workers[375] reported responses in four of seven patients with metastatic renal cell carcinoma following allogeneic non-myeloablative transplantation with thiotepa, cyclophosphamide, and fludarabine conditioning. Pedrazzoli and colleagues[374] reported on 17 patients with treatment-refractory solid tumors, of which seven had renal cell carcinoma, conditioned with fludarabine and cyclophosphamide. Four of the patients had a performance status of 2 or poorer, and the remaining three had a performance status of 1. In Pedrazzoli's report, all renal cell carcinoma patients died of progressive disease before day 100. All studies reported substantial hematological toxicities as well as graft-versus-host disease. Poor outcome was also consistently associated with poorer pre-transplant performance status.
Although promising, non-myeloablative transplantation requires substantial further development before it can be considered for a larger number of patients. The conditioning regimens must be rendered less toxic. Post-transplant immunosuppression must be refined to decrease graft failure and graft-versus-host disease, and to permit unrelated donor bone marrow to be used. Ideally, as our understanding of the antigens that elicit a graft-versus-renal cell carcinoma response is improved, modification of the donor graft or the donor lymphocyte infusion to enrich for RCC-specific T-cell clones may enhance response. With appropriate tumor antigens in hand, it will also be possible to combine transplantation with vaccination.
RENAL PELVIC TUMORS
The cellular lining of the urinary collecting system, originating in the proximal renal pelvis, traversing the ureter and urinary bladder, and ending in the distal urethra, is composed of transitional epithelium or urothelium. This entire surface may be affected by carcinogenic influences, and thus may help explain the multiplicity in time and place of “urothelial” tumors, a term some have called “polychronotropism.” Renal pelvic tumors account for approximately 10% of all primary renal cancers.
Tumors of the upper tract are twice as common in men, usually occur in patients older than 65 years, and are usually unilateral. The disease is more common in the Balkan region (Bulgaria, Greece, Romania, Yugoslavia), and is often bilateral. Similar to urothelial tumors of the urinary bladder, exposure to cigarettes, certain chemicals, plastics, coal, tar, and asphalt may increase the incidence of the disease.
Long-term exposure to the analgesic phenacetin, usually ingested over years by women for headache relief, has been associated with the development of renal pelvic tumors.
Although most tumors of the upper tract are transitional cell carcinomas, accounting for over 90% of lesions, squamous carcinomas also occur, usually in the setting of chronic infections with kidney stones. Adenocarcinomas and other miscellaneous subtypes are rare.
Presenting Features and Diagnostic Evaluation
The most common presenting feature is gross hematuria, occurring in 75% of patients, followed by flank pain, in 30%. Evaluation may reveal either a nonfunctioning kidney and nonvisualization of the collecting system, or more commonly, a filling defect of the calyceal system, or renal pelvis, on intravenous pyelography.
Exfoliative cytology is commonly positive, as it is in bladder cancers. A positive cytology in the presence of a filling defect of the renal pelvis or ureter confirms the diagnosis. Retrograde pyelography with brush biopsy of suspicious lesions may also yield the diagnosis of cancer. If there is still uncertainty in the diagnosis after pyelography, including a retrograde evaluation, ureteroscopy may be performed to further evaluate the filling defect or obstruction.
Staging and Grading of Renal Pelvic Tumors
Transitional cell carcinomas are graded on a scale of I, representing a well-differentiated lesion, to grade IV, or anaplastic and undifferentiated lesion. In a staging system similar to that used for urinary bladder cancer, stage O is limited to the mucosa; stage A, invasion into the lamina propria without muscularis invasion; stage B, into the muscularis; stage C, into the serosa; and stage D, metastatic disease. Lymphatic metastases usually indicate that more widespread metastatic disease is or will be present.
Management
For low-grade, low-stage transitional cancers, the general approach to treatment is conservative, consisting of local excision and preservation of the kidney parenchyma. Five-year survival rates are usually in excess of 60%. For high-stage and high-grade lesions that have infiltrated into the renal parenchyma, the surgical treatment of choice is nephroureterectomy and removal of a cuff of bladder that encompasses the ipsilateral ureteral orifice. This approach is generally required because of the high likelihood of local recurrence in the bladder at the ureterovesical junction. In patients with regionally advanced or metastatic renal pelvic tumors, systemic chemotherapy, identical to that which is administered for bladder cancer, is often employed. Standard first-line regimens for patients with locally advanced or metastatic transitional cell carcinoma include methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC), gemcitabine and cisplatin, or paclitaxel and cisplatin. Initial response rates may vary depending on prognostic factors, but long-term survival is poor.
OTHER KIDNEY TUMORS
Renal Sarcomas
Renal sarcomas account for approximately 1% to 2% of primary renal cancers. Fibrosarcomas are the most common and have a poor prognosis as a result of late presentation and presence of locally advanced involvement into the renal vein or metastatic disease at presentation. Five-year survival rates are less than 20%.
Other, rarer sarcoma variants may occur and include leiomyosarcoma, rhabdomyosarcoma, osteogenic sarcoma, and liposarcoma.
Wilms Tumor
In children, Wilms tumor (nephroblastoma) is the most common cancer of the kidney, accounting for approximately 400 new cases per year in the United States. The success in managing the disease in the 1990s represents the coordinated efforts of a multidisciplinary team of oncologists, radiation therapists, and surgeons.
The disease tends to occur more frequently in African American children. A variety of etiologic factors have been suggested to increase the risk of Wilms tumor, but in none has a definitive link been established.
Genetics
Several well-described genetic abnormalities are associated with Wilms tumor. Patients with Wilms tumor may also manifest other abnormalities, which include aniridia, WAGR syndrome (Wilms tumor, aniridia, other genitourinary abnormalities, and mental retardation), Denys-Drash syndrome (Wilms tumor, glomerulitis, pseudohermaphro-ditism), hemihypertrophy, trisomy,[377] other rare physical abnormalities of macroglossia, and developmental sexual disorders.
Abnormalities of WT1 (chromosome 11p13), WT2 (11p15), and mutations at 16q have all been implicated in the molecular genetics of Wilms tumor. Loss of heterozygosity in WT1 and 16q occur in 20% of patients; inactivation of WT2 has also been described. Other genetic abnormalities have suggested the presence of other abnormal chromosomal locations. Patients with trisomy [386] [387] and XX/XY mosai-cisms have been reported to have an increased incidence of Wilms tumor.
Pathology and Staging
Microscopically, Wilms tumors consist of blastemic, epithelial, and stromal cells, often arranged in patterns that resemble tubular or glomeruloid features. The multipotential aspects of Wilms tumors may be characterized by the presence of teratomatous or teratoid features, including components of mesenchymal structures, such as muscle, cartilage, and lipoid tissues. In contrast to these differentiated structures, undifferentiated or sarcomatoid lesions can also occur and are associated with a worse prognosis. The presence of nephrogenic rests occurring in the setting of Wilms tumors is common; they are thought to be precursor lesions. According to Wilimas and associates,[379] these rests are “defined as a focus of persistent nephrogenic cells, some of which can be induced to form a Wilms tumor.”
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The most common staging system divides Wilms tumor into five categories: |
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Stage 1: tumor limited to the kidney, and completely excised |
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Stage 2: tumor beyond the kidney, but completely resected |
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Stage 3: residual tumor in the local regional area (e.g., peritoneal implants, lymph nodal involvement) |
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Stage 4: hematogenous involvement to metastatic sites |
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Stage 5: bilateral involvement at presentation |
Presenting Features
An abdominal mass, with or without abdominal pain, is the most common sign and symptom, occurring in 80% and 40% of cases, respectively. Other physical abnormalities, including aniridia, genitourinary abnormalities, and hemihypertrophy, may occasionally be detected. Hematuria, anemia, hypertension, or acute severe abdominal pain may also be present. An abdominal ultrasound is an important diagnostic test to further evaluate the mass and its anatomic extension, which may include inferior or superior extension into the vena cava. Intravenous pyelography and CT are also warranted. Metastatic evaluation of liver, chest, and bone complement the evaluation. The diagnosis is usually established by surgery. If the diagnostic tests and clinical features suggest the presence of a Wilms tumor, preoperative needle biopsy should be avoided because of its attendant risks of tumor spillage.
Multimodality Management
High cure rates have been achieved with the concerted effort of multimodality teams performing surgery, radiation therapy, and chemotherapy. Surgical removal of the affected kidney, along with examination of the regional lymph nodes, evaluation of the contralateral kidney, and detailed abdominal exploration are the goal.
Removal of all gross tumor should be attempted, and justifies the radical resection that is often called for. Aside from patients with early-stage lesions of a favorable histology, most patients receive radiation therapy as an adjunct to the surgical removal. Specific recommendations regarding the exact portals utilized are determined by the operative findings, the histologic subtype, and whether there was evidence of tumor spillage during the resection.
Chemotherapy is an important component of therapy in Wilms tumors. In addition to being used after surgery in conjunction with radiation therapy, neoadjuvant chemotherapy can diminish the size of the primary tumor and can cause regressions of metastatic lesions. The agents that have activity against Wilms tumor are vincristine, dactinomycin, doxorubicin, etoposide, ifosfamide, and cisplatin, with the first two agents being the most active. Before the extensive use of chemotherapy, the survival rate for patients with stage 2 or 3 tumors was less than 45%. Now, cure rates approaching 80% to 90% are routinely achieved; survival rates of 92% to 97% are obtainable in earlier stages of disease. For patients who experience relapse or for those with poor prognostic features, bone marrow transplantation has been offered with good results.
As these excellent results continue to accumulate, treatment programs aimed at lessening treatment duration and minimizing long-term consequences, such as induction of second tumors, continue to be evaluated. Such programs include the more selective use of radiation therapy and a decrease in the duration of chemotherapy.
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