The n e w e n g l a n d j o u r n a l of m e d i c i n e
r e v i e w a r t i c l e
m e d i c a l p r o g r e s s
Renal-Cell Carcinoma
Herbert T. Cohen, M.D., and Francis J. McGovern, M.D.
From the Renal and Hematology–Oncolo-gy Sections, Departments of Medicine and Pathology, Boston University School of Medicine (H.T.C.); and the Department of Urology, Massachusetts General Hospital and Harvard Medical School (F.J.M.) — all in Boston. Address reprint requests to Dr. Cohen at the Department of Medicine, Renal Section, Boston University School of Medicine, Evans Biomedical Research Cen-ter, 650 Albany St., Rm. X-535, Boston, MA 02118, or at htcohen@bu.edu.
N Engl J Med 2005;353:2477-90.
Copyright © 2005 Massachusetts Medical Society. n the united states, renal cancer is the 7th leading malignant
condition among men and the 12th among women, accounting for 2.6 percent of all cancers.1 About 2 percent of cases of renal cancer are associated with inherited syndromes. In the United States, 36,160 new cases of renal cancer are predicted to oc-cur in 2005, many of which are being discovered earlier because of the widespread availability of radiographic testing. Nevertheless, 12,660 deaths from the disease are predicted to occur in 2005.1 Renal-cell carcinomas arise from the renal epithelium and account for about 85 percent of renal cancers. A quarter of the patients present with ad-vanced disease, including locally invasive or metastatic renal-cell carcinoma. Moover, a third of the patients who undergo resection of localized disease will have a re-currence. Median survival for patients with metastatic disease is about 13 months. Thus, there is a great need for more effective surgical and medical therapies.
The classic presentation of renal-cell carcinoma includes the triad of flank pain, hema-turia, and a palpable abdominal mass. Few patients now present in this manner. Roughly half the cases are now detected because a renal mass is incidentally identified on radiographic examination. Other common presenting features may be nonspecific, such as fatigue, weight loss, or anemia. Risk factors for renal-cell carcinoma include smoking, obesity, and hypertension,2 as well as acquired cystic kidney disease associ-ated with end-stage renal disease. A 1.6:1.0 male predominance exists,1 and the peak incidence is in the sixth and seventh decades. Gross or microscopic hematuria is an im-portant clinical clue to the diagnosis of renal-cell carcinoma; thus, hematuria should be evaluated promptly by a computed tomographic (CT) scan of the genitourinary tract and, in patients older than 40 years of age, by cystoscopy to rule out bladder cancer. Prognosis is closely related to the stage of disease (Fig. 1). The Heidelberg classifica-tion of renal tumors was introduced in 19976 as a means of more completely correlat-ing the histopathological features with the identified genetic defects (Table 1).
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Von Hippel–Lindau disease (number 193300 in Mendelian Inheritance in Man [MIM]) is a rare, autosomal dominant, familial cancer syndrome consisting chiefly of retinal angiomas, hemangioblastomas of the central nervous system, pheochromocytomas, and renal-cell carcinoma of the clear-cell type (Fig. 2). The von Hippel–Lindau tumor-suppressor gene (VHL) was identified in 1993.7 In this disease, one VHL allele is inher-ited with a mutation. Associated focal lesions, such as renal-cell carcinoma, arise from the inactivation or silencing of the remaining normal (wild-type) VHL allele (Fig. 3). Re-markably, defects in the VHL gene also appear to be responsible for about 60 percent of
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the cases of sporadic clear-cell renal-cell carcino-ma,8 which represents a major portion of all cases of renal-cell carcinoma.
VHL protein, the product of the VHL gene, func-tions as a tumor suppressor, inhibiting growth when reintroduced into cultures of renal-cell carci-noma.9,10 Hypoxia-inducible genes are normally in-hibited by VHL protein,11 including several encod-ing proteins involved in angiogenesis (e.g., vascular endothelial growth factor [VEGF]), cell growth (e.g., transforming growth factor a [TGF-a]), glu-cose uptake (e.g., the GLUT-1 gluglu-cose transporter), and acid–base balance (e.g., carbonic anhydrase IX [CA9]). When VHL protein is lost, these proteins are overexpressed, creating a microenvironment favor-able for epithelial-cell proliferation (Fig. 4A). Thus, cells deficient in VHL protein behave as if they are hy-poxic, even in conditions of normoxia. VHL protein, with elongin proteins C and B, binds cul2 protein (a member of the cullin family of ubiquitin ligase pro-teins), indicating that some VHL protein serves as the receptor subunit of a ubiquitin ligase complex
that promotes the ubiquitination and destruction of proteins (Fig. 4B).12,13 VHL protein binds the transcriptional activators hypoxia-inducible factor 1a (HIF-1a) and 2a (HIF-2a) directly and destabiliz-es them.14 Furthermore, VHL protein promotes the ubiquitination and destruction of HIF-a.15-17 These VHL-regulated pathways are being studied as po-tential targets of therapies for clear-cell renal-cell carcinoma.
HIF is the key regulator of the hypoxic response in multicellular organisms. Thus, VHL protein has a central role in oxygen sensing. For HIF-a to bind VHL protein, a proline residue must undergo hy-droxylation, which is an unusual protein modifi-cation18,19 (Fig. 4B). A family of proline hydroxy-lases operates on HIF-a in a graded fashion, so that the extent of hydroxylation depends on oxygen ten-sion.20,21 Hydroxylation of an asparagine residue blocks the interaction of HIF-a with the transcrip-tional coactivator p300.22 Thus, multiple hydroxyl-ation steps cooperate to inhibit HIF-a activity.
To correlate the genotype with the disease
phe-Figure 1. Staging Overview and Five-Year Survival Rates for Renal Cancer.
Survival data3 are based on the 1997 tumor–node–metastasis (TNM) staging guidelines.4 More recent renal-cancer
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notype, naturally occurring VHL mutations have been evaluated to determine their effect on HIF-a ubiquitination. An intriguing finding is that the
VHL mutations that disrupt HIF-a processing are the same as those associated with the vascular man-ifestations of von Hippel–Lindau disease, such as hemangioblastoma (Fig. 2).15,16,23,24 Since renal-cell carcinoma develops in only a subgroup of pa-tients with hemangioblastoma, the overexpression of HIF-a appears to be necessary for, but not suf-ficient to induce, renal tumorigenesis. Neverthe-less, HIF-a is vitally important to the pathogenesis of this disease. VHL-induced inhibition of HIF-a is sufficient to suppress the growth of clear-cell renal-cell carcinoma in preclinical models.25,26 The cell-matrix protein fibronectin,27 chaperonin TRiC/ CCT,28 microtubules,29 and transcription factor Jade-130-32 are all molecules that interact with VHL protein in a manner that is dependent on VHL mu-tation, suggesting that they may also contribute to disease pathogenesis.
Distinct from von Hippel–Lindau disease, famil-ial clear-cell renal cancer has been reported in pa-tients with translocations of chromosome 3p at a fragile site at 3p14.33 Loss of the translocated chro-mosome 3p probably implicates VHL protein in the development of these tumors. Additional trans-locations of chromosome 3 have been associated with clear-cell renal-cell carcinoma as well.
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Sporadic papillary renal-cell carcinoma has a five-year survival rate approaching 90 percent and a
strik-ing 5:1 male predominance. Localized papillary re-nal-cell carcinoma metastasizes less frequently than clear-cell renal-cell carcinoma.34 However, the sur-vival rate for metastatic papillary renal-cell carci-noma is probably worse than that for clear-cell renal-cell carcinoma.35 The risk of both types is particularly increased among patients with end-stage renal disease. Chromosome 7, which harbors the MET proto-oncogene, is duplicated in 75 percent of sporadic papillary cases. There are two subtypes of papillary renal-cell carcinoma.36 Type 1 tumors are papillary lesions covered by small cells with pale cytoplasm and small oval nuclei with indistinct nucleoli, and type 2 tumors are papillary lesions covered by large cells with abundant eosinophilic cytoplasm. Type 2 cells are typified by pseudostratifi-cation and large, spherical nuclei with distinct nu-cleoli. Type 2 tumors are genetically more heteroge-neous, have a poorer prognosis, and may arise from type 1 tumors.37
Papillary renal-cell carcinoma occurs in several familial syndromes (MIM number 605074). He-reditary papillary renal carcinoma is an autosomal dominant disorder associated with multifocal pap-illary renal-cell carcinoma38 with type 1 histologic features (Fig. 3).39 The causative gene, mutations in which are responsible for hereditary papillary re-nal carcinoma, has been identified at chromo-some 7 and encodes MET, a receptor tyrosine kinase that is normally activated by hepatocyte growth factor40 (Fig. 4C). In hereditary papillary renal car-cinoma, the MET receptor tyrosine kinase domain undergoes autoactivating
amino-acid–substitu-*VHL denotes von Hippel–Lindau, FCRC familial clear-cell renal cancer, SDHB succinate dehydrogenase B, HPRC hered-itary papillary renal carcinoma, HLRCC heredhered-itary leiomyomatosis and renal-cell cancer, and FH fumarate hydratase. † Additional rare syndromes or infrequent associations are not included.
Table 1. Sporadic and Hereditary Renal-Cell Carcinomas and Genetic Defects According to Histologic Appearance.*
Sporadic Renal-Cell Carcinomas Renal-Cell Carcinomas in an Inherited Syndrome
Histologic Appearance Incidence Gene and Frequency Rare Syndrome† Gene percent Conventional 75 VHL, 60 VHL disease FCRC Hereditary paraganglioma VHL Chromosome 3p translocation SDHB Papillary 12 MET, 13 TFE3, <1 HPRC HLRCC MET FH
Chromophobe 4 Birt–Hogg–Dubé syndrome BHD
Oncocytoma 4 Birt–Hogg–Dubé syndrome BHD
Collecting duct <1 Unclassified 3–5
The n e w e n g l a n d j o u r n a l of m e d i c i n e
tion mutations, which promote cellular transforma-tion.41 Subsequently, chromosome 7 harboring the
MET mutation is duplicated, increasing the gene dose.42,43 Only a small percentage of the cases of the sporadic papillary type have MET mutations.40 Thus, the pathogenesis of hereditary papillary re-nal carcinoma is usually different from that of spo-radic papillary renal-cell carcinoma.
Patients with the hereditary leiomyomatosis and renal-cell cancer syndrome (MIM number 605839) are at risk for cutaneous and uterine leiomyo-mas and solitary papillary renal-cell carcinoma with
type 2 histologic features.44 Occasionally, cases of collecting-duct or clear-cell renal-cell carcinoma occur. These cases of papillary renal-cell carcino-ma metastasize early and are the most aggressive of the familial types.45 Intriguingly, FH, the gene that causes this autosomal dominant syndrome, encodes fumarate hydratase, a Krebs-cycle enzyme.46 As with the loss of a tumor-suppressor gene, the wild-type
FH allele is lost in hereditary leiomyomatosis and in lesions of renal-cell carcinoma.47 Along simi-lar lines, cases of renal-cell carcinoma with solid histologic features or cases of the clear-cell form
Figure 2. Schematic Representation of the Clinical Spectrum of von Hippel–Lindau Disease and Potential Biologic Mechanisms.
The three major manifestations of von Hippel–Lindau (VHL) disease — central nervous system hemangioblastoma, pheochromocytoma, and clear-cell renal-cell carcinoma — are represented as Venn diagrams. Affected families may not have all three conditions, depending large-ly on the type of mutation in the VHL gene inherited. Circle sizes are not intended to reflect the numbers of patients in each group. Type 1 VHL disease (Panel A) is most common; it comprises clear-cell renal-cell carcinoma with central nervous system hemangioblastoma and is due to major disruptions in the VHL protein, such as those resulting from truncating mutations. Type 2 VHL disease (Panel A) includes pheochro-mocytoma with one, both, or neither of the other features. Type 2B disease predisposes patients to all three conditions, whereas type 2A in-cludes hemangioblastoma and pheochromocytoma and type 2C inin-cludes only pheochromocytoma. Type 2 is most often due to more subtle VHL gene mutations, such as missense mutations that result in the substitution of a single amino acid. Besides classic von Hippel–Lindau disease, sporadic cases of hemangioblastoma or pheochromocytoma have been shown to be due to germ-line VHL mutations. In addition, familial Chuvash polycythemia, which does not include any of the features of von Hippel–Lindau disease, is an autosomal recessive disorder caused by homozygosity for the specific VHL missense mutation R200W. In Panel B, the spectrum of manifestations of von Hippel–Lindau disease, along with biochemical studies, suggests the involvement of specific biochemical pathways. For example, the mutations in VHL pro-tein that disrupt the ubiquitination and destruction of hypoxia-inducible factor a (HIF-a) are the same as those that correlate with the lesions of hemangioblastoma. Interestingly, von Hippel–Lindau disease type 2A mutations disrupt HIF-a processing and do not cause renal cancer, suggesting that the HIF pathway plus additional, unknown VHL pathways (called X pathways) must be disrupted for clear-cell renal-cell car-cinoma to develop. The probable involvement of additional pathways is supported by the multistep nature of renal tumorigenesis. Alterna-tively, the unknown pathway or pathways may simply reflect a higher level of expression of HIF-a in this subgroup of patients. Pheochromocy-tomas can arise from mutations in the gene for VHL protein that do not affect HIF-a processing, suggesting that they arise through the disruption of other, unknown VHL pathways (called Y pathways). Thus, the overexpression of HIF-a correlates closely with the development of hemangioblastoma; appears to be necessary for, but not sufficient to induce, renal tumorigenesis; and is not necessary for the develop-ment of pheochromocytoma.
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Figure 3. Steps in the Development of Renal-Cell Carcinoma.
In contrast to sporadic renal-cell carcinoma (Panels A and C), fewer steps are required for the development of renal-cell carcinoma in the in-herited forms of the disease (Panels B and D), because all of the patient’s cells have a mutation that predisposes the patient to the disease. As a result, the disease associated with the familial syndromes occurs earlier and is often multifocal. Each familial renal cancer syndrome is autosomal dominant. In von Hippel–Lindau disease, a cellular recessive mechanism is involved, since both copies of the VHL gene are inac-tivated (Panels A and B). VHL is a classic tumor-suppressor gene. In hereditary papillary renal carcinoma, one copy of the MET gene has an activating mutation, which is inherited (Panel D). Chromosome 7, which includes the defective MET allele, becomes duplicated, increasing the level of expression of the activated MET protein, which is a receptor tyrosine kinase for hepatocyte growth factor. Activated MET is a clas-sic oncogene. A plus sign represents the wild-type allele; a minus sign represents a null allele. A plus sign in red type represents a mutated, activated allele; two plus signs in red type represent duplication of that allele.
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have been reported in patients with the hereditary paraganglioma syndrome (MIM number 115310). Certain forms of hereditary paraganglioma are as-sociated with germ-line defects in the succinate de-hydrogenase B gene.48 Succinate dehydrogenase B protein is another mitochondrial, Krebs-cycle en-zyme. Thus, an intriguing connection exists among cellular ATP production, the hypoxic response, and tumorigenesis in both neuronal and kidney tissue. A number of sporadic cases of papillary renal-cell carcinoma have chromosomal translocations in-volving the TFE3 gene at chromosome Xp11.2.49-51 Children and young adults are affected without predilection for sex, and the histologic features of such cases have been variably described as papil-lary renal-cell carcinoma, clear-cell renal-cell carci-noma, or a unique type of pathology. The TFE3 gene encodes a helix–loop–helix transcription factor related to the proto-oncogene product c-myc. Key TRE3 domains become fused with other gene prod-ucts, and renal-cell carcinoma is probably due to
TFE3 overexpression.
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Oncocytomas, which are benign, account for about 4 percent of nephrectomies performed because re-nal-cell carcinoma is suspected. The chromophobe variant of renal-cell carcinoma also accounts for 4 percent of all cases of renal-cell carcinoma52 and may have a benign course after surgery, provided that the tumor stage and grade are favorable.53 On-cocytoma is thought to originate from type A in-tercalated cells of the collecting duct, whereas chromophobe renal-cell carcinoma is thought to originate from type B intercalated cells.
The Birt–Hogg–Dubé syndrome (MIM number 135150) is a rare autosomal dominant disorder characterized by hair-follicle hamartomas (fibro-folliculomas) of the face and neck.54-57 About 15 percent of affected patients have multiple renal tumors, most often chromophobe or mixed chro-mophobe–oncocytomas. Occasionally, papillary or clear-cell renal-cell carcinoma develops in patients with the Birt–Hogg–Dubé syndrome. BHD, the gene implicated in the syndrome, encodes the protein fol-liculin,58 a suspected tumor suppressor. BHD mu-tations occur only rarely in sporadic renal-cell car-cinoma.59,60 The Birt–Hogg–Dubé renal phenotype supports the existence of a close relationship be-tween oncocytoma and chromophobe renal-cell carcinoma.
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Collecting-duct renal-cell carcinoma accounts for less than 1 percent of all cases of renal-cell carcino-ma and is typically an aggressive tumor. Medullary carcinoma of the kidney, which may be a variant of the collecting-duct type, is associated with sickle
Figure 4 (facing page). Molecular Mechanisms of the Development of Renal-Cell Carcinoma.
Pathologic cooperativity between renal-cancer cells of the clear-cell type and adjacent vasculature is shown in Panel A. In clear-cell renal-cell carcinoma, hypoxia-inducible factor a (HIF-a) transcription factor accumu-lates, resulting in the overexpression of proteins that are normally inducible with hypoxia, such as transforming growth factor a and b (TGF-a and TGF-b, respectively), vascular endothelial growth factor (VEGF), and platelet-derived growth factor B chain (PDGF-B). The overex-pressed VEGF, PDGF-B, and TGF-b act on neighboring vascular cells to promote tumor angiogenesis. The aug-mented tumor vasculature provides additional nutrients and oxygen to promote the growth of tumor cells. TGF-a
acts in an autocrine manner on the tumor cells by signal-ing through the epidermal growth factor receptor, which promotes tumor-cell proliferation and survival. The role of von Hippel–Lindau (VHL) protein in clear-cell renal-cell carcinoma and in controlling the expression of the HIF-a transcription factors is shown in Panel B. Under normoxic conditions HIF-a is hydroxylated on two pro-line residues by a propro-line hydroxylase and on an aspar-agine residue by an asparaspar-agine hydroxylase.
Hydroxylation (OH) by proline hydroxylase permits bind-ing of HIF-a to VHL protein, which promotes the ubiquit-ination (Ub) and destruction of HIF-a by the proteasome pathway. Hydroxylation by asparagine hydroxylase blocks the interaction of HIF-a with transcriptional coactivator p300. VHL protein, with elongin proteins C and B, binds cul2 protein (a member of the cullin family of ubiquitin ligase proteins). RING-box protein Rbx1 serves as the ubiquitin transferase for the VHL skp-cullin-F-box pro-tein (SCF) complex. In the absence of wild-type VHL protein, hydroxylated HIF-a accumulates and is able to heterodimerize with HIF-b and activate transcription at hypoxia-response elements (HREs), which are found in genes such as VEGF. In hypoxic conditions, HIF-a is not hydroxylated and so cannot bind VHL protein. Panel C shows the role of MET in papillary renal carcinoma. MET is a receptor tyrosine kinase for hepatocyte growth factor. In the absence of ligand, MET normally exists in an autoinhibited state. MET homodimerizes in the pres-ence of ligand hepatocyte growth factor and undergoes reciprocal phosphorylation and activation. In hereditary papillary renal carcinoma and in occasional sporadic papillary renal-cell carcinoma, activating mutations of MET disinhibit the receptor, even in the absence of ligand. Furthermore, the mutated MET allele on chromo-some 7 becomes duplicated, increasing the expression of the activated MET protein.
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cell trait or disease. The collecting-duct form may be most similar to transitional-cell carcinoma of the urothelium.
An enhancing renal mass on a CT scan obtained after the administration of contrast material is a strong clue that renal cancer is present. A staging workup should be performed before treatment is initiated. Multiple enhancing lesions, or a family his-tory of renal-cell carcinoma, particularly in persons younger than 50 years of age, suggests a hereditary predisposition to the disease. Von Hippel–Lindau disease, hereditary leiomyomatosis and renal-cell cancer, and the Birt–Hogg–Dubé syndrome all have extrarenal manifestations, whereas familial clear-cell renal cancer and hereditary papillary renal carci-noma do not. Thus, a careful physical examination including ophthalmologic, neurologic, and derma-tologic evaluation may be helpful. CT scanning or magnetic resonance imaging (MRI) of the abdomen and pelvis may reveal uterine tumors in patients with hereditary leiomyomatosis and renal-cell can-cer or renal cysts or pancreatic or adrenal involve-ment in patients with von Hippel–Lindau disease.
Patients with hereditary renal-cell carcinoma should be closely monitored. CT before and after the administration of contrast material is the best test for detection and assessment of renal masses, with gadolinium-enhanced MRI as an alternative. Such studies can be performed at intervals ranging from every three to six months to every two to three years, depending on the size of the lesions and the type of syndrome. Larger masses require more fre-quent evaluation. Because small masses are usually of low grade, they can be observed until they reach 3 cm, at which time they should be removed.61,62 However, tumors caused by hereditary leiomyoma-tosis and renal-cell cancer should be excised im-mediately because of their aggressive nature. Pa-tients with von Hippel–Lindau disease should undergo MRI studies of the brain and spinal cord to screen for hemangioblastoma. A family pedigree should be generated, and family members at risk should be encouraged to seek medical attention. Testing is available for the VHL, MET, FH, and BHD
genes. One goal of such testing is to free unaffect-ed family members from continuunaffect-ed cancer
screen-ing. Organizations such as the VHL Family Alli-ance (www.vhl.org) are a vital resource for patients, families, physicians, and researchers.
Defining the prognosis of renal-cell carcinoma is important for both therapeutic decision-making and counseling patients. For metastatic renal-cell carcinoma, poor prognostic factors include a low Karnofsky performance-status score (a standard way of measuring functional impairment in pa-tients with cancer), a high level of serum lactate de-hydrogenase, a low hemoglobin level, and a high corrected level of serum calcium.63,64 The Univer-sity of California, Los Angeles, Integrated Staging System was developed to evaluate the prognosis at diagnosis and in the presence of metastatic dis-ease; it includes tumor–node–metastasis (TNM) staging, the patient’s score on the Eastern Cooper-ative Oncology Group performance-status scale (an-other measure of functional impairment in patients with cancer), and the Fuhrman nuclear grade, which assesses histologic features of the tumor.65 This sys-tem has been used successfully in more than 4000 patients at eight international centers.66
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Surgical excision is the primary treatment for re-nal-cell carcinoma. Radical nephrectomy, which includes removal of the kidney en bloc with Gero-ta’s fascia, the ipsilateral adrenal gland, and re-gional lymph nodes, has been the standard thera-py, although more limited approaches are being explored. The surgical approach is determined by the size and location of the tumor within the kid-ney, the TNM stage, and any special anatomical considerations.
Staging and evaluation for the presence of me-tastases, including a careful history-taking and physical examination, should be completed before surgery. Routine laboratory studies should include measurement of the hematocrit and serum levels of creatinine, calcium, and alkaline phosphatase and a urinalysis for proteinuria. Imaging studies, such as radiographs of the chest, CT of the abdomen and pelvis, and in some cases, MRI evaluation of the re-nal vein and inferior vena cava, CT of the chest or head, or bone scanning may be needed. The fre-m a n a g e fre-m e n t o f s p o r a d i c
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p r o g n o s i s
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quency of follow-up after surgery depends on the stage of the tumor.
s u r g e r y f o r m e t a s t a t i c d i s e a s e
Nephrectomy may be warranted, even in the pres-ence of metastatic disease. The combination of in-terferon alfa and nephrectomy is superior to inter-feron alfa alone, offering a survival advantage of 3 to 10 months.67,68 Surgical excision of a solitary metastasis in patients with advanced renal-cell car-cinoma is recommended in many cases, but this approach has not yet been proved to be effective in prolonging survival.
n e p h r o n - s p a r i n g p a r t i a l n e p h r e c t o m y
Nephron-sparing partial nephrectomy has gained acceptance for treating tumors less than 4 cm in di-ameter. Other indications for partial nephrectomy may include a solitary kidney, bilateral renal masses, or renal insufficiency, as well as the presence of hy-pertension, diabetes, or hereditary renal-cell carci-noma syndromes. Results achieved with nephron-sparing surgery are similar to those with radical nephrectomy, but a disadvantage is a rate of local recurrence of 3 to 6 percent.69
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First reported in 1991,70 laparoscopic nephrecto-my has accelerated the evolution toward minimally invasive surgical management of renal-cell carci-noma. The benefits of the laparoscopic approach include decreased postoperative pain, a shorter hos-pitalization, and a quicker recovery. The laparo-scopic approach has been used for both radical nephrectomy and partial nephrectomy. The laparo-scopic partial nephrectomy, however, is a technically demanding procedure with the potential for in-creased perioperative complications.71
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The most recent evolution in the surgical manage-ment of small tumors has been percutaneous ther-mal ablative techniques that use radiofrequency heat ablation72 or cryoablation73 to destroy tumor cells. A needle probe is advanced through the skin and directed into the tumor under image guid-ance. Although early results of radiofrequency ab-lation and cryoabab-lation are encouraging, larger tri-als with long-term follow-up are needed. The rates of complications appear to be low, but reported ad-verse events include intraoperative and postopera-tive hemorrhage, urinary leakage, and injury to
adjacent structures. Because identification of the type of renal-cell carcinoma is important, a core bi-opsy of the renal mass should be performed as part of the procedure. Ideal candidates for minimally invasive percutaneous ablative therapy are patients with tumors less than 3 cm in diameter who have serious coexisting conditions and for whom stan-dard approaches would pose substantial risks. Pa-tients with multifocal tumors may also benefit from minimally invasive percutaneous procedures. High-frequency focused ultrasound applied externally to the body is being studied as another potential min-imally invasive therapy.
Medical therapies are generally offered for locally advanced or metastatic renal-cell carcinoma (Ta-ble 2), and much of the clinical experience with this approach is in patients with the clear-cell type. Because response rates are low, the need to identify new therapeutic agents is great.74
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Rates of response to chemotherapy alone are low (roughly 4 to 6 percent).75 Drug resistance may be related to the expression of the multidrug resis-tance transporter in proximal-tubule cells — the cells from which clear-cell and papillary renal-cell carcinoma may originate. Chemotherapy may be more efficacious for advanced non–clear-cell re-nal-cell carcinoma, particularly the collecting-duct type.76-78 A phase 2 trial of carboplatin and pacli-taxel for the collecting-duct form of the disease is under way.
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The value of immunomodulatory therapy for clear-cell renal-clear-cell carcinoma is supported by reports of occasional spontaneous tumor regression, infre-quent complete regression of metastatic disease with cytokine therapies, and promising early results with allogeneic stem-cell transplantation and tumor vaccines. The goal of immunomodulatory therapy is to boost either tumor antigenicity or host surveil-lance. Unique tumor antigens may also be induc-ible in renal-cell carcinoma.79
Interferon Alfa
About 14 percent of cases of metastatic clear-cell renal carcinoma respond to interferon alfa alone. Various doses and routes have been used.80 The
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dian duration of response is six months and rarely exceeds two years. Because the side effects of the drug are not onerous, it appears to be a good choice to use in combination with other agents in experi-mental approaches.
Interleukin-2
High-dose interleukin-2 is the standard therapy for advanced renal-cell carcinoma and is the only regi-men for this disease approved by the Food and Drug Administration. However, many patients with metastatic disease cannot take high-dose interleu-kin-2, because it causes a capillary leak syndrome or because it is not available in all treatment cen-ters. High-dose interleukin-2 induces responses in 21 percent of patients, as compared with only 13 percent of patients who receive low-dose interleu-kin-2.81 The median duration of response has been reported to be 54 months overall, and for those with a complete response, the median duration of a response is yet to be reached.82 Interleukin-2 has also been used in combination with other drugs, but it is unclear whether combined therapy achieves better results than interleukin-2 alone. Thus, inter-leukin-2 is a highly effective therapy for a subgroup
of patients with metastatic disease. Identifying fea-tures predictive of a response to interleukin-2 would represent a further advance, and efforts are being made to identify patients with clear-cell renal carci-noma who would be likely to have a response to in-terleukin-2 therapy on the basis of pathological characteristics and expression of CA9.
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Given the high rate of recurrence of renal-cell car-cinoma after nephrectomy, a follow-up adjuvant approach would be desirable, especially for pa-tients with high-risk, locally advanced disease. However, conventional chemotherapy, interferon alfa, or even interleukin-283 has not proved effec-tive as an adjuvant therapy. Approaches currently being tested include tumor vaccines and a mono-clonal antibody directed against CA9.
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Allogeneic stem-cell transplantation performed af-ter the administration of a non–marrow ablative regimen elicits a potent graft-versus-tumor effect and appears promising for treating clear-cell renal-cell carcinoma.84 Protocols developed at the Nation-al Institutes of HeNation-alth have used myelosuppress-ive pretreatment, followed by an infusion of donor CD34+ cells and T cells from an HLA-identical sib-ling.84 A course of immunosuppressive agents, such as cyclosporine, is used to limit graft-versus-host disease and is rapidly tapered. Twenty of the first 45 patients with metastatic renal-cell carcino-ma who underwent stem-cell transplantation had a response (44 percent).85 However, results in some other centers have been less promising. The re-sponses have correlated well with the development of graft-versus-host disease and with the conver-sion of T-cell chimerism to full donor origin. One goal is to identify the tumor epitopes that are initi-ating the graft-versus-tumor response to improve treatment specificity. The two drawbacks to stem-cell transplantation have been severe graft-versus-host disease, which can be life-threatening, and the need for a haplotype-matched sibling donor. Prognosis is also an important guide to patient se-lection, since responses take several months. The next generation of strategies for stem-cell transplan-tation may include the use of tumor vaccines after transplantation as well as the use of cytokine thera-py to boost recipient or even donor immunity.
e v o l v i n g t h e r a p i e s
* FDA denotes Food and Drug Administration, VEGF vas-cular endothelial growth factor, and EGFR epidermal growth factor receptor. The trade name for interleukin-2 is Proleukin; for bevacizumab, Avastin; for sunitinib malate, Sutent; for sorafenib tosylate, Nexavar; for gefi-tinib, Iressa; for erlogefi-tinib, Tarceva.
Table 2. Medical Therapies for Advanced Renal Cancer.* FDA-approved regimen
High-dose interleukin-2 (aldesleukin, immunomodula-tory cytokine)
Commonly used agents
Low-dose interleukin-2
Interferon alfa (immunomodulatory cytokine)
Experimental therapies
Bevacizumab (humanized VEGF-neutralizing antibody) Sunitinib malate (VEGF receptor and multitargeted kinase
inhibitor)
Sorafenib tosylate (VEGF receptor and multitargeted ki-nase inhibitor)
Panitumumab (human EGFR-neutralizing antibody) Gefitinib (EGFR tyrosine kinase inhibitor)
Erlotinib (EGFR tyrosine kinase inhibitor)
Temsirolimus (inhibitor of the mammalian target of rapamycin)
Tumor vaccines
m e d i c a l p r o g r e s s
t u m o r v a c c i n e s
Tumor vaccines represent a potential means of en-hancing host immunity. A promising approach to the treatment of advanced clear-cell renal carcinoma uses autologous or donor dendritic cells, which initiate a primary immune response by presenting antigen in the context of costimulatory molecules. Dendritic cells can be pulsed with tumor protein,86 DNA, or RNA87; they can even be fused with tumor cells88,89 to present tumor antigens in a context fa-vorable for therapy. Such vaccines are generally well tolerated, but they will require further optimi-zation. Concomitant administration of cytokines may improve the response to vaccines.
t a r g e t a n t i g e n s
A goal of stem-cell or vaccine therapies is to char-acterize the tumor antigens involved in the immune response. One potential target is the G250 renal can-cer antigen, which has been identified as CA9. The
CA9 gene is a target of HIF and so is overexpressed in VHL-related clear-cell renal carcinoma, even in the earliest lesions of von Hippel–Lindau disease.90 Thus, in cases of renal-cell carcinoma, a high pro-portion of CA9-positive cells may be associated with a more favorable prognosis.91 As a transmembrane protein, CA9 may also be a therapeutically useful tu-mor antigen.92,93 It will be important to identify additional target antigens.
t h e r a p i e s t a r g e t i n g v e g f a n d t g f -a p a t h w a y s
Originally identified as regulated by VHL, VEGF and TGF-a are now promising therapeutic targets in clear-cell renal carcinoma. The manner in which these molecules interact with the cancer epitheli-um and surrounding vascular endotheliepitheli-um leads to tumor progression (Fig. 4A). A combination of ther-apies based on rational targets such as these may therefore be a powerful approach to advanced renal-cell carcinoma.
VEGF-Pathway Components as Molecular Targets VEGF is overexpressed throughout clear-cell renal-cell carcinoma tissue and may be the most impor-tant tumor angiogenic factor. A randomized phase 2 trial involving patients with metastatic renal-cell carcinoma investigated the efficacy of bevacizu-mab, a humanized VEGF-neutralizing antibody.94 This agent extended the interval before tumor pro-gression to 4.8 months, as compared with 2.5 months for placebo. Bevacizumab therefore
pro-vided a key “proof of principle” of the efficacy of anti-angiogenic therapy and may offer additional benefit when given in combination with other drugs. Inhibitors of VEGF receptor tyrosine kinase are being developed and tested. Indeed, the multi-targeted kinase inhibitors sunitinib and sorafenib have shown great promise in phase 2 and phase 3 trials, with at least stabilization of disease in as many as 70 percent of patients with cytokine-refractory disease.
TGF-a–Pathway Components as Molecular Targets
TGF-a is a potent growth factor for epithelial cells that acts through the epidermal growth factor re-ceptor (EGFR), which is a rere-ceptor tyrosine kinase. TGF-a is overexpressed in the epithelium in clear-cell renal carcinoma and is a VHL target.95 Over-expression of TGF-a is an early event in the patho-genesis of this disease.96 Furthermore, growth of renal cancer cells in culture is dependent on TGF-a.97 Thus, the TGF-a pathway is a logical choice for therapeutic intervention.
Antibodies against EGFR are thought to bind EGFR and promote its down-regulation from the cell surface. A fully human monoclonal anti-body against human EGFR, called panitumumab (ABX-EGF), has been evaluated in a phase 2 trial involving 88 patients with metastatic renal-cell car-cinoma.98 Only one patient had a complete re-sponse, and two had partial responses — a disap-pointing result. Small-molecule inhibitors of the EGFR tyrosine kinase are also being developed.99 The quinazolines gefitinib and erlotinib are now in phase 2 trials. In a phase 1 trial of erlotinib, just one patient with metastatic disease had a com-plete response.100 Erlotinib is also being tested in combination with bevacizumab, although encour-aging initial results could not be confirmed in a randomized phase 2 trial.
Other Approaches
Temsirolimus (CCI-779), a selective inhibitor of the mammalian target of rapamycin, has shown efficacy in a phase 2 trial of metastatic renal-cell carcinoma.101 Temsirolimus may inhibit HIF as well. Partial responses were noted in 7 percent of patients, and minor responses in 26 percent. The median survival rate was 15 months. The notable activity of the drug in patients with poor prognos-tic features prompted a phase 3 trial. Other op-tions are being pursued, including agents target-ing HIF.
The n e w e n g l a n d j o u r n a l of m e d i c i n e
The poor prognosis of advanced renal-cell carci-noma demands an aggressive search for new ther-apeutic agents and strategies. Leads will probably come from both a careful elucidation of the biology of each type of the disease and broader approach-es, such as gene-expression–array and proteome analyses. Much has been accomplished since the identification of the VHL gene in 1993. Already, VHL protein pathways, such as those involving VEGF and TGF-a, are being exploited therapeuti-cally, and agents affecting these pathways might be more effective when used in combination. Identi-fication of the MET gene was another key advance.
The mutated, activated hepatocyte growth factor receptor MET could be targeted in the papillary form of the disease.102,103 The immune respon-siveness of renal-cell carcinoma provides an op-portunity for the development and optimization of vaccines and other immune therapies. Preserva-tion of as much renal funcPreserva-tion as possible and re-duced rates of complications are two goals of new minimally invasive approaches to renal-cell carci-noma; other goals are to identify early markers of disease, prognosis, or responsiveness to therapy.
Supported in part by grants (RO1 CA79830 and RO1 DK67569, to Dr. Cohen) from the National Institutes of Health.
We are indebted to Drs. Michael B. Atkins, William G. Kaelin, Jr., Matthew R. Smith, Walter M. Stadler, and Berton Zbar for careful re-view of the manuscript.
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