Cancer of the Kidney

G. GENITOURINARY Cancer of the Kidney

79 

Megan A. McNamara, Tian Zhang, Michael R. Harrison, and Daniel J. George

S UMMARY

OF

K EY

P OI NT S

• Renal cell carcinoma (RCC) accounts for 4% to 5% of malignancies in adults. • Cigarette smoking (in more than 20% of cases) and obesity (in more than 30%) are established causal factors for RCC. • Four percent of cases of RCC arise from hereditary syndromes. • Different subtypes of RCC are characterized by distinct clinical behavior, genetic abnormalities, and molecular signatures. • Clear cell RCC is the most common histologic subtype, representing approximately 70% of all sporadic RCCs. • The von Hippel-Lindau tumor suppressor gene is genetically and epigenetically altered in more than 75% of sporadic cases of clear cell RCC.

• Prognosis for RCC is dependent on tumor histologic type, grade, and stage. • Nephron-sparing surgery has become the gold standard, when feasible. • Follow-up guidelines for resected RCC include history, physical examination, periodic metabolic panels, and abdominal and chest computed tomography (CT) studies 4 to 6 months after surgery. • Anti–vascular endothelial growth factor (anti-VEGF) targeted drugs are the current standard of care in the first-line setting for metastatic clear cell RCC. • Anti-PD-1 therapy (nivolumab) has proven benefit in patients previously treated with anti-VEGF therapy. Additional immunotherapeutic approaches (with or without

Renal cell carcinoma (RCC) accounts for approximately 4% of adult malignancies, including approximately 90% of primary renal tumors. RCC arises from the renal cortex and consists of several distinct subtypes of adenocarcinoma, with the most common being clear cell carcinoma and papillary carcinoma. In addition to RCC, other benign and malignant tumors occur in the kidney. For example, urothelial (transitional) cell carcinoma of the renal pelvis is a disease that is clinically, pathologically, and biologically distinct from RCC and is much less common, representing only 8% of kidney tumors.1 Other kidney tumors of benign histologic type include oncocytomas, angiomyolipomas (AMLs), fibromas, lipomas, lymphangiomas, and hemangiomas. RCC exists in sporadic and hereditary forms. The sporadic form of the disease is usually first seen in the fifth decade of life or later. The clinical presentation of RCC has been described with the classic triad of symptoms of hematuria, flank pain, and fever. With the increased general use of imaging techniques, however, the vast majority of kidney tumors are now being detected incidentally. Improved surgical techniques for treatment of localized disease and novel systemic therapies for metastatic renal cell carcinoma (mRCC) have changed the management of this condition.

anti-VEGF targeted therapy) are under development in first-line metastatic patients. • Clinical benefit has also been shown with VEGF and mammalian target of rapamycin (mTOR) inhibitors in subsequent lines of therapies either alone or in combination (i.e., lenvatinib and everolimus). Novel targets for therapeutic interventions have been identified and are under clinical development. • Optimal treatment for non–clear cell RCC remains a challenge because of the genetic differences and little knowledge of the dysregulated molecular biology driving these cancers.

EPIDEMIOLOGY The incidence of kidney cancer varies substantially worldwide, with the highest rates observed in Europe, North America, and Australia and the lowest rates in Asia. This suggests that genetic variation and lifestyle factors play a role in the development of RCC. Globally, kidney cancer incidence rates increased from the 1970s to the mid-1990s, then plateaued or decreased. However, in the United States, annual incidence rates of RCC have continued to rise, and the estimated number of new cases of kidney and renal pelvis tumors for 2018 is 65,340.1 The continued upward trend is largely driven by increasing rates of localized disease, whereas rates of regional or metastatic disease have remained relatively stable.2,3 The increasing incidence of RCC has been attributed to increased detection as a result of the widespread use of imaging modalities such as computed tomography (CT), ultrasonography, and magnetic resonance imaging (MRI).4,5 RCC is more common in men, with an approximately 2 : 1 male-to-female predominance.1 In the United States, incidence is lowest among Asian/Pacific Islanders and roughly equivalent among white, black, American Indian/Alaska Natives, and Hispanics.1 1361

1362 Part III: Specific Malignancies

RISK FACTORS FOR SPORADIC RENAL CELL ADENOCARCINOMA The best established risk factors for RCC are cigarette smoking and obesity. A meta-analysis of 24 RCC studies, including 17,245 patients with RCC and 12,501 control subjects, demonstrated increased rates of RCC and worse disease-specific mortality in smokers compared with nonsmokers. In this meta-analysis, the pooled relative risk (RR) rates of RCC incidence were 1.31 (95% confidence interval [CI], 1.22–1.40) for all smokers, 1.36 (95% CI, 1.19–1.56) for current smokers, and 1.16 (95% CI, 1.08–1.25) for former smokers. The related RCC disease-specific mortality risks were, respectively, 1.23 (95% CI, 1.08–1.40), 1.37 (95% CI, 1.19–1.59), and 1.02 (95% CI, 0.90–1.15).6 In addition, smoking has been associated with more advanced RCC stage at presentation.7 Based on these data, smoking significantly increases the risk of developing and dying from RCC, and smoking cessation reduces the risk back close to baseline. In addition to smoking, obesity is also an established independent risk factor for RCC. This has been demonstrated in several prospective cohort studies, including the National Institutes of Health (NIH) and AARP Diet and Health Study, which followed 528,772 participants from 1995 to 2003 and identified an association between the incidence of RCC and elevated body mass index (BMI). In this study, the RR of RCC increased consistently from lower baseline BMI to higher baseline BMI, and this association persisted after adjustment for hypertension and other variables (P-trend < .0005). The multivariate RR of RCC at a BMI of 25 to less than 27.5 kg/m2 was 1.43 (95% CI, 1.07–1.92) for men and 1.57 (95% CI, 1.07–2.29) for women, compared with the 18.5 to less than 22.5 kg/m2 control group. The RR of RCC for participants with BMI ≥35 kg/m2 was 2.47 (95% CI, 1.72–3.53) for men and 2.59 (95% CI, 1.70–3.96) for women.8 The mechanisms underlying the association between obesity and cancer are not fully understood but may relate to dysregulation of three hormonal systems: insulin and insulin-like growth factor, androgens, and adipokines.9

Other possible causes include chronic tissue hypoxia, obesity-induced inflammatory response, and lipid peroxidation and oxidative stress.10,11 With regard to other RCC risk factors, there is evidence that hypertension is associated with an increased risk of kidney cancer, independent of smoking, obesity, or use of antihypertensives.12–14 Patients with end-stage renal disease also have an increased incidence of RCC when compared with the general population. Patients undergoing prolonged dialysis tend to develop acquired renal cystic disease, possibly as a result of disordered proliferation within the native kidney. In these patients, the tumors often are bilateral and multifocal, with a papillary histologic type.15 Accordingly, these patients should be monitored regularly with renal ultrasonography, CT, or MRI. If the patient is on dialysis, then nephrectomy is typically preferred, even when the tumor is smaller than 4 cm, providing the risk of surgery is reasonable. Additional evidence suggests a potential role in RCC for alcohol consumption, occupational exposure to trichloroethylene, and high parity among women. However, further research is needed into the potential causal effects of genetic factors and their interaction with environmental exposures. Large studies employing genome-wide scanning technology are in progress to provide novel discoveries in renal carcinogenesis.16

PATHOLOGY Kidney tumors usually are unilateral but are bilateral in 2% to 4% of cases.17 Vascular involvement is present in 4% to 10% of patients at the time of presentation.18 From a pathologic and surgical prospective, it is important to distinguish a tumor thrombus from a positive margin at the vascular surface, because a true positive margin (with actual invasion into the wall of the vessel) portends a poor prognosis. RCC is a clinically and pathologically heterogeneous disease.19 The 2004 World Health Organization (WHO) classification for renal neoplasms recognized several distinct histologic subtypes of RCC (Table 79.1). These subtypes include clear cell RCC, papillary RCC,

Table 79.1  Histologic Classification of Renal Cell Carcinoma SPORADIC RENAL CELL CARCINOMA (RCC) 2004 WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION Histologic Tumor Type Prevalence (%) Cytogenetic Findings Clear cell RCC Papillary RCC Chromophobe RCC Multilocular cystic RCC Collecting duct carcinoma

70 10–15 4–6 <1 <1

Medullary carcinoma Mucinous tubular and spindle cell carcinoma Neuroblastoma-associated RCC Xp11.2 translocation–TFE3 carcinoma Unclassified lesions

<1 <1 <1 1–2 4–5

3p25-26 (VHL) Trisomy of chromosomes 7 and 17, loss of Y chromosome, 7q34 (c-MET) Loss of multiple chromosomes: 1, 2, 6, 10, 13, 17, 21 Extracellular matrix gene Loss of multiple chromosomes: 1, 6, 8, 13, 14 Sickle cell trait

Translocations involving Xp11.2 (TFE3)

HEREDITARY RCC: SYNDROMES AND HISTOLOGIC TUMOR TYPES Hereditary Syndrome

Chromosome (Gene) Abnormality

Histologic Type of Renal Tumor

von Hippel-Lindau

3p26 (VHL)

Clear cell RCC

Hereditary papillary RCC Hereditary leiomyoma RCC Birt-Hogg-Dube syndrome

7q34 (MET) 1q42–43 (FH) 17p11.2 (BHD)

Type 1 papillary RCC Type 2 papillary RCC Chromophobe RCC, oncocytoma, hybrid tumors

Systemic Manifestations Retinal angiomas, central nervous system hemangioblastomas, pheochromocytoma None Cutaneous and uterine leiomyomas Skin lesions, lung cysts

Modified from Prasad SR, Humphrey PA, Catena JR, et al. Common and uncommon histologic subtypes of renal cell carcinoma: imaging spectrum with pathologic correlation. Radiographics. 2006;26:1795–1806.

Cancer of the Kidney  •  CHAPTER 79 1363

chromophobe RCC, hereditary cancer syndromes, multilocular cystic RCC, collecting duct carcinoma, medullary carcinoma, mucinous tubular and spindle cell carcinoma, neuroblastoma-associated RCC, Xp11.2 translocation–TFE3 carcinoma, and unclassified lesions.20,21 The 2016 WHO update to the RCC classification added several other subtypes: hereditary leiomyomatosis and RCC syndrome–associated RCC, succinate dehydrogenase–deficient RCC, tubulocystic RCC, acquired cystic disease–associated RCC, and clear cell papillary RCC (previously called renal angioadenomatous tumors).22 Clear cell RCC is the most common adult RCC, representing 70% of all RCCs. Less common subtypes include papillary RCC types I and type II (10% to 15%), chromophobe RCC (4% to 6%), collecting duct carcinoma (less than 1%), and unclassified RCC (4% to 5%). Tumors may be composed of mixed histologic subtypes, and each subtype may feature high-grade sarcomatoid characteristics. The conventional histologic pattern is the most common, characterized by large clear cells with abundant cytoplasm. The chromophobe pattern is granular with abundant mitochondria. The papillary or tubulopapillary variant may represent a different type of tumor, because they tend to be smaller with fewer anaplastic features. The most widely used grading system for RCC is the nuclear grading system developed by Fuhrman and colleagues.23 This system assigns a grade from I to IV, based on nuclear size, roundness, and other morphologic features, such as the prominence of nucleoli and the presence or absence of clumped chromatin. Patients with tumors of high Fuhrman grade tend to have poorer clinical outcomes. However, many pathologists omit Fuhrman grade when the apparent aggressiveness of the histologic type is not related to prognosis (e.g., chromophobe carcinoma, which tends to have a favorable prognosis even when the cellular characteristics appear aggressive).

GENETICS AND BIOLOGIC CHARACTERISTICS OF RENAL CELL CARCINOMA Until recently, RCC was thought to represent a monomorphic disease arising from a probable common precursor cell but with different histologic and clinical manifestations. Genetic characterization based on cytogenetics and molecular biology has established that different subtypes of RCCs are characterized by distinct genetic abnormalities and molecular signatures reflecting the differences in the cell type, biology, and underlying molecular mechanisms (Fig. 79.1).24 Additional alterations in metabolic pathways in addition to epigenetic changes may explain the biologic diversity of RCC.

Sporadic Renal Cell Carcinoma Clear Cell Renal Cell Carcinoma A common genetic feature signature of sporadic clear cell RCC is the loss of chromosome 3p, suggesting the presence of one or more RCC tumor suppressor genes at this site. The von Hippel-Lindau tumor suppressor gene (VHL), which resides on chromosome 3p25, is mutated or silenced in more than 50% of sporadic clear cell RCCs.25,26 Germline mutations in VHL give rise to von Hippel-Lindau syndrome, which is characterized by an increased risk of blood vessel tumors (hemangioblastomas), endocrine tumors, and RCC. The VHL gene product, pVHL, is the substrate recognition module of an E3 ubiquitin ligase that targets the hypoxia-inducible factor (HIF) α transcription factors (HIF-1α, HIF-2α, and HIF-3α) for destruction in the presence of oxygen. Hypoxic cells, or cells lacking pVHL (“pseudohypoxic”), accumulate high levels of HIF, which activates the transcription of a variety of genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-3) B, and transforming growth factor alpha (TGF-α). Restoration of pVHL function in VHL−/− mutant renal carcinoma cells suppresses their ability to form tumors experimentally by reducing HIFα levels.27,28 Inhibition of HIFα is necessary and sufficient for tumor suppression by pVHL in RCC nude mouse xenograft assays. This provides a rationale for treating

VHL−/− RCC with inhibitors of HIFα or its downstream targets. Although the HIF-1α isoform was initially believed to be more important, increasing literature supports HIF-2α as the more important HIFα member in mediating tumorigenesis.27,28 Although most investigation has focused on the role of HIFα isoforms, the pVHL protein also has several other targets in addition to HIFα, postulated by some to contribute to tumorigenesis. Elucidating these targets will lead to further knowledge of how pVHL suppresses tumor growth. Analysis of mutations in exon 3 of the VHL gene may be useful in refining the diagnostic criteria for conventional RCC versus chromophobe RCC with clear cell features.29

Papillary Types I and II Renal Cell Carcinoma Genetic studies in familial RCC have led to the identification of genes responsible for non–clear cell histiotypes as well. However, unlike clear cell RCC, gene mutations identified in hereditary non–clear cell RCC are absent in the vast majority of sporadic cases. Activating mutations in the MET oncogene responsible for hereditary papillary renal cell carcinoma (HPRCC) are found in only approximately 10% of sporadic papillary type I RCC cases.30 The MET tyrosine kinase receptor localizes to the cell membrane, where it binds its extracellular ligand, hepatocyte growth factor, triggering intracellular activation of the Akt, Ras, and MAP kinase signaling pathways, promoting cell proliferation and migration. Hyperactivation of MET signaling is believed to promote tumorigenesis by upregulation of these downstream pathways. Both MET and hepatocyte growth factor (HGF) localize to chromosome 7, which is commonly amplified in sporadic papillary type I RCC. The fumarate hydratase (FH) gene encoding a Krebs cycle enzyme and mutated in hereditary papillary type II RCC (as part of hereditary leiomyomatosis and RCC syndrome) has not been identified in sporadic papillary type II.31 However, increased activity of the NRF2 transcription factor resulting from FH loss in hereditary papillary type II has also been demonstrated in sporadic papillary type II renal cancers.32,33 The largest molecular analysis of papillary RCC to date included 161 tumors (75 type I, 60 type II, and 26 unclassifiable). This analysis underscored the tumor heterogeneity of papillary RCCs, as whole-exome sequencing identified 10,380 somatic mutations.34 The most common mutations (representing 24% of tumors) were found in a set of five genes (MET, SETD2, NF2, KDM6A, and SMARCB1).34 Some of the mutations were associated with cancer-associated pathways, including the Hippo signaling pathway, the SWI/SNF complex, and several chromatin remodeling pathways. Papillary RCC was also clustered by mRNA expression panels into four subtypes associated with progressively worse prognosis (cluster C1 associated with type I papillary RCC, mutations in MET, and earlier stage; cluster C2a with type II papillary RCC and early stage; cluster C2b with exclusive type II papillary RCC and unclassified RCC, and later stage at diagnosis; and cluster C3c with a CpG island methylator phenotype in type II papillary RCC).34 Thus with the molecular heterogeneity within each subtype of papillary RCC, this analysis showed the distinct differences between type I and type II papillary RCC.

Chromophobe Renal Cell Carcinoma As with papillary types of RCC, the genetic mutations underlying sporadic chromophobe RCC tumorigenesis remain to be elucidated, and appear to have little mutational overlap with hereditary chromophobe RCC. The folliculin gene mutated in the most common type of hereditary chromophobe RCC (Birt-Hogg-Dube syndrome [BHD]) is rarely mutated (0%–10%) in sporadic chromophobe RCC tumors.35 Whereas PTEN has been implicated in a rarer type of hereditary chromophobe RCC, its mutation is yet to be identified in the sporadic disease.36

TFE3-Fusion Renal Cell Carcinoma Also known as Xp11 translocation kidney cancer, TFE3-fusion RCC represents less than 1% of all sporadic renal cell cancers. It is the most recently designated histologic subtype of RCC by the WHO.

1364 Part III: Specific Malignancies

c-MET

Clear cell good prognosis

Clear cell Chromo poor prognosis Onco

Papl Papll

c-Kit

A

B

1p 1q 2p 2q 3p 3q 4p 4q 5p 5q 6p 6q 7p 7q 8p 8q 9p 9q 10p 10q 11p 11q 12p 12q 13p 13q 14p 14q 15p 15q 16p 16q 17p 17q 18p 18q 19p 19q 20p 20q 21p 21q 22p 22q Xp Xq Yp Yq

VHL

Mutations:

SETD2, UTX, JARID1C, BAP1 (~15% in ccRCC) PBMR1 (~40% in ccRCC)

Figure 79.1  •  Genetic signatures in renal cell carcinoma (RCC). Determining the genetic signature in renal tumors not only has advanced the tumor classification but also will contribute to the optimal selection of therapies. (A) Kinase expression in RCC. These data show the gene expression of approximately 80 kinases (of 518) that have differential expression across the subtypes, with red indicating strong expression. Recognition of c-MET and c-Kit expression allows clustering the samples in specific subtypes. These types of data will guide the selection of patients undergoing treatment with kinase inhibitors. Chromo, Chromophobe; Onco, oncocytoma; PapI, papillary type I; PapII, papillary type II. (B) Summary of the common 3p deletion/5q amplification signature that characterizes clear cell carcinoma. Interesting to note, the 3p region that harbors the VHL gene also contains histone-modifying genes that have been reported to be commonly mutated in this histotype. (A modified from Teh B. Kinome in renal cell carcinoma: mutation analysis of 518 kinases and expression in 400 tumors. J Clin Oncol. 2007;25[18S]:5013.)

Cancer of the Kidney  •  CHAPTER 79 1365

TFE3-fusion RCC occurs in younger patients and is the most common mutation in pediatric RCC tumors. These tumors are clinically aggressive and commonly present with metastasis, particularly to regional lymph nodes. These tumors harbor a pathognomonic fusion between the TFE3 gene of chromosome Xp11.2 and one of a number of possible fusion partners on various chromosomes, most commonly PRCC, ASPRC1, and SFPQ. The TFE3 gene encodes a transcription factor involved in the regulation of many proteins implicated in carcinogenesis, including TGF, MET, Rb, folliculin, Ets, and E-cadherin. It is believed that the fusion promotes tumorigenesis by causing dysregulated transcriptional TFE3 activity. TFE3 and TFEB gene fusions were identified in 10.6% of 161 papillary RCC tumors.34 Immunohistochemical detection of nuclear TFE3 expression is suggestive of the underlying fusion mutation37; however, definitive diagnosis requires genetic confirmation by karyotype, fluorescence in situ hybridization, or polymerase chain reaction (PCR). Rarely, fusions between the related transcription factor gene, TFEB, and the MALAT1/Alpha gene also are found in renal cancers. The histology of these tumors appears to be distinct from that of TFE3fusion tumors. TFEB-fusion cancers similarly occur in younger patients but, in contrast to TFE3-fusion cancers, appear to confer an excellent prognosis. The function of the TFEB transcription factor is unknown, but a central role in lysosome biogenesis and autophagy regulation has been suggested.38

Familial Renal Cell Carcinoma In a small percentage (5%) of cases, RCC is a feature of one of several hereditary syndromes.24,39 Such syndromes are associated with distinct histologic subtypes of RCC, and in each case patients have increased risk of multifocal tumor development.24,39 Management is dependent on preservation of renal function. Close surveillance and minimization of surgical procedures constitute the mainstay of treatment. von Hippel-Lindau syndrome is a disorder of autosomal dominant inheritance that occurs in 1 in 40,000 births. The mean age at onset is in the fourth decade of life. The syndrome is inherited as a result of a germline mutation in a single allele of the VHL gene tumor suppressor gene located on chromosomal band 3p25–26.24,39,40 Sporadic loss of the remaining wild-type VHL allele provides the “second hit” necessary for tumorigenesis, most commonly via chromosome 3p deletion. Multifocal tumorigenesis is observed in multiple organ systems, with each tumor harboring an independent second VHL mutation. Renal manifestations include cysts and clear cell RCC tumors. Both tend to be multifocal and bilateral and are found in the majority of patients with von Hippel-Lindau disease.24,39,40 Hundreds of independent clear cell cancers may be present in a single kidney, including dozens of macroscopic tumors. VHL syndrome patients are at high risk for chronic renal insufficiency because of the lifelong risk of multifocal RCC tumor development and need for repeat renal surgeries. As a result, VHL patients should undergo active surveillance until the largest tumor reaches 3 cm, at which time attempts may be made to resect all tumors in that kidney. Resection by enucleation without clamping of the main renal artery is recommended to maximize nephron sparing. Surgical candidates, particularly those with numerous tumors, are counseled as to the high possibility of local recurrence from de novo tumor formation and future ipsilateral surgery. The discovery of the VHL gene in hereditary clear cell RCC enabled the subsequent identification of a VHL mutation in sporadic clear cell RCC tumors (see earlier).41 In addition to renal cysts and cancer, common manifestations of the VHL syndrome include benign vascular tumors of the spinal cord, cerebellum, and retina, manifesting with neurologic and visual symptoms. The endocrine system may also be affected by adrenal pheochromocytomas and pancreatic neuroendocrine tumors, in addition to pancreatic cysts. Benign papillary cystadenomas of the epididymis or broad ligament also develop in a minority of patients, which, when bilateral are pathognomonic for von Hippel-Lindau disease. The finding

of firm epididymal nodules at physical examination should prompt scrotal ultrasonography and with a family history of VHL provides an easy method to confirm the diagnostic suspicion. Endolymphatic sac tumors of the inner ear also may be seen. Birt-Hogg-Dube syndrome is a disorder of autosomal dominant inheritance. Signs and symptoms usually manifest in the fifth decade of life and include renal tumors and cysts, benign skin tumors (fibrofolliculomas) and pulmonary cysts, which can lead to spontaneous pneumothorax. The renal neoplasms may be multifocal and bilateral tumors and most often have pure chromophobe histologic features or a “hybrid” mixture of chromophobe and oncocytoma; infrequently, pure oncocytoma tumors may be present. Patients can have several different tumor types within the same kidney, and the presence of benign tumors (oncocytoma) and malignant tumors within the same kidney should immediately prompt the suspicion of BHD syndrome. The BHD gene mutated in this syndrome encodes the protein folliculin and is located on chromosome 17p11.2.24,39,40,42,43 The BHD gene appears to have the characteristics of a loss-of-function tumor suppressor gene.44 Folliculin has unknown function but is found in complexes with adenosine monophosphate–activated protein kinase, the major sensor of cell energy and a negative regulator of the mammalian target of rapamycin (mTOR) pathway. Multiple studies have implicated folliculin in adherens junction formation and signaling.45,46 Tuberous sclerosis is a syndrome of autosomal dominant inheritance, with two genes identified: TSC1, located on 9q34, and TSC2, located on 16p13.3. It affects 1 in 6000 people and is usually diagnosed at birth.24,39,40 This syndrome encompasses multiple organ systems, including dermatologic, cardiac, pulmonary, and renal. Skins lesions include facial angiofibromas, periungual fibroma, shagreen patches, and hypopigmented macules. Patients also develop cardiac rhabdomyomas, pulmonary lymphangioleiomyomatosis, retinal hamartomas, subependymal nodules, and giant cell astrocytomas. The renal manifestations include bilateral and multifocal AMLs and, less commonly, clear cell renal carcinoma. In contrast to spontaneous AML, AML in this setting can be associated with a low risk of occult RCC (1%). The TSC1 and TSC2 gene products inhibit activation of mTOR signaling, a major promoter of protein synthesis and cell growth. Hereditary papillary renal cell carcinoma, inherited as an autosomal dominant trait, is caused by mutations in the MET proto-oncogene on chromosomal band 7q31–34.24,40,47 It is characterized primarily by bilateral, multifocal papillary type I RCC. These tumors are not aggressive and rarely metastasize. Age at onset is around the fifth decade. The MET oncogene encodes a membrane tyrosine kinase that, in HPRCC, harbors an activating mutation in the kinase domain. Hyperactivation of the MET oncoprotein leads to upregulation of several intracellular signaling pathways involving Akt, Rac, and MAP kinase. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a disease of autosomal dominant inheritance. The gene for this disorder localizes to chromosomal band 1q42.3–43 and has been identified as FH.24,39,40 Age at onset is between the third and fourth decades of life. The syndrome consists of cutaneous leiomyomas, uterine leiomyomas (fibroids), and papillary type II RCC tumors with high metastatic potential, even when small in size. Unlike the VHL patients, in whom delay in surgical treatment is usually the rule until the largest tumor reaches 3 cm, there should be no delay in treatment of solid renal lesions in these patients, because the disease is aggressive and metastasizes quickly.48 Cystic lesions in these patients should be followed with close surveillance and early surgical intervention for any radiographic development of a potentially solid component. Thirty percent of patients have solitary and unilateral renal tumors.39,40 The FH gene functions as a tumor suppressor, with loss of the second allele detected in kidney tumors. The wild-type gene encodes an enzyme in the Krebs cycle catalyzing fumarate conversion into malate. Loss of the FH enzyme leads to accumulation of fumarate, which has been suggested to promote carcinogenesis through indirect stabilization of transcription factors HIFα and NRF2.32,33,49

1366 Part III: Specific Malignancies

Distinct from HPRCC and HLRCC, Malchoff and colleagues have described a three-generation family with five cases of papillary thyroid carcinoma and two cases with papillary renal neoplasia.47 With the use of linkage analysis, these investigators demonstrated that the fPTC/PRN phenotype was linked to 1q21.47 They characterized a distinct inherited tumor syndrome that may establish a link between papillary RCC and familial papillary thyroid carcinoma.47 Hereditary renal cell cancer associated with melanoma has also been described. The TFE3 gene mutated in sporadic RCC is one of four members of the MiT family of transcription factors; although TFE3 mutations have not been identified in hereditary RCC syndromes, the related MiT member, MiTF, was shown to have a specific amino acid substitution associated with hereditary RCC tumors associated with melanoma.50 This substitution confers hyperactivation of MiTF transcriptional activity by preventing its SUMOylation and degradation. Histologic features of these MiTF renal cancers are yet to be characterized.

DIAGNOSIS OF RENAL CELL CARCINOMA As the use of imaging methods has become more widespread, the frequency of incidental detection of RCC has increased. Patients with RCC typically have a mass involving the kidney that is suggestive of the diagnosis. Nephrectomy is the most effective therapy for RCC that is confined to the kidney and should be used both diagnostically and therapeutically in most patients who are suitable surgical candidates. However, in certain clinical settings, percutaneous biopsy of a renal mass should be considered. In a retrospective study of 115 consecutive percutaneous biopsies performed on renal masses in 113 patients, investigators found percutaneous biopsy to be of high sensitivity in three clinical groups: patients with a known malignancy (n = 55), patients with no known malignancy and suspected unresectable tumor (n = 36), and nonsurgical patients with a mass suspected to be a resectable RCC (n = 8).51 Percutaneous biopsy of renal masses appears to be safe, carrying only a minimal risk of tumor spread. Urologists should consider increasing the indications for renal biopsy of small renal masses that appear to be RCC, especially in elderly and surgically unfit patients. Percutaneous biopsy also may allow better selection of renal tumors for active surveillance and minimally invasive ablative therapies. However, there are certain histologic subtypes that cannot be easily distinguished with percutaneous biopsy. Oncocytoma, for instance, can be diagnosed only by resection, as rarely clear cell carcinoma may harbor regions of oncocytic cells, which are indistinguishable from oncocytoma with a single-needle core. In cases in which oncocytoma may be suspected (e.g., in a patient with prior multifocal oncocytomas in the contralateral kidney), several staged biopsies of the mass can be performed to increase the confidence in the diagnosis. An RCC is unlikely to have three separate biopsies all positive for oncocytic cells but without any clear cell components. Finally, initial therapy for mRCC may potentially be stratified by histologic subtype and, in the future, molecular characteristics.

STAGING SYSTEMS FOR RENAL CELL CARCINOMA The tumor-node-metastasis (TNM) system is a dynamic staging method that continually changes on the basis of new evidence from clinical studies (Table 79.2).52 This staging system is a method of stratifying patients with cancer and is based on data from large multicenter studies with large numbers of patients and a good level of evidence. Despite continual revisions to the methodology to incorporate new clinical evidence, however, the optimal RCC patient stratification using the TNM staging system remains controversial, and further revisions probably will be needed. Revision of the TNM staging system for RCC is likely to result in the simultaneous update of the integrated prognostic systems currently used with this traditional method of staging.

In the most recent (2010), seventh edition of the American Joint Committee on Cancer (AJCC) staging manual for RCC,53 T2 lesions are now subclassified as T2a (>7 cm up to 10 cm) and T2b (>10 cm), and ipsilateral adrenal involvement is now staged based on type of invasion: T4 if contiguous, M1 if not contiguous. In addition, renal vein involvement is reclassified as T3a, and nodal involvement is simplified to either N0 or N1, with the N2 stage dropped. In the previous (2002) edition of the manual, the key change was the subdivision of T1 lesions into T1a and T1b. The rationale was based on evidence from studies of patients undergoing partial nephrectomy, a procedure commonly used for tumors that are 4 cm or smaller. It has been reported that patients who undergo partial nephrectomy for RCC tumors smaller than 4 cm have equivalent survival to those undergoing radical nephrectomy.54 In a separate study of 485 patients undergoing nephron-sparing surgery for RCC with a mean follow-up period of 47 months, patients were divided into four groups based on the size of the primary.55 Patients in group 1 (tumors <2.5 cm in diameter) and those in group 2 (tumors 2.5–4.0 cm) had equivalent survival, although survival was significantly greater for groups 1 and 2 than for group 3 (tumors 4–7 cm) and group 4 (tumors >7 cm). These findings were similar to those previously published in a separate series of 394 patients.56

PROGNOSTIC FACTORS FOR RENAL CELL CARCINOMA Although TNM stage, Fuhrman grade, and Eastern Cooperative Oncology Group (ECOG) Performance Status are the most widely recognized prognostic factors in RCC, research continues to determine strong and easily available prognostic parameters that may help to classify patients into groups with different risks for death from renal cancer. The prognosis for patients with RCC is dependent primarily on disease stage. Patients with histopathologic stage pT1 or pT2 (organ confined) disease have the best prognosis, with 5-year cancerspecific survival rates after nephrectomy ranging from 71% to 97%.57 For patients with locally advanced tumors, 5-year cancer-specific survival rates after nephrectomy decrease by 20% to 53%, and once RCC has metastasized, the 5-year survival rate is less than 10%. Numerous models exist to predict disease recurrence after nephrectomy for all histologic types and specifically for clear cell RCC.58 The natural history and risk group stratification have also been evaluated in those with newly diagnosed mRCC and in patients with previously treated metastatic disease. Currently, RCC histologic subtypes are classified according to the Union for International Cancer Control (UICC) and AJCC recommendations.59 These recommendations are based on the Heidelberg classification system,60 which categorizes RCCs as clear cell, papillary, chromophobe, collecting duct, and unclassified RCC subtypes. Studies have suggested that stratification by histologic subtype could lend prognostic value.61,62 The University of California at Los Angeles (UCLA) Integrated Staging System (UISS) was developed for the purpose of improving the prognostic accuracy of the 1997 TNM staging system by incorporating clinical variables.57 To confirm the ability of the UISS to stratify patients with localized and mRCC into risk groups, an international multicenter study was conducted.58 A total of 4202 patients from eight academic centers were classified according to the UISS. The UISS stratified both localized and mRCC cases into three different risk groups. For localized RCC, the 5-year survival rates were 92%, 67%, and 44% for low-, intermediate-, and high-risk groups, respectively. A trend toward a higher risk of death was observed in all centers for increasing UISS risk category. For mRCC, the 3-year survival rates were 37%, 23%, and 12% for low-, intermediate-, and high-risk groups, respectively. In six of eight centers, a trend toward a higher risk of death was observed for increasing UISS risk category. A greater variability in survival rates among centers was observed for high-risk patients. These results suggest that the UISS is an accurate predictor of survival for patients with localized RCC, applicable to external

Cancer of the Kidney  •  CHAPTER 79 1367

Table 79.2  Tumor-Node-Metastasis (TNM) Staging System for Renal Cell Carcinoma Staging

Classification 1987

Tumor

T1

1997

2002

2010

Tumor ≤7 cm, limited to kidney NA

NA

Tumor ≤7 cm, limited to kidney

T1a

Tumor ≤2.5 cm, limited to kidney NA

Tumor ≤4 cm, limited to kidney

T1b

NA

NA

T2

Tumor >2.5 cm, limited to kidney NA

Tumor >7 cm, limited to kidney NA

Tumor ≤4 cm, limited to kidney Tumor >4 cm and ≤7 cm, limited to kidney Tumor >7 cm, limited to kidney NA

Perinephric or adrenal extension Renal vein or vena cava involvement below diaphragm Vena cava involvement above diaphragm Outside Gerota fascia NA

Perinephric or sinus fat or adrenal extension Renal vein or vena cava involvement below diaphragm Vena cava involvement above diaphragm Outside Gerota fascia NA

Renal vein, perinephric, or renal sinus fat extension IVC involvement below diaphragm

NA Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastases in one regional lymph node

NA Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastases in one regional lymph node

NA Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in regional lymph node(s)

Metastases in more than one regional lymph node

Metastases in more than one regional lymph node

NA

NA

NA

NA

Distant metastasis cannot be assessed No distant metastases Distant metastases

Distant metastasis cannot be assessed No distant metastases Distant metastases

Distant metastasis cannot be assessed No distant metastases Distant metastases

T2a T2b T3

T3a T3b T3c T4 T4a

Node

T4b Nx N0 N1 N2

N3

Metastasis Mx M0 M1

NA Tumor extends into major veins or invades adrenal or perinephric tissues, but not beyond Gerota fascia Perinephric or adrenal extension Renal vein involvement Vena cava involvement below diaphragm Outside Gerota fascia Vena cava involvement above diaphragm NA Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastases in one lymph node ≤2 cm in greatest dimension Metastases in one lymph node >2 cm, but not >5 cm in greatest dimension Metastases in one lymph node >5 cm in greatest dimension Distant metastasis cannot be assessed No distant metastases Distant metastases

Tumor >4 cm and ≤7 cm, limited to kidney Tumor >7 cm, limited to kidney

Tumor >7 cm and ≤10 cm, limited to kidney NA NA Tumor >10 cm, limited to kidney Tumor extends into major Tumor extends into major Tumor extends into major veins veins or invades adrenal or veins or invades adrenal or or invades adrenal or perinephric tissues, but not perinephric tissues, but not perinephric tissues, but not beyond Gerota fascia beyond Gerota fascia beyond Gerota fascia

IVC involvement above diaphragm Outside Gerota fascia NA

IVC, Inferior vena cava; NA, not applicable. From Ficarra V, Galfano A, Mancini M, et al. TNM staging system for renal-cell carcinoma: current status and future perspectives. Lancet Oncol. 2007;8:554–558.

databases. Although the UISS may be useful for patients with mRCC, it may be less accurate in this subset of patients because of the heterogeneity of patients and treatments. A retrospective, single-institution review of 24 consecutive clinical trials conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) using cytokines or chemotherapy for the treatment of advanced RCC (N = 670) identified a small subgroup of patients (n = 30) who were long-term survivors after nephrectomy and treatment with interferon-α, interleukin (IL)-2, or surgical resection of metastasis.63 The five most prominent negative prognostic factors that were identified with multivariate analysis included low Karnofsky Performance Status score (<80%), elevated lactate dehydrogenase (>1.5 times the upper limit of normal), low serum hemoglobin (below the lower limit of normal), high corrected serum calcium (>10 mg/dL), and absence of nephrectomy. Patients with zero risk factors were assigned a favorable-risk

status; those with one or two risk factors, an intermediate-risk status; and those with three or more risk factors, a poor-risk status. All long-term survivors in this study were in either good- or intermediaterisk groups. The natural history and risk group stratification also have been evaluated in patients with newly diagnosed mRCC. For patients diagnosed with disease recurrence, no specific risk stratification tools have been available at the time of recurrence. A retrospective study sought to evaluate the usefulness of the prognostic score suggested by Motzer and coworkers.64 From January 1989 to July 2005, patients with localized RCC treated with nephrectomy in whom recurrent disease subsequently developed were identified. Each patient was given a total risk score of 0 to 5, with 1 point for each of five prognostic variables (recurrence at <12 months after nephrectomy, serum calcium concentration >10 mg/dL, hemoglobin concentration less than the

1368 Part III: Specific Malignancies

lower limit of normal, lactate dehydrogenase level >1.5 times the upper limit of normal, and Karnofsky performance status <80%). Patients were categorized into low- (score = 0), intermediate- (score = 1 to 2), and high-risk subgroups (score = 3 to 5). The final cohort included 118 patients, with a median survival time of 21 months from the time of recurrence. Median duration of follow-up for survivors was 27 months. Overall survival (OS) was associated with risk group category. Low-risk, intermediate-risk, and high-risk criteria were fulfilled in 34%, 50%, and 16% of patients, respectively. Median survival times for low-risk, intermediate-risk, and high-risk patients were 76, 25, and 6 months, respectively. Two-year OS rates for lowrisk, intermediate-risk, and high-risk patients were 88%, 51%, and 11%, respectively. These additional data support the use of a scoring system based on objective clinical and laboratory data to achieve meaningful risk stratification for both patient counseling and clinical trial entry. Heng and colleagues reported a novel model that validates components of the MSKCC model with the addition of platelet and neutrophil counts to establish a prognosticator algorithm for OS in patients with mRCC treated with VEGF inhibitors.65 In their latest report, the authors conducted an external validation and comparison with existing databases in RCC patients treated with VEGF inhibitors in the first-line setting at 13 institution members of the Consortium’s database.66 They compared the Database Consortium model with the Cleveland Clinic Foundation, the International Kidney Cancer Working Group, the French, and the MSKCC models. A total of 1028 patients were assessed, with the majority having complete data. Median OS was 18.8 months. The previously defined prognostic factors (anemia, thrombocytosis, neutrophilia, hypercalcemia, Karnofsky Performance Status <80%, and <1 year from diagnosis to treatment) were independent predictors of reduced survival in this external validation set. The results showed that median OS was 43.2 months in the favorable-risk group (no risk factors), 22.5 months in the intermediate-risk group (one or two risk factors), and 7.8 months in the poor-risk group (three or more risk factors). The concordance index of the Database Consortium with the other models ranged between 0.636 and 0.687. Now that this Database Consortium model has been externally validated, it can be applied to stratify patients by risk in clinical trials involving anti-VEGF therapies and to counsel patients about prognosis.

MANAGEMENT OPTIONS FOR LOCALIZED DISEASE The gold standard treatment for RCC localized to the kidney is surgical resection, which can be a curative treatment in this setting. Resection is performed by means of radical nephrectomy, with removal of the entire kidney and tumor en bloc, or partial nephrectomy, with removal of the tumor alone, maximizing preservation of renal function. Locally advanced tumors may require additional resection of tumor in the renal vein and vena cava and/or partial resection of surrounding organs. The operation can be performed as an open procedure or laparoscopically, the latter with or without robotic assistance, and by using either a transperitoneal or a retroperitoneal anatomic approach. Regional lymphadenectomy in the absence of lymphadenopathy remains controversial and is at present not routinely performed. In patients with significant comorbidity, advanced age, small tumor size, and/or low-risk tumor histologic type, or who are otherwise unwilling to undergo surgery, less invasive options include thermal ablation and active surveillance. However, long-term outcomes supporting the oncologic safety of these alternatives are less well established; therefore these options are currently reserved for select patients with greater operative than oncologic risk.

Radical Nephrectomy Radical nephrectomy, including perifascial resection of the kidney and perirenal fat, is the traditional gold standard treatment for localized

RCC. Long-term cancer-specific survival for pT1a, pT1b, pT2, and pT3 lesions can be approximated at greater than 90%, 80%, 70%, and 60%, respectively. Historically, a radical nephrectomy has included resection of the ipsilateral adrenal gland. However, adrenal resection increases the risk of life-threatening adrenal insufficiency (Addisonian crisis) should the contralateral adrenal gland require resection or become otherwise functionally compromised. Today, it is common practice to limit adrenalectomy to the setting of large or upper pole renal tumors, given a low risk of adrenal involvement with smaller RCC tumors. Even in this setting, ipsilateral adrenalectomy has been challenged by recent studies suggesting that negative CT imaging of the ipsilateral adrenal gland can effectively rule out RCC involvement.67 Although still controversial, in the setting of negative cross-sectional imaging, adrenal gland preservation should be considered to avoid long-term risk of Addisonian crisis. The role of regional lymphadenectomy at the time of radical nephrectomy is also controversial. The most common regional landing sites for RCC are the paracaval, interaortocaval, and retrocaval nodes for the right kidney, and the paraaortic, interaortocaval, and preaortic nodes for the left kidney. In the presence of radiographic or palpable lymphadenopathy, a lymph node dissection is justified. In the absence of such findings, the role of lymphadenectomy is prognostic only, with no Level I evidence to support a therapeutic benefit. Some series have suggested a therapeutic role for lymphadenectomy specifically in patients without lymphadenopathy if their primary tumors are otherwise high risk, but results from large series are overall conflicting and limited by their retrospective nature.68–70 The European Organisation for Research and Treatment of Cancer (EORTC) 30881 trial has provided the only prospective randomized trial investigating radical nephrectomy (N = 772) with or without lymphadenectomy, but showed no benefit with regional lymphadenectomy at a median follow up of 12.6 years.71 This trial has been criticized for its inclusion of patients with predominantly low tumor stage and thus a low rate of nodal positivity (4%), suggesting insufficient power to detect a therapeutic benefit. Further analyses have concluded that extended lymphadenectomy could be beneficial in patients at increased risk for lymph node involvement (e.g., locally advanced [T3 or T4] tumors, grade 3 or 4 tumors, sarcomatoid histology, or presence of coagulative necrosis).72,73 However in the absence of Level I evidence supporting such a role, in general most urologists continue to avoid lymphadenectomy at nephrectomy, given the significant risk for hemorrhage during dissection along the aorta and vena cava.

Nephron-Sparing Surgery Radical nephrectomy has been shown to cause significant decreases in renal function, raising the risk of chronic renal insufficiency and dialysis, and chronic renal insufficiency, which in turn raises the risk of cardiovascular events, hospitalization, and overall mortality.74 Acknowledging the detrimental impact of chronic renal insufficiency on overall health, urologists have increasingly strived over the past two decades to preserve renal function in RCC patients. With increasing sensitivity and use of imaging studies leading to detection of smaller renal tumors, partial nephrectomy has become an effective alternative to radical nephrectomy for patients with localized RCC, resulting in low morbidity and good oncologic outcomes. Traditional indications for partial nephrectomy have included conditions in which radical resection would leave the patient anephric (bilateral RCC, a horseshoe kidney, or a solitary kidney) and requiring immediate dialysis, in addition to unilateral RCC with a contralateral kidney at risk for compromised function, as in diabetes, hypertensive nephrosclerosis, renal artery stenosis, renal calculi, and chronic pyelonephritis. Initial outcomes with such indications supported operative feasibility and oncologic safety of a nephron-sparing approach. Patient selection quickly expanded to include localized primary tumors with diameter of 4 cm or less and exophytic location, regardless of renal function.75 Although the risk of local recurrence is necessarily

Cancer of the Kidney  •  CHAPTER 79 1369

increased with a nephron-sparing approach, risk of cancer-specific mortality appears similar to that of a radical approach. Perioperative complications are, however, more common with partial nephrectomy, largely because of increased bleeding and transfusion and urinary leaks related to collecting system injury. Indications for partial nephrectomy have expanded to include select larger tumors.76 Several studies have now retrospectively compared partial and radical nephrectomy for larger tumors up to 7 cm, demonstrating similar oncologic outcomes.77,78 Leibovich and associates compared outcomes in 91 patients managed with nephron-sparing surgery and 841 patients who underwent radical nephrectomy for 4- to 7-cm tumors.77 These investigators found no statistical difference in cancer-specific survival and distant metastases between the two groups. Dash and colleagues similarly compared 196 patients undergoing partial (n = 45) or radical nephrectomy (n = 151) for clear cell RCC tumors of 4 to 7 cm. They observed no differences in oncologic outcomes between the two groups, but noted better postoperative renal function at 3 months for patients undergoing nephron-sparing surgery.78 With regard to feasibility of partial nephrectomy, tumor location (exophytic versus endophytic) may be a better determinant than tumor size. With either larger size or more endophytic location, ischemic time can be expected to increase, along with complications related to bleeding and collecting system injury (urinary leak).79–81 The indications for nephron-sparing surgery are partly dependent on the experience and skill of the surgeon. The primary oncologic concern with nephron-sparing surgery is the risk of recurrence in the same kidney, avoided with radical nephrectomy. Ipsilateral intrarenal recurrence occurs in 1% to 6% of patients after partial nephrectomy and may result from either primary tumor multifocality (including de novo tumor formation) or positive surgical margins.82 However, it remains controversial whether positive surgical margins during partial nephrectomy increase the risk of RCC recurrence or have no prognostic significance. Many series support good local recurrence-free survival for patients with positive margins and intermediate-term follow up. Furthermore, immediate or delayed radical nephrectomy most often fails to reveal any residual disease in these patients. In a large single-institutional series, Kwon and colleagues found no relation between margin status after partial nephrectomy and primary tumor risk (metastatic potential).83 However, local recurrence occurred in 4% of patients with a positive margin compared with only 0.5% of patients with negative surgical margins, and all cases of local recurrence in both groups were from high-risk primary tumors. The authors concluded that local recurrence may be more likely when positive surgical margins occur in the specific setting of high-risk primary tumor histologic type, whereas positive margins with low-risk primary tumors may have no significance. Other studies regarding the effects of a positive margin on prognosis have produced conflicting results.84–86 Current practice generally assumes no prognostic significance of positive surgical margins; hence, regardless of margin status, after partial nephrectomy surveillance is standard of care. A large volume of existing retrospective literature now suggests survival benefits of partial nephrectomy over radical nephrectomy but suffers from an uncertain selection bias. In a meta-analysis of more than 40,000 patients undergoing radical or partial nephrectomy, the latter was associated with a significant benefit in both survival and renal function; however, the quality of pooled studies was judged to be low.87 A large multiinstitutional randomized trial from EORTC comparing partial and radical nephrectomy for tumors 5 cm or smaller has challenged current thinking on the role of nephron-sparing surgery.88 A total of 541 patients were enrolled in this study, and median follow-up was more than 9 years. Based on an intention-to-treat analysis, the radical nephrectomy group cohort showed better OS compared with patients assigned to partial nephrectomy. Because there were very few cancer-specific deaths in either cohort, the benefit in OS for radical nephrectomy was attributed to a reduction in non–cancer-related deaths. This unexpected outcome has come under intense scrutiny

and the study has been heavily criticized because of underaccrual and its intention-to-treat analysis with frequent study arm crossover. Perhaps unduly, these findings have been largely dismissed by the urologic community. With the standardization of staging and earlier diagnosis of the disease, a more tumor-specific surgical management has proved to be advantageous for maximizing the preservation of functional renal tissue. With increased evidence of the need for long-term dialysis in patients undergoing total nephrectomy, maintenance of renal function in both kidneys represents the strongest argument for nephron-sparing surgery in patients with RCC who have the best chance for cure.

Surgical Approach For cancers confined to the kidney requiring radical nephrectomy, a laparoscopic approach is generally preferred based on its tendency for lower blood loss, faster inpatient and outpatient recovery, and similar oncologic outcomes relative to an open approach, although these differences are inferred largely from retrospective comparisons.89–93 In a prospective randomized comparison between these two approaches among patients with tumors up to 8 cm, Burgess and colleagues found that laparoscopic radical nephrectomy achieved significantly better postoperative pain scores and convalescence, but no reduction in hospitalization.94 In contrast to radical nephrectomy, the gold standard approach to partial nephrectomy remains an open incision. However, with increasing use of minimally invasive therapies and enhanced dexterity afforded by robotic assistance, the indications for laparoscopy are expanding to include partial nephrectomy in select patients. Today, the choice between open and robotic or laparoscopic partial nephrectomy depends on anatomic location of the tumor, body habitus, and ability to tolerate pneumoperitoneum. The optimal tumor for laparoscopic partial nephrectomy is small (<4 cm) and peripheral or exophytic, although experienced laparoscopists may take on larger and more centrally located lesions. In a study from a single high-volume laparoscopic surgeon, similar operative outcomes were observed for laparoscopic resection of tumors larger than 4 cm (n = 58) compared with smaller tumors (n = 367), with the exception of a 6- to 8-minute increase in ischemic time.95 Central tumors resected laparoscopically were associated with increases in both ischemic and overall operative times, but not bleeding. An experienced surgeon can therefore perform technically challenging laparoscopy with good surgical and oncologic outcomes.96 The advent of the da Vinci robotic system has simplified the most difficult technical portion of the operation, namely intracorporeal suturing and reconstruction of the resection defect. This has translated to improvements in several key operative outcomes for minimally invasive partial nephrectomy, in addition to a quicker learning curve. In one experienced minimally invasive surgeon’s series of 492 laparoscopic (n = 231) or robotic (n = 261) partial nephrectomies, the latter approach correlated with a significant reduction in operative time, ischemia time, positive margins, and perioperative complications, despite greater patient comorbidity and tumor complexity.97 Other retrospective series have indicated reduced blood loss with the robotic approach.98,99 The single remaining concern for laparoscopic and robotic nephronsparing surgery is the amount of warm ischemic time and resulting loss of renal function. Precooling of the kidney before renal arterial clamping during open partial nephrectomy is believed to reduce ischemic injury but has thus far not been feasible with a laparoscopic approach. Warm ischemic times during laparoscopy in excess of 20 minutes have been suggested to result in irreversible injury. For this reason, complex resections, including large, endophytic, or multifocal tumors, may require alternative methods, including either open resection with cold ischemia, or resection of the tumor without main renal artery clamping. The latter approach increases blood loss and the likelihood of transfusion, but optimizes preservation of renal function.

1370 Part III: Specific Malignancies

Renal hypoperfusion with pharmacologically induced hypotension has been proposed to avoid main renal artery clamping, but the safety and efficacy require further study.100

Thermal Ablation for Renal Cell Carcinoma With the advent of energy-based ablative alternatives to open and laparoscopic surgeries in selected patients, it is now possible to achieve cancer-specific survival with decreased surgical morbidity. Two types of ablation are currently performed: cryoablation and radiofrequency ablation (RFA). Although either can be performed laparoscopically under direct vision, ablation is most often performed percutaneously under ultrasound or CT guidance. Although the usefulness of ablative therapies is still being evaluated by many groups, in the American Urological Association consensus guidelines the efficacy of ablative techniques is considered to be slightly less than that of surgical resection, and the guidelines state that the procedure should be reserved primarily for patients who decline surgery or who are not good surgical candidates but who desire treatment.101 Furthermore, because cryoablation and RFA are already in widespread use and both have demonstrated efficacy, it is unlikely that a large randomized comparative trial of the two types of ablation will be conducted.102 In selected patients, cryoablation has been shown to decrease hospitalization and be an effective nephron-sparing cancer therapy.103 Patients selected for this option tend to have peripheral lesions 5 cm or less in diameter.103–107 Minimally invasive therapy without the sequelae of open or laparoscopic surgery may be reasonable in these situations, particularly in morbid or elderly patients who are poor surgical candidates. Cryoablation surgery has been described in the literature with open, laparoscopic, and, more recently, imaging-guided percutaneous approaches.108,109 Multiple theories have been proposed for the mechanism of action of cryoablative surgery. The most accepted theory postulates direct cellular injury leading to coagulative necrosis.106,107 Injury to the cancer cells occurs as a result of intracellular ice crystal formation during the freezing phase of the treatment.106,107 The freezing process causes protein damage, which injures the cell membrane and affects essential enzymatic processes.106 Ice crystals that form within the cell disrupt intracellular organelles and membranes. In addition, indirect ischemic injury caused by occlusion of the microvasculature during the thaw phase creates stasis within blood vessels, leading to end-tissue infarction. These ensuing insults to renal tissue lead to liquefactive necrosis.106 Advantages to CT-guided cryotherapy include general availability and its excellent capability to differentiate among the visceral organs. It also provides visualization of the entire ice ball while differentiating between frozen and unfrozen tissue. In addition, it provides real-time guidance in the CT fluoroscopy mode. One major disadvantage with CT guidance is the constant radiation exposure to the patient and the surgeon, which can be avoided with adequate and appropriate protection. Numerous studies of cryoablation support adequate oncologic efficacy with short- and intermediate-term patient follow-up. However, there are at present sparse long-term data available. Aron and colleagues provided the first 10-year oncologic outcomes for cryotherapy with use of a laparoscopic approach. The mean tumor size was 2.3 cm, and cancer-specific survival at 10 years was 83%, comparable but slightly lower than would be expected for surgical resection of renal cancers of this size.110 Because the renal tumor is not excised and histopathologic margins are unknown, whether the entire tumor has been extirpated remains uncertain.104 A systematic review and meta-analysis examined outcomes of laparoscopic cryoablation versus laparoscopic partial nephrectomy and suggested somewhat better perioperative outcomes with cryoablation but a higher local recurrence rate.111 This challenge forces frequent CT and MRI follow-up studies in patients who receive this therapy. Randomized phase III comparison of cryoablation versus surgical resection has not been conducted.

RFA provides an alternative method of renal tumor ablation. In this approach, a 150- to 200-W generator is used to create a high-frequency alternating current (460–500 Hz), causing frictional heating and protein denaturation. Electrode needles with or without tines are placed in the tumor laparoscopically or percutaneously under ultrasound or CT guidance. Temperatures of 60°C to 105°C are generated in the tumor, causing immediate cell death. Heating may be cycled, with each cycle lasting approximately 5 to 12 minutes. Probes may be inserted into the surrounding normal parenchyma for thermal monitoring. A margin of 0.5 to 1.0 cm is typically achieved. Potential complications of RFA are similar to those of cryoablation and include urinary leak or fistula, ureteral stricture or obstruction as a result of tissue sloughing, and injury to adjacent organs. Bleeding complications are infrequently encountered with RFA and make this procedure an attractive option for poor surgical candidates on bloodthinning medication. Allaf and colleagues reported increased pain with RFA compared with cryoablation, attributing this to a potential analgesic effect of the latter.112 As with cryotherapy, numerous studies now support effective short- to intermediate–term oncologic efficacy of RFA; however, longer-term outcomes data are, at present, sparse.113–116 Psutka and colleagues documented oncologic outcomes for 185 RFA patients with a median tumor size of 3 cm and a median follow-up of 6.3 years. Only 2.2% and 1.6% of patients developed metastasis and died, respectively, although 8% and 24% of T1a and T1b patients, respectively, were not disease free.117 The low rate of metastasis and death is promising, and validation of these longer-term outcomes is now awaited. A recent systematic review and meta-analysis examined outcomes of thermal ablation versus surgical nephrectomy and suggested lower complication rates and less decline of renal function with thermal ablation with comparable oncologic outcomes.118 Randomized phase III comparison of RFA versus surgical resection has not been conducted.

Active Surveillance Active surveillance has emerged has an alternative approach to extirpative or ablative management of small renal masses. Approximately 30% of renal tumors are benign when 4 cm or less in diameter. Among small renal masses with malignant histologic type, the vast majority (75%–85%) are low grade and clinically indolent. Hence, the American Urological Association now recommends consideration of active surveillance for small renal masses in select patients willing to accept a low risk of metastasis. Such management may be ideal for select patients with poor renal function or high operative risk, such as the elderly, or comorbid disease, and those with high tumor complexity. The precise risk of metastasis with active surveillance is unclear, but appears to be around 1% to 2% based on current literature.119,120 However, follow up in these studies is mostly short or intermediate term only; therefore this long-term rate may be an underestimate, particularly given the 5% to 10% rate of metastasis expected after surgical resection of pT1a tumors. In addition, reporting bias may further underestimate the rate of metastasis on active surveillance. During patient selection for active surveillance, the metastatic risk must be weighed in light of both the patient’s willingness to undergo treatment and the patient’s operative risk, including general health and performance status, renal function, and tumor complexity. Percutaneous tumor biopsy has not played a routine role during patient selection, probably because of concerns of common undergrading, relatively low negative predictive value, and a historically high nondiagnostic rate, although accuracy of 80% to 90% is described in most contemporary biopsy series.121 Thus currently renal biopsy in small renal masses guides decision making in a limited number of clinical situations.122,123 Presently, there are no standardized guidelines for surveillance regimens or thresholds for implementation of delayed treatment. A

Cancer of the Kidney  •  CHAPTER 79 1371

number of studies have attempted to identify clinical predictors of metastasis for patients on active surveillance, but these are limited by low metastatic case numbers. In many cases of metastasis on active surveillance, the primary tumor has progressed to larger than 4 cm. Accordingly, tumor size may provide a useful trigger for intervention. Increasingly, tumor growth rate is also being used as a trigger. Although growth rate of small renal masses does not differ between malignant and benign tumors (0.2–0.3 cm per year), high-grade and particularly metastatic primary tumors appear to grow faster, with growth of the latter ranging from 1.3 to 2.9 cm per year.119,124–127 A growth rate of more than 0. per year has accordingly been implemented by some urologists as a threshold for intervention. This approach has been challenged by the fact that oncocytomas commonly demonstrate rapid growth rates.128

Surveillance After Treatment of Localized Renal Cell Carcinoma Sporadic renal cell carcinoma

Imaging for surveillance is based largely on risk of metastasis by anatomic site. The major metastatic sites, in order of frequency, include lung (3%–16%), bone (2%–8%), regional lymph nodes, liver (1%–7%), ipsilateral adrenal, contralateral kidney, and brain (2%–4%). Currently, a history and physical examination, serum studies (calcium level, alkaline phosphatase level, and liver transaminases), and imaging studies (chest plain radiographs or chest CT scan and abdominal CT scan), done at time points when disease recurrence is likely, are used for surveillance.129 The lung has the greatest incidence of metastasis, so early diagnosis is pertinent.129 Chest radiography has been shown to detect up to 90% of lung metastases.130 Although chest CT is more sensitive than chest radiography, it yields more false positives, and its role in surveillance is still unknown.130 In the case of bone metastasis, however, only palliative therapies are available, therefore screening bone scintigraphy and radiographs are not warranted.129 Abdominal CT and liver transaminase determination are an integral part of surveillance because of treatment options available for local recurrence or liver recurrence.129 According to the National Comprehensive Cancer Network (NCCN) guidelines, follow-up evaluation for patients with completely resected disease depends on pathologic stage and surgical modality (i.e., partial versus radical nephrectomy). Imaging includes an abdominal CT or MRI within 3 to 6 months after surgery to serve as a baseline and subsequent imaging based on stage and surgical modality. For stage I (pT1a and pT1b), chest radiograph or CT is recommended annually for 3 years, then as clinically indicated. For stage II or III, baseline chest CT within 3 to 6 months after nephrectomy is recommended, with subsequent imaging (CT or chest radiograph) every 3 to 6 months for at least 3 years and then annually to year 5. Patients are seen periodically (every 3–6 months for 2–3 years, then annually), and each visit should include a history, physical examination, and comprehensive metabolic panel (i.e., determination of blood urea nitrogen, serum creatinine, calcium levels, lactate dehydrogenase, and liver enzymes). Lifelong surveillance is necessary for patients with RCC. Late recurrence is arbitrarily defined as a recurrence more than 10 to 20 years after nephrectomy. In sporadic RCC, recurrences have been documented as long as 45 years after initial surgical resection.131 The appropriate intensity of follow-up after 5 years remains to be established. Approximately 85% of recurrences, however, will be detected in the first 3 years after resection of the primary.132

von Hippel-Lindau disease and other familial renal cell carcinomas

Patients with von Hippel-Lindau RCC or other familial forms of RCC are at high risk for local recurrence after nephron-sparing surgery and require close lifelong surveillance. More than 80% of patients with von Hippel-Lindau disease treated with nephron-sparing surgical resection will have a recurrence in the ipsilateral kidney within 10

years, and lesions will develop in the contralateral kidney, if they have not done so already.133 Standard recommendations for surveillance in patients with von Hippel-Lindau disease include (1) CT of the abdomen and pelvis every 6 months in patients with solid renal lesions and every 12 months in patients without solid renal lesions, with alternating MRI and CT in younger patients to avoid secondary malignancies associated with prolonged use of the former, (2) annual physical and ophthalmologic evaluations, (3) estimation of urinary catecholamines every 1 to 2 years, (4) MRI of the CNS every 2 years, and (5) periodic auditory examinations. Molecular genetic and clinical screening should be offered to appropriate family members based on an autosomal dominant pattern of inheritance.133–136

NEOADJUVANT AND ADJUVANT MEDICAL THERAPIES Neoadjuvant Therapy Prior to Debulking Nephrectomy Presurgical approaches targeting the VEGF axis have been studied in the metastatic setting before debulking nephrectomy.137,138 The rationale for the use of VEGF inhibitors in this setting is to downsize locally advanced or nonresectable tumor and offer either organ-sparing surgery or radical nephrectomy, respectively. The use of antiangiogenic therapies perioperatively would also have a potential role in temporarily controlling metastatic disease before surgery. Initially, small, single-institution studies demonstrated that this approach is feasible in terms of safety and may achieve meaningful disease control.139–141 More recently, prospective neoadjuvant use of VEGF-targeted therapy has been tested in multicenter studies before cytoreductive nephrectomy to assess the response to antiangiogenic therapy and to improve local resectability.142 Of greatest concern for this approach is the increased risk of perioperative complications. Powles and colleagues reported a 13% rate of delayed wound complications from two phase II trials of neoadjuvant sunitinib in the metastatic setting.143 However, in another study using axitinib, which has a much shorter half-life than other VEGF-targeted inhibitors, only one patient (4.2%) experienced a superficial wound healing complication, which resolved with conservative management.144 Finally, in the neoadjuvant pazopanib study, none of the patients experienced wound healing complications, supporting the safe use of these agents in the perioperative setting.145 Although the safety in these studies was deemed acceptable, the efficacy was much less clear. Review of several studies revealed that 50% to 90% of patients demonstrated some degree of tumor regression in the primary lesion; however, the degree of regression varied from 9% to 26% from baseline, which is of unclear clinical significance.142 At this time, a neoadjuvant therapeutic approach should be considered only in a clinical trial setting or when patients are not initially deemed surgical candidates.

Adjuvant Therapy Until recently, no studies had demonstrated a clinical benefit to adjuvant therapy after nephrectomy in unselected patients. However, three recently reported phase III studies have offered conflicting results regarding the clinical benefit of adjuvant use of anti-VEGF targeted therapy.146 The ASSURE study compared the adjuvant use of sunitinib, sorafenib, or placebo for 1 year in patients with kidney cancer after nephrectomy. Eligible patients had pathologic stage high-grade T1b or greater disease that was completely resected with no radiographic evidence of metastases and with adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histologic type, ECOG Performance Status score, and surgical approach. Patients were randomly assigned (1 : 1 : 1) to receive 54 weeks of sunitinib 50 mg per day orally for 2 weeks on treatment followed by 2 weeks off treatment for each 6-week cycle; sorafenib 400 mg twice per day orally

1372 Part III: Specific Malignancies

throughout each cycle; or placebo. The primary objective compared disease-free survival (DFS) between each experimental group and placebo in the intention-to-treat population.147 Overall, 1943 patients were randomly assigned to sunitinib (n = 647), sorafenib (n = 649), or placebo (n = 647). The primary analysis showed no significant differences in DFS. Median DFS was 5.8 years (interquartile range [IQR], 1.6–8.2 years) for sunitinib (hazard ratio [HR], 1.02 [97.5% CI, 0.85–1.23]; P = .8038); 6.1 years (IQR, 1.7—not estimable [NE]) for sorafenib (HR, 0.97 [97.5% CI, 0.80–1.17]; P = .7184), and 6.6 years (IQR, 1.5—NE) for placebo. The most common grade 3 or worse adverse events were hypertension (104 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue (104 [17%] patients on sunitinib and 44 [7%] patients on sorafenib). Because of high rates of toxicity-related discontinuation after 1323 patients had enrolled, the starting doses were reduced.147 A recent updated analysis revealed no difference in DFS with longer follow-up, including no evidence of clinical benefit in patients who maintained dose intensity.148 However subset analyses were done in post hoc defined groups and are now powered to specifically evaluate a difference in outcome. S-TRAC was an international phase III trial of adjuvant sunitinib versus placebo in patients with high-risk clear cell RCC after nephrectomy or partial nephrectomy and demonstrated a statistically significant benefit in DFS.149 After surgery, 615 patients were randomized to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was DFS, according to blinded independent central review. Secondary end points included investigator-assessed DFS, OS, and safety. Adjuvant sunitinib treatment was associated with a median duration of DFS of 6.8 years (95% CI, 5.8 to not reached) versus 5.6 years (95% CI, 3.8–6.6) in the placebo group (HR, 0.76 [95% CI, 0.59–0.98]; P = .03).149 Dose reductions to 37.5 mg were allowed and occurred in 34.3 % of patients in the sunitinib arm; 46.4% of patients underwent unplanned dose interruptions, and 28.1% prematurely discontinued sunitinib. However, benefit was seen beyond the treatment period. At 5 years of follow-up, the proportion of patients who were disease free after having taken sunitinib was 59.3% versus 51.3% after placebo, suggesting that the clinical benefit of 1 year of adjuvant treatment with sunitinib is maintained over time. On the basis of these S-TRAC data, sunitinib was approved on November 16, 2018 for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma following nephrectomy. Other adjuvant studies of anti-VEGF targeted therapy have completed accrual and await clinical reporting, which may further influence the interpretation of adjuvant therapy for RCC. The PROTECT study enrolled 1538 patients with pT1b G3 to pT4 or N+ disease and no evidence of metastasis to either 1 year of pazopanib or placebo. After treatment of 403 patients, the starting dose (800 mg) was lowered to 600 mg to improve tolerability, and the primary endpoint was changed to DFS with pazopanib 600 mg. The primary analysis did not show a difference in DFS between the intent-to-treat pazopanib 600 mg group (n = 571), compared to placebo (n = 564) (HR 0.86; 95% CI, 0.70 to 1.06; P = 0.165). However, a statistically significant improvement in DFS was observed among patients treated with the higher dose of 800 mg adjuvant pazopanib (n = 198), compared to placebo (n = 205) (HR of 0.69) (95% CI, 0.51 to 0.94). Overall survival data are still immature; the final data cutoff for OS analysis is planned for April 15, 2019. Although the intent of modifying the protocol to reduce the starting pazopanib dose from 800 mg to 600 mg was to improve tolerability, adverse events were ultimately similar between the 600 mg and 800 mg groups.240 The SORCE study sponsored by the Medical Research Council (MRC) in the United Kingdom enrolled 1656 patients with pT1b to pT4 or N+ disease were randomized 1 : 1 : 1 to sorafenib 400 mg

twice daily (BID) for 1 year versus 3 years versus placebo. In the ATLAS study, 700 high-risk (pT3 or greater) patients were randomized to axitinib or placebo for 1 year. The EVEREST study, sponsored by the NCI and the SWOG cooperative group, evaluated 1545 patients with pT1b G3 to T4 or N+ disease and randomized them 1 : 1 to everolimus 10 mg daily for 1 year versus placebo. Both of these studies have met accrual, and it is anticipated that readouts for each of them for DFS will be available from 2017 to 2020. Clinical studies with immunotherapies have failed to demonstrate a clinical benefit. One randomized, multicenter, prospective study has reported on the efficacy of adjuvant interferon alfa-2b given after nephrectomy to patients with Robson stages II and III RCC.150 More recently, girentuximab (Rencarex), a chimeric monoclonal antibody that binds carbonic anhydrase IX (CAIX), was evaluated in a phase III double-blind adjuvant trial in patients with status post (S/P) nephrectomy or partial nephrectomy with either T3/T4 or N+ disease.151 A total of 864 patients were randomized 1 : 1 to girentuximab weekly or placebo. Girentuximab had no statistically significant DFS (HR, 0.97 [95% CI, 0.79–1.18]) or OS advantage (HR, 0.99 [95% CI, 0.74–1.32]). Median DFS was 71.4 months (IQR, 3 months to not reached) for girentuximab and never reached for placebo group.151 With the advent of anti-PD-1 and anti-PD-L1 immunotherapy, there have been several new phase III trials launched involving both neoadjuvant and adjuvant treatment (nivolumab) and adjuvant treatment (pembrolizumab, atezolizumab). The results from these studies will take several years to accrue and mature.

CYTOREDUCTIVE NEPHRECTOMY FOR PATIENTS WITH METASTATIC RENAL CELL CARCINOMA Approximately one-third of patients diagnosed with RCC have metastatic disease at presentation.152 The role of nephrectomy in patients with metastatic disease at the time of diagnosis has long been the subject of debate. A general consensus exists that nephrectomy before initiation of systemic therapy is appropriate in carefully selected patients with mRCC. Although there are no guidelines for how to identify such patients, good candidates for cytoreductive nephrectomy, in general, meet the following criteria: (1) majority of tumor burden can be debulked with surgery, (2) ECOG Performance Status score of 0 or 1, (3) adequate organ function, and (4) no evidence of extensive liver or bone metastases or any central nervous system involvement.153,154 The evidence for cytoreductive nephrectomy is based on two randomized trials that were conducted before the targeted therapy era and demonstrated an improvement in OS with the addition of cytoreductive nephrectomy to interferon-α, compared with interferon-α alone. The larger of these two studies was conducted by the Southwest Oncology Group (SWOG). In this trial, 246 patients who were acceptable candidates for nephrectomy were randomized to radical nephrectomy followed by therapy with interferon alfa-2b (n = 123) or interferon alfa-2b alone (n = 123). Interferon alfa-2b was continued until disease progression. The primary end point of OS was met; the addition of cytoreductive nephrectomy to interferon alpha-2b improved OS, compared with interferon alpha-2b alone (median OS, 11.1 versus 8.1 months; P = .05).155 The second, smaller randomized trial of cytoreductive nephrectomy in mRCC in the pre–targeted therapy era was conducted by the EORTC. In this study, 83 patients with mRCC were randomized to the same treatments as in the SWOG study.156 Again, a statistically significant improvement in OS was observed (median duration of survival, 17 versus 7 months; HR, 0.54 [95% CI, 0.31–0.94]). An improvement in time to progression (5 versus 3 months; HR, 0.60 [95% CI, 0.36–0.97]) was also seen. As discussed earlier, the two previously described randomized trials were conducted in the interferon era. The development of several

Cancer of the Kidney  •  CHAPTER 79 1373

effective targeted therapies to treat mRCC has raised questions about the role of cytoreductive nephrectomy in the current treatment paradigm. Retrospective series support a survival benefit for cytoreductive nephrectomy in the setting of targeted therapy for mRCC. For example, a National Cancer Database analysis of 15,390 patients with mRCC treated with target therapy showed a median OS of 17.1 months among those undergoing cytoreductive nephrectomy, compared with 7.7 months among nonnephrectomy patients (P < .001).157 A separate retrospective analysis from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 1658 patients with mRCC also showed a survival benefit with cytoreductive nephrectomy that persisted after prognostic factors were controlled for (HR of death, 0.60 [95% CI, 0.52–0.69]; P < .0001).158 Of course, these retrospective series are limited by selection bias. Therefore a randomized study, called the Clinical Trial to Assess the Importance of Nephrectomy (CARMENA) study (NCT00930033), is ongoing to further investigate the role of cytoreductive nephrectomy in the targeted therapy era. This trial will randomize patients with newly diagnosed mRCC to either surgery followed by sunitinib treatment or sunitinib alone, and it will, it is hoped, answer the question of whether cytoreductive nephrectomy should remain the standard of care in the targeted therapy era.

Resection of Metastases in Renal Cell Carcinoma The surgical resection of a solitary metastasis can be associated with long-term survival in selected patients with mRCC. This was demonstrated in a retrospective, single-institution analysis of patients at the MSKCC with recurrent RCC (N = 278) who underwent metastatectomy.159 In this series, 56% of patients had a solitary recurrence and 44% had recurrence in multiple sites, with a median time to first recurrence of 25 months. The 5-year OS rate of patients who underwent curative intent resection for the first recurrence was 44% (n = 141), compared with 14% for those who received noncurative intent resection (n = 70), and 11% for those who were treated nonsurgically (n = 67). Favorable predictors of survival by multivariate analysis included a single site of first recurrence, curative intent resection, and a disease-free interval of more than 12 months. Not surprisingly, the site of metastatic disease also has implications for survival. In the MSKCC series, curative intent resection of isolated metastases to soft tissue was associated with the best 5-year OS rate (75%), followed by resection of glandular tissue (thyroid, salivary gland, pancreas, adrenal, ovary) (63%), then resection of isolated lung metastases (54%). Resection of solitary brain metastases was associated with poor outcome, with an 18% 5-year overall rate. Interesting to note, the 5-year OS rates of patients who underwent a second (46%, n = 62) or third (44%, n = 22) curative intent metastasectomy were not significantly different from the rates in patients who received only initial curative intent resection of metastatic disease (44%, n = 141), suggesting that complete resection is more important for prognosis than the number of sites resected.160,161 Brain metastases from RCC raise specific therapeutic problems owing to the radioresistant and vascular nature of the tumor, which makes it relatively unresponsive to whole-brain radiation therapy (WBRT) and prone to bleed. Historically, surgical resection has been the standard of care in patients with a single operable brain metastasis, good performance status, and controlled systemic disease, based on the findings of several retrospective analyses and two prospective randomized trials demonstrating improved survival with surgery plus whole-brain radiation, compared with radiation alone.162,163 Retrospective studies have also suggested that surgical resection of multiple brain metastases can be associated with a survival and qualityof-life benefit. Surgery should also be considered in patients with symptoms from vasogenic edema or mass effect, requiring prompt palliation. More recently, stereotactic radiosurgery (SRS), a minimally invasive radiation technique that delivers targeted radiation in fewer high-dose fractions, has emerged as an alternative to surgery and

has demonstrated promising results in selected RCC patients with brain metastases.164–167 Surgical resection and SRS for treatment of brain metastases have not been compared prospectively, and data from retrospective series are conflicting; therefore management of brain metastases from RCC is typically guided by patient factors (age, performance status, comorbid conditions, state of systemic disease) and by institutional experience and preference. Local recurrence rates after surgery are high, so adjuvant radiation with SRS or WBRT is usually recommended. Currently, surveillance is recommended after complete resection of metastatic disease in RCC; systemic therapy should be reserved for patients with residual measurable disease. An ongoing phase III study of pazopanib versus placebo in patients with no evidence of disease after metastasectomy (NCT01575548) will attempt to determine the role of systemic therapy in this setting.

FOOD AND DRUG ADMINISTRATION– APPROVED THERAPIES FOR ADVANCED DISEASE Immunotherapy High-Dose Interleukin-2 Inpatient high-dose bolus IL-2 received Food and Drug Administration (FDA) approval for treatment of patients with stage IV RCC in 1992 based on data presented on 255 patients who were studied in seven phase II clinical trials.168,169 In these studies, patients received 600,000 to 720,000 IU/kg of recombinant human IL-2 by 15-minute infusion every 8 hours during two 5-day courses (maximum: 14 doses per course) separated by 5 to 9 days of rest. Stable or responding patients received two to five courses of therapy at 8- to 12-week intervals and then were observed while not receiving any additional therapy. Responses were seen in 37 (15%) of the 255 patients, including 17 complete responses (7%) and 20 partial responses (8%). The median duration of response was 54 months for all of the responders and 20 months for partial responders; the median has not yet been reached for complete responders. The median survival was 16 months for all 255 patients. Most patients who achieved a complete response that lasted longer than 30 months and those with partial responses after resection resulting in “no evidence of disease” after a response to high-dose IL-2 were unlikely to experience disease progression and may actually be cured. High-dose IL-2 has significant toxicities including hypotension, renal failure, cytopenias, fatigue, pruritus, and pyrexia and requires frequent clinical and laboratory monitoring. Therefore high-dose IL-2 is given in the inpatient setting, with limited access in the community setting. The observational PROCLAIM study followed 192 patients with mRCC treated with high-dose IL-2 from 2005 and 2012. The overall response rate (ORR) to high-dose IL-2 was 37%, including 6% of patients who achieved complete response and 9% of patients who achieved partial response. Median OS was 41 months.170 No responses were seen in patients with non–clear cell RCC. As a result of these data, it may be appropriate for patients whose primary tumor is of non–clear cell histologic type, or of clear cell histologic type but with “poor” predictive features, to forgo IL-2–based treatment altogether.171,172 To determine prospectively whether predictive factors, particularly high carbonic anhydrase IX (CAIX) staining, could identify a group of patients with advanced RCC who are significantly more likely to respond to high-dose IL-2–based therapy (“good” risk) than a historical, unselected patient population, the Cytokine Working Group performed the SELECT trial. New factors (including baseline immune function, immunohistochemical markers, and gene expression patterns) that might be associated with response to high-dose IL-2 therapy have been explored in an attempt to enrich the application of IL-2 to those patients most likely to benefit.172

1374 Part III: Specific Malignancies

In this multicenter prospective study, 120 patients with histologically confirmed RCC that was metastatic or unresectable, ECOG Performance Status score of 0 or 1, and adequate organ function received high-dose IL-2 (600,000 U/kg dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses] every 12 weeks). Unexpectedly, 25% of patients had stable disease or better, with 7.5% complete responses and 20.8% partial responses. The median OS in this highly selected group of patients was 42.8 months, and median progression-free survival (PFS) was 4.2 months. Response to IL-2 was not associated with any pretreatment clinical factor and was not seen in patients with non–clear cell histology. Positive immunohistochemistry for PD-L1 and B7-H3 markers were associated with response to IL-2, whereas CAIX staining or single-nucleotide polymorphism (SNP) status, plasma VEGF, and fibronectin levels were not correlated with response.173 Based on these data, CAIX is not used as a predictive marker for response to IL-2.171

Checkpoint Inhibitors Cytotoxic T-lymphocyte antigen 4 (CTLA4), a key negative regulator of T-cell responses, has been shown to impair antitumor immune response. Ipilimumab (MDX-010) is a fully human, monoclonal antibody that, by inhibiting CTLA4, overcomes T-cell suppression to enhance the immune response against tumors. A phase II study of ipilimumab was conducted in patients with metastatic renal cell cancer with a primary end point of ORR.174 Patients enrolled in two sequential cohorts received either 3 mg/kg followed by 1 mg/kg or 3 mg/kg every 3 weeks. Major toxicities observed were enteritis and endocrine deficiencies. Five of 40 patients at the higher dose had partial responses and did not have prior response to IL-2. One-third of the patients experienced a grade 3 or 4 immune-mediated toxicity, with significant association between autoimmune events and tumor regression. The programmed death 1 (PD-1) pathway has emerged as a promising immune checkpoint–targeted cancer therapy. The pathway includes two principal components, PD-1 and PD-L1.175 PD-1 (B7-1) is an inhibitory T-cell receptor expressed on the surface of activated T cells that was first discovered in 1992 by Honjo and colleagues,176 and has since been shown to play an integral role in modulating immune response and in long-term antigen exposure, as occurs in cancer.177 PD-L1 (programmed death ligand 1, also known as B7-H1 and CD274) is a PD-1 ligand found primarily in the tumor microenvironment that has been shown to be highly expressed in aggressive RCC tumors.178 When PD-1 and PD-L1 bind, the ability of the T cell to target and lyse the tumor cell is dampened; thus blockade of interactions between PD-1 and PD-L1 can stimulate an immune response against tumor cells. Nivolumab (MDX-1106, ONO-4538, BMS-936558) is the first-in-class PD-1 inhibitor, a fully humanized immunoglobulin G4 anti-PD-1 antibody. Nivolumab was studied in two phase I trials, which showed safety, tolerability, and clinical efficacy in patients with advanced RCC and other cancers179,180 and provided impetus for other studies. The ORR among 33 patients with RCC was 27%, with responses in 4 of 17 patients (24%) treated with 1 mg/kg and 5 of 16 patients (31%) treated with 10 mg of nivolumab per kilogram.180 Stable disease lasting 24 weeks or more was observed in nine patients (27%), and five of eight responding patients (63%) had durable responses of 1 year or more.180 Adverse events reported in all patients were primarily immune related, with 41 of the 296 (14%) patients exhibiting serious toxicities, including thyroid abnormalities, colon inflammation, and three deaths from pneumonitis. The majority of the patients had less severe toxicities, such as rash, fatigue, and itching. Subsequently, nivolumab was studied in a phase II trial that enrolled 34 patients with metastatic RCC. Patients were treated with either nivolumab 1 mg/kg or 10 mg/kg every 2 weeks. Ten of 34 patients (29%) had an objective response, with median responses lasting 12.9 months.181 Median OS was 22.4 months.181

Nivolumab was further developed in a phase III trial (CheckMate 025) which showed an OS difference between nivolumab and everolimus in 821 patients with previously treated metastatic RCC.182 Patients received either one or two prior antiangiogenic therapies before their enrollment in the study. Patients treated with nivolumab had a median OS of 25.0 months compared with those treated with everolimus, who had a median survival of 19.6 months (HR, 0.73 [98.5% CI, 0.57–0.93]; P = .002).182 Nivolumab also had a better response rate than everolimus (25% versus 5%; odds ratio [OR], 5.98; P < .001). Median PFS did not differ between the two treatments.182 Based on these data, nivolumab was approved by the FDA on November 23, 2015, for the treatment of advanced RCC patients who have received prior antiangiogenic therapy. As an attempt to predict for treatment response, immunohistochemical analysis of PD-L1 in tumor specimens of patients in the anti-PD-1 trial initially showed a positive relationship between PD-L1 expression on tumor cells and objective response (36% of patients with PD-L1–positive tumors exhibited tumor shrinkage as compared with none of the patients with PD-L1–negative tumors).180 In the CheckMate 025 phase III trial, however, although PD-L1 positivity (>1% expression) was a poor prognostic risk factor, PD-L1 positivity did not predict for response to nivolumab.182 Better biomarkers of treatment sensitivity and response are therefore needed for patients undergoing immune checkpoint blockade. The data from these and other studies suggest that antibody-mediated blockade of PD-1 is an important immunotherapeutic approach in RCC. Trials combining anti-CTLA4 therapy with anti-PD-1 agents are ongoing and hold potential for improving immunotherapeutic approaches in RCC. Many other trials are also ongoing to evaluate these immunotherapy agents in combination and in sequence with VEGF-targeting therapies.

Angiogenesis Inhibitors Inhibiting the development of new blood vessels (antiangiogenesis) has been demonstrated to be an effective approach to cancer therapy— particularly for RCC. Thus far, VEGF is the best-characterized proangiogenic factor. It is virtually ubiquitous in human tumors, and higher levels correlate with more aggressive disease in kidney cancer. VEGF-A stimulates angiogenesis by binding to VEGF receptors (VEGFRs), which promotes endothelial cell migration and proliferation, leading to development of new tumor-associated blood vessels. In addition, VEGF-A also increases vascular permeability, which may also contribute to angiogenesis and tumor growth. HIF-1α regulates VEGF gene expression. Several approaches are being taken to block the HIF-1/VEGF axis (Fig. 79.2). The clinical efficacy of antiangiogenic therapy in RCC has led to the FDA approval of seven anti-VEGF therapies for the treatment of advanced kidney cancer (Table 79.3).

Sorafenib Sorafenib (Nexavar) is an oral kinase inhibitor targeting both tumor cells and the tumor vasculature. It was originally developed as an inhibitor of Raf-1, a member of the Raf/MEK/ERK signaling pathway.183,184 Sorafenib was subsequently found to have activity against B-Raf, VEGFR-2, platelet-derived growth factor receptor (PDGFR), Fms-like tyrosine kinase-3 (Flt-3), and stem cell growth factor (c-Kit).185 In phase I studies investigating various oral dosage schedules, sorafenib generally was well tolerated; the recommended dose for future trials was 400 mg BID continuously. Dose-limiting toxic effects seen at continuous doses higher than 400 mg BID were diarrhea, fatigue, and skin toxicity.186,187 A phase III randomized, double-blind, placebo-controlled trial compared sorafenib and placebo in mRCC patients previously treated or not candidates for cytokine therapy.188 From November 2003 to March 2005, 903 patients with RCC that was resistant to cytokine therapy were randomly assigned to receive either continuous treatment

Cancer of the Kidney  •  CHAPTER 79 1375

Tumor suppressor gene silencing/hypoxia Temsirolimus Everolimus

HGF

VEGF

FGF

PDGF

Bevacizumab

HGF

VEGF

FGF

PDGF

Extracellular Plasma membrane

P P

P P

PDGFR

P P

P

FGFR

P

P

Sunitinib Sorafenib Axitinib Pazopanib

Lenvatinib

P

P

Intracellular

VEGFR

PKC

P PLC

P13K

P

P

P

P

c-MET

SPK

Cabozantinib Sorafenib

Akt/PKB

RAF

RAS

eNOS

Pericyte survival

Temsirolimus Everolimus

mTOR

BAD Casp 9

Vascular permeability

MEK

ERK

Endothelial/Tumor cell survival

Endothelial/Tumor cell proliferation/Gene transcription

Figure 79.2  •  Molecular targets for clear cell renal cell carcinoma (RCC). Several steps in the process of tumor angiogenesis are being targeted for therapeutic purposes. Depicted are currently approved agents for advanced RCC.

with oral sorafenib (at a dose of 400 mg BID) or placebo. A total of 451 patients received sorafenib; 452 received placebo. The primary end point was OS. A single planned analysis of PFS in January 2005 showed a statistically significant benefit of sorafenib over placebo. Consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005. Partial responses were reported as the best response in 10% of patients receiving sorafenib and in 2% of those receiving placebo. Diarrhea, rash, fatigue, and hand-foot skin reactions were the most common adverse events associated with sorafenib. Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo. As compared with placebo, treatment with sorafenib prolonged PFS in patients with advanced clear cell RCC in whom previous therapy had failed. On the basis of these data, the FDA approved sorafenib in December 2005 for the treatment of advanced kidney cancer.

Sunitinib Sunitinib (Sutent) is a multitargeted receptor tyrosine kinase inhibitor (TKI) of VEGFRs and PDGFRs. Patients with mRCC who demonstrated progression on first-line cytokine therapy were enrolled into a multicenter phase II trial.189 Sunitinib monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off. ORR was the primary end point, and time to progression and safety were secondary end points. Of 63 patients who received sunitinib, 25 (40%) achieved partial responses; 17 additional patients (27%) demonstrated stable disease with a duration of 3 months or longer. Median time to progression in the 63 patients was 8.7 months. In general, the drug was tolerated well, with manageable toxicities. Based on the phase II study results, the

FDA approved sunitinib in early 2006 at a dose of 50 mg for 4 weeks on treatment followed by 2 weeks off, for the treatment of advanced kidney cancer. Because sunitinib had shown activity in two uncontrolled studies in patients with mRCC, a comparison of the drug with interferon-α in a phase III trial was warranted. A total of 750 patients with previously untreated mRCC were enrolled in a multicenter, randomized phase III trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon-α at a dose of 9 million U given subcutaneously 3 times weekly.190 The primary end point was PFS. Secondary end points included the ORR, OS, patient-reported outcomes, and safety. The median PFS was significantly longer in the sunitinib group (11 months) than in the interferon-α group (5 months), corresponding to an HR of 0.42. Sunitinib was also associated with a significantly higher OR (47% versus 12%) and significantly better quality of life compared with interferon-α. There were more adverse events in the sunitinib group, including more grade 3 diarrhea, vomiting, hypertension, and hand-foot syndrome. Grade 3–4 fatigue was more common in the interferon-α group. Updated analysis of the phase III study showed numerically longer survival in the sunitinib group compared with interferon-α group, although the improvement in survival failed to achieve statistical significance (26.4 versus 21.8 months; HR, 0.82 [95% CI, 0.67–1.00]).191 Because of the toxicities observed with the standard 4-weeks-on, 2-weeks-off sunitinib administration schedule, alternative schedules have been evaluated. Retrospective series and one small, single-arm prospective study have suggested that a 2-weeks-on, 1-week-off schedule may be better tolerated, with fewer adverse events and no significant difference in efficacy.192–196

Placebo

(mo)

IFN-α

Clear cell mRCC; no previous systemic therapy

Sunitinib

0.44 (0.35– 0.55)

~10 vs 2

HR (95% CI)

ORR versus comparator, %

0.88 (0.74– 1.04)

HR (95% CI)

0.818 (0.669–0.999)

26.4 vs 21.8

47 vs 12

0.42 (0.32–0.54)

11 vs 5

AVOREN, 0.91 (0.76–1.10); CALGB, 0.85 (0.74–1.01)

AVOREN, 23.3 vs 21.3; CALGB, 18.3 vs 17.4

Temsirolimus, 10.9 vs 7.3; temsirolimus + IFN, 8.4 vs 7.3 T, 0.73 (0.58–0.92); T + IFN, 0.96 (0.76–1.20)

Temsirolimus, 8.6 vs 4.8; temsirolimus + IFN, 8.1 vs 4.8

NR

T, 3.8 vs 1.9; T + IFN, 3.7 vs 1.9

INF-α

AVOREN, IFN-α + placebo; CALGB, IFN-α AVOREN, 10.2 vs 5.4; CALGB, 8.5 vs 5.2 AVOREN, 0.63 (0.52–0.75); CALGB, 0.71 (0.61–0.83) AVOREN, 31 vs 13; CALGB, 25.5 vs 13.1

Poor-prognosis mRCC; no prior systemic therapy

0.87 (0.65–1.17)

14.8 vs 14.4

1.8 vs 0

0.33 (0.25–0.43)

4.9 vs 1.9

Placebo

Clear cell mRCC; prior VEGFR TKI therapy

Not reached

30 vs 3

0.46 (0.34–0.62)

9.2 vs 4.2

Advanced RCC or mRCC; with or without prior cytokine-based systemic therapy Placebo

Temsirolimus Everolimus Pazopanib

AVOREN and CALGB 90206; clear cell mRCC; no prior systemic therapy

Bevacizumab + IFN-α

Not available yet

19 vs 9

0.67 (0.54– 0.81)

6.7 vs 4.7

Advanced RCC or mRCC; prior VEGFR TKI, cytokine-based systemic therapy Sorafenib

Axitinib

0.66 (0.53–0.83)

21.4 vs 16.5

17 vs 3

0.44 (0.31–0.61)

7.4 vs 3.9

Everolimus

Advanced RCC or mRCC; prior antiangiogenic therapy

0.73 (0.57– 0.93)

25.0 vs 21.8

25 vs 5

0.88 (0.75– 1.03)

4.6 vs 4.4

Everolimus

Advanced RCC or mRCC; prior antiangiogenic therapy

Cabozantinib Nivolumab

0.51 (0.30– 0.88)

25.5 vs 15.4

43 vs 6

0.40 (0.24– 0.68)

14.6 vs 5.5

Everolimus

Lenvatinib + Everolimus

CALGB, Cancer and Leukemia Group B; CI, confidence interval; HR, hazard ratio; IFN-α, interferon-α; mRCC, metastatic renal cell carcinoma; NR, not reported; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.

17.8 vs 15.2

Median

OS VS COMPARATOR (MO)

5.5 vs 2.8

Median

PFS VS COMPARATOR (MO)

Clear cell mRCC; PD after one systemic therapy

Patient population

Sorafenib

Pivotal Phase II or III Clinical Trials

Table 79.3  Efficacy of Approved Targeted Therapies and Immune Checkpoint Inhibitors for Advanced Renal Cell Carcinoma (RCC) in

1376 Part III: Specific Malignancies

Cancer of the Kidney  •  CHAPTER 79 1377

Bevacizumab and Interferon Two phase III trials were conducted to evaluate the efficacy and safety of bevacizumab (Avastin), a monoclonal humanized antibody against VEGF, in combination with interferon-alfa as first-line treatment in mRCC. In the AVOREN study, 649 patients with previously untreated mRCC were randomized to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n = 327) or placebo and interferon alfa-2a (n = 322). The primary end point was OS.197 Median duration of PFS was significantly longer in the bevacizumab plus interferon-alfa group than it was in the control group (10.2 months versus 5.4 months). Increases in PFS were observed with bevacizumab plus interferon-alfa irrespective of risk group or whether reduced-dose interferon-alfa was received. The most commonly reported grade 3 or worse adverse events were fatigue (12% patients in the bevacizumab group versus 8% in the control group) and asthenia (10% versus 7%). In a parallel study (CALGB 90206) patients with previously untreated metastatic clear cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus interferon (9 million U subcutaneously three times weekly) or the same dose and schedule of interferon monotherapy.198 The primary end point was OS, and secondary end points were PFS, ORR, and safety. The median PFS was 8.5 months in patients receiving bevacizumab plus interferon versus 5.2 months in patients receiving interferon monotherapy (log-rank P < .0001; adjusted HR, 0.71). Bevacizumab plus interferon had a higher ORR than interferon (25.5% versus 13.1%). Overall toxicity was greater for bevacizumab plus interferon, including grade 3 hypertension (9% versus 0%), anorexia (17% versus 8%), fatigue (35% versus 28%), and proteinuria (13% versus 0%). The final analysis of the study showed a median OS time of 18.3 months for bevacizumab plus interferon-α and 17.4 months for interferon-α monotherapy (unstratified log-rank P = .097). Interesting to note, patients who developed hypertension on bevacizumab plus interferon-α had a significantly improved PFS and OS versus patients without hypertension.199 Together, these studies demonstrated that the combination of bevacizumab with interferon-α as first-line treatment in patients with mRCC significantly improves PFS, compared with interferon-α alone. Based on these data, the FDA approved bevacizumab in combination with interferon-α for the treatment of patients with mRCC in July 2009.

Pazopanib Pazopanib (Votrient) is a potent and selective multitargeted receptor TKI (of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α/β, and c-Kit) that blocks tumor growth and inhibits angiogenesis. Based on the promising results of a prior phase II study, a randomized, double-blind, placebo-controlled, phase III study evaluating the efficacy and safety of pazopanib in 435 treatment-naïve and cytokine-pretreated patients with advanced RCC was performed.200 This trial demonstrated a statistically significant improvement in PFS with pazopanib, compared with placebo, in the overall study population (median, 9.2 months versus 4.2 months), in the treatment-naïve subpopulation (11.1 months versus 2.8 months), and in the cytokine-pretreated subpopulation (median, 7.4 months versus 4.2 months). A higher OR was also observed with pazopanib, compared with placebo (30% versus 3%). Although there was a trend toward improvement in OS with pazopanib, the final analysis showed that this difference was not statistically significant (22.9 months versus 20.5 months, respectively). However, the crossover from placebo to pazopanib might have confounded the final OS analysis. The most common adverse events in the pazopanib group were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting.201 On the basis of these data, pazopanib was approved in October 2009 by the FDA for patients with advanced RCC. In the COMPARZ study 1110 patients with treatment-naïve advanced RCC were randomized to pazopanib 800 mg daily versus

sunitinib 50 mg for 4 weeks on treatment followed by 2 weeks off. There was no difference in PFS, OS, or rates of drug discontinuation between the two groups. Pazopanib was associated with a significantly higher OR (31% versus 25%), better health-related quality of life, less fatigue (55% versus 63%), less hand-foot syndrome (29% versus 50%), and less thrombocytopenia (41% versus 78%). Increase in alanine aminotransferase levels occurred more commonly with pazopanib compared with sunitinib (60% versus 43%).202 Limitations of this study include potential bias against sunitinib due to the timing of the assessments. Specifically, sunitinib-associated toxicity is known to peak during the 4 weeks on treatment, then improve during the 2 weeks off treatment.

Axitinib Axitinib (Inlyta) is a potent inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3. It is unique among the VEGF TKIs because it offers the ability to titrate the dose based on clinical parameters. Axitinib showed efficacy in the second-line setting in phase II studies in patients with cytokine-refractory and sorafenib-refractory RCC.203,204 Based on these promising results, the randomized phase III AXIS trial was conducted, in which 723 patients with mRCC whose disease had progressed after prior first-line therapy with sunitinib, bevacizumab plus interferon-α, temsirolimus, or cytokines were treated with either axitinib or sorafenib. This was the first phase III study in RCC to compare two targeted therapies and demonstrated a statistically significant improvement in PFS (6.7 versus 4.7 months, P < .0001) and OR (19% versus 9%, P < .0001) with axitinib compared with sorafenib. Diarrhea, hypertension, and fatigue were seen in both groups and were similar to what has been observed with other VEGF TKIs. However, rates of hand-foot syndrome, cutaneous toxicities, and myelosuppression were lower with axitinib, suggesting it may be better tolerated in some patients.205 First-line axitinib was evaluated in a randomized, open-label phase III study in which 192 patients with treatment-naïve mRCC were treated with either axitinib 5 mg orally BID or sorafenib 400 mg orally daily. This study failed to meet its primary end point and did not demonstrate a significant improvement in PFS with axitinib, compared with sorafenib, in the first-line setting.206 Based on these data, the FDA approved axitinib at a starting dose of 5 mg orally BID for treatment of advanced RCC after failure of one prior systemic therapy. Dose adjustments can be made based on individual safety and tolerability. Because of a lack of progression-free or OS benefit in treatment-naïve patients, axitinib is not approved for first-line treatment.

Cabozantinib Cabozantinib (Cometriq) is a potent, orally bioavailable, multitargeted, small-molecule inhibitor of VEGFR-2, c-MET, and AXL. It was originally developed and approved for the treatment of progressive, metastatic medullary thyroid cancer. The safety and activity of cabozantinib in RCC was demonstrated in a phase IB study in patients with previously treated mRCC.207 On the basis of these encouraging results, the randomized, open-label phase III METEOR study was conducted to compare cabozantinib 60 mg daily versus everolimus 10 mg daily in 658 patients with mRCC that had progressed after prior VEGF TKI therapy. After a median follow-up of 19 months, median PFS (7.4 versus 3.9 months; HR, 0.51 [95% CI, 0.41–0.62]), median OS (21.4 versus 16.5 months; HR, 0.66 [95% CI, 0.53–0.83]), and OR (17% versus 3%) were all significantly improved with cabozantinib compared with everolimus. The side effect profile of cabozantinib was similar to what is observed with other VEGF TKIs. Notably, dose reductions were required in 60% of patients in the cabozantinib group, and the median average daily dose of cabozantinib was 44 mg.208 Based on these data, cabozantinib was approved by the FDA in April 2016 for the treatment of advanced RCC in patients who have received prior antiangiogenic therapy. Cabozantinib has also been studied in patients with previously untreated mRCC. In the randomized, open-label phase II CABOSUN

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trial, 157 patients with treatment-naïve, IMDC intermediate- and poor-risk advanced RCC were randomized to cabozantinib 60 mg orally daily or sunitinib 50 mg orally, 4 weeks on treatment followed by 2 weeks off. In this study, treatment with cabozantinib significantly improved median PFS (8.2 versus 5.6 months; HR, 0.65 [95% CI, 0.48–0.99]) and OR (46% versus 18%) compared with sunitinib. OS was numerically longer with cabozantinib, but this difference was not statistically significant. The safety profile of cabozantinib and sunitinib were similar to what has been observed with these agents in prior studies.209 Cabozantinib is currently approved only in patients with advanced RCC who have received prior antiangiogenic therapy.

Lenvatinib and Everolimus Lenvatinib (Lenvima) is an oral multitargeted TKI of VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, FGFR3, FGFR4, PDGFRα, RET, and KIT.210,211 It is approved for the treatment of radioactive iodine–refractory differentiated thyroid cancer. Based on the rationale that the combination of VEGF and mTOR inhibition could have a synergistic antitumor effect in mRCC, a randomized, phase IB/II study of lenvatinib plus everolimus was conducted in patients with advanced RCC and disease progression after prior VEGF therapy. The phase IB part of the study determined the maximum tolerated dose of lenvatinib (18 mg per day) in combination with everolimus (5 mg per day) and demonstrated safety in addition to antitumor activity.212 The phase II part of the study randomized 153 patients to lenvatinib (18 mg per day) plus everolimus (5 mg per day), lenvatinib alone (24 mg per day), or everolimus alone (10 mg per day). The trial met its primary end point, showing improved PFS with the combination of lenvatinib plus everolimus compared with everolimus alone (median 14.6 versus 5.5 months; HR, 0.40 [95% CI, 0.24–0.68]; P = .0005). PFS was also longer for lenvatinib alone versus everolimus alone (7.4 months versus 5.5 months; HR, 0.61 [95% CI, 0.38–0.98]; P = .048). There was no difference in PFS between the groups receiving the combination (lenvatinib plus everolimus) and lenvatinib alone. The ORRs for the three arms were as follows: lenvatinib plus everolimus (43%), lenvatinib alone (27%), everolimus alone (6%). The ORR was significantly higher for the combination compared with everolimus alone (rate ratio 7.2 [95% CI, 2.3–22.5]; P < .0001) but not compared with lenvatinib alone (rate ratio, 1.6 [95% CI, 0.9–2.8]; P = .10). Lenvatinib alone was also associated with a higher ORR compared with everolimus alone (RR, 4.5 [95% CI, 1.4–14.7]; P = .0067). At the primary data cutoff, there was no difference in OS between groups. A post hoc updated analysis demonstrated a statistically significant improvement in OS with lenvatinib plus everolimus compared with everolimus alone (median OS, 25.5 months [95% CI, 16.4–NE] versus 15.4 months [95% CI, 11.8–19.6]; HR, 0.51 [95% CI, 0.30–0.88]; P = .024). There was still no difference in OS between the other groups. With regard to safety, no new treatment-related adverse events were observed with the combination of lenvatinib and everolimus. The rate of all-grade adverse events was slightly higher in the combination arm compared with the monotherapy arms (combination, 99%; lenvatinib alone, 94%; everolimus alone, 96%). However, the rate of grade 3/4 adverse events was lower with the combination compared with lenvatinib alone (combination, 71%; lenvatinib alone, 79%; everolimus alone, 50%).213 Based on these data showing improved PFS, higher ORR, longer OS (at post hoc analysis), and acceptable safety profile compared with everolimus alone, the FDA approved lenvatinib in combination with everolimus for the treatment of advanced RCC after one prior antiangiogenic therapy.

Inhibitors of the Mammalian Target of Rapamycin Pathway mTOR is a serine/threonine kinase that is activated downstream of the PI3K/AKT pathway and plays a critical role in cell proliferation

and survival. Mutations in the PI3K/AKT/mTOR pathway occur in RCC, suggesting that this pathway is important in the pathogenesis of RCC.214 In addition, mutation in the mTOR pathway appears to be involved in the development of a hereditary form of RCC seen in patients with tuberous sclerosis.215

Temsirolimus Temsirolimus (Torisel) is an mTOR kinase inhibitor administered intravenously. It has been shown to bind with high affinity to the immunophilin FKBP, and this complex inhibits mTOR kinase activity as evidenced by inhibition of phosphorylation of the eukaryotic translation initiation factor 4E–binding protein-1 and the 40S ribosomal protein p70 S6 kinase, the primary downstream effectors of mTOR.216–218 Temsirolimus was tested in a multicenter phase III trial in which 626 patients with treatment-naïve, poor-risk mRCC were randomized to receive 25 mg of intravenous temsirolimus weekly, interferon-α subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus interferon-α three times weekly.219 The primary end point was OS. Temsirolimus monotherapy significantly prolonged OS and PFS compared with interferon-α alone (temsirolimus median OS, 10.9 months; interferon-α median OS, 7.3 months; HR for death, 0.73). There was no difference in OS between the combination therapy and interferon-α alone (combination median OS, 8.4 months; HR for death, 0.96). Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon-α group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon-α treatment group. Based on these data showing improved OS in the first-line setting for poor-risk advanced RCC, temsirolimus was approved by the FDA in July 2007 for the treatment of advanced kidney cancer.

Everolimus Everolimus (Afinitor) is an oral mTOR inhibitor. A phase II study in mRCC showed evidence of efficacy and tolerability.220 A phase III randomized, placebo-controlled trial of everolimus versus supportive care in patients with mRCC whose disease had progressed on VEGFtargeted therapy demonstrated improvement in PFS with everolimus compared with supportive care (4.0 versus 1.9 months). Stomatitis (40%), rash (25%), and fatigue (20%) were the most commonly reported adverse events in the everolimus-treated patients, but were mostly mild or moderate in severity. Pneumonitis was detected in 8% patients in the everolimus group.221 Based on these data, everolimus was approved by the FDA for the treatment of advanced RCC after failure with sunitinib or sorafenib. As described previously, two large randomized trials have shown that everolimus is significantly less effective than nivolumab or cabozantinib for previously treated advanced RCC. Everolimus is also approved in combination with lenvatinib for advanced RCC after one prior antiangiogenic therapy.

Future Directions for Antiangiogenesis Therapies Clinical evidence of treatment resistance to VEGF or PD-1 inhibition typically develops within 1 year or less. Reasons for these results can be multifold: (1) the optimal regimen has not been achieved; (2) the signaling pathway is not sufficiently understood; or (3) tumor heterogeneity may be responsible for different dependence from the targeted pathway among patients. Combination therapies have been proposed as a way of potentially producing greater and more durable benefit as compared with single agents. Although critically important, testing of combination regimens must proceed cautiously because of the potential for synergistic toxicity or countervailing activity inherent with use of these multitargeted agents.222 Approaches to combination therapy that have been investigated include “vertical” combinations, in which the HIF/VEGF pathway is blocked at several steps, and

Cancer of the Kidney  •  CHAPTER 79 1379

“horizontal” combinations, in which multiple separate signaling pathways are blocked simultaneously.223 In this regard, combinations targeting immune-mediated mechanisms, particularly anti-PD-1 or anti-PD-L1, with VEGF-targeted therapy appear to be the most promising. The rationale for targeting PD-1 and PD-L1 in kidney cancer has now become well established with the approval of nivolumab in VEGF-treated patients based on the CheckMate 214 study described earlier. Logically, it stands to reason these disparate pathways should combine well in a horizontal approach. Early phase testing of the combination of atezolizumab, an anti-PD-L1 antibody, plus bevacicumab, a monoclonal VEGF antibody, demonstrated an increase in T-cell migration into tumor tissue, suggesting a mechanistic rationale.224 Subsequently a phase II study of atezolizumab plus bevacizumab versus atezolizumab versus sunitinib revealed a significant improvement in PFS for the combination versus sunitinib (HR, 0.64) in PD-L1+ tumors, whereas atezolizumab alone revealed no difference in PFS versus sunitinib (HR, 1.03).225 Additionally, two phase 1 trials of checkpoint inhibition plus VEGF TKI have shown promising antitumor activity with acceptable safety profile in treatment-naive patients with advanced renal-cell carcinoma. Specifically, preliminary results from the JAVELIN Renal 100 phase 1B study of avelumab (anti-PD-L1) plus axitinib in treatment-naive patients with advanced renal-cell carcinoma demonstrated an objective response rate of 58% (32 of 55 patients, 95% CI 44–71),241 and the phase 1B trial of pembrolizumab plus axitinib in patients with treatment-naive advanced renal cell carcinoma showed an objective response rate of 73% (38 of 52 patients, 95% CI 59.0–84.4).242 Phase 3 studies assessing avelumab plus axitinib versus sunitinib (NCT02684006) and axitinib plus pembrolizumab versus sunitinib (NCT02853331) as first-line therapy are ongoing. Currently several phase III trials are underway to evaluate these approaches in previously untreated mRCC patients. These studies include avelumab and axitinib versus sunitinib (NCT02684006), pembrolizumab and axitinib versus sunitinib (NCT02853331), lenvatinib-everolimus or lenvatinib-pembrolizumab versus sunitinib alone (NCT02811861), and atezolizumab and bevacizumab versus

sunitinib (NCT02420821). Ultimately these studies may change the front-line treatment approach for some if not all untreated mRCC patients. The vast majority of patients eventually progress through anti-VEGF therapies. Different hypotheses for the resistance mechanisms have been proposed. A report suggested that in a transgenic mouse model of pancreatic cancer, an early phase of response to anti-VEGF therapy leads to decrease in blood vessel formation and consequent hypoxia with induction of HIF-1α with downstream overexpression of proangiogenesis growth factors.226 It is conceivable that overexpression of HIF-1α is responsible for increased levels of VEGF that cannot be counteracted by VEGF TKI, or that such overexpression induces alternative growth factors such as hepatocyte growth factor, basic fibroblast growth factor, or their associated receptors. Clinical evidence also indicates that circulating VEGF levels are increased in patients receiving TKIs. Taken together, these observations suggest that the anti-VEGF therapy “escape” may be neutralized with a therapeutic strategy aimed to achieve a vertical inhibition of the VEGF pathway. For example, inhibition of tumor cell adaptation to hypoxia induced by TKIs may be achieved with HDAC or mTOR inhibitors that block the HIF pathway. One example of a vertical inhibition strategy has been the combination of VEGF and mTOR targeted therapy. Strong preclinical evidence and a strong scientific rationale have existed for combining VEGF TKIs, VEGF blockers, and mTOR inhibitors, but until recently this approach has proven too toxic or ineffective in combination.212,227,228 The successful development of lenvatinib and everolimus as described earlier, however, suggest that there is a dose range in which these targets can be effectively combined.

FUTURE POTENTIAL STRATEGIES FOR RENAL CELL CARCINOMA Many additional strategies are under development for RCC, and this section will undoubtedly be dated by the time it is in press, but several deserve some mention because they hold the potential to shape the field (Fig. 79.3). Most important are the front-line treatments of mRCC, and the most eagerly awaited trial report currently is from

VEGF/MET/AXL inhibitor Cabozantinib mTOR inhibitors Temsirolimus Everolimus Immunotherapies Aldesleukin Nivolumab

VEGF inhibitors Sunitinib Sorafenib Bevacizumab Pazopaninib Axitinib

Combination therapy Lenvatinib + Everolimus

Tumor cell

Endothelial cell

Immune cell

Figure 79.3  •  Strategies targeting the tumor microenvironment. Dysregulation of the hypoxia-inducible factor (HIF) pathway is likely to contribute to the development of renal cell carcinoma. Therefore drugs that inhibit HIF or its downstream targets warrant testing for treatment of this disease. mTOR, Mammalian target of rapamycin; VEGF, vascular endothelial growth factor.

1380 Part III: Specific Malignancies

the CheckMate 214 study, which is comparing a combination of nivolumab and ipilimumab versus sunitinib (NCT02231749). In this study, 1070 patients were randomized to either combination nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks × 4, followed by nivolumab 3 mg/kg every 2 weeks or sunitinib 50 mg daily, 4 weeks on, 2 weeks off. PFS and OS are coprimary end points. Early phase I data from the ipilimumab-nivolumab combination in VEGF-refractory patients suggest that this is an active combination.229 Additional phase I and II studies of PD-1 and PD-L1 inhibitor combinations in kidney cancer include those with HDAC inhibitors (NCT02909452), IDO inhibition (NCT02178722), and anti-CD27 (NCT02335918). An additional strategy combining Alk-1 inhibition (dalantercept) with axitinib is also undergoing phase I/II investigation (NCT01727336).

Treatment of Kidney Cancers With Nonconventional Histologic Features Less than 10% of patients who receive treatment in clinical trials have non–clear cell histologic characteristics, and consequently data on response rates for non–clear cell RCC are relatively limited.230–232 This is not only because of the rarity of these variants in the metastatic setting, but also because in the past, studies have excluded non–clear cell carcinoma patients. Two recently reported prospective multicenter phase II studies in patients with non–clear cell histologic types (primarily papillary type I and II, chromophobe, and undifferentiated tumors) compared sunitinib and everolimus and give some perspective regarding the management of these patients. The ESPN study randomized 68 patients (27 papillary, 12 chromophobe, 10 unclassified, 7 translocation, and 12 sarcomatoid) 1 : 1 to either sunitinib or everolimus.233 The median PFS in first-line therapy was 6.1 months with sunitinib versus 4.1 months with everolimus (P = .6). At final analysis, median OS times were 16.2 and 14.9 months with sunitinib and everolimus, respectively (P = .18).233 The second study, ASPEN, was a larger multicenter phase II study and enrolled 108 patients (65 papillary, 16 chromophobe, 21 unclassified, and 6 translocation) who were randomly assigned to receive either sunitinib (n = 51) or everolimus (n = 57). Sunitinib significantly increased PFS compared with everolimus (8.3 months [80% CI, 5.8–11.4] versus 5.6 months [5.5–6.0]; HR 1.41 [80% CI, 1.03–1.92]; P = .16), although heterogeneity of the treatment effect was noted on the basis of histologic subtypes and prognostic risk groups.234 In particular, papillary RCC patients had a longer median PFS with sunitinib than everolimus (8.1 versus 5.5 months; HR, 1.52 [1.05–2.20 80% CI]), whereas chromophobe patients exhibited longer PFS with everolimus (5.5 versus 11.4 months; HR. 0.71 [80% CI, 0.31–1.65]).234 All told, these results suggest that (1) overall, non–clear cell histologic types have a worse prognosis than clear cell histologic type in the metastatic setting, driven in large part by papillary types; and (2) non–clear cell histologic types are biologically different and may respond differently to targeted therapies. In the future these non–clear cell histologic types should be studied in separate cohorts. Collecting duct RCC is a rare and aggressive neoplasm of the distal collecting duct system for which no effective therapy has been established. In a case report, a 37-year-old woman with metastatic

collecting duct RCC demonstrated 80% reduction in her tumor burden, including complete regression of lymph node metastases and significant shrinkage of the primary, after treatment with paclitaxel and carboplatin. The patient was subsequently rendered free of disease by nephrectomy without evidence of recurrence at follow-up evaluation at 20 months.235 A number of case reports have described responses of collecting duct carcinoma to gemcitabine- or taxane-based therapies similar to those used in transitional cell carcinoma.236,237 This finding is consistent with expression data, suggesting that these tumors are closely related to transitional cell cancers.238,239

SUMMARY Surgical resection remains the principal therapeutic modality when RCC is confined to the kidney and in selected cases of metastatic disease. OS remains influenced by stage, performance status, Fuhrman grade, and histologic subtype (e.g., sarcomatoid feature is associated with poor prognosis). Patients at high risk for recurrence after nephrectomy include those with positive lymph nodes, high Fuhrman grade, extension beyond the Gerota fascia, or extension into the renal vein or vena cava. The results of S-TRAC suggest for the first time that adjuvant therapy in selected patients may be of benefit. Additional studies of VEGF inhibitors and anti-PD-1 and anti-PD-L1 therapies will further shape this landscape. Cytoreductive nephrectomy for patients with metastatic disease may enhance responsiveness to systemic therapy and also remains the standard treatment modality for patients receiving antiangiogenesis and immunotherapy drugs. Metastasectomy is considered acceptable if all disease can be resected, which, in some instances, may be curative. Recent advances in the use of anti-PD-1 and anti-PD-L1 therapy have begun to reshape the treatment landscape for patients with advanced RCC and are likely to continue. Ongoing trials in combination with VEGFR TKIs and with ipilimumab may reshape first-line treatment strategies. Recent years have witnessed the approval of additional VEGF-targeted therapies that include additional targets (MET, Axl in the case of cabozantinib, and FGFR in the case of lenvatinib). Great progress in the treatment of renal cancer has been made. Three distinct therapeutic approaches (targets) remain the mainstays of therapeutic intervention for recurrent RCC: VEGF/VEGFR blockade or inhibition, mTOR inhibition, and immunotherapies. However, these approaches alone are not sufficiently active to achieve durable clinical benefit in the majority of patients. Continued exploration of molecular pathways and investigations to identify prognostic and predictive markers in this disease remain critical. The genetic studies of RCC have unveiled the potential role of chromatin remodeling genes. Future studies will shed additional light on the possible biologic mechanisms driven by the dysregulation of histone-modifying genes and on novel therapies with chromatin remodeling agents. Physician encouragement of patient participation in clinical trials will dictate the pace of progress in the development of novel, rationally designed, and more effective therapeutic strategies. The complete reference list is available online at ExpertConsult.com.

KEY REFERENCES 1. Siegel RL, et al. Cancer Statistics 2018. CA Cancer J Clin. 2018 Jan;68(1):7–30. PMID: 29313949. 16. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010;7(5):245–257. 53. Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.

64. Motzer RJ, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004;22(3):454–463. 65. Heng DY, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factortargeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794–5799.

66. Heng DY, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141–148. 71. Blom JH, et al. Radical nephrectomy with and without lymph-node dissection: final results of European Organisation for Research and Treatment

Cancer of the Kidney  •  CHAPTER 79 1381 of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol. 2009;55(1):28–34. 87. Kim SP, et al. Comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta-analysis. J Urol. 2012;188(1):51–57. 88. Van Poppel H, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol. 2011;59(4):543–552. 91. Jeon SH, et al. Comparison of laparoscopic versus open radical nephrectomy for large renal tumors: a retrospective analysis of multi-center results. BJU Int. 2011;107(5):817–821. 94. Burgess NA, et al. Randomized trial of laparoscopic v open nephrectomy. J Endourol. 2007;21(6):610–613. 111. Klatte T, Shariat SF, Remzi M. Systematic review and meta-analysis of perioperative and oncologic outcomes of laparoscopic cryoablation versus laparoscopic partial nephrectomy for the treatment of small renal tumors. J Urol. 2014;191(5):1209–1217. PMID 24231845. 118. Katsanos K, et al. Systematic review and meta-analysis of thermal ablation versus surgical nephrectomy for small renal tumours. Cardiovasc Intervent Radiol. 2014;37(2):427–437. PMID 24482030. 119. Smaldone MC, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer. 2012;118(4): 997–1006. 147. Haas NB, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016;387(10032):2008–2016. PMCID: PMC4878938. 149. Ravaud A, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246–2254. PMID: 27718781. 155. Flanigan RC, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655–1659. 156. Mickisch GH, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001; 358(9286):966–970. 157. Hanna N. Survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a National Cancer Database study. J Clin Oncol. 2016;34(27):3267–3275. PMID 27325852. 158. Heng DY. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell

carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 2014;66(4):704–710. PMID 24931622. 159. Kavolius JP, et al. Resection of metastatic renal cell carcinoma. J Clin Oncol. 1998;16(6):2261– 2266. 168. Fyfe G, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688–696. 170. Alva A, Daniels GA, Wong MK, et al. Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma. Cancer Immunol Immunother. 2016;65(12):1533–1544. 181. McDermott DF, Drake CG, Sznol M, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol. 2015;33(18):2013–2020. 182. Motzer RJ, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–1813. 188. Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2): 125–134. 190. Motzer RJ, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007; 356(2):115–124. 196. Bracarda S. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol. 2015;26(10):2107–2113. PMID 26216384. 197. Escudier B, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103–2111. 198. Rini BI, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26(33):5422–5428. 200. Sternberg CN, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6): 1061–1068. 202. Motzer RJ. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722–731. PMID 23964934. 205. Rini BI. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807): 1931–1939. PMID 22056247. 206. Hutson TE. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet. 2013; 14(13):1287–1294. PMID 24206640.

208. Choueiri TK. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814–1823. PMID 26406150. 209. Choueiri TK. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN Trial. J Clin Oncol. 2016;35(6):591–597. PMID 28199818. 213. Motzer RJ. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473–1482. PMID 26482279. 214. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43–49. PMID 23792563. 219. Hudes G, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–2281. 221. Motzer RJ, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008; 372(9637):449–456. 225. McDermott DF, et al. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). J Clin Oncol. 2017;35 (suppl 6S; abstract 431). 227. Kanesvaran R, et al. A single-arm phase 1b study of everolimus and sunitinib in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2015;13(4):319–327. PMID: 26174223. 228. Negrier S, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12(7):673–680, 21664867. 229. Hammers H, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32:5s (suppl; abstr 4504). 233. Tannir NM, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016;69(5):866–874. PMID: 26626617. 234. Armstrong AJ, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016;17(3): 378–388. PMID: 26794930.

Cancer of the Kidney  •  CHAPTER 79 1381.e1 1381.e1

REFERENCES 1. Siegel RL, et al. Cancer Statistics 2018. CA Cancer J Clin. 2018 Jan;68(1):7–30. PMID: 29313949. 2. Cho E, et al. Epidemiology of renal cell cancer. Hematol Oncol Clin North Am. 2011;25(4):651–665. PMID: 21763961. 3. Gandaglia G, et al. Contemporary incidence and mortality rates of kidney cancer in the United States. Can Urol Assoc J. 2014;8(7–8):247–252. PMID: 25210548. 4. Chow WH, et al. Rising incidence of renal cell cancer in the United States. JAMA. 1999;281(17): 1628–1631. 5. Hollingsworth JM, et al. Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst. 2006;98(18):1331–1334. 6. Cumberbatch MG. The role of tobacco smoke in bladder and kidney carcinogenesis: a comparison of exposures and meta-analysis of incidence and mortality risks. Eur Urol. 2016;70(3):458–466. PMID: 26149669. 7. Tsivian M. Cigarette smoking is associated with advanced renal cell carcinoma. J Clin Oncol. 2011;29(15):2027–2031. PMID: 21502558. 8. Adams KF. Body size and renal cell cancer incidence in a large US cohort study. Am J Epidemiol. 2008;168(3):268–277. PMID: 18544571. 9. Renehan AG. Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab. 2006;17(8):328–336. PMID: 16956771. 10. Klingjoffer Z. Obesity and renal cell carcinoma: epidemiology, underlying mechanisms and management considerations. Expert Rev Anticancer Ther. 2009;9(7):975–987. PMID: 19589036. 11. Calle EE. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4(8):579–591. PMID: 15286738. 12. Maitland ML. Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. Clin Cancer Res. 2009;15(19): 6250–6257. PMID: 19773379. 13. Weikert S. Blood pressure and risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition. Am J Epidemiol. 2008;167(4):438–446. PMID: 18048375. 14. Schouten LJ. Hypertension, antihypertensives and mutations in the Von Hippel-Lindau gene in renal cell carcinoma: results from the Netherlands Cohort Study. J Hypertens. 2005;23(11):1997–2004. PMID: 16208141. 15. Bretan PN Jr, et al. Chronic renal failure: a significant risk factor in the development of acquired renal cysts and renal cell carcinoma. Case reports and review of the literature. Cancer. 1986;57(9):1871–1879. 16. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010;7(5):245–257. 17. Moertel CG, Dockerty MB, Baggenstoss AH. Multiple primary malignant neoplasms. I. Introduction and presentation of data. Cancer. 1961;14:221–230. 18. Pritchett TR, Lieskovsky G, Skinner DG. Extension of renal cell carcinoma into the vena cava: clinical review and surgical approach. J Urol. 1986;135(3): 460–464. 19. Grubb RL, Walther MM, Linehan WM. The genetic basis of cancer of the kidney. In: Genetic Diseases of the Kidney. San Diego: Elsevier; 2005. 20. Lopez-Beltran A, et al. 2004 WHO classification of the renal tumors of the adults. Eur Urol. 2006;49(5):798–805. 21. Prasad SR, et al. Common and uncommon histologic subtypes of renal cell carcinoma: imaging spectrum with pathologic correlation. Radiographics. 2006;26(6):1795–1806, discussion 1806–1810. 22. Moch H, Cubilla AL, Humphrey PA, et al. The 2016 WHO classification of tumours of the urinary system and male genital organs—Part A: renal, penile, and

testicular tumours. Eur Urol. 2016;70(1):93–105. PMID 26935559. 23. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982;6(7):655–663. 24. Linehan WM, et al. Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res. 2004;10(18 Pt 2):6282S–6289S. 25. Iliopoulos O, et al. Tumour suppression by the human von Hippel-Lindau gene product. Nat Med. 1995;1(8):822–826. 26. Kaelin WG Jr. The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res. 2007;13(2 Pt 2):680s–684s. 27. Maranchie JK, et al. The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell. 2002;1(3):247–255. 28. Kondo K, et al. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell. 2002;1(3):237–246. 29. Barnabas N, et al. Mutations in the von HippelLindau (VHL) gene refine differential diagnostic criteria in renal cell carcinoma. J Surg Oncol. 2002;80(1): 52–60. 30. Schmidt L, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET protooncogene in papillary renal carcinomas. Nat Genet. 1997;16(1):68–73. 31. Tomlinson IP, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30(4):406–410. 32. Adam J, et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell. 2011;20(4):524–537. 33. Ooi A, et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell. 2011;20(4): 511–523. 34. TCGA Research Network. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2016;374:135–145. PMID: 26536169. 35. Gad S, et al. Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma. Br J Cancer. 2007;96(2):336–340. 36. Sukosd F, et al. Allelic loss at 10q23.3 but lack of mutation of PTEN/MMAC1 in chromophobe renal cell carcinoma. Cancer Genet Cytogenet. 2001;128(2): 161–163. 37. Argani P, et al. Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay. Am J Surg Pathol. 2003;27(6):750–761. 38. Settembre C, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332(6036):1429–1433. 39. Takahashi M, et al. Familial adult renal neoplasia. J Med Genet. 2002;39(1):1–5. 40. Cohen D, Zhou M. Molecular genetics of familial renal cell carcinoma syndromes. Clin Lab Med. 2005;25(2):259–277. 41. Gnarra JR, Tory K, Weng Y, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994;7(1):85–90. 42. Pavlovich CP, et al. Evaluation and management of renal tumors in the Birt-Hogg-Dube syndrome. J Urol. 2005;173(5):1482–1486. 43. Toro JR, et al. Birt-Hogg-Dube syndrome: a novel marker of kidney neoplasia. Arch Dermatol. 1999;135(10):1195–1202. 44. Khoo SK, et al. Inactivation of BHD in sporadic renal tumors. Cancer Res. 2003;63(15):4583–4587. 45. Medvetz DA, et al. Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts

with the adherens junction protein p0071 to regulate cell-cell adhesion. PLoS ONE. 2012;7(11):e47842. 46. Nahorski MS, et al. Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Hum Mol Genet. 2012;21(24): 5268–5279. 47. Malchoff CD, et al. Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome. J Clin Endocrinol Metab. 2000;85(5):1758–1764. 48. Muller M, et al. Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers. Clin Genet. 2017, March 16, epub ahead of print. PMID 28300276. 49. Sudarshan S, et al. Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol. 2009;29(15):4080– 4090. 50. Bertolotto C, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011;480(7375):94–98. 51. Rybicki FJ, et al. Percutaneous biopsy of renal masses: sensitivity and negative predictive value stratified by clinical setting and size of masses. AJR Am J Roentgenol. 2003;180(5):1281–1287. 52. Ficarra V, et al. TNM staging system for renal-cell carcinoma: current status and future perspectives. Lancet Oncol. 2007;8(6):554–558. 53. Edge SB, Byrd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 54. Lee CT, et al. Surgical management of renal tumors 4 cm or less in a contemporary cohort. J Urol. 2000;163(3):730–736. 55. Hafez KS, Fergany AF, Novick AC. Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging. J Urol. 1999;162(6):1930–1933. 56. Lerner SE, et al. Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J Urol. 1996;155(6): 1868–1873. 57. Zisman A, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol. 2001;19(6):1649–1657. 58. Patard JJ, et al. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol. 2005;23(12):2763–2771. 59. Storkel S, et al. Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer. 1997;80(5):987–989. 60. Kovacs G, et al. The Heidelberg classification of renal cell tumours. J Pathol. 1997;183(2):131–133. 61. Moch H, et al. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: a Swiss experience with 588 tumors. Cancer. 2000;89(3): 604–614. 62. Amin MB, et al. Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. Am J Surg Pathol. 2002;26(3): 281–291. 63. Motzer RJ, et al. Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma. J Clin Oncol. 2000;18(9):1928–1935. 64. Motzer RJ, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004;22(3):454–463. 65. Heng DY, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth

1381.e2 Part III: Specific Malignancies factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794–5799. 66. Heng DY, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141–148. 67. Kutikov A, et al. Routine adrenalectomy is unnecessary during surgery for large and/or upper pole renal tumors when the adrenal gland is radiographically normal. J Urol. 2011;185(4):1198–1203. 68. Whitson JM, et al. Lymphadenectomy improves survival of patients with renal cell carcinoma and nodal metastases. J Urol. 2011;185(5):1615–1620. PMID 21419453. 69. Mehta A, et al. Renal lymph nodes for tumor staging: appraisal of 871 nephrectomies with examination of hilar fat. Arch Pathol Lab Med. 2013;137(11):1584–1590. PMID 23651149. 70. Gershman B, et al. Radical nephrectomy with or without lymph node dissection for nonmetastatic renal cell carcinoma: a propensity score-based analysis. Eur Urol. 2017;71(4):560–567. PMID 27671144. 71. Blom JH, et al. Radical nephrectomy with and without lymph-node dissection: final results of European Organisation for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol. 2009;55(1):28–34. 72. Crispen U, et al. Lymph node dissection in renal cell carcinoma. Eur Urol. 2011;60(6):1212–1220. PMID 21940096. 73. Capitanio U, et al. Lymph node dissection in renal cell carcinoma. Eur Urol. 2011;60(6):1212–1220. PMID 21940096. 74. Go AS, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296–1305. 75. Novick AC. Nephron-sparing surgery for renal cell carcinoma. Annu Rev Med. 2002;53:393–407. 76. Simone P, et al. [The diagnosis and treatment of renal oncocytoma. Our experience]. Minerva Chir. 1992;47(10):935–938. 77. Leibovich BC, et al. Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy. J Urol. 2004;171(3):1066–1070. 78. Dash A, et al. Comparison of outcomes in elective partial vs radical nephrectomy for clear cell renal cell carcinoma of 4-7 cm. BJU Int. 2006;97(5):939–945. 79. Simhan J, et al. Objective measures of renal mass anatomic complexity predict rates of major complications following partial nephrectomy. Eur Urol. 2011;60(4):724–730. 80. Patard JJ, et al. Morbidity and clinical outcome of nephron-sparing surgery in relation to tumour size and indication. Eur Urol. 2007;52(1):148–154. 81. Campbell SC, et al. Complications of nephron sparing surgery for renal tumors. J Urol. 1994;151(5): 1177–1180. 82. Porpiglia F, et al. Laparoscopic versus open partial nephrectomy: analysis of the current literature. Eur Urol. 2008;53(4):732–742, discussion 742–743. 83. Kwon EO, et al. Impact of positive surgical margins in patients undergoing partial nephrectomy for renal cortical tumours. BJU Int. 2007;99(2):286– 289. 84. Yossepowitch O, et al. Positive surgical margins at partial nephrectomy: predictors and oncological outcomes. J Urol. 2008;179(6):2158–2163. PMID 18423758. 85. Bensalah K, et al. Positive surgical margin appears to have negligible impact on survival of renal cell carcinomas treated by nephron-sparing surgery. Eur Urol. 2010;57(3):466–471. PMID 19359089. 86. Shah PH, et al Positive surgical margins increase risk of recurrence after partial nephrectomy for high risk renal tumors. J Urol. 2016;196(2):327-334. PMID 26907508.

87. Kim SP, et al. Comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta-analysis. J Urol. 2012;188(1):51–57. 88. Van Poppel H, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol. 2011;59(4):543–552. 89. Shuford MD, et al. Complications of contemporary radical nephrectomy: comparison of open vs laparoscopic approach. Urol Oncol. 2004;22(2):121–126. 90. Ono Y, et al. Laparoscopic radical nephrectomy for renal cell carcinoma: a five-year experience. Urology. 1999;53(2):280–286. 91. Jeon SH, et al. Comparison of laparoscopic versus open radical nephrectomy for large renal tumors: a retrospective analysis of multi-center results. BJU Int. 2011;107(5):817–821. 92. Jeong W, et al. Comparison of laparoscopic radical nephrectomy and open radical nephrectomy for pathologic stage T1 and T2 renal cell carcinoma with clear cell histologic features: a multi-institutional study. Urology. 2011;77(4):819–824. 93. Makhoul B, et al. Laparoscopic radical nephrectomy for T1 renal cancer: the gold standard? A comparison of laparoscopic vs open nephrectomy. BJU Int. 2004;93(1):67–70. 94. Burgess NA, et al. Randomized trial of laparoscopic v open nephrectomy. J Endourol. 2007;21(6):610–613. 95. Simmons MN, Chung BI, Gill IS. Perioperative efficacy of laparoscopic partial nephrectomy for tumors larger than 4 cm. Eur Urol. 2009;55(1):199–207. 96. Lane BR, Campbell SC, Gill IS. Ten-year oncologic outcomes after laparoscopic and open partial nephrectomy. J Urol. 2013;190(1):44–49. 97. Khalifeh A, et al. Comparative outcomes and assessment of trifecta in 500 robotic and laparoscopic partial nephrectomy cases: a single surgeon experience. J Urol. 2013;189(4):1236–1242. 98. Ellison JS, et al. A matched comparison of perioperative outcomes of a single laparoscopic surgeon versus a multisurgeon robot-assisted cohort for partial nephrectomy. J Urol. 2012;188(1):45–50. 99. Pierorazio PM, et al. Robotic-assisted versus traditional laparoscopic partial nephrectomy: comparison of outcomes and evaluation of learning curve. Urology. 2011;78(4):813–819. 100. Gill IS, et al. “Zero ischemia” partial nephrectomy: novel laparoscopic and robotic technique. Eur Urol. 2011;59(1):128–134. 101. Campbell SC, et al. Guideline for management of the clinical T1 renal mass. J Urol. 2009;182(4): 1271–1279. 102. Gervais DA. Cryoablation versus radiofrequency ablation for renal tumor ablation: time to reassess? J Vasc Interv Radiol. 2013;24(8):1135–1138. PMID 23885912. 103. Schwartz BF, et al. Cryoablation of small peripheral renal masses: a retrospective analysis. Urology. 2006; 68(1 suppl):14–18. 104. Gill IS, et al. Renal cryoablation: outcome at 3 years. J Urol. 2005;173(6):1903–1907. 105. Lin CH, et al. Histopathologic confirmation of complete cancer-cell kill in excised specimens after renal cryotherapy. Urology. 2004;64(3):590. 106. Rodriguez R, et al. Renal ablative cryosurgery in selected patients with peripheral renal masses. Urology. 2000;55(1):25–30. 107. Permpongkosol S, Nielsen ME, Solomon SB. Percutaneous renal cryoablation. Urology. 2006;68(1 suppl):19–25. 108. Hegarty NJ, et al. Probe-ablative nephron-sparing surgery: cryoablation versus radiofrequency ablation. Urology. 2006;68(1 suppl):7–13. 109. Silverman SG, et al. Renal tumors: MR imagingguided percutaneous cryotherapy–initial experience in 23 patients. Radiology. 2005;236(2):716– 724.

110. Aron M, et  al. Laparoscopic renal cryoablation: 8-year, single surgeon outcomes. J Urol. 2010;183(3):889–895. 111. Klatte T, Shariat SF, Remzi M. Systematic review and meta-analysis of perioperative and oncologic outcomes of laparoscopic cryoablation versus laparoscopic partial nephrectomy for the treatment of small renal tumors. J Urol. 2014;191(5):1209–1217. PMID 24231845. 112. Allaf ME, et al. Pain control requirements for percutaneous ablation of renal tumors: cryoablation versus radiofrequency ablation–initial observations. Radiology. 2005;237(1):366–370. 113. Varkarakis IM, et al. Percutaneous radio frequency ablation of renal masses: results at a 2-year mean followup. J Urol. 2005;174(2):456–460, discussion 460. 114. Sung HH, et al. Comparison of percutaneous radiofrequency ablation and open partial nephrectomy for the treatment of size- and location-matched renal masses. Int J Hyperthermia. 2012;28(3):227–234. 115. Breen DJ, et al. Management of renal tumors by image-guided radiofrequency ablation: experience in 105 tumors. Cardiovasc Intervent Radiol. 2007;30(5):936–942. 116. Leveillee RJ, et al. Oncological outcomes utilizing real-time peripheral thermometry-guided radiofrequency ablation of small renal masses. J Endourol. 2013;27(4):480–489. 117. Psutka SP, et al. Long-term oncologic outcomes after radiofrequency ablation for t1 renal cell carcinoma. Eur Urol. 2013;63(3):486–492. 118. Katsanos K, et al. Systematic review and meta-analysis of thermal ablation versus surgical nephrectomy for small renal tumours. Cardiovasc Intervent Radiol. 2014;37(2):427–437. PMID 24482030. 119. Smaldone MC, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer. 2012;118(4): 997–1006. 120. Mason RJ, et al. Growth kinetics of renal masses: analysis of a prospective cohort of patients undergoing active surveillance. Eur Urol. 2011;59(5):863–867. 121. Patel HD, et al. A prospective, comparative study of quality of life among patients with small renal masses choosing active surveillance and primary intervention. J Urol. 2016;196(5):1356–1362. PMID 27140071. 122. Kutikov A, et al. Renal mass biopsy: always, sometimes, or never? Eur Urol. 2016;70(3):403–406. PMID 27085625. 123. Burruni R, et al. The role of renal biopsy in small renal masses. Can Urol Assoc J. 2016;10(1–2):E28– E33. PMID 26858784. 124. Kunkle DA, Egleston BL, Uzzo RG. Excise, ablate or observe: the small renal mass dilemma—a metaanalysis and review. J Urol. 2008;179(4):1227–1233, discussion 1233–1234. 125. Chawla SN, et al. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol. 2006;175(2):425– 431. 126. Oda T, et al. Growth rates of primary and metastatic lesions of renal cell carcinoma. Int J Urol. 2001;8(9):473–477. 127. Kato M, et al. Natural history of small renal cell carcinoma: evaluation of growth rate, histological grade, cell proliferation and apoptosis. J Urol. 2004; 172(3):863–866. 128. Kawaguchi S, et al. Most renal oncocytomas appear to grow: observations of tumor kinetics with active surveillance. J Urol. 2011;186(4):1218–1222. 129. Chin AI, et al. Surveillance strategies for renal cell carcinoma patients following nephrectomy. Rev Urol. 2006;8(1):1–7. 130. Janzen NK, et al. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am. 2003;30(4):843–852.

Cancer of the Kidney  •  CHAPTER 79 1381.e3 1381.e3 131. Tapper H, et al. Recurrent renal cell carcinoma after 45 years. Clin Imaging. 1997;21(4):273–275. 132. Rabinovitch RA, et al. Patterns of failure following surgical resection of renal cell carcinoma: implications for adjuvant local and systemic therapy. J Clin Oncol. 1994;12(1):206–212. 133. Steinbach F, et al. Treatment of renal cell carcinoma in von Hippel-Lindau disease: a multicenter study. J Urol. 1995;153(6):1812–1816. 134. Neumann HP, Zbar B. Renal cysts, renal cancer and von Hippel-Lindau disease. Kidney Int. 1997;51(1): 16–26. 135. Zbar B, et al. Third International Meeting on von Hippel-Lindau disease. Cancer Res. 1999;59(9): 2251–2253. 136. Nielsen SM, et al. Von hippel-lindau disease: genetics and role of genetic counseling in a multiple neoplasia syndrome. J Clin Oncol. 2016;34(18):2172–2181. PMID 27114602. 137. Timsit MO, et al. Neoadjuvant treatment in advanced renal cell carcinoma: current situation and future perspectives. Expert Rev Anticancer Ther. 2012;12(12): 1559–1569. 138. Brehmer B, et al. Resection of metastasis and local recurrences of renal cell carcinoma after presurgical targeted therapy: probability of complete local control and outcome. World J Urol. 2016;34(8):1061–1066. PMID: 27287888. 139. Hellenthal NJ, et al. Prospective clinical trial of preoperative sunitinib in patients with renal cell carcinoma. J Urol. 2010;184(3):859–864. 140. Cowey CL, et al. Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. J Clin Oncol. 2010;28(9):1502–1507. 141. Jonasch E, et al. Phase II presurgical feasibility study of bevacizumab in untreated patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(25):4076–4081. 142. Borregales LD, et al. The role of neoadjuvant therapy in the management of locally advanced renal cell carcinoma. Ther Adv Urol. 2016;8(2):130–141. PMID 27034725. 143. Powles T, et al. Safety and efficacy of pazopanib therapy prior to planned nephrectomy in metastatic clear cell renal cancer. JAMA Oncol. 2016;2(10): 1303–1309. 144. Karam J, et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. Eur Urol. 2014;66:874–880. 145. Rini BI, et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J Urol. 2015;194:297–303. 146. Porta C, Chiellino S. ASSURE vs S-TRAC: conflicting results of adjuvant treatments for kidney cancer in the era of targeted agents and genomics. Ann Transl Med. 2016;4(suppl 1):S14. PMCID: PMC5104625. 147. Haas NB, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016;387(10032):2008–2016. PMCID: PMC4878938. 148. Haas NB, et al. Adjuvant treatment for high-risk clear cell renal cancer: updated results of a high-risk subset of the ASSURE randomized trial. JAMA Oncol. 2017;3(9):1249–1252. PMID: 28278333. 149. Ravaud A, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246–2254. PMID: 27718781. 150. Pizzocaro G, et al. Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study. J Clin Oncol. 2001;19(2):425–431. 151. Chamie K, et al. Adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: the ARISER randomized clinical trial. JAMA Oncol. 2016;PMID: 27787547.

152. Matin SF, Madsen LT, Wood CG. Laparoscopic cytoreductive nephrectomy: the MD Anderson Cancer Center experience. Urology. 2006;68(3):528–532. 153. Fallick ML. Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma. J Urol. 1997;158(5):1691–1695. PMID 9334580. 154. Flanigan RC, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004;171(3):1071–1076. PMID 14767273. 155. Flanigan RC, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655–1659. 156. Mickisch GH, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001; 358(9286):966–970. 157. Hanna N. Survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a National Cancer Datbase study. J Clin Oncol. 2016;34(27):3267–3275. PMID 27325852. 158. Heng DY. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 2014;66(4):704–710. PMID 24931622. 159. Kavolius JP, et al. Resection of metastatic renal cell carcinoma. J Clin Oncol. 1998;16(6):2261–2266. 160. Rasco DW, Assikis V, Marshall F. Integrating metastasectomy in the management of advanced urological malignancies—where are we in 2005? J Urol. 2006;176(5):1921–1926. 161. Wente MN, et al. Renal cancer cell metastasis into the pancreas: a single-center experience and overview of the literature. Pancreas. 2005;30(3):218–222. 162. Vecht CJ, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33(6):583–590. PMID 8498838. 163. Patchell RA, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322(8):494–500. PMID 2405271. 164. Sheehan JP, et al. Radiosurgery in patients with renal cell carcinoma metastasis to the brain: longterm outcomes and prognostic factors influencing survival and local tumor control. J Neurosurg. 2003;98(2):342–349. PMID 12593621. 165. Brown PD, et al. Stereotactic radiosurgery for patients with “radioresistant” brain metastases. Neurosurgery. 2002;51(3):656–665; discussion 665-667. PMID 12188943. 166. Chang EL, et al. Outcome variation among “radioresistant” brain metastases treated with stereotactic radiosurgery. Neurosurgery. 2005;56(5):936–945, discussion 936-945. PMID 15854241. 167. Muacevic A, et al. Treatment of brain metastases in renal cell carcinoma: radiotherapy, radiosurgery, or surgery? World J Urol. 2005;23(3):180–184. 168. Fyfe G, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688–696. 169. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000;6(suppl 1):S55–S57. 170. Alva A, Daniels GA, Wong MK, et al. Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma. Cancer Immunol Immunother. 2016;65(12):1533–1544. 171. Negrier S, Perol D, Ravaud A, et al. Do cytokines improve survival in patients with metastatic renal cell carcinoma (MRCC) of intermediate prognosis? Results of the prospective reandomized PERCU Quattro trial. J Clin Oncol. 2005;23:380S.

172. McDermott DF. Update on the application of interleukin-2 in the treatment of renal cell carcinoma. Clin Cancer Res. 2007;13(2 Pt 2):716s–720s. 173. McDermott DF, Ghebremichael MS, Signoretti S, et al. The high dose aldesleukin (HD IL-2) “SELECT” trial in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2110;28(15s):345S (abstract 4514). 174. Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30(8):825–830. 175. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013; 39(1):1–10. 176. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19(7):813–824. 177. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12(4):252–264. 178. Thompson RH, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA. 2004;101(49):17174–17179. 179. Brahmer JR, Topalian S, Wollner I, et al. Safety and activity of MDX-1106 (ONO-4538), an anti-PD-1 monoclonal antibody, in patients with selected refractory or relapsed malignancies. J Clin Oncol. 2008;26(suppl):abstr 3006. 180. Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–2454. 181. McDermott DF, Drake CG, Sznol M, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol. 2015;33(18):2013–2020. 182. Motzer RJ, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–1813. 183. Wilhelm S, Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des. 2002;8(25):2255–2257. 184. Hilger RA, Scheulen ME, Strumberg D. The RasRaf-MEK-ERK pathway in the treatment of cancer. Onkologie. 2002;25(6):511–518. 185. Wilhelm SM, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–7109. 186. Awada A, et al. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer. 2005;92(10):1855–1861. 187. Strumberg D, et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005;23(5):965–972. 188. Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2): 125–134. 189. Motzer RJ, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24(1):16–24. 190. Motzer RJ, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–124. 191. Motzer RJ, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584–3590. 192. Atkinson BJ, et al. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol. 2014;191(3): 611–618. PMID 24018239.

1381.e4 Part III: Specific Malignancies 193. Najjar YG, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer. 2014;50(6):1084–1089. PMID 24559686. 194. Bjarnason GA, et al. Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol. 2014;32(4):480–487. PMID 24321258. 195. Neri B, et al. Biweekly sunitinib regimen reduces toxicity and retains efficacy in metastatic renal cell carcinoma: a single-center experience with 31 patients. Int J Urol. 2013;20(5):478–483. PMID 23113655. 196. Bracarda S. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol. 2015;26(10):2107–2113. PMID 26216384. 197. Escudier B, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103–2111. 198. Rini BI, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26(33):5422–5428. 199. Rini BI, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28(13):2137–2143. 200. Sternberg CN, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6): 1061–1068. 201. Sternberg CN, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49(6):1287–1296. 202. Motzer RJ. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722–731. PMID 23964934. 203. Rini B. Phase II study of axitinib in sorafenibrefractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27(27):4462–4468. PMID 19652060. 204. Negrier S, Perol D, Ravaud A, et  al. Do cytokines improve survival in patients with metastatic renal cell carcinoma (MRCC) of intermediate prognosis? Results of the prospective randomized PERCY Quattro trial. J Clin Oncol. 2005;23(16_suppl):LBA4511. 205. Rini B. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807): 1931–1939. PMID 22056247. 206. Hutson TE. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet. 2013;14(13):1287–1294. PMID 24206640. 207. Choueiri TK. A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Ann Oncol. 2014;25(8):1603–1608. PMID 24827131. 208. Choueiri TK. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814–1823. PMID 26406150. 209. Choueiri TK. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal

cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN Trial. J Clin Oncol. 2016;35(6):591–597. PMID 28199818. 210. Matsui J, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14(17):5459–5465. PMID 18765537. 211. Okamato K, et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett. 2013;340(1):97–103. PMID 23856031. 212. Molina AM, et al. A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer Chemother Pharmacol. 2014;73(1):181–189. PMID 24190702. 213. Motzer RJ. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473–1482. PMID 26482279. 214. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43–49. PMID 23792563. 215. Lieberthal W. The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol. 2009;20(12):2493–2502. PMID 19875810. 216. Dudkin L, et al. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res. 2001;7(6): 1758–1764. 217. Neshat MS, et al. Enhanced sensitivity of PTENdeficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA. 2001;98(18):10314–10319. 218. Yu K, et al. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer. 2001;8(3):249–258. 219. Hudes G, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–2281. 220. Jac J, Khan M, et al. A phase II trail of RAD001 in patients with metastatic renal cell carcinoma (MRRC). J Clin Oncol. 2007. 221. Motzer RJ, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebocontrolled phase III trial. Lancet. 2008;372(9637): 449–456. 222. Atkins MB, et al. Innovations and challenges in renal cell carcinoma: summary statement from the Second Cambridge Conference. Clin Cancer Res. 2007;13(2 Pt 2):667s–670s. 223. Kaelin WG Jr. The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res. 2004;10(18 Pt 2):6290S–6295S. 224. Wallin JJ, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624. PMID: 27571927. 225. McDermott DF, et al. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). J Clin Oncol. 2017;35 (suppl 6S; abstract 431). 226. Casanovas O, et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage

pancreatic islet tumors. Cancer Cell. 2005;8(4): 299–309. 227. Kanesvaran R, et al. A single-arm phase 1b study of everolimus and sunitinib in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2015;13(4):319–327. PMID: 26174223. 228. Negrier S, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12(7):673–680, 21664867. 229. Hammers H, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32:5s (suppl; abstr 4504). 230. Motzer RJ, et  al. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol. 2002;20(9):2376–2381. 231. Upton MP, et al. Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother. 2005;28(5):488–495. 232. Stadler WM, et al. Prognostic factors for survival with gemcitabine plus 5-fluorouracil based regimens for metastatic renal cancer. J Urol. 2003;170(4 Pt 1):1141–1145. 233. Tannir NM, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol. 2016;69(5):866–874. PMID: 26626617. 234. Armstrong AJ, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, openlabel, randomised phase 2 trial. Lancet Oncol. 2016;17(3):378–388. PMID: 26794930. 235. Gollob JA, et al. Long-term remission in a patient with metastatic collecting duct carcinoma treated with taxol/carboplatin and surgery. Urology. 2001;58(6): 1058. 236. Milowsky MI, et al. Active chemotherapy for collecting duct carcinoma of the kidney: a case report and review of the literature. Cancer. 2002;94(1):111–116. 237. Peyromaure M, et al. Collecting duct carcinoma of the kidney: a clinicopathological study of 9 cases. J Urol. 2003;170(4 Pt 1):1138–1140. 238. Yang JC. Bevacizumab for patients with metastatic renal cancer: an update. Clin Cancer Res. 2004;10(18 Pt 2):6367S–6370S. 239. Yang XJ, et al. Gene expression profiling of renal medullary carcinoma: potential clinical relevance. Cancer. 2004;100(5):976–985. 240. Motzer RJ, Haas NB, Donskov F, et al. Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma. J Clin Oncol. 2017;35(35):3916–3923. PMID: 28902533. 241. Choueiri TK, Larkin J, Oya M, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dosefinding and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19(4):451–460. PMID: 29530667. 242. Atkins MB, Plimack ER, Puzanov I, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19(3):405–415. PMID: 29439857.