1. GENERAL INFORMATION
1.1.1 Incidence and mortality
In the European Union (EU) in 2006 among men there were 39,400 new cases of kidney cancer (ranked seventh among cancer and representing 3.1% of the total), whereas in women there were 24,000 new cases (ranks ninth, or 2.3% of all cancers) (Ferlay 2006). In 2002 the incidence rates per 100,000 for Eastern, Northern, Southern, and Western Europe were respectively 13.3, 14.5, 15.1, 17.6 in men and were 9.1, 9.2, 7.2, 10.1 in women. In 2002, in Europe the age specific incidence rates for men aged 0-14, 15-44, 45-54, 55-64 and 65 or more were respectively 0.7, 2.2, 17.0, 37.3, and 62.7, whereas the rates for women of the same age were respectively 0.8, 1.3, 7.6, 16.6, and 30.2. In general, the rates of this cancer are higher in economically developed societies. From 1994 to 2004 the incidence rate is stable or decreasing for both sexes in northern continental Europe, whereas increased in Slovakia, Slovenia and Czech Republic till 2000 and then started a decrease . In Italy kidney cancer incidence was constant from the ’90, whereas in women is slightly increasing. (AIRTum report 2009) In men in the EU, mortality rates from kidney cancer peaked at 4.8 per 100 000 in 1990–1994, and declined to 4.1 (13%) in 2000–2004. In women in the EU, the corresponding values were 2.1 in 1990–1994 and 1.8 (17%) in 2000–2004 (Levi 2008). In Italy mortality follows the same trend of incidence (AIRTum report 2009). (A) The difference in incidence trends may be influenced by improved registration. Moreover incidence trends may be influenced by the more widespread use of diagnostic imaging, which has increased diagnostic accuracy and has also increased the rates of early diagnosis, consequently broadening the therapeutic opportunities. In the USA incidence rates of renal cell cancer are highest among African Americans, whereas rates for whites and Hispanics are similar and Asian/ Pacific islanders has about half the incidence rates of those of the other racial/ethnic groups (Chow 2008).
The relative survival for subject diagnosed with renal cancer in Europe during 2000-2002 was 56% at 5 years with survival 65% or above in Italy, Germany, Switzerland, and Malta, and survival below 50% in Norway, England, and Scotland (Verdecchia 2007). The between-country variation in survival may be largely due to new imaging techniques which allow small lesions to be detected, whereas in the past, lesions were not detected until they had become symptomatic (Sant 2003). Five-year survival is higher in people under 45 years (76%), however, kidney cancers are rare in this age group. Survival declines steadily with increasing age; dropping to 45% in patients over 74 years (Sant 2009). Five-year relative survival improved from 55% in the period 1991–1994 to 58% in 1995-1999, even if the cancer registries involved in the two period are different (Sant 2009; Berrino 2003). Survival is sharply dependent on the stage at which the tumour is diagnosed: in a cohort study from Finland the relative 5-year overall survival was 88%, 63%, 65% and 15% in stages I–IV, respectively (Sunela 2009). The survival data reported in this article were derived from information collected by population-based cancer registries; they provide the means by which we can measure the progress of the fight against cancer.
1.2 Aetiology and risk factors
Tobacco smoking is a well estabished risk factors for renal cell cancer. A recent meta-analysis found an increased risk of renal cell cancer (RCC) of 38% in ever smokers as compared to never smokers (Hunt 2005). The risk was stronger in men (54% increment) than women (22% increment). Smoking cessation reduces the risk, but only for those who had quit smoking for >10 years. Smoking is associated with a strong dose-dependent increase in risk associated with numbers of cigarettes smoked per day. The study found an attributable risk of RCC for smoking between 21% and 23%.
Body fatness, diet and physical activities
Obesity is directly related with RCC risk. The World Cancer Research Fund (WCRF) and Association for International Cancer Research (AICR) panel of experts concluded that the evidence that body fatness is a cause of this cancer is convincing. Subsequently a meta-analysis about obesity and cancer found a risk of renal cancer of 1.24 (p <0•0001) for a 5 kg/m² increase in BMI in men and of 1•34 (p<0•0001) in women (Renehan 2008). This result is consintent with a large cohort study based on 2 milions of Norwegian men and women. In this study the risk was most pronounced in men and women who were never smokers (Bjorge 2004). The proportion of renal cell cancers attributable to overweight and obesity is estimated to be more than 40% in the United States and more than 30% in Europe (Lipworth 2006; Bergstrom 2001; Calle 2004)
Three cohort studies, one time-series study, and nine ecological studies investigated arsenic in drinking water. Arsenic is carcinogenic to humans and causes chromosomal abnormalities. All studies showed increased risk for the highest intake levels. (WCRF)
In a recent large, prospective US cohort study of 482,386 participants was found that current exercise, routine physical activity, and activity during adolescence were associated with a reduced risk of renal cell cancer (Moore 2008). Physical activity may decrease renal cell cancer risk through a number of related pathways, including lowering body weight and blood pressure, improving insulin sensitivity, and reducing chronic inflammation and oxidative stress (Chow 2008; Gago-Dominguez 2002; Jakicic 2003; Stewart 2005; Mora 2007). However for the WCRF panel of experts there is not enough evidence to draw any conclusion about the role of physical activity and renal cancer risk.
For some chemical agents, related to specific occupation, was found some relation with risk of RCC. The U.S. Environmental Protection Agency 2001 draft trichloroethylene (TCE) health risk assessment concluded that epidemiologic studies, on the whole, support associations between TCE exposure and excess risk of kidney cancer (Scott 2006). For the greatest part of studies the risk associated to TCE exposure ranged between 1 and 2. The most recent epidemiological studies strengthen the hypothesis of this association (Scott 2006). Some studies, that analyzed the relation between TCE exposure and Von Hippel-Lindau (VHL) somatic mutation, found a higher incidence of the mutation among RCC cases exposed to TCE compared to not exposed cases.(Brauch 1999; Brauch 2004) Asbestos was linked to Renal cell cancer risk by some epidemiological studies, and a meta-analysis of occupational cohort studies found a non significant increased risk of 10% and concludes that it is unlikely that asbestos exposure is responsible for an important increase in kidney cancer risk; however, high asbestos exposure might entail a small increase in risk (Sali 2000; Lipworth 2006) . Gasoline has long been suspected to be a risk factor for kidney cancer. An old review about the issue concludes that most studies find no link between gasoline exposure and renal cell cancer with a few exception (mcloughlin). More recently no association with gasoline or derivatives was reported by some occupational cohort and case-control studies (IARC 1989; Wong1999; Lipworth 2006; Lewis 2003; Poole 1993; Sclhehofer 1995) whereas others two studies found respectively a significant risk of 1.3 and 1.6. (Lynge 1997; Mandel 1995) The issue remains controversial.
There is a weak evidence of a relation between hormonal factors and renal cell cancer risk. A protective effect was found for consumption of oral contraceptive. Two studies reported a significant effect of contraceptive use ranging from 0.5 and 0.7 (Dhote 2004). However in a recent cohort study there was no association between contraceptive use and kidney cancer but an increased risk for past use of estrogen (Molokwu 2007). Four studies found an increased risk for isterecomy and ovarectomy, the risk ranging from 2.3 to 1.7 (Dhote 2004; Zucchetto 2008).
A recent meta-analyses found a significant increased risks of RCC associated with hypertension (OR=1.62; 95% CI 1.24-2.12), as well as with the use of both diuretics (1.43; 1.12-1.83) and no diuretics (1.51; 1.21-1.87) antihypertensive drugs (Corrao 2007). However the effect of diuretics was significant in women (1.92; 1.59 to 2.33), but not in men (1.18; 0.93 to 1.49) and allowance for the known risk factors of RCC appreciably modified the effect of no diuretic antihypertensives making its pooled estimate not significant (1.17; 0.94 to 1.46). Hypertension and antihypertensive treatment are highly correlated, so it is difficult to disentangle their effects. For this reason, although several observational studies have been published in the last two decades, the relationship between hypertension, antihypertensive treatments and the risk of RCC remains still controversial. (Corrao 2007).
Hereditary kidney cancer syndromes (including RCC) that have been identified with known gene mutations include von Hippel-Lindau disease (VHL), hereditary papillary renal cancer (HPRC), Birt-Hogg-Dube´ syndrome (BHD), hereditary leiomyomatosis renal cell carcinoma syndrome (HLRCC), and tuberous sclerosis complex (TSC) (Coleman 2008). However, these syndromes are rare and probably the greater familiar risk is due to more common genes but with a lower penetrance.(Peto 2001) It was estimated that 3% to 5% of patients who have renal cancer have inherited forms of disease (Coleman 2008; Rini 2006). Family history of renal cell cancer is found to be a risk factor of RCC in many studies, a recent meta-analysis based on 11 studies found a relative risk of RCC for a family history of kidney cancer of 2.21 (95% CI, 1.55-2.87) (Clague 2009). Some studies found a higher risk in siblings than in parents supporting the hypothesis of a recessive model of inheritance (Negri 2006; Hung 2007; Hemminki 2004).
2. PATHOLOGY AND BIOLOGY
2.1 Histological types
As acknowledged by the 2004 WHO classification of adult kidney tumors, biological and clinical properties define a number of entities whose recognition is of value in daily clinical practice. Different subtypes have different clinical outcomes and show different response to therapy.
Pathological classification of renal tumors has been recently refined with the introduction of cytogenetics and molecular biology (Lopez-Beltran 2006). According to the latest WHO classification of kidney tumors, malignant renal cell carcinoma is classified into different histological subgroups: clear cell, multilocular cystic, papillary, chromophobic, medullary, collecting ducts of Bellini, Xp11 translocation carcinoma, carcinoma associated with neuroblastoma, mucinous tubular and spindle cell and unclassified. Different genetic abnormalities have been associated with different subtypes (See Table 1).
Clear cell renal cell carcinomas were first erroneously thought to originate from ectopic adenocortical elements, and this was the reason underlying use of the term “hypernephroma”. Immunohistological and ultrastructural analyses have established that the proximal renal tubular epithelium is the true origin of clear cell renal carcinoma. It represents the most frequent renal cancer (75-80%) and has a worse prognosis than chromophobe or papillary subtypes. However, the response rates to systemic therapies are higher than other histological types. Papillary renal cell carcinoma (10% of all malignant renal cell cancers) has variable proportions of papillae, may be bilateral or multifocal with frequent necrosis, hemorrhage and cystic degeneration. Two subgroups with different prognosis have been identified. Cellular type 1 are low-grade tumors with a chromophilic cytoplasm and a favourable prognosis. Type 2 are mostly high-grade tumors with an eosinophilic cytoplasm and a great propensity for developing metastases. The chromophobe type accounts for 5% of renal tumors. Loss of several chromosomes characterises this cancer. At diagnosis, the most of patients have stage T1 or T2 and mortality is of 10%. Collecting duct carcinoma accounts for <1% of renal malignancies and derives from the cells of the ollecting duct. Most tumors are in advanced stage with metastasis at diagnosis. Medullary carcinoma is a rapidly growing rare tumor of the renal medulla regarded as an aggressive variant of collecting duct carcinoma. With few exceptions, this tumor is seen in young male blacks with sickle cell trait. Prognosis is poor and metastasis are soon present at the time of diagnosis. These latest tumors may respond to chemotherapeutic agents. Renal carcinoma associated with Xp11.2 translocation is a rare tumor, affecting predominantly children and young adults. The histopathologic appearance is that of a papillary carcinoma with clear cells and eosinophilic cells that displayed nuclear immunoreactivity for TFE3 protein, the product of gene fusions involving the TFE3 gene. This tumor has an indolent evolution, even with metastasis.
Fuhrman nuclear grade is the most widely accepted histological grading system in RCC (Fuhrman 1982 ). Although it is subject to intra- and inter-observer discrepancies, it remains an independent prognostic factor (Lang 2005).
|Clear cell||75%||Proximal renal tubular epithelial cells||-3p,+5q22,-6q,-8p,-9p,-14q||Aggressiveness according to grade, stage and sarcomatoid change|
|Multilocular cystic||Rare||Proximal renal tubular epithelial cells||VHL gene mutation||No progression or metastases|
|Papillary||10%||Proximal renal tubular epithelial cells||+3q,+7,+8,+12,+16,+17,+20,
|Aggressiveness according to grade, stage and sarcomatoid change|
|Chromophobe||5%||Proximal renal tubular epithelial cells||-1,-2,-6,-10,-17,-21,hypodiploidy||10% mortality|
|Collecting ducts of Bellini||1%||Cells of collecting ducts||-1q,-6p,-8p,-13q,-21q||Aggressive,2/3 of patients die within two years|
|Medullary||Rare||Cells of renal medulla||Unknown||Mean survival of 15 weeks after diagnosis|
|Xp11 translocation||Rare||Proximal renal tubular epithelial cells||T(X;1)(p11.2;q21),t(X;17)(p11.2;q25)||Indolent|
|After neuroblastoma||Rare||Related to grade and stage|
|Mucinous tubular and spindle cell||Rare||-1,-4,-6,-8,-13,-14,+7,+11,+16,+17||Rare metastases|
2.2 Biological data
Over the past decade there has been an explosion of information regarding the molecular basis of renal cell cancer. Like breast cancer, colon cancer, renal cell carcinoma occurs in both a sporadic (nonhereditary) and a hereditary form. At least four forms of hereditary renal cell carcinoma are recognized: von Hippel-Lindau Syndrome (VHL), Hereditary Papillary Renal Carcinoma (HPRC), Hereditary renal carcinoma associated with Birt-Hogg-Dubè syndrome, Hereditary leiomyoma renal cell carcinoma (HLRCC).
VHL disease is a familial disorder characterized by the development of multiple tumours, including bilateral renal cell carcinoma, pheochromocytoma, hemangioblastomas of the central nervous system, retinal angiomas, and pancreatic cysts. Patients with VHL disease often develop early-onset, bilateral, multifocal renal carcinoma and multiple renal cysts. The renal carcinoma is uniformly clear cell RCC. Using linkage studies, the VHL gene has been localized to the 3p (Pesch 2000; Auperin 1994) region of chromosome 3, and this gene has been cloned and sequenced (Gorospe 1999). The pattern of inheritance is autosomal dominant, with a loss of heterozygosity of the 3p region in renal cell carcinoma and other tumours in patients with VHL disease (Kaelin 1998). Molecular genetic analysis of sporadic renal cell carcinoma and cell lines derived from human renal cell carcinoma revealed a loss of heterozygosity of chromosome 3p in approximately 90% of tumours and nearly all cases of clear cell renal cell carcinoma. Mutations of the VHL gene have been observed in 50% of advanced sporadic clear cell RCC. VHL gene inactivation in RCC may also occur through gene silencing by methylation, which occurs in an additional 10% of clear cell RCC. These data suggest that biallelic VHL gene inactivation occurs in up to 75% of patients with sporadic clear cell RCC and in fact loss of VHL function is an important sentinel event during RCC pathogenesis. Loss of function of the VHL tumour suppressor gene results in loss of E3-VHL ligase activity, stabilizing hypoxia-inducible factor (HIF) and resulting in the expression of hypoxia-inducible genes such as vascular endothelial growth factor (VEGF) (Kaelin 2002; Maxwell 2002). The VHL proteins form a complex with other proteins and target the hypoxia-inducible factors (HIFs), HIF1-alpha and HIF-2alpha, for ubiquitin-mediated degradation. HIF is a transcription factor that regulates the degradation of such downstream genes as VEGF, GLUT-1, PDGF, EGFR and TGF-alpha. Damage to this gene prevents the VHL complex from targeting and degrading HIF. HIF overaccumulates and the result is overexpression of such genes as VEGF, EGFR and TGF-alpha (this has led to an intense effort to develop agents that target the VHL pathway as an approach to therapy for patients with advanced RCC: encouraging clinical results have been reported with vascular endothelial growth factor agents) (Linehan 2004a; Linehan 2004b).
Hereditary papillary renal cell carcinoma is an hereditary cancer syndrome in which affected individuals are at risk of development of bilateral, multifocal type 1 papillary renal carcinoma (Zbar 1994; Lubensky 1999). The gene for HPRC is the oncogene c-Met (Met is the cell surface receptor for the ligand hepatocyte growth factor) (Schmidt 1997; Schmidt 1998). The mutations in this gene in HPRC kindreds are activating mutations in the tyrosine kinase domain of the gene (Schmidt 1998).
Birt-Hogg-Dubè syndrome (Toro 1999) is an autosomal dominantly inherited familiar syndrome in which affected individuals may have cutaneous manifestations (the presence of fibrofolliculomas on the face, neck and anterior trunk), lung cysts which can manifest themselves as spontaneous pneumothorax, and are at risk of developing bilateral multifocal renal tumours. The histology can be chromophobe, oncocytoma, papillary RCC (Pavlovich 2002). The BHD gene was recently identified on the short arm of chromosome 17 (Nickerson 2002). Germline mutations of the BHD gene have been found in a high percentage of affected individuals from BHD kindreds. The BHD gene appears to have the characteristics of a tumour suppressor gene.
HLRCC is a hereditary syndrome in which affected individuals are at risk of developing cutaneous and uterine leiomyomas (a significant percentage have had hysterectomies in their 20s) and kidney cancer. HLRCC kidney cancer is a highly aggressive form of type 2 papillary renal carcinoma. The gene for HLRCC is the Krebs cycle enzyme, fumarate hydratase (FH). Germline mutations of the FH gene have been found in a high percentage of affected individuals from HLRCC kindreds. Efforts are currently underway to determine how alteration of the FH gene leads to the development of kidney cancer in affected individuals in HLRCC kindreds. A variety of molecular changes in renal cell carcinoma proteins has been described, including p53 (Haitel 1999), metalloproteinase (Kugler 1998) and telomerase (Yoshida 1998).
Renal carcinoma may remain clinically occult for most of its course. The classic presentation of pain, haematuria, and flank mass occurs in only 9% of patients and is often indicative of advanced disease. Approximately 30% of patients with renal carcinoma present with metastatic disease, 25% with locally advanced renal carcinoma and 45% with localized disease (Jennings 1997; Maldazys 1986). Some 75% of patients with metastatic renal carcinoma have metastases to the lung, 36% to soft tissue, 20% to bone, 18% to liver, 8% to cutaneous sites and 8% to the central nervous system. Systemic symptoms, such as anaemia, fever, non-metastatic hepatic dysfunction, hypercalcemia, erythrocytosis, are present in around 30% of patients at the time of diagnosis (Marshall 1986). Hypochromic anaemia, due to either haematuria or haemolysis, has been observed in 29% to 88% of patients with renal carcinoma. Fever is observed in 20% and cachexia, fatigue and weigth loss in 33% of patients. Non-metastatic hepatic dysfunction is a reversible syndrome associated with renal carcinoma that tends to occur in association with fever, fatigue and weight loss and resolves when the primary tumour is removed (Staufer syndrome). Non-metastatic hepatic dysfunction is usually associated with poor prognosis and occurs in up to 7% of patients with renal carcinoma. Polycythaemia has been reported in 1-5% of patients with renal carcinoma. Renin levels are often elevated in patients with kidney cancer but tend to return normal after the kidney is removed (Da Silva 1990); whether the tumour itself produces renin or whether it induces renin production by compression of adjacent tissue is unclear. Immunocytochemical studies have suggested that renal carcinoma may produce renin, which however, may be biologically inactive (Lindop 1986). Plasma fibrinogen levels may be elevated in patients with renal carcinoma and may correlate with tumour stage, disease activity and response to therapy. Acquired dysfibrinogenemia has also been reported in association with renal carcinoma and can be a sensitive plasma marker for the disease and for tumour progression (Dawson 1985). Humoral hypercalceamia of malignancy, frequently observed in patients with advanced renal carcinoma, is believed to be caused by a tumour-produced, systemically active bone-resorbing factor. Some investigators have demonstrated that kidney cancer produces a factor with parathyroid hormone-like bioactivity (Thiede 1988; Massfelder 2004).
3.2 Radiographic evaluation
Ultrasonography has a sensitivity of about 60% for detecting small tumours and 85% or more for large tumours. Intravenous pyelography is indicated only when an urothelial tumour of the renal pelvis is suspected. The most important staging technique is a computed tomography (CT) scan of the whole abdomen: it shows the volume of the tumour, its location, the presence of enlarged lymph nodes, the condition of adrenal glands and the liver and provides information on venous involvement. It has a sensitivity of about 90% for tumours less than 3 cm and more than 95% for larger tumours. Tumours usually show a heterogeneous density on CT scan before injection of contrast medium, and increased density (due to their abundant vasculature) after injection. There is no evidence to support the use of magnetic resonance imaging (MRI) in patients with suspected renal carcinoma. Although arteriography and CT are equivalent in depicting renal vein involvement, CT is better for demonstrating local nodal involvement. Magnetic resonance imaging (MRI) can be reserved primarily for patients with locally advanced tumor, possible venous involvement or allergy to intravenous contrast. MRI is also an option for the evaluation of inferior vena cava tumor thrombus extension and the evaluation of unclassified renal masses (Kabala 1991). Ultrasonography and CT can provide information about tumour involvement of the vena cava (Choyke 1997). In patients with tumours involving the inferior vena cava, transesophageal echocardiography has been shown to be an accurate diagnostic technique to document the extent of involvement of the vena cava. Chest CT is the most accurate investigation for chest staging, but at least routine chest radiography must be done for metastatic evaluation. Bone scan is indicated only in symptomatic patients or with increase of alkaline phosphatase level (Seaman 1996). FDG-PET-CT scan does not appear to provide additional information over CT imaging for the characterisation of renal masses, due to FDG is excreted via the kidneys. However, it may be a promising tool for the detection of distant metastasis. Therefore, multiple imaging modalities often are combined to provide the most complete information, particularly when surgical removal of a large tumour is being considered.
4.1 Staging classification
The staging system used in the past by the majority of United States physicians was the Robson classification.
Stage I renal carcinoma is confined to the kidney
Stage II carcinoma extends through the renal capsule but is confined to the Gerota’s fascia
stage III carcinoma involves the renal vein or inferior vena cava (IIIA) or the local hilar lymph nodes (IIIB)
In Stage IV renal carcinoma, the tumour has spread to local adjacent organs (other than the adrenal gland) or distant sites.
The Robson staging system is uncomplicated and widely used, but combines stages that may have significantly different survival prognoses (Robson 1969 ). In this classification system, renal inferior cava involvement (IIIA) is staged the same as is local lymph node metastasis (IIIB). Although patients with stage IIIB renal carcinoma experience a greatly decreased survival, the prognosis for patients with stage IIIA renal carcinoma is not markedly different from that for patients with stage I or stage II renal carcinoma.
The TNM (tumour, node, metastasis) classification proves a more accurate method for classifying the extent of tumour involvement. The TNM classification of renal carcinoma appears to improve stratification of renal carcinoma according to survival and may have enhanced clinical utility as compared with previous classification systems (UICC 2002).
4.2 TNM (Classification)
PRIMARY TUMOUR (T)
Tx Minimum requirements cannot be assessed
T0 No evidence of primary tumour
T1 Tumor 7 cm or less in greatest dimension, limited to the kidney
T1a Tumor 4 cm or less in greatest dimension, limited to the kidney
T1b Tumor more than 4 cm but not more than 7 cm in greatest dimension, limited to the kidney
T2 Tumor more than 7 cm in greatest dimension, limited to the kidney
T3 Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond Gerota’s fascia
T3a Tumor directly invades adrenal gland or perineal and/or renal sinus fat but not beyond Gerota’s fascia
T3b Tumor grossly extends into the renal vein or its segmental (muscle-containing) branches, or vena cava below
T3c Tumor grossly extends into vena cava above diaphragm or invades the wall of the vena cava
T4 Tumor invades beyond Gerota’s fascia
REGIONAL LYMPH NODES (N)*
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Metastases in a single regional lymph node
N2 Metastasis in more than one regional lymph node
* Laterality does not affect the N classification
Note: If a lymph node dissection is performed, then pathologic evaluation would ordinarily include at least eight nodes
DISTANT METASTASIS (M)
Mx Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
T2, N0, M0
T1, N1, M0
T2, N1, M0
T3, N0, M0
T3, N1, M0
T3a, N0, M0
T3a, N1, M0
T3b, N0, M0
T3b, N1, M0
T3c, N0, M0
T3c, N1, M0
T4, N0, M0
T4, N1, M0
Any T, N2, M0
Any T, Any N, M1
Clinical evaluation of patients with metastatic renal cell carcinoma includes the assessment of following laboratory parameters: hemoglobin, serum lactate dehydrogenase, serum albumin and calcium.
The 5-year survival rates for renal cancer patients have been reported by Robson in the 1969 as: 66% for stage I, 64% for stage II, 42% for stage III, 11% for stage IV (Robson 1969). With the exception of stage I carcinoma, these survival statistics have remained essentially the same for a number of years. The renal vein involvement does not have a markedly negative effect on prognosis, but for patients with stage IIIB renal carcinoma 5-year survival is only 18%. Recent studies have reported better survival for patients with tumours confined to the kidney: 95% 5- and 10- year disease-specific survival for T1 renal carcinoma and 88% 5-year and 81% 10-year disease-specific survival for stage T2 disease. In patients with N0M0 tumours, T stage has no statistically significant impact on survival.
Predictive models for recurrence or development of metastatic disease of RCC following definitive surgical treatment with partial or radical nephrectomy are useful for patient counseling, clinical assessment of need for follow-up and additional therapies and clinical trial design. Post-operative predictive models including the MSKCC postoperative prognostic nomogram, the Mayo Clinic SSIGN (stage, size, grade and necrosis) score and UCLA UISS (University of California-Los Angeles Integrated Staging System) score were created using clinical stage, tumor histology, pathological tumor size, pathological stage and grade, pathological necrosis, ECOG performance status and symptomatic presentation to predict the freedom from disease recurrence or overall survival after definitive therapy (Kattan 2001; Patard 2004; Frank 2002).
The outlook for patients with metastatic renal cell carcinoma continues to be poor, with a 5-year survival rate of less than 10% (Motzer 1996). Some authors have identified a model based on pre-treatment clinical features that predicted survival for patients with advanced RCC. Five prognostic factors were identified and used to categorize patients with metastatic RCC into three risk groups. Risk factors associated with a shorter survival period were:
1. Low Karnofsky performance status (< 80%);
2. Low serum haemoglobin (< lower limit of normal);
3. High lactate dehydrogenase (> 1.5 times upper limit of normal);
4. High corrected serum calcium (> 10 mg/dl);
5. Absence of prior nephrectomy.
Median overall survival of patients with zero risk factors (favorable-risk) was 20 months, patients with one or two factors (intermediate-risk) had a median survival of 10 months and patients with three or more risk factors (poor-risk) 4 months (Motzer 1999). The MSKCC group developed their model, along with other groups, and the MSKCC modified prognostic score were based on the original criteria except the no prior nephrectomy risk factor was replaced with time from initial diagnosis to treatment of less than 1 year (Motzer 2000).
The MSKCC model was validated externally in an independent set of 353 previously untreated metastatic RCC patients at the Cleveland Clinic Foundation. In this study, six prognostic factors were found to be statistically significant predictor of survival at multivariable analysis:
1) Time from diagnosis to treatment of less than 1 year;
2) Low serum haemoglobin (< lower limit of normal);
3) High lactate dehydrogenase (> 1.5 times upper limit of normal);
4) High corrected serum calcium (> 10 mg/dl);
5) Prior radiotherapy;
6) Number of metastatic sites.
Median overall survival of patients with zero or one risk factors (favorable-risk) was 26 months, patients with two factors (intermediate-risk) had a median survival of 14.4 months and patients with three or more risk factors (poor-risk) 7.3 months (Mekhail 2005).
These models were developed in the immunotherapy era. Additionally, the cloning of the von Hippel-Lindau tumor suppressor gene, and the elucidation of its role in upregulating growth factors associated with angiogenesis, has provided insight into RCC biology and defined a series of targets for novel therapeutic agents. These targeted agents, including sunitinib, sorafenib, temsirolimus, everolimus, and bevacizumab plus interferon-alpha, have shown benefit in phase III trials in first- and second-line therapy. Analysis of the data from these trials and use of prognostic models have resulted in a new paradigm for the treatment of metastatic RCC.
6.1 Surgical treatment
Radical nephrectomy is the standard intervention for patients with all subtypes of localized renal cancer. It is performed by an anterior approach, with initial ligation of the renal vascular pedicle. The en bloc excision removes the kidney, adrenal gland, and perirenal fat. However, the 2% incidence of ipsilateral adrenal involvement observed in T1 and T2 renal cancers renders a systematic adrenalectomy optional (Kletscher 1996). Owing to the rarity of ipsilateral adrenals metastasis, and the potential morbidity associated with adrenalectomy, many surgeons believe that a macroscopically normal ipsilateral adrenal glands should not be removed with the kidney (Wunderlich 1999; Kardar 1998). When there is tumour in the renal vein, the renal vein can be ligated distal to the tumour thrombus. If there is tumour extension into the vena cava this may need to be partially resected. If the tumour has grown into the side wall of the vena cava or if the vena caval involvement is to too extensive for a simple partial wall resection, a portion of the vena cava itself may be resected. Regional lymphadenectomy may be performed at the time radical nephrectomy and should be restricted to the perihilar tissue for staging purposes. Extended lymphadenectomy cannot be considered to be the therapeutic standard because it does not prolong survival (Angervall 1978). Involvement of lumbo-aortic lymph nodes occurs in 10 to 30 per cent of patients at diagnosis, with 80 per cent of these patients having visceral metastases. Fewer than 10 per cent of patients with localized tumours have lymph node involvement. Only half of the patients with enlarged retroperitoneal lymph nodes on CT scan have eventual lymph node metastases and 6 per cent of patients with normal retroperitoneal lymph nodes on CT scan have histologically involved lymph nodes. In a regional lymphadenectomy, ipsilateral nodal tissue from the diaphragm to the bifurcation of the aorta as well as nodal tissue in the inter aorto-caval region at the hilum of the kidney is removed. If local nodes were the first site of metastasis, resection of microscopic disease might be of value. Long term survival in patients with node-positive disease who underwent lymphadenectomy has been reported (Schafhauser 1999), but the ultimate role of regional lymphadenectomy remains to be determined in further randomized trials. One randomized study revealed a very low incidence of nodal disease (Bloom 1999).
The treatment of patients with either bilateral renal tumors or renal carcinoma in a solitary kidney or renal insufficiency is challenging. Patients with tumour in a solitary kidney may be treated by either partial nephrectomy or nephrectomy followed by dialysis or transplantation (or both).
Historically, a partial nephrectomy is indicated in patients with bilateral renal tumors, renal insufficiency or solitary kidney, as well as patients whose risk for renal deterioration was associated with urolithiasis, diabetes or other medical comorbidities. The efficacy of partial nephrectomy was established in comparison to radical nephrectomy (Becker 2006). In selected patients, nephron-sparing surgery may be recommended for those with sporadic renal cell cancer, particularly those with a single, small (< or = 4 cm) and clearly localized tumour (Hafez 1997; Wunderlich 1998). Recent data further suggest that nephron-sparing surgery provides a long-term renal functional advantage over radical nephrectomy in such patients with a normal opposite kidney, on a type 3 level of evidence (Fergany 2000). The surgical mortality is less than 1% in experienced centres and morbidity is about 10% (retroperitoneal haematoma, lymphocele and damage to the spleen).
Laparoscopic radical nephrectomy has been evaluated as a less invasive procedure for the removal of kidneys with renal cell carcinoma of small volume (Ono1997; Higashihara 1998). Multilple series demonstrate the advantages of laparoscopic compared to open surgery. These advantages include reduced estimated blood loss, decreased pain medication requirements, faster return of bowel activity, shorter length of hospital stay, decreased wound infection rates, faster convalescence and improved cosmesis. The long-term oncologic efficacy of laparoscopic nephrectomy is comparable to traditional open techniques. However, the data are based on comparative studies; randomized prospective trials have not been performed (Al-Qudah 2007). Laparoscopic partial nephrectomy is challenging and the technique is still under development. The intermediate-term oncologic and functional outcomes of laparoscopic partial nephrectomy are similar to those of open partial nephrectomy in experienced centres. Suggested disadvantages of laparoscopic approach are the longer warm ischaemia time and increased intra-operative and post-operative complications when compared with open surgery. The optimal indication for laparoscopic partial nephrectomy is a relatively small and peripheral renal tumor. Larger series with longer follow-up and prospective randomized trials are neede to confirm the safety and efficacy of this approach (Porpiglia 2008).
In the absence of distant metastatic disease but with locally extensive and invasive tumours, adjacent structures such as bowel, spleen, or psoas muscle, may be excised en bloc during radical nephrectomy. This radical approach is justified by a reasonable survival after complete resection; survival after incomplete resection is notoriously poor.
6.1.1 Palliative nephrectomy
Surgery is the main treatment for localized renal cell carcinoma, but the use of radical nephrectomy for metastatic disease is highly controversial. Palliative nephrectomy is not infrequently performed in patients with metastatic renal carcinoma particularly those with pain, haemorrhage, malaise, hypercalcemia, erythrocytosis or hypertension. Removal of the primary tumour may alleviate some or all of these abnormalities (Walther 1997). Although there are isolated reports of regression of metastatic renal carcinoma after removal of the primary tumour, only 4 (0.8%) of 474 patients in nine series who underwent nephrectomy experienced “regression” of metastatic foci (Montie 1977). Furthermore, the term regression does not equate with cure; most patients with regression relapsed within 1 to 2 years. Palliative nephrectomy is not recommended for the purpose of inducing spontaneous regression; rather it is performed to decreased symptoms or to decrease tumour burden in preparation for subsequent therapy in controlled environments (Walther 1997; Flanigan 2004). Two randomized studies (Mickisch 2001; Flanigan 2001) compared radical nephrectomy plus interferon-alfa based immunotherapy with interferon alone. Both conclude that radical nephrectomy before interferon immunotherapy might substantially delay time to progression and improve survival of patients with metastatic renal cell carcinoma. A combined analysis of these two studies showed, on 331 cases, an increased median survival of 5.8 months (13.6 vs 7.8 months, p=0.002) in operated patients. Optimal candidates for this approach are patients in good general conditions without a rapidly progressive disease (Flanigan 2004). The recent use of laparascopic nephrectomy provides a potentially less invasive method for cytoreduction in preparation for administration of systemic therapies such as IL-2 (Walther 1999).
The role of nephrectomy in patients with metastatic renal cell carcinoma in conjuction with systemic therapies depends on data from immunotherapy era. Furthermore, the recent introduction of new targeted agents in the management of advanced renal cell carcinoma may provide more controversy and debate as to the role of cytoreductive nephrectomy in conjunction with these agents. Compared with cytokine-based immunotherapy, targeted therapy has higher response rates in primary and metastatic sites. These findings suggest that the concept of neoadjuvant therapy in RCC should be revisited, particularly in patients deemed to have unresectable disease. Furthermore, neoadjuvant therapy might extend beyond these uses to patients with localized or locally advanced disease (for example patients with tumor thrombus or associated lymphoadenopathy). The optimum duration of therapy and interval before surgery has yet to be elucidated.
6.1.2 Surgical resection of metastases
Almost 25% of patients with newly diagnosed renal cell carcinoma have evidence of metastases at presentation. The treatment of patients with disseminated disease is contingent on the location of the metastatic involvement, whether the metastasis appears to be solitary or multiple, and whether the patient has symptoms from the primary tumour. An aggressive surgical approach should be considered for patients with a solitary metastases from renal cell carcinoma. Sites of solitary metastases that are amenable to this approach include the lung, bone and brain. The majority of patients who undergo resection of a solitary metastasis suffer a recurrence of the primary tumour or metastasis. However, long term survival has been observed in some patients. Several studies have suggested that selected patients may benefit from excision of metastases (Thompson 1975); these patients usually have lung metastases, which are generally solitary, with a long time interval between nephrectomy and metastasis. Data suggest that up to 40% of selected patients can have long-term (>5 years) disease-free survival (Kavolius 1998). For patients with solitary cerebral metastases which appeared more than 1 year following excision of the primary lesion, the 1-year survival rate after local excision and radiation therapy was almost double that seen in the group in which cerebral metastases appeared less than 1 year after primary tumour excision (Galicich 1980). Pulmonary resection in metastatic cell carcinoma is an effective treatment with a survival benefit (overall 5-years survival rate > 30%) (Pfannschmidt 2002). This finding implies that the doubling time of the primary tumour and various host-tumour interactions profoundly affect prognosis in patients with metastases. There are no data from randomly assigned trials, and thus such reports do not prove that surgical resection contributes to the patients’ prolonged survival. Nevertheless, such an approach is typically less morbid than systemic therapy and may have important benefits in terms of preventing local morbidity.
Supportive care remains a mainstay of therapy for patients with metastatic renal cell carcinoma. This includes surgery for patients with solitary brain metastases, spinal cord compression, or impending or actual fractures in weight-bearing bones.
6.2.1 Interferons and interleukin 2
The interferons (IFNs) are natural glycoproteins with antiviral, antiproliferative and immunomodulatory properties. The three major classes are: IFN alfa, derived from leukocytes; IFN beta, derived from fibroblasts and IFN gamma, derived from activated lymphocytes. Both natural and recombinant IFNs showed activity in renal cell carcinoma. Overall response rates are 12 to 14%, with a 2% of maintained complete response. In general, the responded patients have nonbulky pulmonary and/or soft tissue metastases with good performance status (PS ECOG of zero or one). IFN alfa has been administered in a variety of schedules. IFN alfa was generally given three times per week, subcutaneously at dosage from 6 to 50 MU. There is some evidence of a dose-response relationship in the low dose range. Moreover, the possibility of increasing the dosage was limited by toxicity. The major side effects of interferon treatment are fever and a flu-like syndrome at the start of treatment, and anorexia, weight loss, depression and fatigue in the chronic phase. The usual dosage of IFN alfa was limited to 10 to 18 MU/injection, three times per week, for at least 12 weeks and up to 1 year. A Cochrane analysis of six randomized trials, with a total of 963 patients, indicated a hazard rate (HR) for survival of 0.78 (confidence interval, 0.67-0.90) or a weighted average improvement in survival of 2.6 months (Coppin 2005). In summary, disseminated renal cell cancer shows a small but consistent response to interferon but these benefits must be weighed against the toxicity of chronic therapy and the lack of documented long-term benefit, on a type 1 level of evidence (Minasian 1993; Pyrrhonen 1999; MRCRCC 19999).
One of the most exciting prospects was the use of adoptive therapy with lymphokine- activated killer (LAK) cells plus interleukin (IL2) (Rosenberg 1994). After the demonstration of its activity as a T-cell growth factor, and activator of T-cells and natural killer cells, IL2 was used in clinical trials in renal cancer. As a single agent, doses of IL2, ranging from 600,000 to 720,000 IU/Kg every 8h given as i.v. bolus therapy have consistently yielded overall response rates of 17-27%. A substantial number, between 5% and 9%, of these response are complete and durable remissions lasting beyond 5 years are well documented (Fife 1995). However, high dose, intravenous recombinant IL2 invariably induced a wide spectrum of serious adverse effects: weight gain (50% of patients), oliguria, hypotension, nausea and vomiting, diarrhoea, chills, pruritus, skin dryness, somnolence and coma, respiratory distress, angina, myocardial infarction, and arrhythmia. Continuous infusion is somewhat less toxic, but subcutaneous administration has greatly decreased the toxicity of IL2 and can be administered on an outpatient basis (Negrier 1998; Atzpodien 1990; Atzpodien 1995). Various treatment schedules of lower doses of IL2 have been tested. Although generally better tolerated, lower dose schedules are less effective than high-dose bolus IL2 (Yang 2003 ). Several randomized trials have been performed to investigate the efficacy of combinations of cytokines. Most have employed a variety of doses and subcutaneous schedules of IL2 and IFN alfa (Sznol 1990; Mittelman 1991). In phase II and phase III studies these combinations have yielded response rates similar to those observed with high-dose IL2 (Atzpodien 2002 ). Unfortunately in a large randomized French study the significantly higher response rate of the combination IL2 plus IFN alfa did not translate into improved survival (Negrier 2002) .
Numerous trials have been conducted combining immunotherapy with cytotoxic chemotherapy (vinblastine, fluoxuridine, 5FU, gemcitabine). The results of these studies demonstrated no impact on survival (Gez 2002) . A large phase III trial randomized 1006 patients to receive single agent IFN 10 MU three times a week until progression or toxicity or a combination of IFN-IL2-5FU for 2 cycles. Overall survival was the primary endpoint. At a median follow-up of 27.8 months, there was no evidence of differences in median overall survival (18.7 vs 18.5 months, p=0.57) or progression-free survival (5.5 vs 5.3 months, p=0.56). Best overall response was significantly higher in the triple therapy arm (24 vs 16%, p=0.004) (Gore 2008). Also the combination of interferon alfa and retinoic acid failed to demonstrate any advantage (Atzpodien 2004).
6.3 Chemotherapy and Transplant
The list of chemotherapeutic agents used in clinical trials in advanced renal cell carcinoma is impressive. Yagoda reviewed all chemotherapy trials published between 1983 and 1993. Among 4093 evaluable patients a 6% response rate was recorded (Yagoda 1995). Only three single agents have consistently demonstrated some objective responses, but marginal activity: fluoxuridine, 5fluorouracil (5FU) and vinblastine. In fourteen trials the fluoxuridine produced 12% response rates. For 5FU, which has been used primarily in combination with immunotherapy, responses were somewhat fewer, with an overall response rate of 10% for infusional 5FU alone and 19% for 5FU in combination with interferon. Similar results were reported for vinblastine (Samuels 1997; Pyrrhonen 1999). Other agents have been tested including taxanes, camptothecins, anthracyclines, antifolates and alkylating agents. Once again the refractory nature of renal cell carcinoma is observed. The mechanisms of drug resistance have been studied in renal cell cancer and it was found that more than 80 percent of cancer cells have expression of the multiple drug resistance gene that encodes P-glycoprotein (Kakehi 1988). More recently several studies with gemcitabine and 5FU have suggested that this combination leads to responses and survival greater than that expected in a historical risk-factor controlled group (Stadler 2003). Nonetheless, the objective response rate with gemcitabine and 5FU is only in the order of 11%, and a randomly assigned study demonstrating the putative survival advantage has not been conducted. There is no standard chemotherapy regimen for renal cell carcinoma and chemotherapy is not recommended outside the context of a clinical trial (Motzer 2000; Motzer 1996) .
The lack of efficacy of chemotherapy and cytokine-based immunotherapy has catalyzed the preliminary enthusiasm for nonmyeloablative stem cell transplants as a novel investigational tool for treating metastatic renal cell carcinoma. Preliminary results shows that minitransplants are feasible with a relatively low transplant-related mortality and anti-tumour responses are observed in some patients with renal cell carcinoma. The initial excitement with regard to allogeneic stem cell transplantation has tapered. The main concern has been treatment-related toxicity and mortality rates that range from 12% to 33%, with death most often due to graft-versus-host disease or sepsis. Thus, it is limited to a small subgroup of patients and should still be considered experimental (Rini 2002).
6.4 Hormonal treatment
The hypothesis that hormonal therapy might be useful is based on the finding that renal tumours have been induced in male Syrian golden hamsters by prolonged administration of oestrogen. These findings constituted the rationale for administering a progestational agent as hormonal therapy in patients with advanced renal cell carcinoma. A variety of progestational agents, sometimes with testosterone or anti-oestrogens, alone or in combination with corticosteroids, have been tried. Objective response rates have been less than 10%. Most responses are partial and complete responses are rare (Hrushesky 1977) . Initial studies of hormonal therapy with medroxyprogesterone looked promising in the early 1970s, but using stricter criteria for defining objective responses, the overall response rate was less than 5% (Bloom 1971). Except for its value in appetite stimulation, the use of medroxyprogesterone cannot be recommended in the treatment of renal cell carcinoma. Tamoxifen has been used with little, if any, benefit (Weiselberg 1981). Early trials with flutamide, an antiestrogen, have failed to demonstrate any significant benefit from this compound. Thus, most patients with advanced renal carcinoma will not have a meaningful response to hormonal manipulation, either alone or in combination.
6.5 Antiangiogenic agents and kinase inhibitors
Advances in understanding the biology and genetics of RCC have led to identify a number of molecular targets and several novel drugs have been developed to attack these targets.
Genetic studies have elucidated the central role of the von Hippel-Lindau (VHL) tumor-suppressor gene in the pathogenesis of clear cell RCC. Mutations in the VHL tumor-suppressor gene have been shown in 75% of sporadic clear cell RCC, which result in overexpression of several hypoxia-inducible genes involved in angiogenesis, including VEGF, PDGF-b, transforming growth factor-α (TGF-α), erythropoietin. Other activated pathways in RCC are the epidermal growth factor receptor (EGFR) and mTOR (mammallian target of rapamycin) pathways, which regulate survival and cell growth. Against this background, targeting angiogenesis and VEGF in particular, has emerged as a promising therapeutic approach in patients with metastatic RCC.
Three main classes of angiogenic targeting agents (monoclonal antibodies anti-VEGF, small molecule tyrosine kinase inhibitors,mTOR inhibitors) have been evaluated and some of these agents, including sunitinib, sorafenib, temsirolimus, everolimus and bevacizumab plus interferon-alpha, have shown benefit in phase III trials in first- and second-line therapy in advanced RCC.
Bevacizumab is a recombinant humanized monoclonal antibody that inhibits tumor angiogenesis by targeting VEGF. Bevacizumab binds and neutralizes most biologically active isoforms of VEGFA. In a randomized, triple arm, phase II trial, 116 patients with cytokine refractory, metastatic clear cell RCC were randomized to receive placebo, low-dose (3mg/kg) of bevacizumab or high-dose (10mg/kg) of bevacizumab, given intravenously every two weeks. An intention-to-treat analysis showed a significantly increased progression free survival (PFS) in the high-dose of bevacizumab arm in respect to placebo arm (4.8 months vs 2.5 months, p=0.001) and an objective response rate of 10% in the high-dose arm (Yang 2003). In a phase II randomized trial, bevacizumab was combined with erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The rational for this combination was a potential synergy against hyperactive HIF pathway which could result in an increased release of transforming growth factor alpha (TGF-α), a known ligand of EGFR. The results of this study were disappointing in term of response rate and PFS for combination regimen (Hainsworth 2005). A large randomized, phase III trial (AVOREN trial) comparing interferon plus bevacizumab to interferon plus placebo was conducted. The results of this study were recently published (Escudier 2008). The median PFS for patients in the bevacizumab arm was 10.2 versus 5.4 months in the IFN-only arm. The overall response rate (ORR) was 31% versus 13%. Overal survival had not been reached in the bevacizumab arm at the time of the analysis. There was an increased incidence of grade 3 / 4 adverse events in the bevacizumab-containing group. The recommended dose of interferon alfa was 9 MIU three times a week. During the course of treatment, the dose was reduced to 6 or 3 MIU in 40% of patients in the bevacizumab group and in 30% of those in the control group, due to adverse events. An exploratory analysis indicated that patients who reduced their dose of interferon alfa might also benefit from bevacizumab treatment. The median PFS in patients treated with lower-dose of interferon plus bevacizumab was interestingly similar to that in all patients treated with interferon plus bevacizumab (12.4 months and 10.2 months respectively) (Melichar 2008).
A similarly designed international, randomised, phase III trial (CALGB 90206 trial) has also been reported. This trial randomly assigned 732 previously untreated patients with metastatic RCC to treatment with bevacizumab plus interferon or interferon alone (Rini 2008). Primary endpoint of this study, overall survival, has not yet been reached. The median PFS was 8.5 months in patients receiving bevacizumab plus interferon versus 5.2 months in patients receiving interferon monotherapy. Bevacizumab plus interferon had a higher ORR as compared with interferon (25.5% versus 13.1%). The slightly lower absolute value of PFS and ORR in this trial may be a reflection of the worse risk group distribution of treated patients, the requirement for only a component of clear cell histology as compared with clear cell predominant in the AVOREN trial and the lack of nephrectomy in 15% of patients in each arm of the CALGB trial,
Sunitinib maleate is an oral, multitargeted tyrosine kinase inhibitor, mainly acting on VEGFR-2, PDGFR and cKIT. Two open label, phase II trials enrolled patients with cytokine refractory, metastatic renal cell carcinoma. Sunitinib was administered at a dose of 50 mg/day for the first 4 weeks of repeated 6-week cycles. These studies reported high objective response rates (42%), extended PFS (8.2 months) and acceptable toxicities. The most commonly reported grade 3, non-haematological treatment-related adverse events included fatigue (11%) and hand-foot syndrome (7%) (Motzer 2006). On the basis of the favourable phase II data, a randomized phase III trial was launched to compare sunitinib to subcutaneous interferon-α as first line therapy in metastatic renal cell cancer. A total of 750 patients were included. A significant increased response rate was achieved with sunitinib in respect to interferon (31% vs 7%) and median PFS was significantly longer with sunitinib than IFN (11 months vs 5 months) (Motzer 2007). At the 2008 ASCO Annual Meeting data of overall survival of this study were presented. In the sunitinib arm overall survival was 26.4 months versus 21.8 months in IFN-arm (Figlin 2008).
Sorafenib tosylate is an oral, multikinase inhibitor that inhibits mainly VEGFR-2 and -3, PDGFR and Raf kinase. Sorafenib was studied in a large phase II trial in cytokine refractory, metastatic renal cell cancer patients. The trial design was “randomized discontinuation”, intended to evaluate the primary effect of tumor growth inhibition rather than tumor shrinkage. 202 patients with metastatic RCC were treated in this study. The median PFS was significantly longer with sorafenib compared with placebo (24 weeks vs 6 weeks). Adverse effects included skin rash, hand-foot skin reaction and fatigue. The study demonstrated significant disease-stabilizing activity in advanced RCC (Ratain 2006).
Results from this study then led to an international, randomized phase III trial comparing sorafenib with placebo in cytokine-refractory metastatic RCC patients. Approximately 900 patients were accrued. Results of the first pre-planned interim analysis of the study were reported at the 2005 ASCO Annual Meeting. Median PFS was twice as long for the sorafenib group compared with the placebo group (5.9 months versus 2.8 months) and tumor control rate was 80% for sorafenib treated patients, despite a low partial response rate (2%). A favourable trend in survival benefit was observed (19.3 months vs 15.9 months). As a consequence of these results, after the interim analysis patients in placebo-group crossed over to sorafenib. This likely has an effect on the subsequent survival analysis (Escudier 2007).
Two m-TOR inhibitors have shown antitumor activity in RCC: temsirolimus and everolimus.
Temsirolimus has been tested in a randomized phase II trial, in which 111 patients with advanced pretreated RCC were treated with three different dose levels of temsirolimus (25, 75 and 250 mg intravenously weekly). The overall response rate was 7.2% and the median PFS was 5.8 months. In this study patients in the intermediate and poor risk groups experienced a longer survival than historical controls treated with interferon. The investigators advocated the 25 mg intravenous weekly dose for future studies (Atkins 2004). A multicenter randomized phase III trial compared temsirolimus alone with interferon-α alone and with low-dose combination of both drugs in advanced untreated RCC classified as poor risk, according to the MSKCC prognostic score. This study showed a significantly longer overall survival (10.9 months vs 7.3 months) and PFS (4 months vs 2.1 months) in patients treated with temsirolimus alone than interferon alone (Hudes 2007).
Everolimus is a serine/threonine kinase inhibitor of m-TOR. In a large randomized phase III trial comparing everolimus with placebo in patients with clear-cell renal-cell carcinoma progressing after treatment with sorafenib or/and sunitinib, treatment with everolimus prolongs progression free survival (4 months vs 1.9 months). The most commonly reported adverse effects in the everolimus arm were stomatitis (40%), rash (25%), fatigue (20%), but were mostly mild or moderate in severity (Motzer 2008).
Analysis of the data from these trials and use of Memorial Sloan- Kettering Cancer Center (MSKCC) risk model have resulted in a new paradigm for the treatment of metastatic RCC, shown in Table 2.
Table 2. New paradigm for the treatment of metastatic RC
|Treatment Naïve Patient||Good/Intermediate MSKCC Risk||Poor MSKCC Risk|
|Treatment Refractory Patient (≥2nd line)||Previous Cytokine||Previous VEGF/VEGFR or mTOR-inhibitors|
|Options||Sunitinib||Sequential TKI’s or VEGF inhibitor
Questions about the efficacy and toxicity of sequenced or combinated approaches are emerging as resistance to these agents develops. Combinations of these and other targeted agents may overcome the resistance that develops with single-agent therapy and could be incorporated either as part of initial therapy or later when disease resistance develops. Approaches aimed at combining these agents can be based on the genetics and biology of clear cell RCC. von Hippel-Lindau loss leads to an increase in cellular levels of HIF (HIF-1aor HIF-2a) leading to increased expression of a number of hypoxia-regulated genes critical to cancer progression. Combinations of targeted agentsmay block several of these mediators (VEGF, epidermal growth factor receptor and PDGF), so-called horizontal blockade. Blockade could also take place at two levels of the pathways (vertical blockade), either at HIFand VEGFor at VEGFand VEGFreceptor signaling. Many of the above strategies are ongoing.
Sunitinib has been investigated in 61 metastatic RCC patients resistant to prior bevacizumab based therapy and showed an ORR of 23% and overall tumor shrinkage rate of 74%, supporting the clinical hypothesis that VEGF and related receptor signaling are still therapeutically relevant after VEGF ligand blockade (Rini 2008). There is also evidence of activity of sunitinib or sorafenib on failure of the other agent (). There is as yet no insight into mechanism of resistance to these agents and whether the most appropriate maneuver on disease progression is dose/schedule modification, incorporation of an additional agent, or targeting another pathway with a different agent. Several trials are ongoing or planned in patients with metastatic RCC who are refractory either to bevacizumab, sorafenib, or sunitinib. These data will provide insight into the degree of clinical crossresistance to these therapies and perhaps begin to identify an optimal sequence of agents.
A number of promising agents are also undergoing phase I/II testing in the treatment of metastatic RCC, including pazopanib, axitinib, insulin-like growth factor and PDGF inhibitors.
6.6. Adjuvant treatments
The standard management for localized tumours after nephrectomy remains surveillance. There are three phase III trials of adjuvant interferon alfa compared with observation for patients with locally advanced renal cell carcinoma completely resected by nephrectomy. None showed a delay in time to relapse or improvement in overall survival with interferon alfa therapy, which is therefore not recommended (Messing 2003; Perzsolt 1992; Pizzocaro 1997; Atzpodien 2005). Data are lacking for studies of interleukin-2 as adjuvant therapy. Adjuvant chemotherapy is not recommended in renal cell carcinoma because of the poor activity of cytotoxic drugs. Trials with antiangiogenic agents, sorafenib and sunitinib, are ongoing to evaluate the role of these drugs in adjuvant setting.
Renal cancer is generally considered to be radioresistant. Four randomized studies have addressed the question of the role of preoperative or adjuvant radiotherapy. None of these studies has demonstrated a survival advantage for patients receiving radiotherapy and in three of them there is a trend to poorer survival. Some of them are old studies which used suboptimal radiotherapy with high toxicity, and none of them has included a sufficient number of patients to be able to demonstrate or rule out a meaningful difference in survival (Van der Werf-Messing 1973; Juusela 1977; Kajaer 1987). Recent studies have suggested that use of more sophisticated radiation techniques is less likely to result in treatment-related complication (Kortmann 1999). With the introduction of three dimensional conformal radiotherapy and intensity modulated treatment delivery system, it now is possible to deliver higher radiation doses in the adjuvant setting with potentially less toxicity. Using CT-based treatment planning, the outcome of postoperative radiotherapy have been retrospectively reported for selected patients with positive surgical margins or perinephric disease extension. The overall local failure rate was 100% as compared to 30% for similar patients who underwent nephrectomy alone (Kao 1994). Nevertheless randomized trials limited to high-risk patients will be required to fully assess the benefit of postoperative radiotherapy in local control. Palliative radiotherapy for patients with symptomatic metastatic osseous lesions can be effective. Previous reports have noted response rates of 50% to 70% after local palliative radiotherapy for patients with renal cell carcinoma (Di Biase 1997). Large volume metastatic lesions such as those found within the renal bed require higher radiation doses to achieve palliation and, in general, this therapy is successful in fewer than 50% of treated patients. Brain metastases from renal cell carcinoma are often haemorrhagic in nature and the rapid initiation of radiotherapy may be necessary to halt potential neurological progression. Surgery should be considered for solitary lesions of the brain or spine, followed by postoperative radiotherapy. For selected patients with good performance status and solitary lesions, radiosurgery alone or in combination with whole brain radiotherapy provides an opportunity to deliver higher doses and should be considered (Becker 1999) . Gamma knife gives similar results to surgery for lesion smaller than 3-4 cm.
7. LATE SEQUELAE
A mild renal insufficiency can constitute a tardive sequel in patients in whom nephrectomy has been performed for renal cancer. In particular it can manifest in patients who show risks factors such as age, hypertension and diabetes.
The modality and timing of follow-up of patients with localized disease that have undergone radical nephrectomy is controversial. Surveillance after radical surgery should monitor or identify post-operative complications, renal function, local recurrence, recurrence in the controlateral kidney and development of metastases. Post-operative complications and renal function are readily assessed by history, physical examination and measurement of serum creatinine. Local recurrence is rare (2%), but early detection is useful since the most effective treatment is surgery. The most frequent sites of recurrence are lung, retroperitoneal lymph nodes, liver, bone, contralateral adrenal gland and kidney. Early diagnosis of metastatic disease can improve the possibility of surgical resection, which is considered the standard therapy in cases of respectable and preferably solitary metastatic lesions.
There is no consensus on the modality, timing and optimal duration of follow-up. According to the guidelines on RCC of the European Association of Urology of 2008, it appears reasonable to modify follow-up, taking into account the risk of developing recurrence or metastases. Where the likelihood of relapse is low, chest X-ray and abdominal ultrasound are probably appropriate; where the risk is intermediate or high, CT of chest and abdomen is the investigation of choice. A reasonable schedule of follow-up should include a clinical examination, serum biochemistry, chest radiograph and abdominal ultrasound every year in patients without adverse prognostic factors and every 6 months in patients with adverse prognostic factors. Follow-up should continue for at least 5 years.
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Dr. Maura Betti (Author)
Ospedale Silvestrini – Perugia, Italy
Dr.ssa Enrichetta Corgna (Author)
Ospedale Silvestrini – Perugia, Italia
Prof. P.H.M. De Mulder (Reviewer)
University Medical Center – Nijmegen, The Netherlands
Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
Dr. Fausto Roila (Associate Editor)
Ospedale Policlinico Monteluce – Perugia, Italy