Renal-cell carcinoma (RCC) is curable only in patients presenting with resectable, early-stage disease. Advanced local or metastatic disease carries an approximate 15% 5-year survival rate. However, the natural history of metastatic RCC is heterogeneous, and aggressive palliative treatment is recommended, especially for patients with a solitary metastatic site and good performance status.
Renal-cell carcinoma (RCC) is curable only in patients presenting with resectable, early-stage disease. Advanced local or metastatic disease carries an approximate 15% 5-year survival rate. However, the natural history of metastatic RCC is heterogeneous, and aggressive palliative treatment is recommended, especially for patients with a solitary metastatic site and good performance status. Response rates to cytokine therapy remain generally less than 25%, and complete responses are rare. To improve these results, combinations of biologics with and without cytotoxic chemotherapy are being investigated. Important advances in understanding the molecular aspects of RCC have been made in recent years. Modulation of the expression of genes involved in RCC is an approach awaited with great interest.
In the following discussion, we review the natural history of RCC, current methods for diagnosis and treatment, and promising therapeutic agents for metastatic disease.
In the United States, the age-adjusted incidence of RCC has been rising steadily, and 28,800 new cases are expected to be diagnosed in 1995 . The male-to-female ratio ranges from 2:1 to 3:1 . Renal-cell carcinoma occurs most commonly in adults over the age of 40 years [2,3], but family clustering with younger ages at presentation has been reported .
Etiology: Numerous investigators have attempted to link the occurrence of RCC to environmental factors, dietary patterns, and occupational or medical exposures. In general, strong associations have not been found, partly because RCC is a relatively rare disease, and many associations, therefore, fall short of statistical significance. These epidemiologic studies have been extensively reviewed [2,5] and will be briefly summarized here.
The most prominent risk factor, and the only one that has been firmly established, is tobacco use. Multiple cohort and case-control studies have found the relative risk of RCC in smokers to be at least 1.5 . Furthermore, the risk appears to increase with the level of cigarette smoking in a dose-dependent fashion .
A number of other potential risk factors have been investigated. Results of studies to determine the roles of dietary fat, alcohol, and obesity have been inconsistent . Occupational exposures to cadmium , asbestos , and petroleum products  have been implicated in disease development, but their involvement has not been demonstrated convincingly. RCC has been reported in several patients previously exposed to thorotrast contrast media . There are also reports of RCC in association with various nephropathies, including acquired renal polycystic disease , xanthogranulomatous pyelonephritis , and phenacetin-related analgesic nephropathy .
Several forms of dominantly inherited RCC have been described [4,14,15]. One of the earliest reported associations of cancer to a germline cytogenetic abnormality was in a family with kidney cancer who had a translocation at the p21 locus in the short arm of chromosome 3 (3p) . RCC is known to develop in 40% to 70% of patients with von Hippel-Lindau (VHL) disease [4,17]; these patients are also at risk of developing pheochromocytomas or cerebellar and retinal hemangioblastomas. Familial cases of RCC represent less than 5% of the total patient population, but their study has proven fruitful, as the same genetic mutations seen in germlines of affected families are being described in nonhereditary cases [14,15].
Three tumor suppressor genes appear to reside on 3p: the VHL gene at 3p25-26 and two more proximal genes, at 3p14 (proposed name, nonpapillary renal carcinoma gene, or NRC-1) and 3p21 [15,18-22]. The VHL gene was recently cloned, but its specific cellular function is still unknown . The NRC-1 gene has been postulated to control the growth of RCC cells by inducing apoptosis . Further clarification of the function of these genes is expected to enable the development of specific therapeutics at the cellular level. Other described changes in RCC are abnormal expression of the p53 gene and mutations in chromosomes 11p, 17q, and 5q [23,24].
On gross examination, RCC is characteristically a solid hemorrhagic and necrotic mass. Microscopic examination reveals numerous vessels and vascular channels. Histologically, RCC can be separated into three cellular types: clear, granular, and sarcomatoid [25,26]. Clear-cell carcinoma, the most common-cell type, is present in more than 90% of tumors. It is characterized by unusually clear cells with a cytoplasm rich in lipids and glycogen. Granular cells display an eosinophilic cytoplasm secondary to an abundance of mitochondria and organelles. Sarcomatoid, or spindle-type, cells resemble fibroblasts of mesenchymal origin and represent 1% to 2% of kidney tumors. Clinically, however, a sarcomatoid component is predictive of a more aggressive behavior .
A further distinction can be made by the pattern of cellular arrangement, dividing RCCs into solid and papillary tumors. Most RCCs are solid. In this solid tumor pattern, sinusoidal vessels provide the blood supply, whereas in the papillary tumor pattern, cells aggregate in papillae supplied by a single fibrovascular stalk. Genetic analysis of the latter tumor pattern seems to indicate a different cellular origin, as mutations in chromosome 3p are absent [14,19,27].
A grading scale for RCC based on nuclear size and shape is frequently used. The most commonly used system is that of Fuhrman et al, which classifies cells from grades 1 to 4 . Nuclear grade appears to provide prognostic information, particularly for grades 1 and 4 tumors.
Common presentations of RCC include hematuria, abdominal mass, weight loss, anorexia, or symptoms arising from metastatic sites. The classic triad of flank pain, hematuria, and a palpable mass occurs in only 10% to 15% of patients and suggests advanced disease .
A unique aspect of RCC is the frequent occurrence of various paraneoplastic syndromes, including hypercalcemia, polycythemia, fever, cachexia, hypertension, and hepatic dysfunction (Stauffer's syndrome) [30,31]. Resolution of symptoms or biochemical abnormalities frequently follows successful treatment (eg, excision) of the primary tumor or metastatic foci.
Metastatic disease is detectable in 25% to 30% of patients at the time of diagnosis . Frequent sites include the lung (50% to 60%), bone (30%), lymph nodes (30%), liver (30%), and adrenal glands (20%). Metastases to the brain, contralateral kidney, pancreas, or skin are found in 5% to 15% of these patients.
Computed tomography (CT) is the most useful tool for the study of kidney masses . The overall accuracy of CT in the staging of RCC is 90% to 95% [32,33]. Advantages of this method include the ability to more clearly define nodal disease, ability to detect caval thrombi under most circumstances, reproducibility of studies, and ease of interpretation. In addition, other sites of intra-abdominal metastasis, such as the liver, adrenal glands, or contralateral kidney, may be detected. Magnetic resonance imaging offers few advantages over CT ; based on availability of resources, overall staging accuracy, and expense, CT remains the modality of choice.
Renal arteriograms are occasionally still performed during evaluation of a solid renal mass. Renal-cell carcinoma characteristically appears as a hypervascular tumor. However, RCC with a predominantly papillary tumor pattern or a sarcomatoid component will appear as a hypovascular mass. Under these circumstances, renal arteriography may be misleading.
Imaging studies are also performed to detect metastases. Because a significant number of patients have pulmonary metastasis at presentation, a chest x-ray film should be obtained as part of the initial evaluation. Bone scans have been traditionally used as part of the staging workup; however, in the absence of bone pain or an elevated alkaline phosphatase level, abnormal bone scan findings are uncommon . Of note, bone metastasis from RCC may be purely lytic and may produce a weak signal or no signal on bone scan. If clinical suspicion of bone metastasis is high, a negative bone scan should be confirmed by a plain radiograph of the site in question. Computed tomographic scans of the brain are usually reserved for patients with neurologic symptoms or for those entering clinical trials.
Renal-cell carcinoma is commonly associated with the development of reactive lymph nodes, particularly those draining the primary tumor. If the presence of local nodal metastasis has bearing on therapeutic decisions, enlarged nodes seen on CT scan should be sampled to confirm the presence of metastasis.
One of the most popular staging systems is that of Robson et al, introduced in 1963, later updated in 1969, and still commonly used in clinical practice (Table 1)[29,36]. This system was employed in early studies correlating stage at presentation with prognosis.
More recent studies have used the tumor, nodes, and metastasis (TNM) system (Table 2), thus making comparisons between early and recent studies somewhat difficult. One of the major advantages of the TNM system is that it clearly separates individuals with tumor thrombi from those with local nodal disease. These two groups are combined in Robson's stage III category. The presence of local nodal metastasis is associated with shorter survival, whereas this is not necessarily the case for an inferior vena cava thrombus.
|T1||Tumor = 2.5 cm or less, confined to kidney|
|T2||Tumor > 2.5 cm, confined to kidney|
|T3||Extension into renal vein, infradiaphragmatic vena cava, adrenal gland, or perinephric fat|
|T4||Extension beyond Gerota's fascia|
|N1||Single node = 2 cm or less|
|N2||Single node > 2 cm and = 5 cm or less or multiple nodes = 5 cm or less|
|N3||Any node > 5 cm|
The 5-year survival for surgically treated patients who present with Robson's stage I disease (T1 or T2 N0 M0) is greater than 90%; stage II disease (T3a N0 M0), 65% to 70%; stage III disease (T3b–d or N1–3 M0), 40%; and stage IV disease (T4a or M1), 15% to 20% [29,36,38,39].
Regardless of the staging system, there is a general consensus that poor survival is associated with increasing tumor size, regional lymph node involvement, and distant metastasis. In addition to advanced disease stage, other predictors of poor outcome include high nuclear grade (particularly Fuhrman's grade 4), sarcomatoid elements , aneuploidy [25,40,41], and an inferior vena cava thrombus extending into or above the hepatic veins .
Radical nephrectomy is the mainstay of treatment for localized RCC. The classic description of radical nephrectomy includes excision of the kidney with all of the Gerota's fascia and removal of the ipsilateral adrenal gland; regional lymphadenectomy may also be included in the surgery . The actual benefit derived from adrenalectomy and lymphadenectomy has been debated [43,44], and in some cases these procedures are omitted from the resection. When present, intracaval tumor thrombi are also resected during the operation . Radical nephrectomy is associated with a mortality rate of 2%, with most deaths occurring in patients with advanced disease. Intraoperative and postoperative complication rates are each approximately 20%. The most common complications are injuries to the spleen and large vessels .
Partial nephrectomy or tumor enucleation is performed when RCC occurs in a patient with a solitary kidney, in both kidneys, or occasionally in the setting of significant renal insufficiency . Long-term follow-up studies of these patients have suggested that the modified surgical procedures do not compromise survival for individuals with small, early-stage lesions [48,49]. However, beyond the indications mentioned above, the role of partial nephrectomy has not been established, and at present, the procedure cannot be recommended for patients with unilateral disease and a normal contralateral kidney.
For patients with metastatic RCC, palliative nephrectomy is offered for intractable hematuria, severe pain, or compression of adjacent viscera. Radical nephrectomy in patients with unresectable local or distant metastasis does not improve survival. Spontaneous regression of metastatic lesions has occurred objectively in less than 1% of cases after nephrectomy . Palliative resection of solitary metastatic lesions is indicated for patients with RCC and may provide excellent, durable symptom control [51,52].
Whether control of the primary carcinoma determines the clinical response of the metastatic disease is unsettled. An improved response was initially suggested by clinical trials of biologic agents, and for this reason, many trials of investigational agents now include prior nephrectomy in the entry criteria. Randomized trials to clarify this issue are under way.
Renal-cell carcinoma is generally radioresistant, and the indications for radiation therapy are limited [53-55]. The major indication for radiation therapy is for palliation of symptomatic metastatic disease, most commonly painful bone lesions and brain metastases [56,57].
The vascular nature of RCC lends itself to treatment with angio-infarction. This modality has two general applications. First, preoperative infarction of the primary tumor or metastatic focus may be performed to minimize the amount of intraoperative morbidity . Second, embolization may be performed for palliation of symptoms from an unresectable primary tumor or metastasis . Embolization of a large renal mass frequently produces a postinfarction syndrome consisting of pain, fever, and gastrointestinal disturbances, occurring immediately after the procedure. Symptoms are managed with supportive care and usually resolve after several days.
Hormonal Therapy: A number of hormonal agents, most commonly progestins such as medroxyprogesterone acetate (Depo-Provera), have been used both in the adjuvant setting and for treatment of metastatic disease. There appears to be no benefit from the use of progestins as adjuvant therapy , and in metastatic disease the objective response rate is at best 5% [61,62].
Cytotoxic Chemotherapy: Renal-cell carcinoma is refractory to most traditional chemotherapeutic agents [63,64], a property currently hypothesized to be the result of the high cellular expression of the multidrug resistance (MDR1) phenotype [64,65]. Several studies of single-agent or combination cytotoxic chemotherapy have found marginal efficacy at best . Only two drugs, vinblastine and floxuridine, have shown reproducible significant activity.
Most of the recent trials of vinblastine have used monthly, 5-day infusions of 0.75 to 1.9 mg/m²/d. Objective responses are usually partial and occur in approximately 15% of patients .
Floxuridine was first reported to be an active agent for metastatic RCC by von Roemeling et al in 1988 . These investigators used programmable infusion pumps to deliver continuous floxuridine in such a way that most of the dose was given in the afternoon and evening, based on animal studies showing improved tolerance when the drug was administered in a circadian fashion. Compared with constant-rate (flat-rate) infusions, this schedule resulted in reduced toxicity and permitted dose escalations . The overall response rate was 28%, and some responses were durable. The dose range was usually 0.15 to 0.20 mg/kg administered daily for 14 days and repeated in 28-day cycles.
According to the recommended circadian schedule, 68% of the floxuridine dose is given between 1500 and 2100 hours, 15% between 2100 and 0300 hours, 2% between 0300 and 0900 hours, and 15% between 0900 and 1500 hours. When administered according to this schedule, floxuridine is generally well tolerated, producing only occasional gastrointestinal side effects (abdominal cramping, diarrhea, or mucositis), which are manageable.
The logistic difficulties of delivering floxuridine with programmable pumps generated interest in studying infusion of floxuridine at a constant rate . Usually, the flat-rate dose is started at 0.075 to 0.125 mg/kg/d and given for 14 days in 28-day cycles. Wilkinson et al reported a response rate of 21%, which is comparable to that in the literature on the circadian schedule . Administration of floxuridine in circadian rhythms permits delivery of greater amounts of drug, but whether the larger amounts in turn induce greater antitumoral effect remains to be determined in ongoing phase III studies .
Among the biologic agents used in clinical trials to treat metastatic RCC, three have shown reproducible activity: alpha interferon (IFN-alfa), interleukin-2 (IL-2, aldesleukin [Proleukin]), and gamma interferon (IFN-gamma [Actimmune]).
Alpha Interferon: IFN-alfa was the first biologic agent found to have significant activity in patients with metastatic RCC. The mechanism of antitumoral activity of IFN-alfa may result from immunomodulation, antiangiogenesis, or direct cytotoxicity . Several studies have consistently demonstrated response rates of 15% [70-73]. Therapy is usually started at doses of 2 to 5 million U/m²/d by subcutaneous injection. Higher doses, ranging from 10 to 20 million U/m²/d, have been used, but toxicity at these dose levels usually results in poor patient compliance.
Initiation of IFN-alfa therapy produces flu-like symptoms in most patients, but tolerance usually develops after several days to several weeks of treatment. Common toxic effects of chronic IFN-alfa therapy include fatigue, depression, anorexia, weight loss, and mild leukopenia. At high doses, central nervous system toxic effects can occur. Side effects of IFN-alfa can often be ameliorated by changing to an every-other-day or three-times-weekly schedule or by giving breaks in therapy. Most responses to IFN-alfa are partial and not sustained.
Interleukin-2: IL-2 is a cytokine produced by helper T-cells. IL-2 activates natural killer cells and T-cells and transforms a population of peripheral blood mononuclear cells into lymphokine-activated killer (LAK) cells. The first reports of IL-2 administration to patients with cancer appeared between 1983 and 1985 [74,75]. The product used was a purified preparation obtained from mitogen-stimulated peripheral blood leukocytes or cultured cells from the Jurkat T-cell line. Shortly thereafter, recombinant IL-2 became available, permitting treatment of a substantial number of patients in phase I and II clinical trials.
A consistent observation from these studies was the apparent sensitivity of metastatic RCC to IL-2 therapy. This sensitivity was confirmed in several phase II studies that reported response rates of 10% to 30%, with a number of complete responses that persisted after cessation of therapy. However, selection criteria for these studies favored inclusion of younger patients with good performance status, low tumor burden, and the lung as the only site of disease, factors that may represent an already favorable subgroup of patients with RCC .
In 1992, IL-2 was approved by the Food and Drug Administration (FDA) for the treatment of metastatic RCC. In the United States, IL-2 is currently manufactured only by recombinant techniques and dispensed in international units (IU). In reviewing the literature, however, one must take careful account of the units used in different reports. (A value of 6 IU is equivalent to 2 Roche units and to 1 Cetus unit.)
Initial trials of IL-2 used variations of what is now considered high-dose therapy, administered either as a rapid intravenous bolus or a continuous infusion [77-79]. High-dose intermittent bolus therapy is recommended by the FDA because this dose and schedule has produced the greatest number of complete responses in clinical trials.When treating patients according to these recommendations, the physician should be prepared to manage significant toxic effects and should have an intensive care facility available. The extreme toxicity of high-dose IL-2 is mainly characterized by fever, hypotension, oliguria with marked fluid retention, pulmonary edema, mental confusion, and hepatic dysfunction. These side effects usually resolve within 24 to 48 hours of discontinuation of therapy [77,78].
Published trials of low-dose IL-2 therapy administered by continuous infusion or subcutaneous injection show less toxicity than and response rates comparable to those obtained for high-dose bolus therapy [80-83]. Ongoing clinical trials continue to investigate various doses and schedules of IL-2 in order to minimize toxicity and expense and permit incorporation of other cytotoxic or biologic agents into the regimen. Other trials are attempting to modulate the side effects of the cytokines by administering additional novel compounds. Of these, encouraging early reports are available for two particular agents: CT1501R, a pentoxifylline analog that inhibits interleukin-1 and tumor necrosis factor signal transduction , and N(G)-methyl-L-arginine, a nitric oxide synthesis inhibitor that counteracts the hypotensive side effects of IL-2 [85,86].
Gamma Interferon: IFN-gamma is also a product of activated T-cells. This cytokine is unique in its ability to activate macrophages. When this agent is used at the maximum tolerated dose, responses are rarely seen in RCC or in other tumors. However, using serologic markers of macrophage activation, Aulitzky et al found the biologically active dose to be considerably lower than the maximum tolerated dose . Their subsequent trial of fixed low-dose IFN-gamma, administered as a weekly subcutaneous injection of 100 mg, produced a 30% response rate in patients with metastatic RCC . The activity of low-dose IFN-gamma has been confirmed in a second study, which reported a 15% response rate . A notable advantage of this drug is its complete lack of serious toxicity, making it an ideal candidate for combination therapy.
Experimental models of antitumor synergy induced by the combination of IFN-alfa and IL-2  prompted interest in developing combination protocols [82,90]. The initial studies attempted to deliver the maximally tolerated doses of IL-2 and IFN-alfa but encountered extreme toxicity . Trials of “low-dose” schedules (IL-2 at 4 to 18 million IU/m² and IFN-alfa at 4 to 6 million U/m²) were able to increase compliance because the side effects were less intense, but the antitumoral effects reported have fluctuated from 0% to 50% [90,91].
With expectations of obtaining greater antitumor activity by altering the drug pharmacodynamics, more recent trials have added chemotherapeutic agents such as fluorouracil and floxuridine [92-94]. Response rates around 35% have been described [92-94]. Interest in the development of “combination” biochemotherapies for RCC continues to increase, but to date there is no consensus on whether this approach is clinically superior to single-agent treatment.
Adjuvant therapy is also under active clinical investigation, but no specific treatment has proven to be superior to close surveillance in the care of patients who undergo surgery.
In summary, patients with disseminated RCC represent a challenge for the oncologist. Patients with a good performance status should be offered the opportunity to participate in clinical trials until more effective and safe therapies can be widely adopted.
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