Hiram A. Gay and Jeff M. Michalski
ANATOMY
The kidneys are retroperitoneal structures located at the level between the 11th rib and the transverse process of the 3rd lumbar vertebral body. Usually, the right kidney is inferior to the right hepatic lobe and slightly more inferior than the left kidney. The renal axis runs parallel to the lateral margin of the psoas muscle. Each kidney is approximately 11 to 12 cm in length. The kidney is encased by a fibrous capsule and surrounded by perinephric fat, which is enveloped by Gerota’s fascia. At the renal hilus are the pelvis, ureter, renal artery, and vein. The organs adjacent to the right kidney include the liver superiorly, the duodenum and the vertebral bodies medially, and the transverse colon and small bowel anteriorly. On the left, the kidney abuts the spleen laterally; the stomach, pancreas, and vertebral bodies medially; and the small bowel and colon anteriorly.
The kidney consists of the cortex (glomeruli, convoluted tubules) and the medulla (Henle’s loops, collecting ducts, and pyramids of converging tubules). Each papilla opens in the minor calices, which unite in the major calices and drain into the renal pelvis. The caliceal collecting systems lie on the anteromedial surface of each kidney. The ureteropelvic junction is variable in position but serves as the landmark to separate the renal pelvis and the ureter. The ureters course posteriorly and inferiorly, paralleling the lateral border of the psoas muscle until they curve anteriorly to join the bladder at the trigone. The mucosal surfaces of the renal collecting tubules, calyces, renal pelvis, ureter, bladder, and urethra all have the same embryologic origin. The renal pelvis and ureter have the following layers: epithelium, subepithelial connective tissue, and muscularis, which is continuous with a connective tissue adventitial layer.
The lymphatics of the kidney and renal pelvis drain along the renal vessels. The right kidney drains predominantly into the paracaval and interaortocaval lymph nodes, and the left kidney drains exclusively to the paraaortic lymph nodes.1 The lymphatic drainage of the ureter is segmented and diffuse and may involve any of the renal hilar, abdominal para-aortic, paracaval, common iliac, internal iliac, or external iliac lymph nodes.
EPIDEMIOLOGY AND RISK FACTORS
The lesions discussed in this chapter are limited to adult renal cell carcinoma (RCC; e.g., hypernephroma, Grawitz’s tumor) and urothelial carcinoma of the renal pelvis and ureter. Lymphomas, primary retroperitoneal sarcomas, and Wilms’ tumors are discussed in Chapters 78, 83, and 85, respectively. Approximately 88% of solid renal masses are malignant, and the probability of malignancy is proportional to the size of the lesion.2 RCCs comprise 80% to 85% of primary kidney tumors, whereas urothelial (transitional cell) carcinomas of the renal pelvis account for 7% of kidney tumors.
Renal Cell Carcinoma
Globally in 2008, the male kidney cancer incidence and mortality age-standardized rate per 100,000 (ASR) was 11.8 and 4.1 in more developed areas, and 2.5 and 1.3 in less developed areas, respectively. The estimated new kidney cancer cases in males in developed countries were 111,100, with 43,000 deaths. In contrast, the female kidney cancer incidence and mortality ASR was 5.8 and 1.7 in more developed areas, and 1.4 and 0.8 in less developed areas, respectively.3
In the United States in 2011, the estimated number of new cases of kidney and renal pelvis cancer was 60,920, with 13,120 deaths.4 These figures represent approximately 4% of all new cancers and 2% of cancer-related deaths. The incidence of RCC has been increasing in the United States, whereas the size of primary RCCs has been gradually decreasing.5 This is partly because the increased use of abdominal computed tomography (CT) and ultrasound for nonmalignant medical illnesses has increased the number of incidental RCCs.
The median age of RCC diagnosis is 65 years, and males are affected more commonly than females, with a ratio of 1.5:1. Occupations associated with a higher risk of RCC are employment in the blast-furnace, coke-oven, or iron and steel industry, as well as exposure to asbestos, cadmium, dry-cleaning solvents, gasoline, and other petroleum products.6 In addition, several other environmental (e.g., exposure to thorium dioxide), hormonal (e.g., diethylstilbestrol), dietary (e.g., high total energy intake and fried meats increase the risk, whereas vegetables, fruits, and alcohol are protective), cellular, and genetic factors have been associated with the development of RCC.7–9
Long-term cigarette smoking is associated with an increased risk of developing RCC. Obesity, diabetes, hepatitis C, and hypertension are also associated with a higher relative risk for development of these tumors.10–12 Cytotoxic chemotherapy may predispose childhood cancer survivors to translocation RCC, bearing TFE3 or TFEB gene fusions.13
Acquired cystic kidney disease (ACKD), which occurs in up to 50% of patients on dialysis for >3 years, is associated with a 50-fold increased risk of developing RCC.14,15 ACKD-associated RCC is seen mostly in males, occurs approximately 20 years earlier than in the general population, and is frequently bilateral (9%) and multicentric (50%).15
Several inherited cancer syndromes affect the kidney: von Hippel-Lindau (VHL) disease, hereditary papillary renal cancer (HPRC), hereditary leiomyomatosis and renal cell carcinoma (HLRCC), Birt-Hogg-Dubé (BHD), and constitutional chromosome 3 translocation. VHL is autosomal dominant and is caused by germline mutations of the VHL tumor suppressor gene, located on chromosome 3p25–26. The VHL protein is involved in cell cycle regulation and angiogenesis. In patients with VHL disease, loss of the sole functioning VHL allele in somatic tissues causes a situation similar to hypoxia, with elevated levels of HIF-1alpha, despite the presence of normal oxygen tension.16 The renal manifestations of VHL are kidney cysts and clear cell RCC. The mean age onset for VHL associated clear cell RCC is 37 years, and periodic screening with magnetic resonance imaging (MRI) should start after the age of 10 years.17
HPRC is autosomal dominant with high penetrance and is characterized by multiple, bilateral, late-onset papillary RCCs. HLRCC is autosomal dominant with a predisposition to papillary type 2 RCC. BHD is autosomal dominant with incomplete penetrance and is associated with multiple chromophobe and clear cell RCCs, papillary RCCs, and oncocytomas. Constitutional chromosome 3 translocation is associated with multiple, bilateral clear cell RCCs.18Autosomal dominant polycystic kidney disease does not appear to increase the incidence of RCC; however, the tumors are more often multicentric (28% vs. 6%), bilateral (12% vs. 1% to 5%), and sarcomatoid in type (33% vs. 1% to 5%) than in the general population.19
Renal Pelvis and Ureter Carcinoma
Urothelial carcinoma of the upper urinary tract accounts for 7% of all kidney tumors and 5% of all urothelial malignancies.20 The incidence of bilateral upper urinary tract tumors is 1.5% to 2% for synchronous and 6% to 8% for asynchronous presentations.21 Renal pelvis tumors are found two to three times more commonly in men than in women, and the peak incidence is in the fifth and sixth decades of life. Because the mucosal surfaces of the renal pelvis, ureter, and bladder have the same embryologic origin, many of the etiologic factors in renal pelvis and ureter tumors also apply to tumors of the urinary bladder. Urothelial carcinomas of the upper urinary tract tend to be multifocal owing to field cancerization, which may be caused by exposure of the urothelium to potential carcinogens. Urothelial tumors can also spread to urothelial structures that are either distal or proximal to the primary tumor and are referred to as drop metastases. About 40% to 50% of patients with upper urinary tract tumors will have a synchronous or metachronous bladder cancer.22,23
Cigarette smoking is the most important factor contributing to the overall incidence of urothelial cancer in Western countries. Patients with Lynch syndrome, an autosomal dominant genetic condition attributable to inherited mutations that impair DNA mismatch repair, have an increased risk of developing urinary tract cancer.24
Exposure to aristolochic acid has been associated with acute, near end-stage renal disease. Aristolochic acid is commonly found in the Aristolochiaceae family of plants commonly used in Chinese herbal medicine. A high incidence of cellular atypia and urothelial carcinoma of the renal pelvis, ureter, and bladder has been associated with aristolochic acid nephropathy.25 Arsenic-contaminated water has been associated with a high incidence of upper urinary tract urothelial carcinoma in Taiwan.26 Prolonged heavy phenacetin-containing analgesic use can lead to urothelial carcinomas of the renal pelvis, ureter, and bladder (which may be multiple and bilateral).27
Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease of unknown etiology most commonly reported in southeastern Europe. A high frequency of urothelial atypia, occasionally progressing to tumors of the renal pelvis and urethra, but also involving the bladder, is associated with BEN.27
NATURAL HISTORY
Renal Cell Carcinoma
Primary renal cell tumors may spread by local infiltration through the renal capsule to involve the perinephric fat and Gerota’s fascia. The tumor may grow directly along the venous channels to the renal vein or vena cava. Lymph node metastases occur with an incidence of 9% to 27%, and most often involve the renal hilar, para-aortic, and paracaval lymph nodes.28,29 The renal vein is invaded by tumor in 21% of cases, and the inferior vena cava is invaded in as many as 4% of cases.30
Approximately 45% of patients with RCC have localized disease, 25% have regional disease, and about 30% have evidence of distant metastases at the time of diagnosis.29,31 Of patients with metastases, about 1% to 3% have solitary lesions.32 About half of the patients with RCC eventually develop metastatic disease.33
Among patients presenting with metastatic RCC, the sites of metastases include lung, bone, brain, liver, and adrenal gland. Patients with metastatic disease at diagnosis have an extremely poor prognosis, with an expected survival <5 years regardless of the site of metastasis.29,31
Renal Pelvis and Ureter Carcinoma
Upper urinary tract carcinoma is frequently a multifocal process. Patients with cancer at one site in the upper urinary tract are at significant risk for the development of tumors elsewhere along the urothelium. The probability of multifocal occurrence is greatest in patients with large tumors and those with carcinoma in situ. Ureteral tumors tend to occur in the distal third of the ureter.
Urothelial carcinoma of the upper urothelial tract may spread by direct extension, and by hematogenous and lymphatic metastases. Implantation of tumor cells in the bladder has been demonstrated, especially in previously traumatized areas. The incidence of lymph node metastases highly depends on the grade of the primary tumor. Low-grade tumors have a very low metastatic propensity. In a series of 94 patients, none of 43 low-grade tumors had lymph node metastases, compared with 3 of 22 grade 3 or 4 tumors.34 Lymph node metastases were reported in 9 of 26 patients selected to receive adjuvant radiotherapy.35
CLINICAL PRESENTATION
Renal Cell Carcinoma
Patients with RCC may present with an occult primary tumor, or with signs and symptoms attributable to a local mass or systemic paraneoplastic syndromes. Gross hematuria, palpable flank mass, and pain describe a classic triad that occurs only in 5% to 10% of patients.36,37 Indeed, a finding of the classic triad often suggests advanced disease with a poor prognosis. The most frequent symptom associated with RCC is hematuria, either gross or microscopic, when there is invasion of the collecting system.38 Scrotal varicoceles, mostly left-sided, are observed in as many as 11 % of men with RCC.39 Other symptoms include anemia, hepatic dysfunction in the absence of liver metastases (called Stauffer’s syndrome and attributable to a paraneoplastic elevation in alkaline phosphatase), secondary AA amyloidosis, fever, hypercalcemia, cachexia, erythrocytosis, thrombocytosis, and a syndrome resembling polymyalgia rhumatica.39,40,41–44,45 RCC presenting as an incidental mass on a diagnostic imaging study ordered for other purposes accounts for 61% of all diagnoses.46
A wide range of paraneoplastic syndromes has been associated with RCC. Parathyroidlike hormones, erythropoietin, renin, gonadotropins, placental lactogen, prolactin, enteroglucagon, insulinlike hormones, adrenocorticotropic hormone, and prostaglandins have been identified in patients with RCC.47,48
Renal Pelvis and Ureter Carcinoma
Gross or microscopic hematuria occurs in 70% to 95% of patients with renal pelvis or ureter tumors.20 The other less common symptoms include pain (8% to 40%), bladder irritation (5% to 10%), or other constitutional symptoms (5%). About 10% to 20% of patients may present with a flank mass secondary to tumor or hydronephrosis.
DIAGNOSTIC WORKUP
Renal Cell Carcinoma
Renal masses are not uncommon, and most of them are benign. A central renal mass may suggest urothelial carcinoma; if so, urine cytology or ureteroscopy should be considered. Renal masses are frequently diagnosed as an incidental finding during abdominal imaging for metastatic evaluation of an unrelated malignancy or other disease.
An algorithm for the workup of renal masses has been proposed.49 If CT or ultrasound clearly identify the mass as a cyst, no further workup is necessary. If a solid lesion is identified, then tumor removal by nephrectomy should be considered. In the case of small lesions, a follow-up CT scan to evaluate potential growth of the mass may raise the suspicion of malignancy. The diagnostic and staging workup for RCC is given in Table 63.1. The diagnosis of RCC is established clinically and radiographically in most cases. Pathologic confirmation often is made at the time of nephrectomy.
Once a radiographic diagnosis is made, a staging evaluation should be undertaken, which should include: a complete history and physical examination, complete blood count, and liver and kidney function tests. A metastatic workup should include a chest CT and an abdominal/pelvic CT (preferred) or abdominal MRI scan. Patients with symptoms suggestive of bone metastases and those with an elevated alkaline phosphatase level should undergo a bone scan. If metastatic lesions are detected, histologic confirmation should be made by biopsy of either the metastatic focus or the primary tumor. MRI can be valuable when evaluating the extent of involvement of the collecting system or inferior vena cava, or radiographic contrast cannot be administered. Renal arteriography is sometimes helpful in planning surgery.
Renal Pelvis and Ureter Carcinoma
The diagnostic workup for renal pelvis and ureter carcinoma is listed in Table 63.2. Staging includes a complete history and physical examination, complete blood count, and liver and kidney function tests. CT urography is now used to evaluate patients with renal pelvis carcinoma. CT or MRI of the abdomen and pelvis before and after contrast administration gives useful information regarding the possible extension of tumor outside the collecting system. Uteroscopic visualization of the tumor is desirable, and tissue biopsy through a uteroscope should be performed if feasible. Cystoscopy is very important because of the high incidence of multiple tumors. Urine cytology may help to determine tumor grade if tissue is not available; however, false-negative rates can be high for upper tract and low-grade tumors.
TABLE 63.1 DIAGNOSTIC WORKUP FOR RENAL CELL CARCINOMA
TABLE 63.2 DIAGNOSTIC WORKUP FOR RENAL PELVIS AND URETER CARCINOMA
STAGING
Renal Cell Carcinoma
The American Joint Committee on Cancer (AJCC) system is utilized to stage patients with RCC50 (Table 63.3). T1 and T2 cancers are limited to the kidney. T3 tumors extend into major veins or perinephric tissues, although not into the ipsilateral adrenal gland, and not beyond Gerota’s fascia. T4 tumors invade beyond Gerota’s fascia (including contiguous extension into the ipsilateral adrenal gland). Regional lymph node metastases may involve spread to the renal hilar, paracaval, aortic, or retroperitoneal drainage sites. Metastasis in regional lymph node(s) is classified as N1. This staging system underwent significant modifications in the 2010 AJCC 7th edition of its Cancer Staging Manual: T2 lesions were divided into T2a (>7 cm but ≤10 cm) and T2b (>10 cm); ipsilateral adrenal involvement was reclassified as T4 if contiguous invasion and M1 if not contiguous; renal vein involvement was reclassified as T3a; and nodal involvement was simplified to N0 versus N1.
TABLE 63.3 AMERICAN JOINT COMMITTEE ON CANCER 2010 STAGING CLASSIFICATION FOR KIDNEY TUMORS
TABLE 63.4 AMERICAN JOINT COMMITTEE ON CANCER 2010 STAGING CLASSIFICATION FOR RENAL PELVIS AND URETER TUMORS
Renal Pelvis and Ureter Carcinoma
Tumors of the renal pelvis and ureter have a natural history that is not too dissimilar from that of other urothelial malignancies originating in the bladder. Their prognoses depend on tumor invasiveness and pathologic grade. The 2010 AJCC 7th edition staging classification for renal pelvis and ureter carcinoma is shown in Table 63.4.51
PATHOLOGIC CLASSIFICATION
Renal Cell Carcinoma
RCC is a group of malignancies arising from the epithelium of the renal tubules and comprises 90% of all malignancies in the kidney.18 The World Health Organization (WHO) classifies renal cell tumors as clear cell RCC, multilocular clear cell RCC, papillary RCC, chromophobe RCC, carcinoma of the collecting ducts of Bellini, renal medullary carcinoma, Xp11 translocation carcinomas, carcinoma associated with neuroblastoma, mucinous tubular and spindle cell carcinoma, papillary adenoma, oncocytoma, and RCC unclassified.18
Clear cell RCC is the most common (80% to 90% of tumors), followed by papillary RCC (10% to 15%) and chromophobe RCC (4% to 5%). Papillary RCC can be subdivided into type 1, which tends to be low grade and have a better prognosis, and type 2, which is the opposite. Renal medullary carcinoma is a very aggressive malignancy mostly associated with young black patients with sickle cell trait and, less commonly, sickle cell disease.52
Renal Pelvis and Ureter Carcinoma
More than 90% of malignant tumors arising from the renal pelvis and ureter are urothelial (also called transitional cell) carcinomas. The WHO classifies urothelial tumors as infiltrating urothelial carcinoma (with squamous differentiation, glandular differentiation, trophoblastic differentiation, nested variant, microcytic variant, micropapillary variant, lymphoepitheliomalike carcinoma, lymphomalike variant, plasmacytoid variant, sarcomatoid variant, with giant cells, and undifferentiated carcinoma).18 The most common histologic variant is squamous differentiation followed by glandular.18 Squamous cell carcinomas account for only 7% to 8% of renal pelvis and ureter carcinomas, and are often associated with chronic calculus disease and infection. Squamous cancers of the renal pelvis and ureter are often locally advanced and associated with a high local recurrence rate.53
PROGNOSTIC FACTORS
Renal Cell Carcinoma
The 5-year survival rate of patients with kidney cancer has doubled over the past 50 years, from 34% in 1954 to 70.9% in 2007.54,55 The stage at initial presentation remains the most important prognostic factor for RCC survival. Using the current 7th edition AJCC staging, the 5-year kidney cancer survival for stage I is 80.9%, 73.7% for stage II, 53.3% for stage III, and 8.2% for stage IV. Prognostic features for RCC are tumor, patient, and laboratory related. Tumor-related prognostic factors include stage, tumor size, tumor grade, histologic type, tumor necrosis, sarcomatoid transformation, and more than two sites of organ metastases. Patient-related factors include asymptomatic versus local symptoms versus systemic symptoms, weight loss, paraneoplastic syndromes, and an interval <1 year from original diagnosis to start of systemic therapy. Laboratory prognostic factors include thrombocytosis as well as elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP).50,56
For patients with metastatic RCC, the following factors were predictive of survival in a retrospective study of 670 patients: low Karnofsky performance status (KPS; <80), high lactate dehydrogenase (LDH; >1.5 times upper limit of normal), low hemoglobin (less than the lower limit of normal), high “corrected” serum calcium (>10 mg/dL or 2.5 mmol/L), and absence of prior nephrectomy.57
Lymph node metastases are associated with increased rates of local recurrence and distant metastasis.36,58–59,60 Nuclear grade, sarcomatoid component, tumor size, stage, and the presence of tumor necrosis increase the likelihood of lymph node involvement.61 The overall risk of lymph node metastases is 20%.62,63 Patients with lymph node metastases in radical nephrectomy specimens have a local failure rate of 21%, compared with only 4% in patients without lymph node metastases (p = .0002).60 A select group of patients with solitary metastases may have a 5-year survival rate of 25% to 35%.64,65
Nuclear grade, after stage, is the most important prognostic feature of clear cell carcinoma. Fuhrman et al.66 developed a four-tier grading system that is based on nuclear and nucleolar size, shape, and content. Fuhrman’s grade is the most widely used grading system. Grade is also an independent prognostic factor for papillary RCC and chromophobe RCC especially when using standardized criteria.67 Worsening pathologic grade is associated with a poor 5-year disease-free survival.31,36
Papillary RCC has a 5-year survival rate that approaches 90% and metastasizes less frequently than clear cell RCC. The spindle cell or sarcomatoid variants of RCC are associated with statistically significant inferior 5-year survival rates, compared with pure clear, or clear and granular, histologic variants.31,36
Nuclear morphology is a strong predictor of tumor stage and prognosis.66 High nuclear grade is associated with an increased incidence of advanced tumor stage, lymph node involvement, distant metastases, renal vein involvement, tumor size, and perirenal fat involvement. In a series of 190 patients reported by Bretheau et al.,68 the 5-year actuarial survival rates of patients with grade I, II, III, and IV tumors were 76%, 72%, 51%, and 35%, respectively. Sarcomatoid differentiation carries a significantly poorer prognosis than the clear cell or granular cell subtypes. Almost half of patients with sarcomatoid RCC have bone metastases at presentation. The median survival time of patients with sarcomatoid renal cell cancer is only 6.6 months, compared with 19 months for other histologic types.69
Nomograms and algorithms have been described to facilitate the determination of cancer-free survival in patients with RCC. Based on 601 patients treated at Memorial Sloan-Kettering Cancer Center with radical nephrectomy, Kattan et al.70 used variables including patient symptoms (incidental, local, or systemic), histology (chromophobe, papillary, or conventional), tumor size, and pathologic stage to predict risk of recurrence after surgery. (Note: Kattan et al.70 uses the older 1997 staging and is available at the Memorial Sloan-Kettering Cancer Center website, http://nomograms.mskcc.org/Renal/PostSurgery.aspx.) Frank et al.71 from the Mayo Clinic developed a predictive algorithm based on 1,801 patients treated with radical nephrectomy. This system combines stage, size, grade, and necrosis (SSIGN) to predict patient survival. Finally, Zisman et al.72 from the University of California–Los Angeles (UCLA) have developed an algorithm that utilizes the AJCC TNM stage, Fuhrman’s grade, and Eastern Cooperative Oncology Group (ECOG) performance status to divide patients into low-, intermediate-, and high-risk groups. This model is also known as the UISS, or the UCLA integrated staging system.
Several molecular markers are being explored for their prognostic significance, including lack of B7H1 expression,73 immunohistochemical detection of carbonic anhydrase IX (CAIX),74 the proliferative marker Ki67,74immunohistochemical expression of IMP3,75 and others.
Renal Pelvis and Ureter Carcinoma
The major prognostic factors in patients with renal pelvis or ureter carcinoma are initial stage and grade of the tumor. There is no significant difference in prognosis between urothelial carcinomas originating in the ureter compared to those arising in the renal pelvis.76 Using the current 7th edition AJCC staging, the 5-year renal pelvis and ureter cancer survival is as follows: stage 0a, 72.3%; stage 0is, 70.0%; stage I, 63.9%; stage II, 56.7%; stage III, 36.5%; and stage IV, 10.2%.
High-grade tumors are associated with a higher incidence of metastases and worse survival. Corrado et al.77 reported 5-year survival rates of 83%, 75%, 52%, and 0% for grades 1 through 4, respectively. These results are comparable to those described by Heney et al.,78 who reported 100% survival for grade 1, 81% for grade 2, and 0% for grade 3. Local recurrence was identified in 3 of 24 patients with grade 3 tumors. No survival differences were seen for patients with papillary versus solid tumors. In the series of Charbit et al.,23 lymph node metastases were seen exclusively in patients with high-grade tumors. Of tumor-related deaths, 90% were in patients with high-grade tumors. Hall et al.79 reported a retrospective series of 252 patients treated surgically for upper urinary tract urothelial cancers. Significant factors for recurrence included high tumor grade and advanced clinical stage. Older patients and patients treated with parenchymal-sparing surgical procedures had higher rates of recurrence. In their series of 77 patients, Akdogan et al.80 reported from a multivariate analysis that higher recurrence rates were associated with tumor location, higher grade, and advanced T-stage. Tumors in the ureters were more likely to recur than tumors involving the renal pelvis. In a series of 86 patients, Park et al.81 also reported a higher rate of recurrence in ureteral tumors, compared to those arising in the renal pelvis.
A prior history of bladder cancer has been reported to worsen the prognosis of patients with second urothelial cancers involving the upper tracts.80,82 From the Memorial Sloan-Kettering Cancer Center series of 129 patients, a multivariate analysis demonstrated that patients with advanced primary tumors and a prior history of bladder cancer were associated with worse disease-free survival.82
Flow cytometry may aid in estimating long-term prognosis. In a multivariate analysis, Corrado et al.77 demonstrated that although stage and grade were the most important prognostic indices, DNA pattern (diploid vs. nondiploid) and the number of lesions (unifocal vs. multifocal) identified at initial diagnosis also determined prognosis. Patients with diploid tumors had a 79% survival rate, compared with only 46% in patients with nondiploid tumors (p = .0003). Recent data suggest that hypermethylation of the promoter region of patients with urothelial cancers is associated with a worse prognosis. Tumors of the renal pelvis and ureters demonstrate hypermethylation in 94% of cases compared to 76% of similar-appearing tumors in the bladder (p <0.0001). Hypermethylation was also associated with higher tumor stage, tumor progression, and mortality.83
GENERAL MANAGEMENT
Renal Cell Carcinoma
Surgery is the therapeutic foundation for the management of kidney cancer. Radiotherapy has an important and growing role in the palliative management of RCC. Although RCC is traditionally considered to be radioresistant, it has a clear dose response to radiation.84,85 As long as sufficient radiation dose is delivered to the tumor while respecting normal tissue dose constraints, RCC “radioresistance” can be overcome with modern techniques. At present, no effective, clinically proven, adjuvant therapy exists for RCC. The kidney cancer National Comprehensive Cancer Network (NCCN) guidelines (version 1.2013) offers the following surgical options depending on the stage86:
• Stage IA: Partial (preferred) or radical nephrectomy, active surveillance in selected patients, or ablative techniques for nonsurgical candidates
• Stage IB: Partial or radical nephrectomy
• Stage II and III: Radical nephrectomy
• Stage IV: Nephrectomy and surgical metastasectomy for a solitary metastasis if feasible, followed by systemic first-line therapy; cytoreductive nephrectomy if feasible when multiple metastatic sites, followed by systemic first-line therapy; or systemic first-line therapy if surgery is not feasible.
Active surveillance should be considered for patients with localized disease and short life expectancy, or significant comorbidities placing them at a surgical risk.
Surgery
A radical nephrectomy includes a perifascial resection of the kidney, perirenal fat, regional lymph nodes, and ipsilateral adrenal gland. It is the preferred treatment if the tumor extends into the inferior vena cava and usually requires the assistance of a cardiovascular surgeon if there is a caval or atrial thrombus. An experienced team should be involved in the context of a thrombus, as treatment-related mortality can reach 10%.86 This operation is undertaken by a thoracoabdominal or transabdominal approach. Improved preoperative assessment with CT can identify patients who have no significant risk of adrenal gland involvement.87 In 76% of cases, the adrenal gland can be spared at the time of surgery. The European Organisation for Research and Treatment of Cancer88 (EORTC) conducted a randomized trial of radical nephrectomy with or without an elective lymph node dissection, and there was no survival advantage between the two study groups. The incidence of unsuspected lymph node metastases was low (4%).88 Nevertheless, lymph node dissection does provide valuable prognostic information.
Radical nephrectomies should be avoided if nephron-sparing surgery is feasible for T1a and T1b renal tumors. In this setting, nephron-sparing surgery has shown equivalent outcomes to radical nephrectomy.89,90 Radical nephrectomy–induced chronic renal insufficiency is associated with an increased risk of cardiovascular death and death from any cause.91 For this reason, nephron-sparing surgery is preferred in T1a and T1b tumors. Nephron-sparing surgery is also preferred in patients with hereditary RCC to preserve renal function and decrease the risk of cardiovascular events.92 In a matched pair analysis of 164 patients undergoing nephron-sparing surgery at the Mayo Clinic, the disease-free survival was 79%, which compared favorably to 77% in patients undergoing radical nephrectomy.93 In 117 patients with renal tumors ≤4 cm undergoing partial nephrectomy at the Memorial Sloan-Kettering Cancer Center, the 5-year freedom from recurrence was 98.6% compared to 96.4% in a similar group of 173 patients undergoing radical nephrectomy. Compared to patients undergoing partial nephrectomy, those undergoing radical nephrectomy were at a higher risk of chronic renal insufficiency.94 There is some risk that sparing of the renal parenchyma may leave microscopic residual tumor or inadequately treat multifocal cancers.95–96,97 Bilateral RCC occurs in 2% to 3% of patients. In these patients, nephron-sparing surgery is an attractive option because bilateral radical nephrectomy sentences the patient to a lifetime of renal dialysis or the need for a renal transplant.
Following surgery, 20% to 30% of patients with localized tumors relapse, with a median time to relapse of 1 to 2 years, and most occurring within 3 years.86 Although at present there is no role for adjuvant therapy after surgery, several recent trials are exploring the role of targeted therapy.
Patients who have local symptoms, such as hematuria, pain, hypertension, or other paraneoplastic syndromes, may benefit from palliative nephrectomy. Spontaneous regression of metastatic renal cell cancer after nephrectomy has been reported. In an extensive literature review, the incidence of regression of metastatic foci induced by nephrectomy was 0.8% (4 of 474 patients).33 Cytoreductive surgery performed to prolong or increase the response of metastatic disease in response to systemic therapy may be beneficial.98,99–100,101
Thermal Ablation
Recently, the minimally invasive ablative technologies of cryoablation and radiofrequency ablation (RFA) have emerged as potential treatment options for clinically localized RCC, especially in the elderly or in patients with a solitary kidney or comorbidities impeding surgery. Long-term oncologic efficacy for these modalities remains to be established. The most favorable lesions for this approach are <4 cm and in the periphery of the kidney. Relative contraindications for RFA and cryoablation include distant metastases, tumors >5 cm, tumors in the hilum or central collecting system, and life expectancy <1 year. A meta-analysis comparing cryoablation and RFA suggested that cryoablation results in fewer re-treatments and improved local tumor control, and that cryoablation may be associated with a lower risk of metastatic progression compared with RFA.101
Renal Stereotactic Body Radiotherapy
Renal stereotactic body radiotherapy (SBRT) as an alternative to thermal ablation is in its infancy. Beitler et al.102 identified nine RCC patients with primary kidney tumors who received SBRT to 8 Gy é five fractions. The tumors ranged from 1.5 to 10 cm in diameter. With a median follow up of 26.7 months, four of the nine patients were alive. One of the nine patients failed in the ipsilateral kidney, away from the initial radiation treatment volume, while the other eight patients had durable local control. One patient had a radiation injury to the stomach resulting in a 30 lb weight loss in 1 month.102 Wersall et al.103 reported eight patients treated with stereotactic radiotherapy to medically inoperable primary tumors using a radiation treatment schedule of 8 Gy é five fractions. Seven of the eight patients were locally controlled, and the median survival exceeded 58 months.103 Ponsky et al.104 also reported their initial experience on three patients treated with 4 Gy é four fractions. Two of three patients had evidence of residual disease at these low doses at the time of partial nephrectomy 8 weeks later.104
Svedman et al.105 reported their SBRT experience with seven patients who were treated for metastases from a malignant kidney to its contralateral counterpart. Dose/fractionation schedules varied between 10 Gy é three fractions and 10 Gy é four fractions depending on target location and size. Local control was obtained in six of seven patients and regained after retreatment in the one patient whose lesion progressed. Side effects were generally mild, and in five of the seven patients kidney function remained unaffected after treatment. In two patients, the creatinine levels remained moderately elevated but dialysis was not required.105
TABLE 63.5 SURVIVAL AFTER NEPHRECTOMY OR NEOADJUVANT RADIOTHERAPY AND NEPHRECTOMY FOR RENAL CELL CARCINOMA, PROSPECTIVE RANDOMIZED TRIALS
TABLE 63.6 SURVIVAL AFTER NEPHRECTOMY OR NEPHRECTOMY AND ADJUVANT RADIOTHERAPY FOR RENAL CELL CARCINOMA, PROSPECTIVE RANDOMIZED TRIALS
Neoadjuvant (Preoperative) Radiotherapy
Neoadjuvant radiotherapy is not recommended in patients with resectable RCC. Two European studies were undertaken to test the efficacy of neoadjuvant/preoperative radiotherapy in renal cell cancer (Table 63.5). A prospective randomized study of neoadjuvant radiotherapy and nephrectomy versus nephrectomy alone was conducted in Rotterdam. No advantage was demonstrated in patients receiving radiotherapy with respect to overall survival or survival free from distant metastases. In this trial, patients received a 30-Gy midplane dose to the involved kidney and regional lymph nodes, with 2 Gy daily fractions administered over a period of 3 weeks. Nephrectomy immediately followed the completion of radiotherapy. Neoadjuvant radiotherapy did appear to increase the rate of complete resectability in patients with locally advanced tumors.106 This study was continued after the preliminary 1973 analysis. Subsequent patients received 40-Gy neoadjuvant radiotherapy. No benefit was demonstrated at the higher radiation dose.107 In Sweden, a second prospective randomized clinical trial was also unable to demonstrate an advantage for neoadjuvant radiotherapy. In this trial, patients were randomly assigned to receive neoadjuvant radiotherapy to 33 Gy in 15 fractions administered to the flank with a betatron unit followed by nephrectomy or nephrectomy alone. Patients receiving neoadjuvant radiotherapy had a 5-year survival rate of 47%, compared with 63% for patients undergoing surgery alone.108
Adjuvant (Postoperative) Radiotherapy
Adjuvant radiotherapy is not recommended in RCC after complete resection. Two prospective randomized studies testing the value of adjuvant radiotherapy did not demonstrate an advantage to patients receiving radiotherapy after surgery (Table 63.6). The first study from New Castle, United Kingdom, demonstrated an inferior survival for patients receiving adjuvant radiotherapy compared with those treated by surgery alone.109 Local recurrence rates were not affected by adjuvant radiotherapy. No stratification of patients by tumor stage or grade was made. Four patients died of fatal hepatotoxicity after radiotherapy to a right-sided nephrectomy bed. Patients in this study received 55 Gy in 2.04 Gy daily fractions.7 A second randomized study conducted by the Copenhagen Renal Cancer Study Group compared patients with stage II or III renal cell cancer treated with nephrectomy alone with patients who received nephrectomy and adjuvant 50 Gy in 20 fractions to the kidney bed and regional ipsilateral and contralateral lymph nodes. No difference in the relapse rate was found between the two study groups. There were significant complications involving the stomach, duodenum, and liver in 44% of patients receiving adjuvant radiotherapy. In fact, 19% of deaths in the radiotherapy group were attributed to radiation-induced complications.110
Aref et al.111 analyzed at the patterns of failure in 116 patients undergoing nephrectomy for RCC. They observed that locoregional failure is rare following nephrectomy and that distant metastases is the main pattern of failure. Consequently, their data did not support the role of adjuvant radiation in RCC.111 Moreover, a retrospective study of 1,344 patients who underwent 1,390 partial nephrectomies for kidney cancer found that positive surgical margins were not associated with an increased risk of local recurrence or metastatic disease.112 This further supports avoiding adjuvant radiotherapy for RCC.
In contrast, a meta-analysis including the two prospective randomized trials previously mentioned and five retrospective trials with a total of 735 patients observed a significant reduction in locoregional failure with adjuvant radiotherapy (p <0.0001). The patient accrual for all studies combined spanned from 1968 to 1999. There was no difference in overall survival or disease-free survival. The authors proposed a prospective randomized trial using modern radiotherapy techniques for high-risk patients with tumor size >5 cm, positive margins or gross residual disease, perinephric fat invasion, capsule invasion, renal vein/inferior vena cava invasion, positive lymph nodes, or high-grade histology.113
Systemic Therapy in the Treatment for Relapsed, Metastatic, or Unresectable Renal Cell Carcinoma
Until recently, systemic treatment for RCC was mostly limited to cytokine therapy. High-dose interleukin-2 (IL-2; category 2)-based immunotherapy can achieve long-lasting complete or partial remissions in a small subset of patients with predominantly clear cell carcinoma. Cytoreductive nephrectomy is recommended for patients with metastatic RCC prior to immunotherapy based on results from phase III trials from the Southwest Oncology Group (SWOG) and the EORTC. A combined analysis of these trials showed that median survival favored the surgery plus interferon (IFN)-α group (13.6 vs. 7.8 months for IFN-α alone).99,100,114,115 Treatment with IL-2 is associated with considerable toxicity and is limited to patients with excellent performance status and normal organ function. Currently, newer targeted agents are often favored over cytokine therapy as first-line therapy owing to their efficacy and more favorable toxicity profile.
At present, seven targeted agents are U.S. Food and Drug Administration (FDA) approved in the treatment for advanced RCC: sunitinib, sorafenib, pazopanib, temsirolimus, everolimus, axitinib, and bevacizumab in combination with IFN. As first-line therapy for relapsed or medically unresectable predominantly clear cell carcinoma, the options are sunitinib (category 1), bevacizumab with IFN (category 1), pazopanib (category 1), temsirolimus (category 1 for poor-prognosis patients), sorafenib and high dose IL-2 for selected patients. Subsequent category 1 therapy following a tyrosine kinase inhibitor for predominant clear cell carcinoma includes everolimus or axitinib. Subsequent category 1 therapy following cytokine therapy for predominant clear cell carcinoma includes sorafenib, sunitinib, pazopanib, and axitinib. For non–clear cell RCC, temsirolimus is a category 1 agent.86
Sunitinib, an oral small-molecule multi–tyrosine kinase inhibitor, was studied in a large multinational phase III trial of 750 patients with largely good- or intermediate-prognosis metastatic clear cell RCC who had not received prior systemic therapy. Patients were randomly assigned to 6-week cycles of sunitinib (50 mg daily for 4 weeks, followed by 1 week off) or IFN-α (9 million units three times per week). The objective response rate was significantly increased with sunitinib (47% vs. 12% with IFN-α). Median progression-free survival was significantly prolonged with sunitinib (11 months vs. 5 months, hazard ratio [HR] 0.54). As well, overall survival was prolonged with sunitinib (median 26.4 months vs. 21.8 months, HR 0.82, 95% confidence interval [CI] 0.673 to 1.001, p = .051).116
Pazopanib, a multitargeted receptor tyrosine kinase inhibitor, was evaluated in a phase III trial of 435 patients who were previously untreated or had received only cytokine therapy and were randomly assigned to pazopanib or placebo. There was a significant increase in progression-free survival with pazopanib compared with placebo (median 9.2 months vs. 4.2 months, HR 0.46, 95% CI 0.34 to 0.62).117
Temsirolimus, a parenterally administered mTOR inhibitor, was evaluated in a phase III trial in which 626 previously untreated poor-prognosis patients with metastatic or recurrent RCC were randomly assigned to temsirolimus (25 mg intravenously per week), temsirolimus (15 mg intravenously per week) plus IFN-α (escalated up to 6 million units three times per week as tolerated), or IFN-α monotherapy (escalated up to 18 million units three times per week as tolerated). Temsirolimus as a single agent significantly prolonged the median overall survival compared to IFN-α as a single agent (10.9 months vs. 7.3 months; HR for mortality 0.73, 95% CI 0.58 to 0.92). Both overall and progression-free survival rates for the combination of temsirolimus plus IFN-α were not significantly better than with IFN-α alone.56
Bevacizumab, a recombinant monoclonal antibody against vascular endothelial growth factor (VEGF), was evaluated in the phase III AVOREN trial, where 649 previously untreated patients were randomly assigned to IFN-α (9 million units three times per week for 1 year) plus either bevacizumab (10 mg/kg every 2 weeks) or placebo. There was a significant prolongation of progression-free survival (10.2 months vs. 5.5 months, HR 0.63, 95% CI 0.45 to 0.72) and a significantly increased objective response rate (31% vs. 13%).118
Sorafenib, a small-molecule multi–tyrosine kinase and Raf inhibitor, was studied in the phase III TARGET trial, in which 903 patients with advanced RCC who had failed prior standard therapy were randomly assigned to sorafenib (400 mg orally twice daily) or placebo. The median progression-free survival was significantly longer in those receiving sorafenib compared with placebo (5.5 months vs. 2.8 months, HR 0.44, 95% CI 0.35 to 0.55). Overall survival with sorafenib was not significantly prolonged compared to placebo.119,120
Everolimus, an orally administered mTOR inhibitor, was studied in 410 patients with metastatic clear cell RCC whose disease had progressed on VEGF receptor–tyrosine kinase inhibitors (sunitinib, sorafenib). The median progression-free survival with everolimus was significantly prolonged compared to placebo (4.9 months vs. 1.9 months, HR 0.30, 95% CI 0.22 to 0.40). There was no statistically significant difference in overall survival.121 Other targeted agents in development are cediranib, tivozanib, and regorafenib.
Chemotherapy has limited use in RCC because it is one of the most chemotherapy-resistant solid tumors. For patients with relapsed or medically unresectable stage IV disease with non–clear cell histology, gemcitabine in combination with doxorubicin or capecitabine has shown moderate activity in patients with sarcomatoid tumors and may be considered as first-line therapy.86
Metastasectomy
Patients with a solitary metastatic lesion have a 5-year survival rate of 24% (compared with 4% for those with more than one metastatic focus), and they may benefit from aggressive therapy.122 The resection of one or a limited number of metastases in combination with nephrectomy or at relapse has been associated with a 13% to 50% 5-year survival in small series of selected patients.123,124–125 Selected lung, bone, brain, liver, and even pancreatic metastases, among other sites, have been treated using this approach.
Whole-Brain Radiotherapy for Brain Metastases
A retrospective study of 60 patients receiving whole-brain radiotherapy (WBRT) for RCC brain metastases showed that local control at 6 months was 21% after 3 Gy é 10 fractions and 57% after higher doses of 2 Gy é 20 fractions or 3 Gy é 15 fractions (p = .013). The local control at 12 months was 7% and 35%, respectively. The overall survival at 6 months was 29% after 3 Gy é 10 fractions and 52% after higher doses (p = .003). The overall survival at 12 months was 13% and 47%, respectively. The authors126 concluded that escalating the WBRT dose beyond 3 Gy é 10 fractions could improve the outcomes in RCC patients with brain metastases and proposed a randomized trial.
Stereotactic Radiosurgery for Brain Metastases
A retrospective study of 280 consecutive patients with metastatic brain tumors (of which 80 were RCC) treated with Gamma Knife radiosurgery (GKS) observed that to control symptomatic peritumoral edema, a higher marginal dose ≥25 Gy was necessary. The authors127 developed an algorithm for the management of RCC metastases where lesions ≥3 cm undergo resection; lesions >2 cm with symptomatic peritumoral edema undergo resection (because 25 Gy was not considered safe for tumors >2 cm) and those without it GKS; and lesions ≤2 cm receive GKS. Another retrospective study of 46 patients and 99 RCC brain lesions treated with radiosurgery observed that the good-response group (as assessed by MRI) survived significantly longer than the poor-response group (median survival times of 18 and 9 months, respectively; p = .025).128
Kano et al.129 reported 158 consecutive RCC patients (531 lesions) who underwent stereotactic radiosurgery (SRS). The overall survival after SRS was 60%, 38%, and 19% at 6, 12, and 24 months, respectively, with a median survival of 8.2 months. Median survival for patients with <2 brain metastases, higher KPS (>90), and no prior WBRT was 12 months after SRS. Sustained local tumor control was achieved in 92% of patients. Symptomatic adverse radiation effects occurred in 7%. Overall, 70% of patients improved or remained neurologically stable.129
Conventional Radiotherapy for Extracranial Metastases
Palliative radiotherapy is effective in relieving symptoms from metastatic RCC.130–131,132,133 A patient with a solitary bone metastasis may have a long survival time, and a sufficient radiation dose should be administered to allow durable pain relief. If surgery is used to remove a metastatic lesion, postoperative radiotherapy is indicated to prevent its recurrence. In a prospective phase II study using validated quality-of-life questionnaires, Lee et al.132 from the Princess Margaret Hospital demonstrated that 83% of patients treated for pain had experienced significant pain relief with 30-Gy delivered in 10 fractions. DiBiase et al.84 observed a dose response in the palliative treatment of 107 patients with RCC. A biologically effective dose (BED) >50 Gy10 (α/β ratio of 10) was associated with a statistically significant increased rate of response: 59% versus 39% (p = 0.001).
Figure 63.1 illustrates a painful RCC cutaneous metastasis that had a complete response after 375 cGy é 13 fractions (BED = 67 Gy10) over 5 weeks. The lesion was treated with electrons, a custom bolus, and a 2-cm peripheral margin.134
FIGURE 63.1. Patient with renal cell carcinoma (RCC) who received 375 cGy é 13 fractions over 5 weeks to a painful, fixed, and pulsatile cutaneous RCC metastasis. Appearance after 3 fractions (A) and complete response 6 months after the completion of treatment (B). The patient had durable pain palliation without local recurrence until death. (From Gay HA, et al. Complete response in a cutaneous facial metastatic nodule from renal cell carcinoma after hypofractionated radiotherapy. Dermatol Online J 2007;13:6; © 2007 Dermatology Online Journal.)
Stereotactic Body Radiation Therapy for Extracranial Metastases
In a series of 50 patients with metastatic RCC, Wersall et al.103 reported that stereotactically delivered radiation to sites including the lung, liver, and adrenal resulted in complete regression in 30% of cases and either partial regression or stabilization of the lesions in 60%. Of 162 treated tumors, only 3 tumors recurred. Dose and fractionation ranged from 8 Gy é four fractions, 10 Gy é four fractions, and 15 Gy é three fractions all delivered in 1 week.
A retrospective study of 17 patients with metastatic melanoma (28 lesions) and 13 patients with RCC (25 lesions) to the lung, liver, and bone concluded that to achieve high rates of durable control, SBRT of at least 16 Gy é three fractions were necessary.135 Another retrospective study of 126 extracranial metastases in 103 patients treated with single fractions observed that RCC displayed a profound dose-response effect, with an 80% local relapse-free survival at the high-dose level (23 to 24 Gy) versus 37% at low doses (≤22 Gy) (p = .04).136 Further analysis of RCC patients revealed that a single 24-Gy dose had a 3-year local progression-free survival of 88%.85
In study of 48 patients (55 lesions) with metastatic RCC to the spine, patients received 24 Gy é one fraction, 9 Gy é three fractions, or 6 Gy é five fractions. The actuarial 1-year spine tumor progression-free survival was 82.1%. At pretreatment baseline, 23% of patients were pain free; at 1 month and 12 months post-SBRT, 44% and 52% of patients were pain free, respectively. No grade 3 or 4 neurologic toxicity was observed.137
A unique case report showed how a large 7-cm RCC metastasis in the parieto-occipital vertex of the skull was treated with SBRT to 7 Gy é five fractions. No significant bleeding was observed 5 weeks later at the time of tumor resection. Histologically, the tumor was largely avascular and necrotic, and the authors138 proposed SBRT as a potential alternative to preoperative embolization.
A potential added benefit of extracranial stereotactic radiotherapy is what is called the abscopal effect, in which there is tumor response at a distance from the irradiated volume. Wersall et al.139 observed an abscopal effect in 4 out of 28 RCC patients with treated and untreated metastatic lesions. In these 4 patients, nonirradiated metastases regressed either temporarily or seemingly permanently after treatment with SBRT of either the primary tumor or other metastatic lesions. The authors’139 findings argued for a more active and liberal use of SBRT in metastatic RCC. They suggested that further studies were necessary to define the underlying mechanisms behind such responses or to combine SBRT with immunomodulating agents.
Ongoing Phase III Clinical Trials
There are numerous clinical trials taking place in advanced RCC. Many of these trials are employing antiangiogenesis agents, thymidine kinase inhibitors, mTOR inhibitors, and immunological therapies, alone or in combination.
Renal Pelvis and Ureter Carcinoma
Surgery is the therapeutic foundation for the management of renal pelvis and ureter carcinoma. The bladder cancer NCCN guidelines (version 1.2013) recommend the following treatment options for renal pelvis low-grade tumors: nephroureterectomy with a cuff of bladder, a nephron-sparing procedure, or endoscopic resection with or without postsurgical intrapelvic chemotherapy or bacille Calmette-Guerin (BCG).140 High-grade renal pelvis tumors or large tumors that invade the renal parenchyma have the following management options: nephroureterectomy with a cuff of bladder and regional lymphadenectomy, with neoadjuvant chemotherapy in selected patients, extrapolating from bladder cancer series.
The management of ureter tumors depends on the location of the tumor—upper, mid, or distal—and on disease extent. Neoadjuvant chemotherapy may be considered in selected patients.141 Tumors in the upper ureter are more commonly treated with nephroureterectomy with a cuff of bladder and regional lymphadenectomy for high-grade tumors. Low-grade tumors may be managed endoscopically.
Tumors in the mid portion of the ureter can be managed according to grade and size. Small, low-grade tumors can be treated with ureteroureterostomy, endoscopic resection, or nephroureterectomy with a cuff of bladder with or without regional lymphadenectomy. High-grade lesions are managed with nephroureterectomy with a cuff of bladder and regional lymphadenectomy with consideration of neoadjuvant chemotherapy in selected patients.
Finally, distal ureteral tumors may be managed with a distal ureterectomy and reimplantation of the ureter (ideal if feasible), endoscopic resection, or nephroureterectomy with a cuff of bladder and regional lymphadenectomy for high-grade tumors. Neoadjuvant chemotherapy may be considered in select patients.
For both renal pelvis and ureter tumors, once the pathologic staging is obtained, patients with pathologic stage pT2, pT3, pT4, or N+ should be considered for adjuvant chemotherapy with or without radiotherapy.
Surgery
Radical nephroureterectomy is the only potentially curative treatment for most patients with urothelial carcinoma of the renal pelvis or ureter. This operation includes removal of the contents of Gerota’s fascia, including the ipsilateral ureter with a cuff of bladder at its distal extent. Less radical surgeries have been plagued by high local or regional recurrence rates, sometimes approaching 30%.142 Hall et al.79 reported an increase rate of recurrence when parenchymal-sparing procedures were performed. Conservative surgical excision should be considered only in patients with low-grade, low-stage, solitary tumors in whom radical nephrectomy is not indicated because of poor kidney function or an absent contralateral kidney.
Adjuvant Radiotherapy
There are no randomized trials on the role of postoperative radiotherapy in patients who have had a complete resection of an upper urinary tract cancer. Tumors of the renal pelvis and ureter have a significantly high local recurrence rate after nephroureterectomy, particularly in patients with high-grade tumors or deep invasion.53 Retrospective studies suggest that adjuvant radiotherapy may diminish the likelihood of local recurrence, although it does not appear to have an impact on overall survival or reduction of future distant metastases.34,143
Cozad et al.143 reported a retrospective study of 94 patients with urothelial carcinoma of the renal pelvis, of which 77 patients had resections without residual. On multivariate analysis, adjuvant radiotherapy had a significant effect on local control (p = .02). In terms of survival, the use of adjuvant radiotherapy was of borderline significance (p = .07). Of the 27 patients who were excluded from local failure and survival analysis, 19 patients had unresectable local disease, and of these, 11 patients received radiotherapy. Two long-term disease-free survivors in this group received 45 and 50.4 Gy, respectively.The authors34 recommended consideration of adjuvant radiotherapy in patients with high grade or stage, close surgical margins, or positive lymph nodes to improve local control.
In another retrospective study of 133 patients with urothelial carcinoma of the renal pelvis, 67 patients received external-beam radiotherapy following surgery (radiotherapy group), and 66 patients received intravesical chemotherapy (nonradiotherapy group). The clinical target volume included the renal fossa, the course of the ureter to the entire bladder, and the paracaval and para-aortic lymph nodes (Fig. 63.2). The tumor bed or residual tumor was targeted in 14 patients. The median radiation dose administered was 50 Gy. There was a significant difference between the survival rates for these groups based on patients with stage T3 and T4 cancer. A significant difference was observed in the bladder tumor relapse rate between the irradiated and nonirradiated bladder groups (p = .004). The authors144 concluded that radiotherapy may improve the overall survival for patients with T3 and T4 cancer of the renal pelvis or ureter and may delay bladder tumor recurrences.
The patterns of failure were described in 252 patients undergoing surgery at the University of Texas Southwest Medical Center for urothelial carcinoma of the upper urinary tract.79 Local recurrence occurred only 9% of the time, whereas new invasive urothelial tumors or distant metastases occurred in 69% and 22% of cases, respectively. Isolated local recurrences were rare. Another series from the Princess Margaret Hospital confirms the high rate of distant metastases. Although local failure occurred in 35% of patients with locally advanced disease, most patients also experienced distant metastases as well.145
Systemic Chemotherapy
The pathologic similarity of urothelial carcinoma of the renal pelvis and ureter to bladder cancer has encouraged medical oncologists to use similar chemotherapeutic regimens in the management of upper-tract urothelial carcinomas. The MVAC regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) has objective response rates of almost 70% in patients with metastatic urothelial carcinoma of the bladder, ureter, and kidney.146,147 Gemcitabine plus cisplatin is also effective in urothelial carcinoma. Palliative chemotherapy may be considered in patients with metastatic disease.
A series of 31 patients treated with adjuvant radiotherapy for nonmetastatic urothelial cancer of the upper urinary tract was reported by Czito et al.148 Nine patients also received chemotherapy consisting of methotrexate, cisplatin, and vinblastine prior to receiving radiation concurrent with cisplatin. The 5-year locoregional control rate was 67%. The 5-year overall and disease-specific survival appeared to be improved with the administration of concurrent chemotherapy. The overall survival for patients receiving concurrent chemotherapy and radiotherapy was 67% compared to 27% receiving postoperative radiation alone (p = .01). The disease-free survival for patients receiving concurrent chemotherapy and radiotherapy was 76% compared to 41% receiving postoperative radiation alone (p = .06).
In circumstances in which conservative resection is performed, postoperative radiotherapy should be considered. Conservative surgical options in selected cases include laparoscopic nephroureterectomy, nephrectomy and partial ureterectomy, endoscopic resection, and fulguration. The role of lymph node dissection in this disease is unclear. Patients who have the highest risk of lymph node metastases also have a high risk of systemic disease.
Ongoing Phase III Clinical Trials
Phase III Randomized Study of Gemcitabine Hydrochloride and Cisplatin with Versus without Bevacizumab in Patients with Advanced Transitional Cell Carcinoma of the Urinary Tract (NCT00942331).
FIGURE 63.2. Dose distribution of a patient with renal pelvis cancer and beam arrangements of 0-degree, 129-degree, and 229-degree gantry. A: Renal fossa. B,C: Course of ureter. D: Bladder. Digitally reconstructed radiograph for views of 0-degree gantry (E) and 90-degree gantry (F). Internal pink and yellow lines represent the clinical tumor volume (CTV)50 and CTV40, respectively. (From Chen B, et al. Radiotherapy may improve overall survival of patients with T3 and T4 transitional cell carcinoma of the renal pelvis or ureter and delay bladder tumour relapse. BMC Cancer 2011;11:297; © 2011 Chen et al; licensee BioMed Central Ltd.)
RADIOTHERAPY TECHNIQUES
Normal Tissue Dose Constraints
Several organs at risk have to be taken into consideration when palliating an unresected kidney tumor or a kidney tumor bed recurrence. These organs include the spinal cord, liver, spleen, stomach, duodenum, small bowel, any normal contralateral or ipsilateral kidney, and normal adrenal gland(s).
There are no established dose constraints for sparing the remaining kidney after nephrectomy or in the palliative setting when both kidneys are present. In the context of two normal kidneys, the Qualitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) Kidney Cancer Panel recommended a mean bilateral kidney dose <15 to 18 Gy and a bilateral kidney dose-volume histogram (DVH) with a V12 <55%, V20 <32%, V23 <30%, and V28<20%.149 The dose to the stomach should be kept at <45 Gy, and the small bowel V45 <195 cc when it is contoured as a bowel bag150 (Fig. 63.3). The male and female Radiation Therapy Oncology Group (RTOG) normal pelvis atlases illustrate how to contour the bowel bag (accessible at http://www.rtog.org/CoreLab/ContouringAtlases.aspx). The mean liver dose should be kept at <30 to 32 Gy, excluding patients with pre-existing liver disease or hepatocellular carcinoma who have a lower tolerance. Sparing at least 700 cc of liver from radiation is another potential strategy to avoid complications.151 There are no recognized splenic or adrenal dose constraints. Nevertheless, based on the spleen’s exquisite radiosensitivity and experience with palliative radiotherapy for myeloproliferative disorders,152 it seems prudent to limit the spleen to a total of 5 to 10 Gy. The spinal dose should be limited to an absolute maximum of 45 Gy.
FIGURE 63.3. Patient with metastatic clear cell renal cell carcinoma (RCC) who developed a painful, destructive, 55-cc metastasis in the left 12th rib. Treatment plan (A) and dose-volume histogram (B) showing the normalized volume versus dose (cGy). The metastasis was treated with 10 Gy é five fractions using a six-field step and shoot, 6-MV IMRT technique. The isodose-based methodology was used to evaluate the plan.158 The skin was limited to the 40% isodose (400 cGy é five fractions), the spinal cord to the 30% isodose (300 cGy é five fractions), and the spleen to the 10% isodose (100 cGy é five fractions) or less as feasible. The cyan-filled contour is the gross tumor volume (GTV). Doses to the bowel, liver, remaining kidney, and duodenum were well below tolerance. Patient was pain free one month later.
Renal Cell Carcinoma
Neoadjuvant or adjuvant radiotherapy is not routinely recommended for patients with RCC. However, there may be special cases where the clinician may consider neoadjuvant radiotherapy to improve respectability or adjuvant radiotherapy if there are clinical tumor features suggestive of a high risk of local recurrence. Careful planning is paramount because ignoring any of the critical structures surrounding the kidney or nephrectomy bed could result in serious, even fatal, patient toxicity.
Patients receiving radiotherapy to the kidney may be simulated supine, arms up, using a wing board or alpha cradle, a wire on the surgical scar, and a planning CT scan. The kidneys are mobile organs and move vertically within the retroperitoneum an average of 0.9 to 1.3 cm, and as much as 4 cm during normal respiration.153–154,155 In going from the supine to upright position, the kidneys can shift inferiorly between 0.5 cm and 7.5 cm with an average of 3.6 cm.156 This finding, although critical for total body irradiation treatments, further highlights the mobility of the kidneys.
The high complication rates reported in the prospective trials of postoperative radiotherapy have taught radiation oncologists an important lesson regarding radiation therapy planning, patient selection, and the tolerance of the upper abdominal viscera. Intensity-modulated radiotherapy (IMRT) may be a reasonable consideration owing to the sensitivity of adjacent surrounding structures. If IMRT is considered, a plan to manage the uncertainties in target localization such as four-dimensional (4D) CT treatment planning, image-guided radiotherapy (IGRT), abdominal immobilization devices, gating, or breathing control needs to be considered. Renal function scans may assist in the treatment planning or patient selection process, although this has not been formally studied.
In unresectable lesions, 40 to 50 Gy neoadjuvant radiotherapy (1.8 to 2 Gy per fraction) directed to the kidney tumor and regional lymphatics may improve resectability.107 Multiple-field techniques, similar to those described for adjuvant radiotherapy, should be considered in patients receiving preoperative treatment.
CT-based treatment planning contributes to good local control with minimal morbidity. Careful definition of the target volume to encompass the nephrectomy bed, lymph node drainage sites, and surgical clips on the planning CT scan is important. Exclusive use of anterior- and posterior-field arrangements, particularly on the right side, is likely to result in irradiation of large volumes of bowel and liver beyond tolerance. The use of multiple beams is paramount for protecting the surrounding normal structures. Total radiation doses of 45 to 50 Gy (1.8 to 2 Gy per fraction) to the nephrectomy bed and regional lymph nodes with a boost to small volumes of microscopic or gross residual disease of 10 to 15 Gy (total dose 50 to 60 Gy) are appropriate. Stein et al.157 reported two scar recurrences and recommended that the incision site be included in the target volume. If the scar cannot be covered without increasing the amount of normal tissue irradiated, an additional electron-beam field to treat the scar may be considered.
Figure 63.3 illustrates a patient with metastatic clear cell RCC, with sarcomatoid and rhabdoid differentiation, status post left radical nephrectomy, pT3aN1M1. The kidney tumor was Fuhrman nuclear grade IV and 15.5 cm in diameter. The patient was treated with temsirolimus, pazopanib, bevacizumab, and finally Adriamycin plus gemcitabine with some objective response. The patient developed a painful, destructive, 55-cc metastasis in the left 12th rib. The metastasis was treated with 10 Gy é five fractions using a six-field (RPO 210, LAO 60, LT LAT 90, LPO 120, LPO 150, PA) step and shoot, 6-MV IMRT technique. The isodose-based methodology was used to evaluate the plan and is explained in detail in Gay et al.158 The skin was limited to the 40% isodose (400 cGy é five fractions), the spinal cord to the 30% isodose (300 cGy é five fractions), and the spleen to the 10% isodose (100 cGy é five fractions) or less as feasible. Doses to the bowel, liver, remaining kidney, and duodenum were well below tolerance (Fig. 63.3A). Daily imaging with two-dimensional (2D):2D match and cone-beam CT was used prior to the delivery of the five fractions over 3 weeks.
Because of the possibility of long survival even in the presence of distant metastases, aggressive treatment for palliation should be considered in patients who have limited metastatic disease with good performance status. Treatment fields should encompass metastatic foci with adequate (2- to 3-cm) margins. (See the following previous sections: Conventional Radiotherapy for Extracranial Metastases, Whole-Brain Radiotherapy for Brain Metastases, and Stereotactic Radiosurgery for Brain Metastases.)
Renal Pelvis and Ureter Carcinoma
Adjuvant radiotherapy has been used in the management of renal pelvis and ureter cancers. For elective radiotherapy, the clinical target volume should include the renal fossa, the course of the ureter to the bladder, the entire bladder, and the paracaval and para-aortic lymph nodes144 (Fig. 63.2). As in RCC, CT-based planning may facilitate dosimetric coverage of the regions at risk while minimizing dose to normal tissues. Radiation doses of 45 to 50 Gy at 1.8 to 2 Gy per day are appropriate to treat subclinical and microscopic disease. For more extensive disease (e.g., multiple positive nodes), R1 (microscopic positive margins) or R2 (macroscopic residual margins) resections, a boost of 5 to 10 Gy should be considered. For unresectable or gross residual disease, higher doses may be necessary. In this case, multiple-field arrangements including oblique and lateral fields with field reductions are important to minimize toxicity to surrounding normal structures (Fig. 63.2). CT-based simulation, three-dimensional (3D) treatment planning, and contrast-enhanced radiographs are helpful in defining the radiotherapy target volume. IMRT can be considered if organ motion is managed to avoid underdosing the planning target volume. Chemotherapy may allow a lower radiation dose for gross disease. Cozad et al.143 reported two patients with gross residual disease who achieved local tumor control with radiation doses of 45 and 50.4 Gy. One of these patients had a pathologically proven complete response at reoperation after receiving radiotherapy and concomitant MVAC.
FOLLOW-UP
Renal Cell Carcinoma
The NCCN Kidney Cancer Panel recommends that patients be seen every 6 months for the first 2 years after surgery, then annually thereafter. Each visit should include a history and physical examination and comprehensive metabolic panel (blood urea nitrogen, serum creatinine, calcium, LDH, and liver function tests). The NCCN recommends abdominal and chest imaging 2 to 6 months after surgery and as clinically indicated thereafter.86 The UCLA UISS (described in the Prognostic Factors section) uses the older 1997 TNM staging and also provides surveillance recommendations according to risk category.159 The greatest risk of recurrence following surgery for RCC is in the first 3 to 5 years; however, recurrences can occur more than a decade later. Early diagnosis of metastatic disease could identify patients who may be candidates for metastasectomy and potentially result in long-term survival.
Renal Pelvis and Ureter Carcinoma
Patients with urothelial carcinoma of the upper urinary tract are at a high risk of urothelial tumors of the bladder, thus monitoring with cystoscopy at periodic intervals is necessary. For patients who have undergone a renal-sparing procedure, imaging with CT or MRI and/or ureteroscopy may be necessary. The NCCN Bladder Cancer Panel recommends a cystoscopy every 3 months for 1 year, then at increasing intervals. For endoscopic procedures, imaging (intravenous pyelogram [IVP], CT urography, retrograde pyelogram, ureteroscopy, or MRI urogram) of the upper tract collecting system at 3- to 12-month intervals is recommended. Imaging to exclude metastatic disease such as a chest radiograph, or CT scan or MRI, should be considered.
SEQUELAE OF RADIOTHERAPY
The side effects and complications from radiotherapy for cancer of the kidney, renal pelvis, and ureters are similar to those expected from irradiation of the upper abdomen and pelvis. These side effects include nausea, vomiting, diarrhea, and abdominal cramping. Patients with right-sided tumors may have significant portions of the liver irradiated, and radiation-induced liver damage is possible. The Copenhagen Renal Cancer Study Group reported that 12 (44%) of 27 patients developed significant complications: 3 patients had biochemical changes indicating radiation hepatitis, 3 patients had duodenum and small bowel stenosis, and 6 patients had duodenum and small bowel bleeding.110 Surgery was performed on 4 of 9 patients with bowel-related radiotherapy complications, and 5 patients died of treatment-related complications. The total radiation dose in this study was 50 Gy given in 2.5-Gy fractions per day—a fractionation schedule that may account for the high rate of complications. Fugitt et al.109 also reported four cases of “liver” failure among 52 patients who received postoperative radiotherapy.
The complication rate after radiotherapy for tumors of the kidney and upper urinary tract is related to the total dose, fraction size, and technique of irradiation. CT-based simulation and 3D treatment planning may decrease the risk of complications after elective radiotherapy in patients with upper urinary tract malignancies. In a series of 56 patients receiving 46 Gy postoperatively reported by Stein et al.,157 significant toxicity was seen in only 3 patients (5%). These 3 patients were treated before the routine use of CT-based treatment planning. In 12 patients receiving a median dose of 45 Gy reported by Kao et al.,160 no long-term treatment-related morbidity was identified.
ACKNOWLEDGMENTS
Thanks to Michael Watts, MS, CMD, for masterfully planning the case in Figure 63.3 and obtaining screen captures of the plan.
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