Bethesda Handbook of Clinical Oncology, 2nd Edition

Genitourinary

13

Renal Cell Cancer

Hung T. Khong*

Christopher Klebanoff

Susan Bates

*USA Cancer Research Institute, University of South Alabama, Mobile, Alabama

Emory School of Medicine, Atlanta, Georgia

Cancer Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

EPIDEMIOLOGY

  • In the year 2003, there was an estimated 3% of adult malignancies, with 31,900 new cases and 11,900 deaths from renal cancer.
  • The male-to-female ratio for renal cancer is 2:1.
  • In the United States, the incidence rates for renal cell carcinoma (RCC) are higher among blacks than among whites (Table 13.1).
  • Age at diagnosis is usually greater than 40 years, with the median age in the mid-60s.
  • Cancer of the renal tubular epithelium accounts for 90% of all malignancies arising in the kidney. Most of the remaining cases are transitional cell carcinoma of the renal pelvis.
  • Surveillance, Epidemiology, and End Results (SEER) data indicate that the incidence and mortality rates for RCC have increased steadily in all race and sex groups from 1975 through 1995 (Figs. 13.1 and 13.2; Table 13.1).
 

FIG. 13.1. Age-adjusted incidence rates for renal cell carcinoma.

 

FIG. 13.2. Age-adjusted mortality rates for renal cell carcinoma.

TABLE 13.1. Age-adjusted Incidence Rates per 100,000 Person-years

Race/Sex

Incidence rate (%)

% increase/yr

White men

9.6

2.3

White women

4.4

3.1

Black men

11.1

3.9

Black women

4.9

4.3

ETIOLOGY AND RISK FACTORS

  • Tobacco use contributes to one third of all cases of RCC in the United States—current smokers exhibit 40% higher risk than nonsmokers; the risk increases per pack-year history.
  • High consumption of fried or sautéed meat is another risk factor.
  • Obesity, particularly in women, contributes to the risk for developing RCC.
  • Exposure to asbestos and petroleum products increases the chances of developing RCC.
  • End-stage renal disease with development of acquired cystic disease of the kidney is a major risk factor; patients with cystic changes in the kidney who undergo dialysis exhibit a 30-times higher risk than the general population.

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  • Hereditary disease:
  1. von Hippel-Lindau (VHL) disease is a familial syndrome with an autosomal dominant inheritance pattern, associated with retinal hemangiomas, central nervous system (CNS) hemangioblastomas, renal cysts and RCC, pheochromocytoma, and epididymal cysts. RCC is found to develop in 25% of VHL patients (data have been collected from literature reviews: total number of VHL patients is 706 and total number of RCC cases reported is 176). The mean age at onset is 44 years.
  2. Hereditary nonpapillary RCC develops because of translocation between the short arm of chromosome 3 (3p) and chromosome 6, 8, or 11, as is seen in some familial RCC kindreds.
  3. Hereditary papillary RCC (HPRCC) type I is associated with a mutation of the aMET protooncogene at 7q31.3. aMET encodes a transmembrane receptor tyrosine kinase.
  4. Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer that was recently linked to mutations in the fumarate hydratase (FH) gene. The renal cancers may have either type II papillary or collecting duct morphology
  5. Renal chromophobe and oncocytoma is linked to the Birt–Hogg–Dubé syndrome, a dermatologic disorder characterized by cutaneous hair follicle tumors (fibrofolliculomas), pulmonary cysts, and renal tumors. The Birt–Hogg–Dubé syndrome gene has been found at 17p11.2 and is associated with chromophobe (34%), oncocytoma (5%), hybrid chromophobe–oncocytomas (50%), clear cell carcinoma (9%), and papillary renal cancer (2%).

PATHOLOGIC CLASSIFICATION

For pathologic classification, see Table 13.2.

TABLE 13.2. Pathologic Classification of Renal Cell Carcinoma

Type of carcinoma

Frequency (%)

Genetic changes

5-yr survival (%)

Sarcomatoid variant is not a histologic type of renal cancer but a high-grade change that has been found to arise in all types.
VHL gene, a tumor-suppressor gene, is located on chromosome 3p, which is deleted in 81%–98% of sporadic clear cell RCC. Therefore, 3p implies loss of one allele of the VHL gene. The remaining allele is mutated in 57% of cases.

Clear cell

70–80

3p (81%–98%), von Hippel-Lindau (VHL) gene mutation (57%)a

55–60

Papillary

10–15

Trisomies (3q, 7, 12, 16, 17, and 20), Y, and c-met gene mutation

80–90

Chromophobe

5

Monosomy of multiple chromosomes (1, 2, 6, 10, 13, 17, and 21) and hypodiploidy

90

Collecting duct

<1

18 Y

<5

Unclassified

4–5

 

 

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CLINICAL PRESENTATION

The classic triad of hematuria, abdominal pain, and abdominal mass occurs in only 10% of patients (Tables 13.3, 13.4, 13.5, 13.6 and 13.7).

TABLE 13.3. American Joint Committee for Cancer Stage (1987 Version: T1, ≤2.5 cm; T2, >2.5 cm) at Diagnosis

Stage

Frequency (%)

There is a shift from stage II to stage I under the 1997 version of the AJCC stage, which defines T1 as ≤7 cm and T2 as >7 cm. From one recent study, stage I is reported to be 45%, and stage II 13%, as per the 1997 version.

I

9.3

II

39.5

III

16

IV

24.6

Unknown

10.6

TABLE 13.4. Common Presenting Symptoms or Laboratory Abnormality

Symptom/lab finding

% of patients

Hematuria

56–59

Pain

38–41

Abdominal mass

36–45

Weight loss

28

Anemia

21

Fever

11

Nonmetastatic hepatic dysfunction (Stauffer syndrome)

7

Polycythemia

<5

Hypercalcemia

<5 (up to 25% in metastatic disease)

Acute varicocele

2

TABLE 13.5. Common Sites of Metastatic Involvement

Site

%

CNS, central nervous system.

Lung

75

Lymph node/soft tissue

36

Bone

20

Liver

18

Skin

   8

CNS

   8

TABLE 13.6. Adverse Prognostic Factors in Patients with Metastatic Renal Cell Carcinoma

LDH, lactate dehydrogenase.

Karnofsky performance status >80%

LDH <1.5 × upper limit of normal

Hemoglobin greater than lower limit of normal

Corrected serum calcium <10 mg/dL

Absence of prior nephrectomy

TABLE 13.7. Risk Groups Based on the Prognostic Factors in Table 13.6

Risk group

Number of risk factors listed in Table 13.6

Median survival time (mo)

Survival rate (%)

1-yr

2-yr

3-yr

Favorable

0

20

71

45

31

Intermediate

1 or 2

10

42

17

   7

Poor

3 or more

   4

12

   3

   0

DIAGNOSIS

For diagnosis of RCC in patients, see Table 13.8.

TABLE 13.8. Initial Evaluation

H&P, history and physical; CBC, complete blood count; PT/PTT, prothrombin time/partial thromboplastin time; CT, computerized tomography; CXR, chest x-ray; IVC, inferior vena cava; RCC, renal cell carcinoma.
A recent study found pelvic CT scan to have a negligible yield in the staging of 119 patients with RCC (no malignancy found).

H & P

CBC/Chemistry profiles (including PT/PTT)

Urinalysis

CT scan of the abdomen and pelvis with contrast

CXR

CT scan of the chest if

1. Abnormal CXR or

2. Large primary tumor or

3. IVC involvement

Bone scan not done routinely unless

1. bone pain is present or

2. when serum alkaline phosphatase level is elevated

STAGING AND PROGNOSIS

Two commonly used staging systems for RCC are the modified Robson system and the tumor–node–metastases (TNM) system proposed by the American Joint Committee for Cancer

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(AJCC) (Table 13.9). The TNM system is preferred because it more accurately describes the extent of tumor involvement.

TABLE 13.9. TNM Staging of Renal Cell Carcinoma

Laterality does not affect the N classification.
Note: If a lymph node dissection is performed, then pathological evaluation would ordinarily include at least eight nodes.
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York, http://www.springer-ny.com .

Primary tumor (T)
   TX   Primary tumor cannot be assessed
   T0   No evidence of primary tumor
   T1   Tumor 7 cm or less in greatest dimension, limited to the kidney
   T1a   Tumor 4 cm or less in greatest dimension, limited to the kidney
   T1b   Tumor more than 4 cm but not more than 7 cm in greatest dimension, limited to the kidney
   T2   Tumor more than 7 cm in greatest dimension, limited to the kidney
   T3   Tumor extends into major veins or invades adrenal gland or perinephritic tissues but not beyond Gerota's fascia
   T3a   Tumor directly invades adrenal gland or perirenal and/or renal sinus fat but not beyond Gerota's fascia
   T3b   Tumor grossly extends into renal vein or its segmental (muscle-containing) branches, or vena cava below the diaphragm
   T3c   Tumor grossly extends into vena cava above diaphragm or invades the wall of the vena cava
   T4   Tumor invades beyond Gerota's fascia

Regional lymph nodes (N)a
   NX   Regional lymph nodes cannot be assessed
   N0   No regional lymph node metastasis
   N1   Metastasis in a single regional lymph node
   N2   Metastasis in more than one regional lymph node

Distant metastasis (M)
   MX   Distant metastasis cannot be assessed
   M0   No distant metastasis
   M1   Distant metastasis

Stage grouping

   Stage I

T1

N0

M0

   Stage II

T2

N0

M0

   Stage III

T1

N1

M0

T2

N1

M0

T3

N0

M0

T3

N1

M0

T3a

N0

M0

T3a

N1

M0

T3b

N0

M0

T3b

N1

M0

T3c

N0

M0

T3c

N1

M0

   Stage IV

T4

N0

M0

T4

N1

M0

Any T

N2

M0

Any T

Any N

M1

Prognosis: 5-year survival rates in patients with RCC based on gender and race is given in Table 13.10 (see Fig. 13.3).

 

FIG. 13.3. Survival rates in renal cell carcinoma (RCC) given by American Joint Committee for Cancer/Union Internationale Contre le Cancer (AJCC/UICC) stage (1997 version) at diagnosis.

TABLE 13.10. Five-year Survival Rates (%) in Renal Cell Carcinoma Based on Sex and Racea

Stage

White men (%)

White women (%)

Black men (%)

Black women (%)

aSEER, 1975–1995; Time period from 1986 to 1995.

Localized

89

86

75

84

Regional

62

59

52

44

Distant

   9

   7

   7

   8

Unstaged

31

21

21

35

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TREATMENT

Surgery

  • Nephrectomy is the only curative treatment for localized RCC.
  • Radical nephrectomy is defined as resection of the kidney, ipsilateral adrenal gland, regional lymph nodes, and perirenal fat.
  • Lymph node dissection is not therapeutic but allows more accurate staging.
  • Ipsilateral adrenalectomy may be reserved for patients with large upper-pole disease and/or with tumor involvement of the adrenal gland, as suggested by computerized tomography (CT).
  • Partial nephrectomy may be performed in patients for whom standard nephrectomy would significantly impair renal function. Recent studies have shown that in patients with localized tumors 4 cm or less in greatest dimension (including those patients with unilateral disease and a normal contralateral kidney), nephron-sparing surgery offers long-term disease survival comparable to that obtained after radical nephrectomy.
  • In selected stage IV patients who present (or relapse) with a solitary metastasis, nephrectomy and resection of the metastasis may be the primary treatment of choice.
  • Adjuvant therapies (radiation or systemic therapy) have not been shown to prevent or decrease relapse rates.
  • Nephrectomy should be considered before systemic therapy in select patients with metastatic RCC. Studies have shown improved survival in patients who have undergone nephrectomy followed by immunotherapy for metastatic disease.

Systemic Treatment

Hormone Therapy and Chemotherapy

  • Hormone therapy and chemotherapy appear to have little effect on the treatment of metastatic RCC.
  • A review of 155 trials that studied 80 single chemotherapeutic agents showed a median overall response rate of 4%. The overall response rates for vinblastine and 5-fluorouracil (5-FU) and for vinblastine and 5-fluorodeoxyuridine (FUDR) were 6% to 9% and 5% to 8%, respectively. A recent trial combining gemcitabine with infusional 5-FU reported a 17% response rate. However, follow-up trials adding to that regimen yielded lower response rates.

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  • Patients should be encouraged to enroll in clinical trials.
  • A randomized placebo-controlled clinical trial testing the vascular endothelial growth factor (VEGF) antibody, bevacizumab (Avastin), demonstrated an improved time to progression in patients receiving the highest dose, that is, 10 mg per kg (P<0.001).
  • New therapeutic agents reported at the 2004 American Society of Clinical Oncology (ASCO) meeting indicated significant response rates in patients with metastatic disease. These agents include SU11248 and BAY 43-9006; both agents are tyrosine kinase inhibitors thought to inhibit the VEGF receptor. It has been reported in abstracts that 24% of patients treated with SU11428 have shown partial response.

Interleukin-2

  • High-dose interleukin-2 (IL-2) is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic RCC (Table 13.11).
  • Long-acting therapeutic response was seen in a small number of patients treated with high-dose IL-2. (8% of patients showed partial responses, with a median response duration of 54 months for all responses, and 7% of patients exhibited complete responses; median duration for all complete responses has not been reached.) These results have been confirmed in other clinical studies.
  • High dose of IL-2: 600,000 to 720,000 U per kg i.v. infused over 15 minutes once every 8 hours until toxicity or up to 14 doses for 5 days. The cycle is repeated once after a 7- to 10-day rest, with one or two additional courses repeated every 6 to 12 weeks if there is evidence of tumor stabilization or regression.
  • Low dose (i.v.): 72,000 U per kg i.v. bolus every 8 hours to a maximum of 15 doses every 7 to 10 days for two cycles (one course), with an additional course if there is evidence of tumor stabilization or regression. One or two additional courses may be given if further regression is observed.
  • Low dose (s.c.): First 5-day cycle—18 million units per day s.c., for 5 days (week 1). Subsequent 5-day cycles—9 million units per day s.c., for 2 days, and then 18 million units per day s.c., 3 days per week (weeks 2 to 6).

TABLE 13.11. Treatment Regimens with Recombinant Interleukin-2 (rIL-2) and/or Recombinant Interferon-α (rIFN-α)

Regimen

Treatment

Comment

Reference

High-dose rIL-2

600,000–720,000 U/kg i.v. over 15 min q8h until toxicity or 14 doses for 5 d

Repeat once after a 7- to 10-day rest

Fyfe G, Fisher RI, Rosenberg SA, et al., 1995

Low-dose rIL-2 (i.v.)

72,000 U/kg i.v. bolus q8h to a maximum of 15 doses q7–10d for 2 cycles (1 course)

One more course if tumor stabilization or regression occurs; one or two more courses if there is further tumor regression

Yang JC, Topalian SL, Parkinson D, et al., 2003

Low-dose rIL-2 (s.c.)

18 MU/d s.c. for 5 d, then 9 MU/d s.c. for 2 d, then 18 MU/d s.c. 3 d a wk, for 6 wk

 

Sleijfer DTh, Janssen RAJ, Buter J, et al., 1992

rIFN-α 2

5 to 10 MIU/m2 s.c., 3 to 5 times a wk, or daily

 

Horoszewicz JS and Murphy GP, 1989

rIL-2 +

20 MU/m2 s.c., d 3–5, wk1 and 4

Repeat cycle every 8 wk

Atzopodiem J, Kirchner H, Hannien EL, et al., 1993

5 MU/m2 s.c., d 1, 3, 5, wk 2, 3, 5, and 6

rIFN-α 2

6 MU/m2 s.c., d 1, wk 1 and 4

 

 

6 MU/m2 s.c., d 1, 3, and 5, wk 2, 3, 5, and 6

 

 

Interferon-α

  • Interferon-α (IFN-α) produces response rates of approximately 12% to 15%; 2% to 5% complete responses are generally seen in patients with pulmonary metastases.
  • Usual regimens: 5 to 10 MU per m2s.c., three to five times a week or daily.
  • A recent randomized study demonstrated a modest survival benefit for nephrectomy in patients with metastatic kidney cancer who were being treated with interferon; the survival in patients treated with interferon and nephrectomy was 11.1 months compared to 8.1 months for patients treated with interferon alone (p= 0.05). A survival advantage was also observed in a similar randomized trial from the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group.

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Combination of Interleukin-2 and Interferon-α

  • Recombinant interleukin-2 (rIL-2): 20 million units per m2s.c., days 3 to 5, weeks 1 and 4; 5 million units per m2 s.c., days 1, 3, and 5, weeks 2, 3, 5, and 6.
  • Recombinant interferon-α 2 (rIFN-α 2): 6 million units per m2s.c., day 1, weeks 1 and 4; 6 million units per m2 s.c., days 1, 3, and 5, weeks 2, 3, 5, and 6. Cycle is repeated every 8 weeks.

Notably, several trials reported response rates and overall survival of combination regimens (IL-2 and IFN-α, with or without 5-FU) similar to that of high-dose IL-2 alone.

Other Biologic Therapy

In a recent randomized, phase II trial, the anti-VEGF antibody, bevacizumab, was shown to significantly prolong the time to progression of disease in metastatic–renal cancer patients. There was no statistical difference in overall survival between the treatment and placebo groups in the last analysis.

Suggested Readings

Atzopodiem J, Kirchner H, Hannien EL, et al. European studies of interleukin-2 in metastatic renal cell carcinoma. Semin Oncol1993;20:23.

Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell cancer in the United States JAMA 1999;281:1628–1631.

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Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:1655–1659.

Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13:688–696.

Horoszewicz JS, Murphy GP. An assessment of the current use of human interferons in therapy of urological cancers. J Urol1989;142:1173–1180.

Javidan J, Stricker HJ, Tamboli P, et al. Prognostic significance of the 1997 TNM classification of renal cell carcinoma. J Urol1999;162:1277–1281.

Minasian LM, Motzer RJ, Gluck L, et al. Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up. J Clin Oncol 1993;11:1368–1375.

Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol 2000;163:408–417.

Motzer RJ, Mazumdar M, Bacik J, et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999;17:2530–2540.

Motzer RJ, Mazumdar M, Bacik J, et al. Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma. J Clin Oncol2000;18:1928–1935.

NCI-PDQ Web-Page at http://www.nci.nih.gov/cancertopics/pdq/treatment/renalcell/ Health Professional. 2003.

Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med 1998;338:1273–1278.

Parkinson DR, Sznol M. High-dose interleukin-2 in the therapy of metastatic renal cell carcinoma. Semin Oncol 2003;22:61–66.

Sleijfer DT, Janssen RAJ, Buter J, et al. Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis. J Clin Oncol 1992;10:1119–1123.

Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–434.

Yang JC, Topalian SL, Parkinson D, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21:3127–3132.