Renal Cell Cancer

Renal cell cancer, also called renal adenocarcinoma, or hypernephroma, can often be cured if it is diagnosed and treated when still localized to the kidney and to immediately surrounding tissue. The probability of cure is directly related to the stage or degree of tumor dissemination. Even when regional lymphatics or blood vessels are involved with tumor, a significant number of patients can achieve prolonged survival and probable cure. 1 When distant metastases are present, disease-free survival is poor; however, occasional selected patients will survive after surgical resection of all known tumor. Because a majority of patients are diagnosed when the tumor is still relatively localized and amenable to surgical removal, approximately 40% of all patients with renal cancer survive 5 years. Occasional patients with locally advanced or metastatic disease may exhibit indolent courses lasting several years. Late tumor recurrence many years after initial treatment occasionally occurs.

Renal cell cancer is one of the few tumors in which well-documented cases of spontaneous tumor regression in the absence of therapy exist, but this occurs very rarely and may not lead to long-term survival. Surgical resection is the mainstay of treatment of this disease. Even in patients with disseminated tumor, locoregional forms of therapy may play an important role in palliating symptoms of the primary tumor or of ectopic hormone production. Systemic therapy has demonstrated only limited effectiveness.

Cellular Classification

Approximately 85% of renal cell cancers are adenocarcinomas, and most of those are of proximal tubular origin. Most of the remainder are transitional cell carcinomas of the renal pelvis Adenocarcinomas may be separated into clear cell and granular cell carcinomas; however, the 2 cell types may occur together in some tumors. Some investigators have found that granular cell tumors have a worse prognosis, but this finding is not universal. The distinction between well-differentiated renal adenocarcinomas and renal adenomas can be difficult. The diagnosis is usually made arbitrarily on the basis of size of the mass, but size alone should not influence the treatment approach, since metastases can occur with lesions as small as 0.5 centimeters.

Staging of RCC

The staging system for renal cell cancer is based on the degree of tumor spread beyond the kidney. [1] [2] [3] Involvement of blood vessels may not be a poor prognostic sign if the tumor is otherwise confined to the substance of the kidney. Abnormal liver function test results may be caused by a paraneoplastic syndrome that is reversible with tumor removal and do not necessarily represent metastatic disease. Except when computed tomography (CT) examination is equivocal or when iodinated contrast material is contraindicated, CT scanning is as good as or better than magnetic resonance imaging (MRI) for detecting renal masses.

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.

TNM definitions

Primary tumor (T)

TX: Primary tumor cannot be assessed

T0: No evidence of primary tumor

T1: Tumor =7 cm in greatest dimension, limited to the kidney

T1a: Tumor =4 cm in greatest dimension, limited to the kidney

T1b: Tumor >4 cm but =7 cm in greatest dimension, limited to the kidney

T2: Tumor >7 cm in greatest dimension, limited to the kidney

T3: Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond Gerota's fascia

T3a:Tumor directly invades adrenal gland or perirenal and/or renal sinus fat but not beyond Gerota's fascia

T3b: Tumor grossly extends into the renal vein or its segmental (i.e., muscle-containing) branches, or the vena cava below the diaphragm

T3c: Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava

T4: Tumor invades beyond Gerota's fascia

Regional lymph nodes (N)*

NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Metastasis in a single regional lymph node

N2: Metastasis in more than 1 regional lymph node

Laterality does not affect the N classification.

If a lymph node dissection is performed, then pathologic evaluation would ordinarily include at least 8 nodes.

Distant metastasis (M)

MX: Distant metastasis cannot be assessed

M0: No distant metastasis

M1: Distant metastasis

AJCC stage groupings

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

Treatment Option Overview

Current treatment cures more than 50% of the patients with stage I disease, while the results in patients with stage IV disease are very poor. Thus, all patients with newly diagnosed renal cell cancer can appropriately be considered candidates for clinical trials when possible.

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

Stage I Renal Cell Cancer

Stage I renal cell cancer is defined by the following clinical stage grouping:

T1, N0, M0

Surgical resection is the accepted, often curative, therapy for stage I renal cell cancer. Resection may be simple or radical. The latter operation includes removal of the kidney, adrenal gland, perirenal fat, and Gerota's fascia, with or without a regional lymph node dissection. Some, but not all, surgeons believe the radical operation yields superior results. In patients who are not candidates for surgery, external-beam radiation therapy or arterial embolization can provide palliation. In patients with bilateral stage I neoplasms (concurrent or subsequent), bilateral partial nephrectomy or unilateral partial nephrectomy with contralateral radical nephrectomy, when technically feasible, may be a preferred alternative to bilateral nephrectomy with dialysis or transplantation. [1] Increasing evidence suggests that a partial nephrectomy is curative in selected cases. A pathologist should examine the gross specimen as well as the frozen section from the parenchymal margin of excision. [2]

Standard treatment options:

  1. Radical nephrectomy. [3]
  2. Simple nephrectomy. [3]
  3. Partial nephrectomy (selected patients). [1] [3]
  4. External-beam radiation therapy (palliative). [3]
  5. Arterial embolization (palliative). [3] [4]
  6. Clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Stage II Renal Cell Cancer

Stage II renal cell cancer (T2, N0, M0)

A surgical resection is the accepted, often curative, therapy for stage II renal cell cancer. Resection should be radical. The operation includes removal of the kidney, adrenal gland, perirenal fat, and Gerota's fascia, with or without a regional lymph node dissection. [1] Lymphadenectomy is commonly employed, but its effectiveness has not been definitively proven. External-beam radiation therapy has been given before or after nephrectomy without conclusive evidence that this improves survival when compared with the results of surgery alone; however, it may be of benefit in selected patients with more extensive tumors. In patients who are not candidates for surgery, arterial embolization can provide palliation.

Standard treatment options:

  1. Radical nephrectomy. [2]
  2. Nephrectomy before or after external-beam radiation therapy (selected patients). [2]
  3. Partial nephrectomy (selected patients). [2]
  4. External-beam radiation therapy (palliative). [2]
  5. Arterial embolization (palliative).

Stage III Renal Cell Cancer

Stage III renal cell cancer:

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

Treatment information for patients whose disease has the following classification:

T3a, N0, M0

A surgical resection is the accepted, often curative, therapy for stage III renal cell cancer. Resection should be radical. The operation includes removal of the kidney, adrenal gland, perirenal fat, and Gerota's fascia, with or without a regional lymph node dissection. [1] Lymphadenectomy is commonly employed, but its effectiveness has not been definitively proven. External-beam radiation has been given before or after nephrectomy without conclusive evidence that this improves survival when compared with the results of surgery alone; however, it may be of benefit in selected patients with more extensive tumors. In patients who are not candidates for surgery, arterial embolization can provide palliation. In patients with bilateral stage T3a neoplasms (concurrent or subsequent), bilateral partial nephrectomy or unilateral partial nephrectomy with contralateral radical nephrectomy, when technically feasible, may be a preferred alternative to bilateral nephrectomy with dialysis or transplantation.

Treatment information for patients whose disease has the following classification:

T3b, N0, M0

A surgical resection is the accepted, often curative, therapy for this stage of renal cell cancer. Resection should be radical. The operation includes removal of the kidney, adrenal gland, perirenal fat, and Gerota's fascia, with or without a regional lymph node dissection. Lymphadenectomy is commonly employed, but its effectiveness has not been definitively proven. Surgery is extended to remove the entire renal vein and caval thrombus and a portion of the vena cava as necessary. [3] External-beam radiation therapy has been given before or after nephrectomy without conclusive evidence that this improves survival when compared with the results of surgery alone; however, it may be of benefit in selected patients with more extensive tumors. In patients who are not candidates for surgery, arterial embolization can provide palliation. In patients with stage T3b neoplasms, who manifest concurrent or subsequent renal cell carcinoma in the contralateral kidney, a partial nephrectomy, when technically feasible, may be a preferred alternative to bilateral nephrectomy with dialysis or transplantation. [2] [4] [5]

Treatment information for patients whose disease has the following classifications:

T1, N1, M0

T2, N1, M0

T3, N1, M0

T3a, N1, M0

T3b, N1, M0

T3c, N1, M0

This stage of renal cell cancer is curable with surgery in a small minority of cases. A radical nephrectomy and lymph node dissection is necessary. The value of preoperative and postoperative external-beam radiation therapy has not been demonstrated, but external-beam radiation therapy may be used for palliation in patients who are not candidates for surgery.

Arterial embolization of the tumor with gelfoam or other materials may be employed preoperatively to reduce blood loss at nephrectomy or for palliation in patients with inoperable disease.

Standard treatment options:

Stage IV Renal Cell Cancer

Stage IV renal cell cancer is defined by the following stage groupings:

T4, N0, M0

T4, N1, M0

Any T, N2, M0

Any T, any N, M1

Almost all of these patients are incurable. Tumor embolization, external-beam radiation therapy, and nephrectomy can aid in the palliation of symptoms caused by the primary tumor or related ectopic hormone production. Minimal evidence suggests that nephrectomy induces regression of distant metastases. Hence, nephrectomy, in the hope that it will be followed by spontaneous regression of metastases, is not advised. Spontaneous regressions occasionally occur; indeed, a prospective surveillance series of 73 patients with advanced renal cell cancer demonstrated apparent temporary objective regression in 5 (7%) patients without nephrectomy or any therapy. Selected patients with solitary or a limited number of distant metastases can achieve prolonged survival with nephrectomy and surgical resection of the metastases. Even patients with brain metastases had similar results. The likelihood of achieving therapeutic benefit with this approach appears enhanced in patients with a long disease-free interval between the initial nephrectomy and the development of metastatic disease.

Responses to cytotoxic chemotherapy generally do not exceed 10% for any regimen that has been studied in adequate numbers of patients. Because of early reports of success, progestational agents have been administered to patients with metastatic renal cell cancer, but the frequency of response is disappointingly low, and there is no rationale for their use as anticancer therapy. They may offer subjective palliation, however. Various biologic therapies have been evaluated. Interferon alfas have approximately a 15% objective response rate in appropriately selected individuals. In general, these patients have nonbulky pulmonary and/or soft tissue metastases with excellent performance status (ECOG 0,1) and no weight loss. The interferon alfa doses used in studies reporting good response rates have been in an intermediate range of 6-20 MU - TIW. These responses are rarely complete or durable. More promising are treatments using interleukin-2 (IL-2). Administration of IL-2 appears to have a similar overall response rate to interferon alfa but with approximately 5% of the appropriately selected patients having durable complete remissions. Combinations of IL-2 and interferon have been studied but have not been shown to be better than high-dose IL-2 alone. The optimum dose of IL-2 is unknown. High-dose therapy appears to be associated with higher response rates but with more toxic effects. Low-dose inpatient regimens can retain efficacy with fewer toxic effects, especially hypotension. Outpatient, subcutaneous administration has also demonstrated responses with acceptable toxic effects. Because of the overall poor results with drug treatment, patients with metastatic renal cell cancer should be considered for clinical trials, especially phase I and II trials evaluating newer chemotherapeutic agents, biologics such as interferons or IL-2, and strategies to modulate multidrug-resistant phenotype, which is highly expressed in renal cell cancers.

Standard treatment options:

  1. IL-2.
  2. Interferon alfa.
  3. External-beam radiation therapy (palliative).
  4. Palliative nephrectomy.
  5. Radical nephrectomy (for T4 lesions).
  6. Surgical excision of metastatic disease with radical nephrectomy (for selected M1 patients).
  7. Clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Recurrent Renal Cell Cancer

The prognosis for any treated renal cell cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage. The question and selection of further treatment depends on many factors, including prior treatment, site of recurrence, and so on, as well as individual patient considerations. Carefully selected patients may benefit from surgical resection of localized metastatic disease, particularly if they have had a prolonged, disease-free interval since primary therapy.

Responses to cytotoxic chemotherapy generally do not exceed 10% for any regimen that has been studied in adequate numbers of patients. Because of early reports of success, progestational agents have been administered to patients with metastatic renal cell cancer, but the frequency of response is disappointingly low, and there is no rationale for their use as anticancer therapy. They may offer subjective palliation, however. Various biologic therapies have been evaluated. Interferon alfas have approximately a 15% objective response rate in appropriately selected individuals. In general, these patients have nonbulky pulmonary and/or soft tissue metastases with excellent performance status (ECOG 0,1) and no weight loss. The interferon alfa doses used in studies reporting good response rates have been in an intermediate range of 6-20 MU daily - TIW. These responses are rarely complete or durable. More promising are treatments using interleukin-2 (IL-2). Administration of IL-2, with or without lymphokine-activated killer lymphocytes, appears to have a similar overall response rate to interferon alfa but with approximately 5% of the appropriately selected patients having durable complete remissions. Combinations of IL-2 and interferon have been studied but have not been shown to be better than high-dose IL-2 alone. Low-dose inpatient regimens can retain efficacy with fewer toxic effects, especially hypotension. Outpatient, subcutaneous administration has also demonstrated responses with acceptable toxic effects. Because of the overall poor results with drug treatment, patients with metastatic renal cell cancer should be considered for clinical trials, especially phase I and II trials evaluating newer chemotherapeutic agents, biologics such as interferons or IL-2, and nonmyeloablative allogeneic stem cell transplantation.

Standard treatment options:

  1. IL-2.
  2. Interferon alfa.
  3. External-beam radiation therapy (palliative).
  4. Vinblastine.

Submitted By:
PROF. M. A. SALAM, MBBS, FCPS, FICS
The author is a Professor of Urology, BSMMU.

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