Kidney Cancer (Renal Cell Carcinoma)
by Ch. Bakogiannis, M.D., Medical Oncologist

Epidemiology

Renal cell carcinoma (RCC) affects mostly individuals 50-70 years old, and accounts for 3% of all malignant diseases in adults. It occurs in a male-to-female ratio of 1.6:1.

Renal Cell Carcinoma is the 6th most common cancer in men and the 8th most common in women. The incidence is about 271,000 new cases per year and 116,000 deaths per year globally.

People with a family history of Renal Cell Carcinoma have a 2.5-fold greater risk of developing RCC during their lifetimes, and comprise about 4% of all RCC.

 

Etiology

Smoking is an important risk factor for Renal Cell Carcinoma, increasing the risk by about 2 or 3 times.

Obesity is also a known risk factor, particularly in women. High body mass index (BMI) is associated with an increased RCC risk.

Renal Cell Carcinoma has an increased incidence in patients with end-stage renal failure and acquired renal cystic disease.

Furthermore, analgesics have been suspected to be a risk factor, but the association has not been confirmed.

Environmental and occupational factors have been associated with Renal Cell Carcinoma. The industrial solvent trichloroethylen (TRI), exposure to asbestos, to cadmium, to petroleum products and leather tanners, shoe-workers are postulated to be at an increased incidence of RCC. However, large epidemiological studies have not confirmed association between these exposures or occupations with RCC risk.

 

Hereditary forms of Renal Cell Carcinoma (RCC)

Renal Cell Carcinoma can be both sporadic (non hereditary) and hereditary, i.e. associated with specific gene alterations.

There are six forms of hereditary Renal Cell Carcinoma:

  1. Von Hippel-Lindau (VHL)
  2. Hereditary papillary renal carcinoma (HPRC)
  3. Birt-Hogg-Dube (BHD)
  4. Hereditary leiomyomatosis RCC (HLRCC)
  5. Succinate dehydrogenase (SDH)-associated familial renal cell carcinoma
  6. Tuberous sclerosis complex (TSC).

 

Symptoms

Patients with Renal Cell Carcinoma can present with local or systemic symptoms, although they may remain clinically occult for most of their course.

The local symptoms are hematuria, pain and a palpable abdominal mass, often indicative of advanced disease. Systemic symptoms can be due to paraneoplastic events (i.e. not due to the specific local mass) or metastases.

The paraneoplastic manifestations may include hypercalcemia, hypertension, erythrocytosis, fever, anemia, cachexia, fatigue, weight loss, amyloidosis, polycythemia and nonmetastatic hepatic dysfunction.

Early stage, incidental detection of many asymptomatic RCC cases is usually through ultrasonography and cross-sectional imaging.

For complete evaluation and staging, the UICC TNM 2009 staging system should be used (Table 1). In order to assess local invasiveness, lymph node involvement or metastases, Computed Tomography (CT), Magnetic Resonance Imaging (MRI), ultrasound and bone scan are necessary.

 

Table 1. A simplified staging of RCC (UICC TNM classification of malignant tumors, 7th edition, 2009)

T

Primary Tumor

T1

Tumor ≤ 7cm in greatest dimension, limited to the kidney

T2

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

T3

Tumor extends to major veins or perinephric tissues, but not into the ipsilateral adrenal gland, and not beyond Gerota fascia

T4

Tumor invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)

 

 

N

Regional lymph nodes

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in regional lymph node(s)

 

 

M

Distant metastases

cM0

Clinically no distant metastasis

cM1

Clinically distant metastasis

pM1

Distant metastasis proven pathologically (e.g. via needle biopsy)

 

 

Stage grouping

 

Stage 1

T1-N0-M0

Stage 2

T2-N0-M0

Stage 3

T3-N0-M0

T1-3N1-M0

Stage 4

T4-Any-M0

Any-Any-M1

 

Pathology

Several distinct RCC types have been identified, including: 

  • Clear cell (approximately 75% of kidney cancers)
  • Papillary carcinoma (15%) with two variants (type 1, and a more aggressive type 2 variant)
  • Chromophobe carcinoma (5% of renal carcinomas)
  • Carcinoma of the collecting ducts of Bellini
  • Renal medullary carcinoma
  • Other, unclassified types

 

Treatment of Localized Renal Carcinoma

Surgery plays a major role in the treatment of Renal Cell Carcinoma and is still the only curative therapeutic option.

For patients with stage 1 RCC for whom surgery maybe curative, the 5-year survival rate is higher than 80%. For patients with metastatic disease, however, 5-year survival rates are <20%.

Partial (nephron-sparing) nephrectomy and radical nephrectomy are options for surgery of Renal Cell Carcinoma. For both options, the operation can be open or laparoscopic.

Chronic kidney disease is much more common after radical nephrectomy, than after partial nephrectomy.

 

Partial nephrectomy

The majority of patients (70%) are diagnosed after incidental detection with small renal masses. Management of small kidney masses must provide adequate tumor control with maximum preservation of renal function. Partial (nephron-sparing) resection techniques are appropriate for the majority of these patients.

Partial nephrectomy is now the gold standard for most patients with small renal tumors (≤ 4cm). Renal tumors of 4-7 cm should be considered for nephron-sparing approaches if tumor location is amenable to partial nephrectomy.

Research conducted during the 1990s reported that nephron-sparing techniques resulted in better functional and equal oncologic outcome.

The Open Partial Nephrectomy (OPN) is the standard treatment for small RCC (≤ 4cm) and thus for the majority of patients. This procedure can also be extended for tumors T1b (of 4-7cm).

For nephron-sparing surgery, important factors are the tumor size and the technical feasibility.

Indications for partial nephrectomy are absolute (i.e. bilateral tumors or solitary kidney) or relative (i.e. hereditary forms of RCC, or increased risk for chronic or acute renal failure).

 

Radical nephrectomy

The most common treatment for localized RCC greater than 4cm is radical nephrectomy.

In radical nephrectomy, routine adrenalectomy is not necessary, except if there are signs of direct invasion of the adrenal gland or large upper-pole tumors and synchronous solitary adrenal metastasis.

 

Laparoscopic Radical Nephrectomy (LRN) is a very good alternative for patients with RCC whose tumors are not suitable for nephron-sparing techniques. This procedure has similar oncological outcomes to Open Radical Nephrectomy (ORN) and has more rapid recovery, shorter hospitalization time, less post-operative pain and less estimated blood loss.

This procedure should be performed in centers with laparoscopic expertise. Five-year survival rates for LPN have been published with similar rates for OPN, but data are retrospective. Prospective randomized studies are required to validate such data for LPN.

The ORN is no longer the standard of care for RCC, but it is the preferred technique for renal vein or vena cava involvements for stage T4 disease and gross lymphadenopathy.

 

Local ablative therapy

Another option for the management of small renal tumors is thermal ablation. The procedure is nephron-sparing, with the potential for parenchyma preservation, without the need for conventional surgery.

There are currently two procedures, RadioFrequency Ablation (RFA) and cryoablation; both can be administered percutaneously or laparoscopically. The limitation is the tumor size due to the difficulty to ablate tumors larger than 3.5cm in diameter.

Such treatment is most appropriate for elderly patients with comorbidities or hereditary RCC, as well as patients with multiple bilateral tumors.

 

Treatment of Advanced Renal Carcinoma

Cytoreductive nephrectomy

In patients with locally advanced or metastatic RCC, nephrectomy should be considered as part of a treatment plan to decrease tumor burden. This is in order to better prepare the patient’s condition for subsequent systemic treatment or for palliation and symptom control (i.e. hemorrhage, pain, hypercalcemia, hypertension, erythrocytosis).

In particular, laparoscopic procedure in patients with advanced disease is most often used due to minimally invasive cytoreductive nephrectomy.

Radical nephrectomy in the presence of metastatic disease (called cytoreductive nephrectomy or debulking) is often indicated as part of an integrated management strategy.

It is not curative, and is not applicable to all patients with advanced or metastatic Renal Cell Carcinoma.

Two prospective randomized trials have demonstrated the benefits of cytoreductive nephrectomy in conjunction with cytokine-based immunotherapy.

Important risks from this surgery are disease progression during recovery and surgery-related morbidity or mortality.

 

Surgery for metastases

Surgical resection of metastases should be considered in a small portion of patients with RCC and limited metastatic disease as solitary metastasis, limited multiple metastases, and residual tumor after response to systemic treatment.

Resection of metastases will render few cures and will produce some long-term survivors.

 

Medical Treatment

Advanced renal cancer is the typical cancer type in which targeted treatment is the only effective treatment.

Chemotherapy is mostly ineffective, and the role of immunotherapy with the use of Interleukin-2 is now limited to very few patients.

There are two groups of approved targeted agents for metastatic renal cancer.

  1. Vascular Endothelial growth factor (VEGF) - directed therapies
  2. Inhibitors of the mammalian target of rapamycin (mTOR) 

Anti-VEGF (Anti-Vascular Endothelial growth factor)

Anti-VEGF directed agents include the monoclonal antibody bevacizumab, and the Tyrosine Kinase Inhibitors (TKIs) sunitinib, pazopanib, sorafenib and axitinib.

 

Bevacizumab

Bevacizumab is given together with Interferon-a, as first line treatment in advanced clear cell renal cancer. It is given intravenously usually every three weeks. The main side effects are hypertension and bleeding. The concomitant use of Interferon-a may induce fever, headache, asthenia and loss of appetite.

 

Sunitinib

Sunitinib is given as first line treatment in metastatic renal cell carcinoma. It is given as a pill orally for 4 weeks continuously, followed by 2 weeks of rest. The main side effects are weakness, stomatitis, nail changes, thyroid dysfunction, hypertention, dry skin, diarrhea and decreased blood counts.

 

Pazopanib

Pazopanib is given as first line treatment, or following failure of Sunitinib. It is given orally continuously. The main side effects are stomatitis, diarrhea, hypertention, dry skin. It seems to be better tolerated than Sunitinib.

 

Sorafenib

Sorafenib is given as second line therapy following resistance to TKIs. It is given orally continuously. The main side effects are weakness, hypertention, diarrhea, skin changes especially in hands and foot, decreased blood phosphorum, etc.

 

Axitinib

Axitinib is the newest Tyrosine Kinase Inhibitor (TKI), and is given following failure of Sunitinib or Pazopanib as second line targeted treatment in advanced renal carcinoma. It seems to be better than Sorafenib in terms of cancer progression interval. It is given orally continuously, and the dosage is adjusted based on the liver function. The main side effects are hypertention, weakness, loss of appetite, thyroid dysfunction, skin changes especially in hands and foot, diarrhea.

 

m-TOR inhibitors

m-TOR inhibitors approved for advanced renal cell carcinoma include everolimus and temsirolimus.

 

Everolimus

Everolimus has been evaluated in patients with clear cell renal carcinoma who have been previously exposed to TKIs. It is given as a pill orally every day as a second- or third- line treatment.  The main side effects include mucositis, stomatitis, pneumonitis, skin rash, elevated blood sugar and triglycerides.

 

Temsirolimus

Temsirolimus is an intravenously given m-TOR inhibitor, principally, to patients with poor risk cancer who have not received any treatment in the past. The main side effects are the same with everolimus: mucositis, stomatitis, pneumonitis, skin rash, elevated blood sugar and triglycerides.

 

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