Kidney Cancer

Epidemiology

Kidney cancer accounts for 3% of adult malignancies. In the EU in 2006 were 39,400 new cases diagnosed in men is the 7th leading cause of cancer in women while 24,000 cases were located on the 9th place among cancers in women. In the US for 2011 it is estimated 60,920 new cases of kidney cancer and 13,120 deaths from kidney cancer. Overall cancer rates are higher in economically developed countries. The highest incidence rate is the age group 55-65 years.

            In Romania the estimated incidence for 2000 was 8.38 per 100,000 and 3.64 deaths per 100,000 inhabitants. Incidence trends may be influenced by the widespread use of diagnostic imaging has increased accuracy also diagnose and early diagnosis rate increased consecutively expanding therapeutic opportunities.

Risk factors:

                 1. Gender and age: Is 2 times more common in men as in women. Most cases of kidney cancer were reported between 4th decade and 6th age but can occur at any age. Most forms of kidney cancer are rare and sporadic forms (2%) as a familial form.

                2. Smoking

Smoking is a well-established factor for kidney cancer. A recent meta-analysis found an increased risk of renal cancer by 38% in smokers compared with nonsmokers. The risk was higher in men (54% increase) than women (22% increase). Discontinuation of smoking reduces the risk, but only for those who have stopped smoking for more than 10 years. There is a correlative between the risk of kidney cancer and the number of cigarettes smoked per day. The risk of kidney cancer attributable to smoking is between 21% -23%.

                3. Obesity is directly related to the risk of kidney cancer. It was concluded that the evidence that body fat is a cause of kidney cancer is compelling. A meta-analysis on obesity and cancer found a kidney cancer risk of 1.24 for an increase of 5kg / m2 in BMI in men and 1.34 in women. The proportion of cancers attributable to overweight and obesity kidney is estimated to be greater than 40% in the US and more than 30% in Europe.

               4. Physical activity may decrease risk of kidney cancer by a number of horse related, including decreasing body weight, lowering blood pressure, improving insulin sensitivity, reduces chronic inflammation and oxidative stress. However there is currently insufficient evidence to draw a conclusion on the role of physical activity and the risk of kidney cancer.

              5. Arsenic in drinking water arsenic is carcinogenic to humans and cause chromosomal abnormalities. The risk of cancer is higher for arsenic intakes.

             6. Exposure to trichlorethylene is associated with a risk of kidney cancer ranging from 1 to 2. It was found a higher incidence of somatic mutation von Hippel-Lindau in patients exposed to trichlorethylene and found a higher incidence of somatic mutation Kidney cancer patients exposed to trichlorethylene.

             7. Exposure to asbestos is improbable to be a risk for kidney cancer. However heavy exposure to asbestos could attract a higher risk of kidney cancer.

             8. Exposure to gasoline is a controversial risk factor. Most studies find no connection between gasoline and kidney cancer, while the other two studies found a significant risk of 1.3 and 1.6.

            9. Family history risk of kidney cancer is renal cancer relatively 2.21.

           10. Hypertension and antihypertensive treatment are risk factors controversial.

           11 Genetic factors:

a) family renal cancer occurring chromosome translocations involving 3: translocation t (3: 8), t (3:11) and t (3: 6). In kidney cancer, rarely deletions of chromosome 3 p

b) von Hippel-Lindau disease is an autosomal dominant is associated with renal carcinomas frequently occurring deletions of chromosome 3 p.

Kidney cancer like breast cancer and colon occurs both as sporadic (non-heritable) as well as hereditary form. It is estimated that 3-5% of patients with kidney cancer have inherited forms of the disease.

We know at least four forms of hereditary renal cancer syndrome von Hippel-Lindau, hereditary papillary renal cell carcinoma, renal cell carcinoma associated with hereditary syndrome Birt Hogg-Dube-hereditary renal carcinoma associated with leiomyoma.

Von Hippel-Lindau is a familial disease characterized by the appearance of multiple tumors including bilateral renal cell carcinoma, pheochromocytoma, hemangioblastomas of the CNS, retinal angioma and pancreatic cysts. Renal cell carcinoma is a clear cell carcinoma. VHL gene on chromosome 3 was localized, and the mode of transmission is autosomal dominant 3p loss of heterozygosity region in kidney cancer and other tumors with VHL disease. Analysis of the molecular genetics of sporadic renal cell carcinoma showed the disappearance of heterozygosity of chromosome 3p in about 90% of tumors and and almost all cases of clear cell renal carcinoma. VHL gene mutations were observed in 50% of clear cell carcinomas. VHL gene inactivation can occur by affecting gene by methylation which Aparri to 10% of patients with clear cell carcinoma. VHL gene inactivation occurs Biallelic up to 75% di patients with sporadic clear cell renal cancer and disappearance VHL gene function is an important event in the pathogenesis of kidney cancer. The disappearance of the tumor suppressor gene function will result in activation of hypoxia inducible genes, for example vasculoendotelial growth factor (VEGF).

Hereditary papillary renal carcinoma is a hereditary cancer syndrome in which affected individuals have an increased risk of renal papillary carcinomas develop multifocal type 1. The gene is involved in oncogene c-Met (Met cell-surface receptor for hepatocyte growth factor). Mutations of this gene are mutations in the tyrosine kinase activation.

Birt-Hogg-Dube syndrome is an autosomal dominant inherited a family syndrome in which affected individuals may have skin manifestations (fibrofoliculomas on face, neck and torso above), lung cysts may manifest spontaneously pneumotorax have an increased risk of developing tumors bilateral multifocal renal. BHD gene was identified on chromosome 17 and has characteristics of tumor suppressor gene.

Hereditary renal carcinoma associated with leiomyoma in which affected individuals are at increased risk of developing cutaneous leiomyomas and uterine cancer and kidney. The gene for this syndrome gene is a fumarate hydratase enzyme of the Krebs cycle.

Histological Types:

Adenocarcinoma (the most common, are also called hipernefromas or Grawitz tumor)

Adenocarcinomas are classified into 5 types (classification Mainz) based on histopathology and cytogenetic:

a) clear cell carcinoma 75-85% of cancers renal proximal tubule origin and present deletion in the short arm of chromosome 3.

b) papillary carcinoma (cromophilic) <15% of renal cancers do not show 3p deletion are bilateral and multifocal

c) chromophobe carcinoma <4% of kidney cancers originate in the cortical collecting tubules and has good prognosis

d) Oncocitomas are considered benign renal

e) Ductal carcinoma takes birth from medullary collector tubules and is very aggressive.

Transitional cell carcinoma

Neuroblastoma (Wilms tumor) in children

Lymphomas and sarcomas

Juxtaglomerular tumors (reninomas)

Hemangiopericitomas

7. Metastatic renal tumors from lung, ovarian, colon and breast cancer.

Predictors of short survival:

– LDH> 1.5X upper limit of normal

                                    – Hemoglobin

                                    – Corrected serum calcium level> 10mg / dl

                                    – Interval less than 1 year after diagnosis and before the commencement of systemic therapy.

                                    – Karnofsky performance status ≤ 70

                                    – ≥ 2 headquarters distant metastasis

Patients who have none of these factors have a low risk of relapse, or good prognosis. Patients with 1-2 intermediate risk factors. Patients with poor prognosis are defined patients ≥ 3 predictors of shorter survival.

            Signs and symptoms:

Renal cell carcinoma may remain clinically occult throughout the evolution.

Classic triad of hematuria, back pain, flank tumor occurs in 10% of cases, evidence of advanced disease and is associated with a poor prognosis.

            About 30% of kidney cancer patients present with metastatic disease, 25% with locally advanced disease and 45% with localized disease. Metastases that cause kidney cancer occur in the lung (75%), soft tissue (36%), bone (20%), liver (18%), skin (8%) and central nervous system (8%).

Other signs such as anemia, fever, weight loss, non-metastatic hepatic dysfunction, hypercalcemia, erythrocytosis are present in 30% of patients at diagnosis.

Hypochromic anemia due to hemolysis and hematuria was observed in 29% -80% of patients with renal cancer. Fever occurs in 20% of cases and cachexia fatigue, weight loss in 33% of patients.

Non-metastatic hepatic dysfunction (Staufer syndrome) is a syndrome associated with reversible renal carcinoma which is associated with fever, fatigue and weight loss, hepatomegaly, elevated transaminases and alkaline phosphatase. It resolves when the primary tumor is removed. Liver dysfunction usually associated with nonmetastatic bad prognosis appears to 7% of patients with renal cell carcinoma.

Policitremy has been reported in 1-5% of patients.

Renin level is increased in patients with renal cancer and Aesta returns to normal after removal of the kidney.

Plasma fibrinogen can be increased and correlate with disease stage, disease activity and response to therapy.

Disfibrinogenemia won has been reported in association with renal cell carcinoma and may be a sensitive marker for the disease plasma and tumor progression.

Hypercalcemia of malignancy is frequently observed in renal cell carcinoma. It is due to a factor produced by the tumor, a bone resorption active systemic factor. It has been shown that renal tumor activity produces a factor with parathyroid like.

Paraneoplastic syndromes:

1. Polycythemia

2. Hypercalcemia occurs in 25% of patients with metastatic disease.

3. Fever

4. Hepatomegaly with alkaline phosphatase and elevated transaminases without liver metastases (Stauffer syndrome). It resolves after nephrectomy.

5. Hypertension

           Percutaneous fine needle aspiration biopsy may cause tumor seeding in the needle tract bleeding. It is indicated in patients with complex kidney cysts that do not support or surgical treatment for patients with metastatic disease.

           The diagnosis is confirmed based on histopathological examination.

For diagnosis and staging is recommended:

· History, clinical examination,

· Blood count, liver and kidney tests,

· Chest x-ray,

· Ultrasound

· Intravenous barium enema,

· C. T. and abdominal MRI.

·

TNM staging:

            primary tumors (t)

                        Tx – primary tumor cannot be assessed

                       T0 – there is no evidence of primary tumor

                        T1 – Tumor <7 cm, limited to kidney

                                T1a – tumor ≤ 4 cm

                                T1b – Tumor> 4 – <7cm

                        T2 – tumors> 7 cm limited to the kidney

                                T2a- tumors> 7 ≤ 10 cm, limited to kidney

                                 T2b-tumor> 10 cm, limited to kidney

T3a – tumor invades adrenal gland or perinephritic tissue but does not exceed the Gerota fascia

                        T3b – Tumor extends into renal vein and inferior vena cava under the diaphragm

T3C – tumor extends into the renal vein and inferior vena cava above the diaphragm

                        T4 – Tumor beyond Gerota fascia

            Lymph node (N)

            Nx – regional lymph nodes cannot be assessed

            N0 – no metastases in the lymph nodes

            N1 – metastases in regional lymph node

            Metastasis (M)

            M0 – no distant metastases

            M1 – distant metastases present

            Stages:

Stage

            T1 N0 M0 I

            T2 N0 M0 II

            T1-2 N1 M0 III

                                    T3a, b, c N0-1 M0

            IV T4 N0-1 M0

                              Any T Any N Any M

TREATMENT

Therapeutic Indication

I. localized disease

1) T1 – T3 N0M0 radical nephrectomy is recommended.

Partial nephrectomy is indicated in case of T1 tumors, bilateral renal tumors or kidney. After surgery adjuvant therapy is not recommended.

2) T4 – N0M0 or surgical treatment is recommended

Whenever possible despite bad cytoreductive nephrectomy results.

Radical nephrectomy involves excision GEROTA fascia and its contents, including kidney, adrenal and tumor extension into the renal vein and inferior vena cava.

Treatment after surgery

After surgery 20-30% of patients with localized tumors will present local recurrence of the disease. Lung is the seat of distant metastasis most frequently occurs in 50-60%. The average time of relapse after surgery is 1-2 years, most recurrences occur in the first 3years. Currently has no role adjuvant treatment in patients with renal cell carcinoma after nephrectomy if complete resection of their tumor was performed. Improvement not demonstrated any time until relapse or in overall survival in adjuvant therapy with interferon alpha or interleukin 2 in high doses to patients kept under observation.

After nephrectomy remains the standard of care observation. Patients are called in the first 2 years to 6 months and then annually. At each visit historic recommended, clinical examination, complete blood count, biochemical tests, LDH, urea, creatinine, liver function tests. Abdominal and chest CT in the first 2-6 months and then according to indications. Abdominal ultrasound and radiography tioracica recommended for evaluating patients with small tumors and low risk of relapse.

II. Advanced disease.

N + M0 or M1 (metastatic disease, unresectable disease medical or surgical)

Patients with stage IV may benefit from surgical treatment consisting of nephrectomy and metastasesectomy or lymphadenectomy. Candidates for this treatment are: 1. primary RCC metastatic a single location. 2. patient develops a solitary recurrence after nephrectomy. The premises is suitable metastatic lung call this treatment, bone and CNS

a). Histology of clear cell carcinoma:

                      – Clinical trial or

                      -Sunitinib (Category 1) or

                      -Temsirolimus (Category 1 patients with poor prognosis 2B category for other risk groups) or

                        -Bevacizumab Plus interferon (category 1) or

                        -Pazopanib (Categoria1) or

                        -Interleukina (IL-2) in patients with good general condition without organic dysfunction

                        -Sorafenib For selected patients and best supportive care.

b). Histology of the non-clear cell carcinoma:

                        – clinical trial (preferred) or

                        -Temsirolimus Category 1 patients with poor prognosis for category 2A for other risk groups) or

                        -Sorafenib Or

                        -Sunitinib Or

                        – Pazopanib (category 3) or

                        -Erlotinib (Category 30 or

                       -Axitinib (Category 3) or

                        -Chemotherapy only sarcomatoid forms (categoria3): Gemcitabine plus Doxorubicin and

                        -Best Supportive care

Therapeutic Modalities

   1). Surgery:

Partial nephrectomy (nephron sparing surgery) is recommended:

– small tumors-T1a and some T1b

– single kidney, bilateral renal tumors, kidney cancer family.

– Radical nephrectomy involves excision GEROTA fascia and its contents, including kidney, adrenal and tumor extension into the renal vein and inferior vena cava.

Regional lymph node dissection is optional but is recommended for patients with preoperative lymph nodes or lymphadenopathy images or palpable lymphadenopathy at surgery.

Adrenal gland resection may be omitted if not whether the tumor has invaded and increased risk based on size and location.

Resection of the vena cava or atrial thrombus often requires the assistance of a physician and may involve Cardiac by-step techniques veno-venous or cardiopulmonary and treatment-related mortality can reach 10%.

                        Palliative nephrectomy is indicated in patients with metastases to relieve some symptoms of such pain, severe bleeding or endocrine paraneoplastic syndrome, in selected patients, which expects life to be more than 6 months and who meet the following criteria:

a) Status of Efficiency> 30% (Karnofski)

b) The only symptoms are primary tumor area and premises are asymptomatic metastatic disease.

c) The tumor must have a good chance to be resected.

The chance of spontaneous remission of metastases after nephrectomy is well known but rare, less than 1%. There is never an indication for surgical treatment.

Metastasis resection considers the following situations:

· The time interval from nephrectomy to detect metastasis of at least 2 years.

Metastasis is isolated.

2) Radiation therapy. Generally renal tumors are relatively radio-resistant. It has an important role in palliation of metastatic renal cell carcinoma. It is used to control bleeding and pain due to primary tumor and palliation of symptoms from bone metastases and brain metastases

Skeletal metastases usually respond with marked improvement in pain and often complete necrosis of the tumor. It noted the disappearance of the abdominal wall and lung metastasis after radiotherapy in low doses.

            Radiation therapy on renal lodge in incompletely resected tumor patients was ineffective.

3) drug treatment.

a) Interleukin-2 administered alone in large doses produces a response rate of 15-20% with a duration of more than 10 years. It is recommended as first-line option (Category 2A).

Interleukin-2 is a cytokine produced and secreted by activated T lymphocytes. It is involved in all immune responses in which T cells play a role and have immunostimulatory properties. No direct antitumor effect but leads to destruction of immunologically-mediated tumor. Recommended doses of interleukin-2 are between 600,000 to 720,000 IU / kg x 3 / day for 14 doses for 5 days, pause 6-10 days and repeat the cycle. If there is response repeat the treatment.

            Using high-dose interleukin-2 was associated with significant side effects: hypotension, pulmonary edema, renal failure.

            Names: Proleukin, aldesleukin.

            b) Inferferon produces a response rate of 15-20%, but without an effect on survival.

            It was reported regression of metastatic carcinoma, administration in doses of 3,000,000 IU / day – 5 days / week. Complete remission occurs in 26% of patients and partial remissions in 16% of patients.

            The average duration of response was 4.3 months. In the majority of patients with a course of interferon sufficient to judge whether or not there is answered. Intron or Roferon is used.

Although interleukin 2 and interferon alpha have been useful in some patients, in most cases the benefit is modest and is achieved with significant toxicity.

C. Targeted therapy Targeted therapy utilizing tyrosine kinase inhibitors are widely used in the treatment of front row or II. Until now six FDA approved agents for the treatment: sunitinib, sorafenib, pazopanib, temsirolimus, everolimus and bevacizumab in combination with interferon.

Sunitinib is an inhibitor to target more receptors multikinazic triozin kinases including platelet-derived growth factor (PDGFR), vasculoendotelial growth factor (VEGFR), stem cell factor receptor (c-KIT), colony stimulating factor (CSF 1 ), neurotrophic factor receptor (RET). Sunitinib has activity resulting from the inhibition of angiogenesis and cellular proliferation. In a Phase IIII trial of 750 patients with RCC multinational clear cell metastatic were randomized to receive either sunitinib or interferon alpha. Smne progression free survival (PFS) was 11 months for sunitinib arm and 5 months for interferon alpha. The objective response rate was 31% for sunitinib and 6% for interferon alpha. General survival time was of 4.5 months for sunitinib versus interferon (26.4 months versus 21.8 months). Sunitinib is recommended in patients with clear cell renal cancer stage IV relapsed or medically unresectable, as a first line option (category 1).

Bevacizumab associated with interferon alfa. Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes vascular-endothelial growth factor A (VEGF-A). In a multicenter Phase III trial (AVOREN), 641 patients with clear cell RCC were treated with either Avastin plus interferon alpha or placebo and interferon alpha. In bevacizumab arm survival without progression (PFS) was 10.2 months versus 5.4 months in the placebo arm and the objective response rate was 30.6% in the bevacizumab arm versus 12 4% in the placebo arm. There is a difference in overall survival but not statistically significant (23.3 months to 21.3 months in bevacizumab and interferon alpha. Bevacizumab in combination with interferon alfa is recommended as an option for front row (Category 1) in patients with RCC , clear cell relapsed or medically unresectable.

Pazopanib

Pazopanib is an oral angiogenesis inhibitor that targets PDGFR alpha and beta, VEGFR 1.2 SI3 and Ckit. In a Phase III international study, 435 patients were randomized 2: 1 to receive pazopanib or placebo. PFS was 9.2, and 4.2 months pazopaniob months on placebo. The objective response rate was 30% in the pazopanib and placebo 3%. It noted a grade 3 hepatotoxicity indicated by elevated transaminases and cardiac rhythm disorders manifested by heart. It is recommended as an option for front row (Category 1) in patients with RCC, clear cell relapsed or medically unresectable.

Temsirolimus is an inhibitor of protein m TOR. MTOR protein regulates trace, cell growth, apoptosis and angiogenesis through effects on a variety of downstream proteins. In one trial (ARccOS) multicenter Phase III in patients with clear cell RCC, advanced untreated with 3 or more unfavorable prognostic factors, 626 patients were randomized to receive Temsirolimus or interferon alpha, or both. The average overall survival in patients who received temsirolimus was 10.9 months vs. 7.3 months for those treated with interferon alpha. PFS was 3.1 months for patients treated with interferon and 5.5 months in those treated with temsirolimus alone. It is recommended as an option for front row (Category 1) in patients with RCC, clear cell relapsed or medically unresectable. Temsirolimus is the only agent that has shown effectiveness in patients with Non-clear cell RCC. It is recommended that Take-line therapy in patients with advanced RCC Non-clear cell, recommendation tier

Sorafenib tosylate is a molecule that inhibits multiple isoforms of the serine / threonine kinase intracellular RAF and other receptor tyrosine kinases, including VEGFR 1,2 and 3, PDGFR-beta, Flt3, and RET Ckit. A Phase III trial investigated the efficacy of sorafenib versus interferon alpha-naive patients with clear cell RCC. There were included 189 patients who received sorafenib 400mg 2 x / day. PFS was 5.7 months for sorafenib versus 5.6 months for interferon alpha. More patients treated with sorafenib had 68.2% tumor regression versus 39% treated with interferon. PFS for sorafenib vs. interferon was 90% versus 70% at 3 months, 45% to 46% at 6 months and 11% to 30% at 12 months. It is recommended as first-line option (Category 2A) and the second line patients who have been previously treated with interferon alpha or sorafenib.

Everolimus is an oral inhibitor of mTOR. The RECORD trial, Phase III trial of everolimus was compared with placebo in patients with metastatic RCC coror disease progressed under treatment with sorafenib or sutinib.PFS was 4.6 months for everolimus compared to placebo 1,9luni. It is recommended that patients with advanced clear cell RCC after treatment with sorafenib or sutinib ineffective as second-line treatment (class 1)

Axitinib is a selective inhibitor II generation, the VEGFR 1,2 and 3. It is recommended in patients with advanced RCC with relapsed after previous systemic therapy tratatament (sutinib, sorafenib, interferon, interleukin, temsirolimus) -Category 1.

c) Chemotherapy has little effect on metastatic disease, or an improvement in survival. Gemcitabine plus Doxorubicin is recommended as first-line therapy (category 3) in patients with Non-clear cell metastatic RCC.

            Prognostic

            The survival of 3 years in untreated patients is 4% and 1-2% at 5 years.

1. Nodal invasion is a bad prognostic factor and is associated with a 5-year survival of 20%.

2. Invasion of tumor in kidney fat is a poor prognostic factor lowers the 5-year survival ≈45%.

3. The extension of the contiguous tumor bodies is a negative prognostic factor, and is associated with a decrease in survival at 5 years.

            4. unfavorable histological markers:

q tumors with sarcomatoid component

q high histological grade

q aneuploidy

5. In patients with metastatic disease survival at 5 years is 5-10%.

            Favorable prognostic factors are:

an appearance of metastases in more than two years after nephrectomy

a good performance status

lung metastases

Predictors of brief survival

Patients with poor prognosis are defined patients ≥ 3 short survival predictive factors: – LDH> 1.5X upper limit of normal

                                    – Hemoglobin

                                  – Corrected serum calcium level> 10mg / dl

                                    – Interval less than 1 year after diagnosis and before the commencement of systemic therapy.

                                    – Karnofsky performance status ≤ 70

                                    – ≥ 2 headquarters distant metastasis

            Survival:

            The survival rate at 5 years depending on disease stage:

100% I

              96% CI

              53% III

              16% IV

            Patient follow-up

Patients are followed in the first 2 years to 6 months and then annually. At each visit historic recommended, clinical examination, complete blood count, biochemical tests, LDH, urea, creatinine, liver function tests. Abdominal and chest CT in the first 2-6 months and then according to indications. Abdominal ultrasound and chest radiography recommended for evaluating patients with small tumors and low risk of relapse.