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Renal Cell Carcinoma

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Renal Cell Carcinoma Jennifer L. Rogers September 18, 2007 Kidney Neoplasms Primary or Secondary (metastatic) Renal cell carcinoma (RCC) represents 80-85% of primary ... – PowerPoint PPT presentation

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Title: Renal Cell Carcinoma


1
Renal Cell Carcinoma
  • Jennifer L. Rogers
  • September 18, 2007

2
Kidney Neoplasms
  • Primary or Secondary (metastatic)
  • Renal cell carcinoma (RCC) represents 80-85 of
    primary renal neoplasms
  • Transitional cell carcinoma 8
  • Rare tumors include
  • - Oncocytomas
  • Collecting duct tumors
  • Renal sarcomas
  • Nephroblastoma (Wilms tumor in children)
  • Renal medullar carcinoma (Sickle cell disease)

3
Incidence
  • RCC represents 2 of overall cancer incidence and
    mortality
  • 50,000 cases diagnosed and 13,000 deaths annually
    in the US
  • 126 increase in incidence and 35 increase in
    annual mortality over the last 50 years
  • All stages increased, but greatest increase in
    localized disease
  • 5-year survival rate has doubled since 1954

4
Increasing Incidence
  • Pantuck, AJ, et al. J Urology 2001 1661612

5
Epidemiology
  • Male predominance (1.61.0 MF)
  • Highest incidence between age 60-80
  • -Median age of diagnosis is 66 years
  • -Median age of death 70 years
  • Highest incidence in Scandinavia and North
    America, lowest in Africa
  • No racial differences in the US

6
Risk Factors
  • Majority of RCC occurs sporadically
  • Tobacco smoking contributes to 24-30 of RCC
    cases
  • - Tobacco results in a 2-fold increased risk
  • Occupational exposure to cadmium, asbestos,
    petroleum
  • Obesity, HTN
  • Chronic phenacetin or aspirin use
  • Acquired polycystic kidney disease due to
    dialysis results in 30 increase risk

7
Genetic Factors
  • 2-4 of RCC associated with inherited disorder
  • Von Hippel-Lindau disease
  • - AD familial cancer syndrome of retinal
    angiomas, CNS hemangioblastomas,
    pheochromocytomas and clear cell RCC.
  • Inherited mutation in one VHL allele
  • Malignancy arises from inactivation of the
    remaining VHL allele
  • VHL gene mutation associated with 60 sporadic
    RCC

8
Pathogenesis of VHL
  • Von Hippel-Lindau protein, product of VHL gene,
    is a tumor suppressor
  • VHL inhibits hypoxia-inducible genes involved in
    angiogenesis such as VEGF, TGF-a, GLUT-1
  • VHL destabilizes and promotes ubiquination of
    HIF-a (hypoxia-inducible factor)
  • Loss of VHL results in tumor angiogenesis,
    tumor-cell proliferation epithelial cell
    proliferation

9
Genetic Factors cont.
  • Hereditary papillary renal cancer
  • Multiple, bilateral papillary renal tumors
  • C-met oncogene on ch 7
  • Birt-Hogg-Duke syndrome
  • - Fibrofolliculomas, lung cysts, and RCC
  • - Mutation in BHD gene ch 17p
  • Reed syndrome
  • - Cutaneous and uterine leiomyomas and RCC
  • - Mutation in FH gene

10
Clinical Presentation
  • Variety of symptoms, most asymptomatic
  • Hematuria present 40 of patients
  • Classic triad flank pain, hematuria, palpable
    abdominal mass occur in 9 of patients
  • 45 present with localized disease, 25 with
    locally advanced disease, 30 with metastatic
    disease

11
Paraneoplastic syndromes
  • Anemia- anemia of chronic disease 29-88
  • Hepatic dysfunction in the absence of mets 21
  • Hypercalcemia 15
  • Cachexia and Fever 20
  • Erythrocytosis 1-5 produce erythropoietin
  • Secondary AA amyloidosis 3-5

12
Diagnosis
  • No screening for the general population
  • Radiographic evaluation
  • - Ultrasound solid vs. cystic lesions
  • - Contrast CT test of choice to evaluate tumor
    size, location, lymph node involvement
  • MRI to evaluate collecting system and IVC
    involvement

13
Tissue Diagnosis
  • Tissue diagnosis obtained from nephrectomy or
    biopsy of metastatic lesion
  • Surgery indicated for solid renal masses gt1.5cm
  • Tumors lt1.5cm require periodic follow-up

14
Histology
  • Clear cell 75-85 of RCC
  • Chromophilic papillary 10-15
  • Chromophobic 5-10

15
Staging
  • TNM staging system
  • - Stage I-III Localized disease
  • - Stage IV Advanced, metastatic disease

16

17
Staging and Prognosis

  • Cohen HT, McGovern FJ. NEJM. 20053532477.

18
Prognosis
  • Prognosis depends upon stage
  • Other poor prognostic indications include poor
    performance status, anemia, hypercalcemia, and
    elevated LDH

Five-year relative survival rates by tumor stage
at diagnosis based on cases diagnosed during
19921999, followed through 2000. Drucker BJ.
Cancer Treat Rev. 200531536.
19
Localized RCC Treatment
  • Surgery is the only curative therapy for stage
    I-III
  • Radial nephrectomy is gold standard
  • Partial nephrectomy in selected patients
  • No role for adjuvant therapy except under
    investigational protocol
  • 20-30 of patients relapse within 2-3 years
  • - Metastases to the lung most common 50
  • - Local recurrence is rare 2-3

20
Advanced RCC Treatment
  • Primary treatments are systemic therapy with
    molecularly targeted therapy or immunotherapy
  • Surgery is palliative therapy
  • Solitary metastatic site
  • Solitary recurrence following nephrectomy
  • Symptoms related to bulkiness of disease
    including pain, nausea, or GI obstruction

21
Targeted Therapy
  • Based on advances in the understanding of the
    molecular biology of RCC
  • Highly vascularlized tumor with increased VEGF
    and EGFR expression
  • Tumor growth mediated via VEGF pathway and
    mammalian target of rapamycin (mTOR) pathway

22
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23
VEGF Pathway Inhibition
  • Tyrosine kinase (TK) inhibitors block the
    intracellular domain of the VGEF receptor
  • Sunitinib (Sutent)
  • Sorafenib (Nexavar)
  • Monoclonal antibody that binds circulating VEGF
    preventing the activation of the VEGF receptor
  • - Bevacizumab (Avastin)

24
Sunitinib
  • Two phase II trials evaluating activity and
    safety in previously treated advanced RCC
  • 25-36 of patients had an objective response
  • Progression free survival (PFS) 8.3-8.7 months
  • Median survival 16.4 months
  • Side effects include fatigue, HTN, nausea,
    diarrhea, mucositis, and hypothyroidism

25
Sunitinib
  • Phase III trial 750 pts with untreated stage IV
    RCC Sunitinib vs. INFa
  • Sunitinib showed prolonged median PFS 11 vs. 5m
    and higher response rate of 31 vs. 6
  • Motzer RJ, et al. NEJM. 2007356115-124

26
Sorafenib
  • Phase II and phase III trials in advanced RCC
  • Phase III TARGET study of 903 previously tx pts
    w/ stage IV RCC randomized to Sorafenib vs.
    placebo
  • Sorafenib improved median PFS 5.5 vs. 2.8m
  • No statistically significant survival benefit,
    median survival of 17.8 vs. 15.2 m
  • Side effects include HTN, fatigue, rash,
    hand-foot syndrome, diarrhea, nausea

27
Bevacizumab
  • Phase II trial of 116 pts, Bevacizumab increased
    TTP 4.8 vs. 2.5m for placebo group.
  • -No difference in median survival
  • Phase III AVOREN trial of 648 untreated pts
  • INFa plus Avastin or placebo
  • Avastin group resulted in PFS of 10.2 vs. 5.4 m.
  • Unclear activity as single agent however
  • Not FDA approved, but can be used as second-line
    therapy

28
mTOR Pathway Inhibition
  • Temsirolimus (TMSR) is a rapamycin analog that
    inhibits mTOR kinase
  • Phase III trial 626 untreated poor-prognosis pts
    with stage IV RCC tx w/ TMSR, TMSR INFa, or
    INFa.
  • - TMSR prolonged survival compared to INFa (10.9
    vs. 7.3m) and prolonged PFS (3.8 vs. 1.9m)
  • Benefit greater in non-clear cell RCC

29
Immunotherapy
  • Immunotherapy with IL-2 activates immune response
    against RCC resulting in tumor remission rates
    10-20 with median duration of 19-91 months
  • Severe toxicity including hypotension, capillary
    leak syndrome, MI, renal insufficiency, pulmonary
    edema, hepatic dysfunction, CNS dysfunction
  • Treatment requires ICU monitoring
  • Used for patients that can tolerate side effects

30
Chemotherapy
  • RCC is only minimally responsive to chemotherapy
  • 83 clinic trials involving over 4000 pts, overall
    response rate is only 6
  • On-going clinical trials of combination
    chemotherapy including Gemcitabine and 5-FU
  • Limited data reveals some response in non-clear
    cell RCC to Carboplatin, Cisplatin plus
    Gemcitabine

31
Radiation Therapy
  • RCC relatively radioresistant
  • XRT has limited use in metastatic disease
  • Painful bone or recurrent abdominal metastases
  • Brain metastases

32
Summary
  • RCC is relatively rare but increasing incidence
  • Associated with tobacco and inherited disorders
  • Surgery is the only curative modality for Stage
    I, II, and III
  • Stage IV disease holds poor prognosis despite
    advancements in molecular understanding
  • IL-2, Sorafenib, Sunitinib, and Temsirolimus are
    FDA approved treatments for advanced RCC

33
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34
References
  • 1. Pantuck AJ, et al. The changing natural
    history of renal cell carcinoma. J Urology 2001
    1661612.
  • 2. Cohen HT, McGovern FJ. Renal-cell carcinoma.
    NEJM. 20053532477.
  • 3. Clinical Practice Guidelines in Oncology
    Kidney Cancer, version 2.2006. National
    Comprehensive Cancer Network. www.ncc.org
  • 4. Motzer RJ, et al. Sunitinib versus Interferon
    Alfa in Metastatic Renal-Cell Carcinoma.
    NEJM356115.
  • 5. Drucker BJ. Renal cell carcinoma current
    status and future prospects. Cancer Treat Rev.
    200531536.
  • 6. Lam JS et al. Renal cell carcinoma 2005 new
    frontiers in staging, prognostication and
    targeted molecular therapy. J Urol. 2005
    1731853.
  • 7. Twardowski PW et al. Emerging targeted
    therapies for renal cell carcinoma. 2006.
    www.cancerpublications.com
  • 8. Escudier B, Eisen T, et al. Sorafenib in
    advanced clear-cell renal-cell carcinoma. NEJM.
    2007365(2)125.
  • 9. Hudes G. et al. Temsirolimus, Interferon alfa,
    or both for advanced renal-cell carcinoma. NEJM.
    20073562271.
  • 10. Atkins MB. Renal cell carcinoma. 2007.
    www.uptodate.com
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