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Medical Students 2011 - J.B. Vermorken - GYNAECOLOGICAL CANCER SESSION - Cervical Cancer
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Medical Students 2011 - J.B. Vermorken - GYNAECOLOGICAL CANCER SESSION - Cervical Cancer

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Medical Students 2011 - J.B. Vermorken - GYNAECOLOGICAL CANCER SESSION - Cervical Cancer Medical Students 2011 - J.B. Vermorken - GYNAECOLOGICAL CANCER SESSION - Cervical Cancer Presentation Transcript

  • Cervical Cancer Clinical Presentation, Diagnosis, Staging (1) Treatment (2) Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium ESO student course, Ioannina, 2011
  • < 87.3 < 16.2 < 32.6 < 9.3 < 26.2 2009 11,270 cases* 2009 4,070 deaths* Estimates of the Worldwide Incidence of Cervical Cancer / 100,000 women GLOBOCAN 2002; IARC. / 100,000 women *American Cancer Society Facts and Figures 2009
  • Cervical Cancer Epidemiology
    • Second most common cancer in women worldwide, comprising 12% of all cancers in women
    • Nearly 500.000 new cases worldwide, responsible for 274.000 deaths
    • Up to 80% in developing countries
    • Mean age for cervical cancer is 52.2 years. Distribution bimodal (peaks at 35-39 and 60-64 years)
    • The crude incidence in the European Union is 13.2/100.000 and the crude mortality rate is 5.9/100.000 women/year
  • Cervical Cancer Risk factors
    • Multiple partners
    • Partners more promiscuous
    • First sexual intercourse at early age
    • Low socio economic status
    • Reproductive history
    • Smoking habits
    • Oral and barrier contraceptive use
    • Dietary factors
    • Immunosuppression
    • Frequency of obtaining Pap smears
  • Cervical Cancer Etiology
    • Important role for HPV infection
      • HPV detectable in > 90% of tumor specimen
      • HPV detectable in > 90% of preinvasive lesions
      • HPV detectable in > 40% of those with normal cytology
    • Association particularly strong with specific HPV types (16, 18, 33 and 45), increasing viral load and infection with multiple HPV types
    • Many other risk factors are confounding, but cave smoking habits, hormonal and dietary factors
  • Cervical Cancer Detection: Dr. George Papanicolau
    • First Pap at age 18 or onset of sexual relations, whichever comes first
    • Annual Pap for all women with risk factors
    • Following three normal exams in the absence of risk factors, less frequent Paps may be considered in consultation with a physician
    • Bethesda system Dysplasia / CIN system Pap system
    • Normal limits Normal I
    • Infection Inflammatory atypia II
    • Squamous cell abnorm.
    • Atypical of Undertermined Squamous atypia
    • Significance (ASCUS) IIR
    • Low-grade Intra-epithelial HPV atypia
    • Lesion (LSIL) Mild dysplasia CIN 1
    • High-grade Intraepithelial Moderate dysplasia CIN 2 III
    • lesion (HSIL) Severe dysplasia
    • carcinoma in situ IV
    • - Squamous cell ca Squamous cell ca V
    CIN 3
  • Cervical Cancer: Colposcopy
  •  
  •  
  • Cervical Cancer: Signs and Symptoms of Invasive Disease
    • May be silent until advanced disease develops
    • Postcoital bleeding
    • Foul vaginal discharge
    • Abnormal bleeding
    • Pelvic pain
    • Unilateral leg swelling or pain
    • Pelvic mass
    • Gross cervical lesion
  • Pretreatment work-up
    • Physical examination: pelvic (exam)
    • Biopsy/conisation
    • blood count, serum, glucose, blood urea nitrogen, creatinine, liver function tests, chest x-ray, mammogram
    • Indication: IVP, barium enema, cystoscopy, proctoscopy
    • Indication: CT or MRI (not FIGO)
  • FIGO Classification (2009) Stage I: carcinoma confined to the cervix IA: No clinically visible lesion IB: clinically visible lesion IB1: tumor ≤ 4 cm IB2: tumor > 4 cm
  • FIGO Stage II: I nvasion beyond the uterus, but not to the pelvic wall or to the lower third of the vagina IIA: Without parametrial invasion (IIA1 ≤4.0 cm IIA2 > 4.0 cm) IIB: With obvious parametrial invasion
  • FIGO Stage III Stage IV: IVA: Extension to the rectum or the bladder IVB: Extension to distant organs IIIA: Invasion to the lower third of the vagina IIIB : Invasion to the pelvic wall and/or with hydronephrosis
  • Treatment of Cervical Cancer “ What is standard?” “ What is new?”
  • Prognostic Factors in Cervical Cancer
        • Stage (FIGO) IIB, IIIA/B, IV (advanced)
    • IB, IIA (early)
        • Histology
        • Tumor size
        • Tumor grade
        • LI / VI
        • Dept of stromal infiltration
        • Level of SCC-antigen
        • Nodal metastases*
    • *Predominant adverse prognostic factor
  • Standard Treatment of Cervical Cancer 1990s
    • Early-stage disease: Radical hysterectomy with PLND,
    • or
    • Radical radiation therapy
    • Advanced-stage disease: Radical radiation therapy
    • R/M disease: BSC or palliative CT
  • The Role of Chemotherapy in Cervical Cancer Applications
    • For palliation
      • Patients with stage IV B disease
      • Patients with recurrent disease
    • As part of primary therapy
      • Neoadjuvant chemotherapy (NACT)
      • Adjuvant chemotherapy (ACT)
      • Concurrent chemoradiation (CRT)
  • Single Agent Chemotherapy in CC
    • Cyclophosphamide 15% Chlorambucil 25%
    • Dibromodulcitol 23% Galactitol 19%
    • Ifosfamide 25% Melphalan 20%
    • Carboplatin 15% Porfiromycin 22%
    • Cisplatin 23% 5-fluorouracil 20%
    • Doxorubicin 17% Methotrexate 18%
    • Hexamethylmelamine 19% Vincristine 18%
    • Eifel, Berek & Thigpen, 2001
  • Lessons learned in the 1980s and 1990s R/M cervical cancer
    • Platinum-based therapies most effective
    • Cisplatin seems more active than carboplatin or iproplatin
    • More response and toxicity (no survival benefit):
      • Increased platinum dose
      • Add other agents
    • Single agent cisplatin at 50 mg/m² became standard
  • New Cytotoxic Agents in R/M Cervical Cancer Agent No. studies No. pts Prior CT RR Paclitaxel 2 87 -/+ 17 - 25 Docetaxel 1 18 -/+ 25 Irinotecan 5 218 -/+ 0 - 24 Topotecan 3 105 -/+ 13 – 18 Vinorelbine 2 81 - 17 – 18 Gemcitabine 3 92 -/+ 8 - 11
  • Four-arm Trial in Stage IVB, Recurrent or Persistant Cervial Carcinoma: GOG #204  cisplatin + paclitaxel Stage IVB  cisplatin + topotecan Recurrent CC  cisplatin + vinorelbine Persistent CC  cisplatin + gemcitabine May 2003-April 2007, 513 pts enrolled. Interim analysis (April 2007): closure (advantage unlikely) Monk BJ et al, J Clin Oncol 2009; 4649-4655 R A N D O M I Z E
  • GOG 204 Progression-Free Survival Monk BJ et al, J Clin Oncol 2009; 4649-4655
  • GOG 204 Overall Survival Monk BJ et al, J Clin Oncol 2009; 4649-4655
  • Rational Targeted Therapies for Recurrent Cervical Cancer: Beyond GOG 204
    • Therapeutic HPV Vaccines
    • Oncolytic viruses
    • Anti-EGFR
    • Anti-angiogenesis
      • Cardinal processes in cervical cancer growth, invasion, and metastasis
      • E6 mediated inactivation of wild-type p53 up-regulates VEGF 1 and down-regulates TSP-1 2
    • EGFR=Epidermal growth factor receptor
    • VEGF=Vascular endothelial growth factor
    • TSP-1=Thrombospondin-1
    • Toussaint-Smith E et al Oncogene. 23(17):2988-95. 2004
    • Dameron KM et al Science 265:1582-1584. 1994
  • GOG 240 Schema Eligibility : 1. Primary stage IVB or Recurrent/persistent carcinoma of the cervix 2. Measureable disease 3. GOG PS 0-1 Regimen I Paclitaxel 135 mg/m 2 IV d1 (24 h) Cisplatin 50 mg/m 2 IV d2 Q21d to progression/toxicity Regimen II Paclitaxel 135 mg/m 2 IV d1 (24 h) Cisplatin 50 mg/m 2 IV d2 Bevacizumab 15 mg/kg IV d2 Q21d to progression/toxicity Regimen IV Paclitaxel 175 mg/m 2 IV d1 (3 h) Topotecan 0.75 mg/m 2 d1-3 (30 m) Bevacizumab 15 mg/kg IV d1 Q21d to progression/toxicity Regimen III Paclitaxel 175 mg/m 2 IV d1 (3 h) Topotecan 0.75 mg/m 2 d1-3 (30 m) Q21d to progression/toxicity R A N D O M I Z E
  • The Role of Chemotherapy in Cervical Cancer Applications
    • For palliation
      • Patients with stage IV B disease
      • Patients with recurrent disease
    • As part of primary therapy
      • Neoadjuvant chemotherapy (NACT) - Experimental
      • Adjuvant chemotherapy (ACT) - Experimental
      • Concurrent chemoradiation (CRT) – Standard 1999!
      • CRT + ACT standard in 2009?
  • Standard Treatment of Cervical Cancer 2011
    • No standard for R/M disease: cisplatin good option
    • Patient preferably should be treated in trials
    • Cisplatin plus paclitaxel control arm in randomized trials of combinations (USA)
    • NACT and ACT experimental
    • Chemoradiation is the standard for patients, who otherwise would be treated with radiotherapy
    • Cisplatin-based two drug regimen during RT followed by platinum-based ACT possibly new standard for locally advanced cervical cancer
  • New Approaches in Cervical Cancer
        • New drugs
        • New combinations
        • Dose dense therapies
        • Non-cytotoxic therapies
        • Hyperthermia and chemotherapy (and/or RT)
        • Cytotoxics / non-cytotoxics to enhance RT effect
        • Methods to overcome hypoxia during RT
        • Vaccine approaches
        • Gene therapy
  •