Cervical Cancer Clinical Presentation, Diagnosis, Staging (1) Treatment (2) Jan B. Vermorken, MD, PhD Department of Medica...
< 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 C...
Cervical Cancer Epidemiology <ul><li>Second most common cancer in women worldwide, comprising 12% of all cancers in women ...
Cervical Cancer Risk factors <ul><li>Multiple partners </li></ul><ul><li>Partners more promiscuous </li></ul><ul><li>First...
Cervical Cancer Etiology <ul><li>Important role for HPV infection </li></ul><ul><ul><li>HPV detectable in > 90% of tumor s...
Cervical Cancer Detection:  Dr. George Papanicolau <ul><li>First Pap at age 18 or onset of sexual relations, whichever com...
<ul><li>Bethesda system Dysplasia / CIN system Pap system </li></ul><ul><li>Normal limits Normal I </li></ul><ul><li>Infec...
Cervical Cancer: Colposcopy
 
 
Cervical Cancer: Signs and Symptoms of Invasive Disease <ul><li>May be silent until advanced disease develops </li></ul><u...
Pretreatment work-up <ul><li>Physical examination: pelvic (exam) </li></ul><ul><li>Biopsy/conisation </li></ul><ul><li>blo...
FIGO Classification (2009) Stage I: carcinoma confined to the cervix IA: No clinically visible lesion IB: clinically visib...
FIGO Stage II:  I nvasion beyond the uterus,  but not to the pelvic wall or to the lower third of the vagina IIA:  Without...
FIGO Stage III Stage IV: IVA: Extension to the rectum or the bladder  IVB: Extension to distant organs IIIA: Invasion to t...
Treatment of Cervical Cancer “ What is standard?” “ What is new?”
Prognostic Factors in Cervical Cancer <ul><ul><ul><li>Stage (FIGO)  IIB, IIIA/B, IV (advanced) </li></ul></ul></ul><ul><li...
Standard Treatment of Cervical Cancer  1990s <ul><li>Early-stage disease: Radical hysterectomy with PLND, </li></ul><ul><l...
The Role of Chemotherapy in Cervical Cancer Applications <ul><li>For palliation </li></ul><ul><ul><li>Patients with stage ...
Single Agent Chemotherapy in CC <ul><li>Cyclophosphamide 15% Chlorambucil  25%  </li></ul><ul><li>Dibromodulcitol 23% Gala...
Lessons learned in the 1980s and 1990s R/M cervical cancer <ul><li>Platinum-based therapies most effective </li></ul><ul><...
New Cytotoxic Agents in R/M Cervical Cancer Agent No. studies No. pts  Prior CT RR Paclitaxel 2 87 -/+ 17 - 25 Docetaxel 1...
Four-arm Trial in Stage IVB, Recurrent or Persistant Cervial Carcinoma: GOG #204    cisplatin + paclitaxel Stage IVB    ...
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 <ul><li>Therapeutic HPV Vaccines </li></ul><ul><...
GOG 240 Schema Eligibility : 1. Primary stage IVB or Recurrent/persistent carcinoma of the cervix 2. Measureable disease 3...
The Role of Chemotherapy in Cervical Cancer Applications <ul><li>For palliation </li></ul><ul><ul><li>Patients with stage ...
Standard Treatment of Cervical Cancer 2011 <ul><li>No standard for R/M disease: cisplatin good option </li></ul><ul><li>Pa...
New Approaches in Cervical Cancer <ul><ul><ul><li>New drugs </li></ul></ul></ul><ul><ul><ul><li>New combinations </li></ul...
 
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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

  1. 1. 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
  2. 2. < 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
  3. 3. Cervical Cancer Epidemiology <ul><li>Second most common cancer in women worldwide, comprising 12% of all cancers in women </li></ul><ul><li>Nearly 500.000 new cases worldwide, responsible for 274.000 deaths </li></ul><ul><li>Up to 80% in developing countries </li></ul><ul><li>Mean age for cervical cancer is 52.2 years. Distribution bimodal (peaks at 35-39 and 60-64 years) </li></ul><ul><li>The crude incidence in the European Union is 13.2/100.000 and the crude mortality rate is 5.9/100.000 women/year </li></ul>
  4. 4. Cervical Cancer Risk factors <ul><li>Multiple partners </li></ul><ul><li>Partners more promiscuous </li></ul><ul><li>First sexual intercourse at early age </li></ul><ul><li>Low socio economic status </li></ul><ul><li>Reproductive history </li></ul><ul><li>Smoking habits </li></ul><ul><li>Oral and barrier contraceptive use </li></ul><ul><li>Dietary factors </li></ul><ul><li>Immunosuppression </li></ul><ul><li>Frequency of obtaining Pap smears </li></ul>
  5. 5. Cervical Cancer Etiology <ul><li>Important role for HPV infection </li></ul><ul><ul><li>HPV detectable in > 90% of tumor specimen </li></ul></ul><ul><ul><li>HPV detectable in > 90% of preinvasive lesions </li></ul></ul><ul><ul><li>HPV detectable in > 40% of those with normal cytology </li></ul></ul><ul><li>Association particularly strong with specific HPV types (16, 18, 33 and 45), increasing viral load and infection with multiple HPV types </li></ul><ul><li>Many other risk factors are confounding, but cave smoking habits, hormonal and dietary factors </li></ul>
  6. 6. Cervical Cancer Detection: Dr. George Papanicolau <ul><li>First Pap at age 18 or onset of sexual relations, whichever comes first </li></ul><ul><li>Annual Pap for all women with risk factors </li></ul><ul><li>Following three normal exams in the absence of risk factors, less frequent Paps may be considered in consultation with a physician </li></ul>
  7. 7. <ul><li>Bethesda system Dysplasia / CIN system Pap system </li></ul><ul><li>Normal limits Normal I </li></ul><ul><li>Infection Inflammatory atypia II </li></ul><ul><li>Squamous cell abnorm. </li></ul><ul><li>Atypical of Undertermined Squamous atypia </li></ul><ul><li>Significance (ASCUS) IIR </li></ul><ul><li>Low-grade Intra-epithelial HPV atypia </li></ul><ul><li>Lesion (LSIL) Mild dysplasia CIN 1 </li></ul><ul><li>High-grade Intraepithelial Moderate dysplasia CIN 2 III </li></ul><ul><li>lesion (HSIL) Severe dysplasia </li></ul><ul><li>carcinoma in situ IV </li></ul><ul><li>- Squamous cell ca Squamous cell ca V </li></ul>CIN 3
  8. 8. Cervical Cancer: Colposcopy
  9. 11. Cervical Cancer: Signs and Symptoms of Invasive Disease <ul><li>May be silent until advanced disease develops </li></ul><ul><li>Postcoital bleeding </li></ul><ul><li>Foul vaginal discharge </li></ul><ul><li>Abnormal bleeding </li></ul><ul><li>Pelvic pain </li></ul><ul><li>Unilateral leg swelling or pain </li></ul><ul><li>Pelvic mass </li></ul><ul><li>Gross cervical lesion </li></ul>
  10. 12. Pretreatment work-up <ul><li>Physical examination: pelvic (exam) </li></ul><ul><li>Biopsy/conisation </li></ul><ul><li>blood count, serum, glucose, blood urea nitrogen, creatinine, liver function tests, chest x-ray, mammogram </li></ul><ul><li>Indication: IVP, barium enema, cystoscopy, proctoscopy </li></ul><ul><li>Indication: CT or MRI (not FIGO) </li></ul>
  11. 13. 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
  12. 14. 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
  13. 15. 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
  14. 16. Treatment of Cervical Cancer “ What is standard?” “ What is new?”
  15. 17. Prognostic Factors in Cervical Cancer <ul><ul><ul><li>Stage (FIGO) IIB, IIIA/B, IV (advanced) </li></ul></ul></ul><ul><li>IB, IIA (early) </li></ul><ul><ul><ul><li>Histology </li></ul></ul></ul><ul><ul><ul><li>Tumor size </li></ul></ul></ul><ul><ul><ul><li>Tumor grade </li></ul></ul></ul><ul><ul><ul><li>LI / VI </li></ul></ul></ul><ul><ul><ul><li>Dept of stromal infiltration </li></ul></ul></ul><ul><ul><ul><li>Level of SCC-antigen </li></ul></ul></ul><ul><ul><ul><li>Nodal metastases* </li></ul></ul></ul><ul><li>*Predominant adverse prognostic factor </li></ul>
  16. 18. Standard Treatment of Cervical Cancer 1990s <ul><li>Early-stage disease: Radical hysterectomy with PLND, </li></ul><ul><li>or </li></ul><ul><li>Radical radiation therapy </li></ul><ul><li>Advanced-stage disease: Radical radiation therapy </li></ul><ul><li>R/M disease: BSC or palliative CT </li></ul>
  17. 19. The Role of Chemotherapy in Cervical Cancer Applications <ul><li>For palliation </li></ul><ul><ul><li>Patients with stage IV B disease </li></ul></ul><ul><ul><li>Patients with recurrent disease </li></ul></ul><ul><li>As part of primary therapy </li></ul><ul><ul><li>Neoadjuvant chemotherapy (NACT) </li></ul></ul><ul><ul><li>Adjuvant chemotherapy (ACT) </li></ul></ul><ul><ul><li>Concurrent chemoradiation (CRT) </li></ul></ul>
  18. 20. Single Agent Chemotherapy in CC <ul><li>Cyclophosphamide 15% Chlorambucil 25% </li></ul><ul><li>Dibromodulcitol 23% Galactitol 19% </li></ul><ul><li>Ifosfamide 25% Melphalan 20% </li></ul><ul><li>Carboplatin 15% Porfiromycin 22% </li></ul><ul><li>Cisplatin 23% 5-fluorouracil 20% </li></ul><ul><li>Doxorubicin 17% Methotrexate 18% </li></ul><ul><li>Hexamethylmelamine 19% Vincristine 18% </li></ul><ul><li>Eifel, Berek & Thigpen, 2001 </li></ul>
  19. 21. Lessons learned in the 1980s and 1990s R/M cervical cancer <ul><li>Platinum-based therapies most effective </li></ul><ul><li>Cisplatin seems more active than carboplatin or iproplatin </li></ul><ul><li>More response and toxicity (no survival benefit): </li></ul><ul><ul><li>Increased platinum dose </li></ul></ul><ul><ul><li>Add other agents </li></ul></ul><ul><li>Single agent cisplatin at 50 mg/m² became standard </li></ul>
  20. 22. 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
  21. 23. 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
  22. 24. GOG 204 Progression-Free Survival Monk BJ et al, J Clin Oncol 2009; 4649-4655
  23. 25. GOG 204 Overall Survival Monk BJ et al, J Clin Oncol 2009; 4649-4655
  24. 26. Rational Targeted Therapies for Recurrent Cervical Cancer: Beyond GOG 204 <ul><li>Therapeutic HPV Vaccines </li></ul><ul><li>Oncolytic viruses </li></ul><ul><li>Anti-EGFR </li></ul><ul><li>Anti-angiogenesis </li></ul><ul><ul><li>Cardinal processes in cervical cancer growth, invasion, and metastasis </li></ul></ul><ul><ul><li>E6 mediated inactivation of wild-type p53 up-regulates VEGF 1 and down-regulates TSP-1 2 </li></ul></ul><ul><li>EGFR=Epidermal growth factor receptor </li></ul><ul><li>VEGF=Vascular endothelial growth factor </li></ul><ul><li>TSP-1=Thrombospondin-1 </li></ul><ul><li>Toussaint-Smith E et al Oncogene. 23(17):2988-95. 2004 </li></ul><ul><li>Dameron KM et al Science 265:1582-1584. 1994 </li></ul>
  25. 27. 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
  26. 28. The Role of Chemotherapy in Cervical Cancer Applications <ul><li>For palliation </li></ul><ul><ul><li>Patients with stage IV B disease </li></ul></ul><ul><ul><li>Patients with recurrent disease </li></ul></ul><ul><li>As part of primary therapy </li></ul><ul><ul><li>Neoadjuvant chemotherapy (NACT) - Experimental </li></ul></ul><ul><ul><li>Adjuvant chemotherapy (ACT) - Experimental </li></ul></ul><ul><ul><li>Concurrent chemoradiation (CRT) – Standard 1999! </li></ul></ul><ul><ul><li>CRT + ACT standard in 2009? </li></ul></ul>
  27. 29. Standard Treatment of Cervical Cancer 2011 <ul><li>No standard for R/M disease: cisplatin good option </li></ul><ul><li>Patient preferably should be treated in trials </li></ul><ul><li>Cisplatin plus paclitaxel control arm in randomized trials of combinations (USA) </li></ul><ul><li>NACT and ACT experimental </li></ul><ul><li>Chemoradiation is the standard for patients, who otherwise would be treated with radiotherapy </li></ul><ul><li>Cisplatin-based two drug regimen during RT followed by platinum-based ACT possibly new standard for locally advanced cervical cancer </li></ul>
  28. 30. New Approaches in Cervical Cancer <ul><ul><ul><li>New drugs </li></ul></ul></ul><ul><ul><ul><li>New combinations </li></ul></ul></ul><ul><ul><ul><li>Dose dense therapies </li></ul></ul></ul><ul><ul><ul><li>Non-cytotoxic therapies </li></ul></ul></ul><ul><ul><ul><li>Hyperthermia and chemotherapy (and/or RT) </li></ul></ul></ul><ul><ul><ul><li>Cytotoxics / non-cytotoxics to enhance RT effect </li></ul></ul></ul><ul><ul><ul><li>Methods to overcome hypoxia during RT </li></ul></ul></ul><ul><ul><ul><li>Vaccine approaches </li></ul></ul></ul><ul><ul><ul><li>Gene therapy </li></ul></ul></ul>

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