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V. Kesic - Cervical cancer - State of the art

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  • Prevention is not a new invention. It took a long way, 4000 years way, from old Egypt to Zur Hausen who identified HPV virus and got Nobel Prize, to realize
  • This is when precancer develops and which will eventually progress to CC
  • In two words…
  • This means that there must be something to modify the course of HPV - Immune response

Transcript

  • 1. Vesna Kesić Institute of Obstetrics and Gynecology Clinical Center of Serbia EASO Masterclass in Clinical Oncology 27-29. October, 2011, Amman, Jordan Cervical Cancer - State of Art -
  • 2. It has been estimated that approximately 500 000 women develop cervical cancer every year, and 260 000 women die of the disease. WHO, 2009
  • 3. 370,000 96,000 Parkin, 2000
    • Commonest among women in developing world
    • 80% of new cases and deaths occur
    • Less than 5% of global cancer resources
    • Disease of inequality of access to health care
    Facts about Cervical cancer
    • Curable if detected early !
  • 4. Life-time risk (%) for cervical cancer USA 0,83 Scandinavia 1,01 India 2,22 South Amerika 5,31 5.8 West Asia 7.4 East Asia 7.4 Australia/N. Zeal. 7.7 North America 9.0 North Europe 10.0 West Europe 10.7 South Europe 12.1 North Africa 14.5 East Europe 18.7 South East Asia 26.2 South Cent. Asia 28.0 Central Africa 28.6 South America 29.3 West Africa 30.6 Central. America 38.2 South Africa 42.7 East Africa
  • 5. Incidence of Cervical Cancer per 100,000 Females in Arab World < 4.0 4.0 – 7.9 8.0 – 11.9 12.0 – 15.9 ≥ 16.0 Algeria Map produced by Prof. Inas Elattar Pakistan Pakistan Morocco Afghanistan Palestine Bahrain Iran Iraq Sudan Somalia Libya Egypt Saudi Arabia Oman Yemen UAE Jordan Qatar Kuwait Syria Lebanon Djibouti
  • 6. Two key reasons : 1. The vast majority of women still know little about cervical cancer or what they should do to prevent it. 2. Many countries have ineffective prevention programmes or no prevention programmes at all.
  • 7. As the consequence, a high proportion of cervical cancer is diagnosed when already advanced and metastatic, leading to low probability of cure and high mortality rates . 85% Cervical Cancer: Groote Schuur Hospital, 1984 – 2000 (n = 3098)
  • 8. Every 2 minutes , one women dies of cervical cancer !
  • 9. Most of these deaths could be prevented!
  • 10. From old Egypt, 2200 B.C… … Harald Zur Hausen Nobel Prize, 2008
    • The first known description of uterine
    • cancer
    • Documentation of linen sheath as
    • condom for prevention of disease
    to…
  • 11. Cervical cancer Human papiloma virus (HPV) infection has a causal role in the development of cervical cancer. HPV infection 99.7% !
  • 12. 10 years > 5 years Normal HPV H-SIL Cancer Cervical carcinogenesis
  • 13. Majority of HPV infections are transient and will resolve spontaneously within two years. The 5-year clearance rate of HPV is 92%
  • 14. Human papiloma virus (HPV) infection is necessary for the development of H-SIL and invasive cancer but it is not a sufficient cause.
  • 15. Cervical carcinogenesis
  • 16. HPV infe c tion Low-grade changes High-grade lesions Cancer 300 milion s 30 milion s 10 milion s 0. 5 milion s HPV E6, E7 Cellular changes Many years 8-15 HPV infe ction Parkin DM, Bray F, Ferlay J, Pisani P. CA Cancer J Clin. 2005;55:74–108 World Health Organization. Geneva, Switzerland: World Health Organization; 1999:1–22. Number of cases 0.15% ! Estimated World Burden of HPV-related Disease and Diagnoses
  • 17. Is it possible ? Preven tion of Cervical Cancer
  • 18. Natural history of cervical cancer and prevention Precancerous lesion Invasive disease Normal Cervix Persistent infection with HR types HPV Clearance Progression Initial HPV infection
  • 19. HPV va ccine
  • 20. Vaccination is not a substitute for routine cervical cancer screening Vaccinated females should have cervical cancer screening as recommended !
  • 21. C ytology George Pappanicolao u , 1945
  • 22. Colposcopy Hans Hinselmann, 1920
  • 23. Cervical cancer has become detectable and curable disease.
  • 24. Biops y and/or ECC H istopathology
  • 25. Invasive cervical cancer
  • 26. Treatment modalities in Management of Cervical Cancer Surgery Radiation Chemotherapy
    • All combinations are possible!
    • All schedulings are possible!
  • 27. Staging of cervical cancer is based on clinical evaluation The next step – staging !
  • 28.
    • Vaginal and rectal examination
    • Colposcopy
    • Biopsy / ECC
    • Conization
    • Chest X-ray
    • IVP
    • Cystoscopy
    • Recto-sygmoidoscopy
    Staging procedure
  • 29.
    • Lymphangiography
    • Arteriography
    • Laparoscopy
    • Ultrasound
    • CT
    • NMR
    • PET
    Optional diagnostic procedures
  • 30. FIGO 2009 Stage of the disease I II III IV Surgery Radiation
  • 31. Surgery is the mainstay of treatment in early-stage disease, whilst radiotherapy is used for more advanced stages. Treatment of Cervical Cancer
  • 32. Treatment of Early Stage Cervical Cancer
  • 33. Most patients with early stage cervical cancer are treated by either radical surgery or radical radiotherapy. Both treatment modalities have proven to be equally effective . Landoni et al : Lancet 1997 350 535- 540
  • 34.
    • Treatment decisions are based on:
    • Age
    • Medical condition of the patient
    • Tumor related factors
    • Treatment preferences
  • 35. Standard surgical procedure for cervical cancer is radical hysterectomy with pelvic lymphadenectomy
    • Uterus
    • Paracervical tissues
    • Upper part of vagina
    • Pelvic lymphnodes
  • 36.
    • Acute
    • Blood loss
    • Urinary fistula
    • Pulmonary embolus
    • Small bowel obstruction
    • Febrile morbidity
    Complications of Radical Hysterectomy
    • Subacute/chronic
    • Bladder dysfunction
    • Lymphcyst formation
    • Ureteral obstruction
    • Partial venous obstruction
    • Thrombosis
  • 37. ? Do all patients with early invasive cervical cancer need a radical hysterectomy?
    • Microinvasive carcinoma (Ia)
    • Small volume invasive disease (small Ib1)
  • 38. Modern approach to the surgical management of cervical cancer Conservative Radical for early disease for advanced disease Tailored
  • 39.
    • The reasons of conservative surgery
    • To prevent the potential complications
    • of radical treatment
    • To preserve fertility
  • 40. Age adjusted incidence rate of cervical cancer in Europe, 2008 GLOBOCAN 2008, International Agency for Research on Cancer http://globocan.iarc.fr/ 21/1/2011 11 331 patients (20.78%) < 39 years
    • Physical ability
    • Social life
    • Sexual responsiveness
    • Body image
    • Future reproductive
    • capabilities !
  • 41. FIGO Ia Kapetown , 2009 Ib + Some proximal IIB (MRI provides size information in 3D)
    • Stage I a 1
    • depth <3 mm
    • width <7 mm
    Stage I a 2 depth <5 mm width <7 mm
  • 42. x The diagnosis of stage Ia cervical cancer should be based on conization !
  • 43. If distant spread is very unlikely, simple but complete excision of the lesion suffices. If it is likely that the cancer has spread, than an extended operation should be performed.
  • 44. Depth of invasion LVSI Risk of node metastases 0-3 - < 1 / 1000 0-3 + 2 / 100 3-5 - 2/ 100 3-5 + 5 / 100 Stage Ia cervical cancer
  • 45.
    • Complete excision (conization or
    • radical trachelectomy) in women
    • who wish to retain fertility
    • Simple hysterectomy or modified
    • hysterecotmy in women who do not
    • wish more pregnancies
    • Pelvic node dissection ?
    • decision based on LVSI
    Management of microinvasive cervical cancer
  • 46. Early invasive cervical cancer - stage Ib-IIa -
  • 47. Stage Ib1 < 4 cm Stage Ib2 > 4cm Stage IIa
  • 48. Parametria Lymphnodes Uterus Radical Hysterectomy
  • 49.
    • Recurrence in 3,4% cases
    • Successful pregnancy in 26.5% cases
    Plante et al. Gynecol Oncol. 2004 ;94:614-23 Daniel Dargent, 1996 Radical vaginal trachelectomy with laparoscopic pelvic lymphadenectomy
  • 50.
    • Prerequisites for trachelectomy
    • Strong fertility desire
    • Patient < 40 years
    • Tumor < 2 cm ( Ia2, Ib1)
    • No lymphovascular invasion
    • Negative lymphnodes
    • Favorable histology
    • Length of cervix > 2 cm
  • 51.
    • How often is the parametrium involved?
    Small Volume Cervical Cancer- Important issue
  • 52.
    • Tumor less than 2 cm
    • Infiltration depth less than 10 mm
    • Negative pelvic lymphnodes
    Parametrial involvement 5/799 (0.63%) The incidence of parametrial tumor involvement in early invasive cervical cancer Stegman M et al. Gynecol Oncol, 2007; 105:475-480
  • 53. T y p e II I T ype II Types of hysterectomy- Piver 40% Magrina, 1995 0.8% Urinary dysfunction 7% 1.1% Thromboembolism 0.3% 0.5% Deaths 1% 0.3% Digestive fistulas 4.8% 0.3% Urinary fistulas Type III Type II Complication
  • 54. Nerve sparing radical hysterectomy
  • 55. Cervical cancer- R i sk for lymphnode metasta ses Modified from Barakat, Bevers. Handbook of gynecologic oncology, 2000 40 55 IVa 30 45 III 20 25-35 IIb 11-13 20-25 IIa 20 25 Ib2 2 16 Ib1 < 1 4.8 Ia2 0 < 1 Ia1 % paraaortic pN1 % pelvic pN1 Stage
  • 56.
    • What is to be gained by removal of so many
    • normal lymph nodes?
    • What harm is done to the immune system
    • by doing so?
    • Should it be rather modest node dissection or
    • even sentinel node biopsy?
    Concerns about lymphadenectomy:
  • 57. Several pilot studies on the feasibility of lymphatic mapping/ sentinel node biopsy in cervical cancer have yielded promising results
    • Technique
      • Day-1 : cervical injection of 400µCi of 99mTc radiocolloid
      • Preop : cervicial injection of 4ml blue dye (patent or isosulfan blue)
      • Laparoscopy : SN detection (using gammaprobe and blue), elective dissection of SN(s) / side + frozen section
  • 58. Progno stic factors in stage Ib cervical cancer
    • P value Relative C.I.
    • Hazard 95%
    • Tumor size 0.005 2.1 1.3 - 3.6
    • Stromal invasion 0.013 1.7 1.1 - 2.5
    • Lymph met. 0.014 4.0 1.3 -12.1
    • to iliac com
    • Vascular invasion 0.232 1.7 0.7 - 4.0
    Adjuvant therapy in early cervical cancer When it will be necessary ?
  • 59. Prognostic significance of lymph node metastases 5-year survival Negative pelvic lymphnodes ………… 89% . Positive pelvic lymph nodes ………… 59%
  • 60.
    • Stage Ib Cervical Cancer - Independent Prognostic Factors
    • Clinical tumour size
    • Positive capillary-lymphatic spaces
    • Depth of invasion
    • Delgardo et al.
    • Gynecol Oncol 38: 352, 1990.
  • 61.  
  • 62. Adjuvant therapy in early cervical cancer For adjuvant irradiation - High risk, negative nodes - Positive nodes (1-3) - Poorly differentiated or undiferentiated tumor (G3) - LVSI (lympho-vascular space invasion) - Primary tumor > 3cm (tumor-cervix volume > 3cm ) - Endocervical invasion (barrel shaped ) - Inadequate surgery - Insufficient HP report For adjuvant chemo-irradiation - Positive resection margins - Involvement of parametria - Residual tumor
  • 63. Postoperative pelvic radiation in patients with nodal metastases has been the standard approach. It increases local control, but not the overall survival , due to inability of adjuvant pelvic irradiation to influence distant metastases
  • 64. Stage Ib2
  • 65. Stage Ib2- Management Options
    • Primary chemoradiation
    • Primary chemoradiation and completion TAH
    • Primary radical surgery and tailored adjuvant
    • radiation
    • Neoadjuvant chemotherapy then RH
  • 66.
    • Advanced cervical cancer
    • - stage IIb - IV -
    • Limited role of surgery
    • Extraperitoneal surgical debulking of
    • enlarged lymphnodes
    • After neoadjuvant chemotherapy
    An overall survival benefit has been shown for concurrent chemo-radiation therapy .
  • 67. The survival of patients that had bulky nodes removed has been significantly improved compared to those who had not the nodes resected (31% vs 6%) Hacker et al. Int. J Gynecol Cancer, 1995;5: 250-256 1.     KiKim et al. Gynecol Oncol, 1998; 69: 243-7
  • 68. Standard treatment for advanced stage Cervical Cancer has been Radiation
    • External beam radiotherapy using Linear accelerator
    • Four field technique to the central pelvis
    • Parametrial or side wall boosts controversial
    • Doses between 45 and 52 Gy in 25/30 fractions
    • All fields being treated daily
    • Brachytherapy
    • Preferably with no interval or gap
    • Low or intermediate dose 24 to 28 Gy, single insertion
    • High dose 14Gy/2 fractions, 18 Gy/3, 24 Gy/4 up to 30/5
  • 69. Extended-field radiotherapy is the standard part of treatment achieving the long-term survival of 30-40% for stage Ib patients with positive PALN. Consistent benefit of concurrent chemo-radiation with Cis-platin based chemotrerapy incorporated in extended-field irradiation.
  • 70. Systemic Chemotherapy in Treatment of Cervical Cancer
    • Neoadjuvant to Surgery
    • Neoadjuvant to Radiation
    • Concomitant chemo-radiation
    • Post operative adjuvant or maintenance?
    Chemotherapy for Cervix Cancer 1999 : the year the world changed !
  • 71. Neo-adjuvant chemotherapy followed by radical surgery has emerged as a possible alternative to conventional chemo-radiation, which may improve a survival in patients with stage Ib2 disease Benedetti -Panici P.J Clin Oncol, 2002; 20: 179-188 Tierney J. Eur J Cancer, 2003; 39: 2470-2486 14%
  • 72.
    • NACT to Radiation
    • Meta-analysis shows no overall benefit
    • Subset with > 25 mg/m2 per week
    • Subset treated q 14 days or less
    • Short, intense courses 3-7% improvement
    Tierney J. Eur J Cancer, 2003; 39: 2470-2486
  • 73. Potential advantages Concurrent chemoradiation (CRT) in cervical cancer
    • No delay or prolongation of RT
    • Inhibition of the repair of radiation – induced
    • sublethal damage
    • Sensitizing hypoxic cells to radiation damage
    • Eradication of systemic micrometastases
    • (not eradicated by local radiation)
  • 74. Radio- chemotherapy for Cervix Cancer Progression free survival ( 12%) Overall survival ( 16%)
    • Green, Lancet, 2001; 358: 781-6
    • Meta-analysis
    • 19 randomized trials
    • Significant local control and
    • distance recurrence benefit
    • Significant increase in grade 3 and 4
    • Haematological and gastro-intestinal
    • toxicities
  • 75. Concurrent Cis-platin based chemoradiation is considered the treatment of choice in locally advanced, metastatic and recurrent cervical cancer.
    • Weekly single agent Cisplatin
    • Dose 40mg/m², 6 weeks
    • Survival benefit of 12% over
    • RT alone
    Systemic Chemotherapy in Treatment of Cervical Cancer GOG 109
  • 76. Recurrent cervical cancer Recurrence rate Stage Ib-IIa ……………. 10-20% Stage IIb- IV……………. 50-70%
    • Treatment of recurrent disease depends on
    • previous tretament
    • site or extent of recurrence
    • disease-free interval
    • patient’s performance status
  • 77. Exenteration Survival Anterior exenteration: 30-60% Posterior exenteration: 20-46%
  • 78.
    • The overall prognosis
    • for most cervical cancers
    • is reasonably good, providing
    • they are detected early
    • adequate treatment is ensured
  • 79. Cervical cancer- survival by FIGO stage FIGO 25. Annual report, 1996-1998 98.7% 95.9%
  • 80. The incidence of cervical cancer in one country is an indicator of how much the whole society takes care about its women.