1. Gynecologic malignancies
Kocsis Judit

2. Cancer Statistics – 2010 Estimated New Cases Estimated Deaths
28% Breast
14% Lung and bronchus
10% Colon and rectum
6% Uterine corpus
5% Thyroid
4% Non-Hodgkin lymphoma
4% Melanoma
3% Kidney
3% Ovary
3% Pancreas
207,090
26% Lung and bronchus
15% Breast
9% Colon and rectum
7% Pancreas
5% Ovary
4% Non-Hodgkin lymphoma
3% Leukemia
3% Uterine corpus
2% Liver
2% Brain
39,840
43,470
13,850
7,950
21,880
Jemal, A. et al. CA Cancer J Clin 2010; 60:

3. Estimated New Gynecologic Cancers: 2010
Uterus 43,470 Vulva 3,900
Ovary 21,880 Vagina & Other 2,300
Cervix 12,200
Jemal, A. et al. CA Cancer J Clin 2010; 60:

5. GENERAL OVERVIEW OF GYNECOLOGIC CANCERS
79,480 new cases/yr of female genital system cancers in the U.S.
28,910 deaths in U.S. from genital system cancers in 2005
Diet, exercise and lifestyle choices play important roles in the prevention of cancer
Knowledge of family history also increases prevention and early diagnosis rates
Regular screening and self-examinations for appropriate cancers  early detection early intervention & therapy

6. Cervical cancer

7. Cervical Cancer Year Cases Deaths % 2006 9,710 3,700 38 2007 11,150
3,670 33
2008
11,070
3,870 35
2009
11,270
4,070 36
2010
12,200
4,210
Jemal A, et al. CA Cancer J Clin

8. Distribution of Patients
Cervical Carcinoma
Stage
Distribution of Patients
Five-year Survival I
62%
85% II
18%
60%
III
11%
35%

9. At risk groups Young (immature TZ)
Early age of first sexual intercourse
Multiple partners
Smoking
Type of contraception
Screening history

11. Treatment modalities
Surgery Radiotherapy Chemotherapy Radiochemotherapy

12. Treatment Depends on stage of disease
Surgery in early stage
Cone biopsy
Radical trachylectomy
Radical hysterectomy (Wertheim 1898)
Exenteration (Brunschwig)

13. Surgery Wertheim operation
first in 1898
radical hysterectomy
today standard procedure in operable cervix cancer (with bilateral pelvic lymphadenectomy)
Organ sparing technics (tachylectomy, radical trachylectomy)
in young patients, early stage

14. Chemotherapy Radiotherapy
Chemo-radiation as a primary treatment
In stage IB2-IVA-- Neoadjuvant chemotherapy combined with radical surgery- best overall survival
Radiotherapy as post operative treatment for poor prognostic disease
Chemotherapy or radiotherapy for palliation

15. Chemotherapy for Advanced or Recurrent Cervical Cancer
Combination chemotherapy
GOG 76X; Cisplatin + paclitaxel, 46% RR (Rose et al, 1999)
GOG 169; cisplatin + paclitaxel vs cisplatin; improved RR not OS (Moore et al 2004)
GOG 179; topotecan + cisplatin; improved OS (Long et al, 2005)
GOG 204; topotecan, gemcitabine, vinorelbine, paclitaxel
Interim analysis: so sig benefit; RR, PFS and OS favors cisplatin + paclitaxel (Monk et al, 2009)
Favored regimen: cisplatin + paclitaxel
Role of carboplatin + paclitaxel?

16. Cervical cancer Milestones
Surgery vs radiotherapy in early CC
NCI consensus statement in 1999 on the role of concurrent chemotherapy and radiation
The importance of Hb-level during radiation therapy for CC
The potential of hyperthermia

17. Cervical cancer and pregnancy
0,02-0,9% (real: 0,5-5%)
Obligatory screening at first pregnancy FU
Therapy: Conisation from 2. trimester
Treatment time and type of surgery depends on tumor stage and trimester!
trimester : maternal life is the priority
3. trimester: foetal life is priority

18. Endometrial cancer

19. ENDOMETRIAL CANCER Tumor of the endometrial layer of uterus
Most common gynecologic cc.
40,000 new case/year
7,000 death/year
4. most common female cc. (US)
2. most commmon female cc. (UK)
5. most common female cc.(worldwide)
West developed > South East Asia
1970s increase
Due to HRT (estrogen)
Histology: adenocarcinoma
These are the statistics for the US population 19

20. Uterine Neoplasia Hyperplasia Adenocarcinoma Sarcoma Sporadic
Inherited
Lynch syndrome (HNPCC)
Cowden’s disease
BRCA syndrome?
Type I
Type II
Estrogen-dependent
Endometrioid
MMR/MSI
PTEN, KRAS
Estrogen-independent
Serous, clear cell
TP53, HER-2/neu, p16

21. RISK FACTORS FOR ENDOMETRIAL CANCER
Early menarche
(<age 12)
Late menopause (>age 52)
Infertility or nulliparous
Obesity
Treatment with tamoxifen for breast cancer
Estrogen replacement therapy (ERT) after menopause
Diet high in animal fat
Diabetes
Age greater than 40
Caucasian women
Family history of endometrial cancer or hereditary nonpolyposis colon cancer (HNPCC)
Personal history of breast or ovarian cancer
Prior radiation therapy for pelvic cancer

22. Protective factors Oral Contraceptives Tobacco Smoking
Combined OC => 50% reduced rate
Actual reduction number small because uncommon in women of child bearing age
Long term offers protection
Reduced risk presumably => progesterone
Tobacco Smoking
Some evidence that it reduces the rate
Smokers have lower levels of estrogen and lower rate of obesity

23. Adipose tissue: Consequences of Obesity on Cancer Development
Obesity has been implicated in the development of
Type 2 diabetes
Heart disease
Stroke
Hypertension
Gallbladder disease
Osteoarthritis
Sleep apnea
Asthma
Psychological disorders or difficulties
Some cancers, including ovarian, cervical, breast, and endometrial
Dyslipidemia
Complications of pregnancy
Hirsuitism
Menstrual abnormalities
Stress incontinence
Increased surgical risk

24. Endometrial Cancer and Lifestyle24

25. Important Definitions
Obesity: having a very high amount of body fat in relation to lean body mass, or Body Mass Index (BMI) of 30 or higher for adults.
Body Mass Index (BMI): a measure of weight in relation to height, specifically weight in kilograms divided by the square of his or her height in meters.
Morbid Obesity-100 pounds above ideal weight or BMI over 40 (indication for bariatric surgery)
Bariatric surgery is the term for operations to help promote weight loss.

26. Endometrial Carcinoma
Etiology
Unnoposed estrogen hypothesis: exposure to unopposed estrogens
Pathology
Spreads through uterus, fallopian tubes, ovaries and out into peritoneal cavity
Metastasizes via blood and lymphatic system
Unopposed estrogen hypothesis is the theoretical framework used to explain the relationship between endogenous steroid hormones and endometrial cancer risk. This hypothesis proposes that that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when these are insufficiently counterbalanced by progesterone. In etiological terms, any factor that increases exposure to unopposed estrogens (such as estrogen therapy obesity, and irregular menstrual cycles) tends to increase the risk of the disease, while factors that decrease exposure to estrogens or increase progesterone levels (such as oral contraceptives or smoking) tend to be protective. 26

27. SYMPTOMS OF ENDOMETRIAL CANCER
Non-menstrual bleeding or discharge
Especially post-menopausal bleeding
Heavy bleeding
Dysuria
Pain during intercourse
Pain and/or mass in pelvic area
Weight loss
Back pain

28. ENDOMETRIAL CANCER Treatment Diagnosis Surgery-standard th
Pelvic examination
Pap smear (detect cancer spread to cervix)
Endometrial biopsy
Dilation and curettage
Transvaginal ultrasound
Treatment
Surgery-standard th
Hysterectomy
Salpingo-oophorectomy
Pelvic lymph node dissection
Laparoscopic lymph node sampling
Radiation therapy
Chemotherapy
Hormone therapy
Progesterone
Tamoxifen

29. Adjuvant Treatment Summary
Low Risk
Inter-mediate Risk
High Risk
Stage/ Grade
IA G1/2
IA (G3)
IB (all grades)
IIA
IIB
Stage III
Stage IV
UPSC (all stages)
CCC (all stages)
Undiff (all stages)
Post-operative
(complete
surgical
staging)
None
Vaginal Cuff Brachy Therapy or Observation
(*exception is in stage IIB)
Chemotherapy consider RT (Vaginal Cuff Brachy Therapy vs. whole pelvic)

30. Ovarian cancer

31. Risk Factors
Family history (primarily 2 or more first degree relatives)
Age (besides family history, this is the most important risk factor)
Nulliparity
Early menarche, late menopause
Late childbirth (age <35)
Environmental factors not yet defined

32. Risk Reduction OCP’s Breast Feeding Tubal ligation
Several Case-controlled studies have documented that OCP users have a 30-60% smaller chance of developing EOC than non-users
WHO study documented a RR 0.75
Greater reduction in risk with nulliparous women and increased duration of use
Breast Feeding
Tubal ligation
Risk reducing oophorectomy

33. Hereditary Ovarian Cancer
Account for 10% of EOC
BRCA1, BRCA2 (Hereditary Breast and Ovarian Cancer –HBOC)
Estimated 1/300 to 1/800 individuals carry a BRCA 1 or 2 mutation
Estimated 1/40 Ashkenazi Jews carry a BRCA 1 or 2 mutation
Hereditary Nonpolyposis Colorectal Cancer (HNPCC), Lynch II
Colorectal Cancer before age 50
Endometrial cancer before age 50
2 or more “Lynch” family members: colorectal, endometrial, ovarian, ureter/renal pelvis, gastric, biliary tract, small bowel, pancreatic, brain and sebaceous adenoma

34. Hereditary Ovarian Cancer
Risk relative to family history
Overall risk (OR) for women with a single first degree relative is 3.1 (5% lifetime risk)
OR with 2 or 3 relatives is 4.6 (7.2% lifetime risk)

35. Hereditary Ovarian Cancer
BRCA 1 Germline Mutations
Tumor suppressor gene on 17q21 (long arm)
Autosomal dominant
65 to 74% Breast Cancer risk
39-46% Ovarian Cancer risk
For women with Breast Cancer, the 10-year actuarial risk of developing Ovarian Cancer is 12%
Predominately high grade, serous or endometrioid adenocarcinoma
ACOG Practice Bulletin #103, 2009.

36. Hereditary Ovarian Cancer
BRCA2 Germline Mutations
Tumor suppressor gene on chromosome 13q12
65-74% Breast Cancer risk
12-20% Ovary Cancer risk
For women with Breast Cancer the 10-year actuarial risk of developing Ovarian Cancer is 6%
Predominately high grade, serous or endometrioid adenocarcinoma

37. Lancaster et al. Gynecol Oncol 2007; 107: 159-62.
Genetic Counseling
Patients with a >20-25% chance of having an inherited predisposition to breast or ovarian cancer and for whom genetic risk assessment is recommended
Women with a personal history of both breast and ovarian cancer
Women with ovarian cancer and a close relative with breast cancer at ≤50 or ovarian cancer at any age
Women with ovarian cancer at any age who are an Ashkenazi Jew
Women with breast cancer at ≤50 and a close relative with ovarian cancer or a male breast cancer
Women who are an Ashkenazi Jew and breast cancer ≤40
Women with a 1st or 2nd degree relative with a BRCA 1 or 2 mutation
Lancaster et al. Gynecol Oncol 2007; 107:

38. Lancaster et al. Gynecol Oncol 2007; 107: 159-62.
Genetic Counseling
Patients with a >5-10% chance of having an inherited predisposition to breast or ovarian cancer and for whom genetic risk assessment may be helpful
Women with breast cancer at ≤40
Women with bilateral breast cancer (particularly if breast cancer was at ≤50 years)
Women of Ashkenazi Jewish ancestry with breast cancer at ≤50 years
Women with breast or ovarian cancer at any age with two or more close relatives with breast cancer at any age (particularly if at least 1 breast cancer was at ≤50 years)
Unaffected women with a 1st or 2nd degree relative that meets one of the above criteria
Lancaster et al. Gynecol Oncol 2007; 107:

39. Hereditary Ovarian Cancer
HNPCC
Autosomal dominant
80% risk of developing colon cancer
60% risk of developing endometrial cancer
10-15% risk of developing ovarian cancer
Mismatch repair gene defects
MSH2, MSH6, PMS2 and MLH1 (chromosome 3)

40. Risk-reducing Salpingo-oophorectomy (RRSO)
Estimated 1000 cases of ovarian cancer could be prevented if elective SO was performed in all women undergoing hysterectomy at 40 years or older
5-10% of women with ovarian cancer have had a previous hysterectomy at age 40 or older
Obtain a family history for BRCA and HNPCC
ACOG Practice Bulletin #89, 2008

41. Screening for Ovarian Cancer
There is no evidence that screening for Ovarian Cancer leads to earlier detection or improved survival…
Nonetheless, the following have been or are being used
TVS
CA125
Multimodal
Symptoms
Biomarkers

42. EOC

43. Histology Histology Incidence Serous (high and low grade) 40-50%
Most common
Endometrioid
15-25%
2nd most common
Mucinous
6-16%
Clear Cell
5-11%
Other

44. Symptoms of Ovarian Cancer
Largely non-specific
Increase in abdominal girth (ascites)
Bloating
Fatigue
Abdominal pain
Early satiety
Indigestion
Constipation
Weight loss, unexplained
New onset of urinary frequency or incontinence

45. FIGO Staging
Stage I
IA Tumor confined to a single ovary, negative washings, capsule intact, surface of ovary uninvolved
IB Tumor found in both ovaries, negative washings, capsule intact, surface of ovary uninvolved
IC Tumor on one or both ovaries, ruptured capsule, positive cytology or ovarian surface involvement
Stage II
IIA Extension or metastasis to uterus and/or tubes
IIB Extension to other pelvic structures
IIC Tumor on one or both ovaries, ruptured capsule, positive cytology or ovarian surface involvement
Stage III
IIIA Tumor on one or both ovaries with microscopic spread to abdominal peritoneal surface (ex. Liver serosa)
IIIB Tumor implant <2cm to abdominal peritoneal surface
IIIC Tumor implant >2cm to abdominal peritoneal surface and/or positive retroperitoneal or inguinal lymph nodes
Stage IV
Distant metastasis
Pleural effusion with positive cytology
Parenchymal liver metastasis

46. 5-year Survival Rates Stage I 76-93% Stage II 60-74% Stage III
IIIA 41%
IIIB 25%
IIIC 20%
Stage IV 11%

47. Principles of Ovarian Cancer Surgery
Purpose of Surgery
Staging of disease
Prognosis and treatment depend upon surgical findings and subsequent stage
Debulking (cytoreduction)
Overall reduction of tumor burden to less than 1 cm (preferably no gross residual disease) improves survival
Palliation of symptoms
Goldie-Coldman Hypothesis
Resistance to chemotherapy will develop in fraction of remaining viable cells

48. Primary Debulking Aggressive surgical procedures
Multiple or extensive bowel resection
Rectosigmoid resection
Resection of ureteral/bladder segment
Diaphragm stripping
Resection of liver, spleen, kidney, diaphragm

49. Primary Debulking
optimal primary debulking (residual disease <1 cm) is an independent prognostic factor
Even in patients with unresectable liver metastasis, optimal debulking of extrahepatic disease is associated with a significant survival advantage

50. Patterns of spread Direct extension Exfoliation of clonogenic cells
Lymphatic spread

51. Assessment of extent of disease Optimal tumor reduction
Ovarian Cancer Surgical Debulking and Staging
Exploration
Biopsies
(Staging)
TAH/
BSO
Goals (Debulking)
Assessment of extent of disease
Optimal tumor reduction
Washings/
Ascites
(Staging)
TAH = total abdominal hysterectomy
BSO = bilateral salphingo-oophorectomy 51

52. First-line Therapy – Standard Treatment Options
Surgery with maximum cytoreduction effort <1cm residual disease
Surgery is usually the first step in the care of patients.
Every effort should be made to leave behind minimal residual disease.
Most patients with ovarian cancer will receive chemotherapy as part of their primary treatment.
Drugs:
carboplatin (Paraplatin®)
paclitaxel (Onxol®, Taxol®)
Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) 52

53. Systemic therapy for EOC
Highly chemosensitive tumor (esp. histology subtype: high grade serosus, endometrioid)
Basic drugs: platinum compounds with paclitaxel
First line therapy: carboplatin + TAX
New biologic therapy: bevacizumab (addition of bev. to standard KT and maintance bevacizumab prolongs PFS)
Relapse: platina reinduction (in platinum sensitive cases, >12 month DFS)
or second line treatment with other agents (topothecan, L-ADM, gemcitabine, weekly TAX, etoposid, cyclophosphamid)
or clinical trial

55. Secondary Cytoreduction
Kidney
Resected Liver
Diaphragm
Vena Cava
Tumor Mass
Renal Vein
Secondary Cytoreduction
Controversial
Inconsistent definitions
Benefit appears confined to patients likely to respond to additional chemo:
>12 month PFI
Isolated site of recurrence
Disease completely resectable
PFI = progression-free interval 55 55

56. History of Intraperitoneal Chemotherapy Ovarian Cancer
1970’s : IPCT used for its cytotoxic properties
High concentrations, large volumes
1978 : Landmark paper by Dedrick et al.
A sound pharmacokinetic rationale for IPCT
1991 : IP therapy: time’s up (Ozols)
Time’s not up (Muggia, Alberts)
1996 : Survival benefit for IPCT (Alberts et al.)
2004 : IPCT not widely adopted (GCIG OCCC)
2006 : NCI Clinical Announcement / Survival benefit with IP therapy

57. How to improve outcome?
Better screening (OVA test etc?) Surgical treatment in selected centers by well trained gynecologyc oncologist Better systemic therapy: addition of biologic agents to KT, weekly TAX protocolls, intraperitoneal chemotherapy

58. Potential targets in the future
Angiogenesis PARP inhibitors Folate receptor antagonists PI3kinase inhibition RAS/RAF Etc.

59. IPCT vs IVCT in Advanced Ovarian Cancer Overall survival
Investigators No. of Overall survival (mo)
year published pts Control arm Exp. Arm
Alberts et al,
Polyzos et al,
Gadducci et al,
Markman et al,
Yen et al,
Armstrong et al,
1 p = 0.02; 2 p = 0.05; 3 p = 0.03

60. Conclusions on IPCT
Combined use of IV and IP chemotherapy leads to a significant survival benefit in women with optimally debulked EOC (median + 12 mo).
Based on the most recent trials, strong consideration should be given to a regimen with IP cisplatin (100 mg/m²) and a taxane (whether IV or IP).
Toxicities, inconvenience and costs of IP therapy are justified by the improved survival.

61. Intraperitoneal Chemotherapy
Conclusions
IP chemotherapy had a significantly better PFS and OS for women with optimally cytoreduced Stage III EOC
Significant toxicity with IP chemotherapy (only 40% of women completed 6 cycles)
Most patients had abdominal port/catheter issues that resulted in conversion to IV carboplatin rather than IP chemotherapy
Opponents of IP chemotherapy argue that the IP regimen is not being compared to the current standard of care (Carboplatin and Taxol)
Proponents argue that Cisplatin and Taxol is equally effective as Carboplatin and Taxol (GOG #158)