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Epithelial Ovarian Carcinoma

Epithelial Ovarian Carcinoma. 高雄榮總婦產科 劉文雄醫師. Introduction. Malignant neoplasms of the ovary present an increasing challenge to the physician. They are the cause of more deaths than any other female genital tract cancer. It accounts for 5% of all cancers among women.

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Epithelial Ovarian Carcinoma

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  1. Epithelial Ovarian Carcinoma 高雄榮總婦產科 劉文雄醫師

  2. Introduction • Malignant neoplasms of the ovary present an increasing challenge to the physician. They are the cause of more deaths than any other female genital tract cancer. • It accounts for 5% of all cancers among women. • In U.S, deaths from this cause occur at a rate of one every 45 min, and one in every 56 women will develop this disease.

  3. Classification • The early development of the ovary may be divided into four major stages : • During the first stage, undifferentiated germ cells (primordial germ cells) become segregated and migrate from their sites of origin to settle in the genital ridges. • The second stage occurs after arrival of the germ cells in the genital ridges and consists of proliferation of the coelomic epithelial and the underlying mesenchyme. • During the third stage, the ovary becomes divided into a peripheral cortex and a central medulla. • The fourth stage is characterized by the development of the cortex and involution of the medulla.

  4. Relative Frequency of Ovarian neoplasms Type% Coelomic epithelial 50-70 Germ cell 15-20 Specialized gonadal stroma 5-10 Nonspecific mesenchyme 5-10 Metastatic tumor 5-10

  5. Classification • The majority(85 to 90% ) of malignant ovarian tumors seen in the US are epithelial. • Serous cystadenocarcinoma :42% • Mucinous cystadenocarcinoma : 12% • Endometrioid carcinoam : 15% • Undifferentiated carcinoma : 17% • Clear cell carcinoma : 6%

  6. Incidence, Epidemiology, and Etiology • Approximately 23 % of gynecologic cancers are of ovarian origin, but 47% of all deaths from cancer of the female genital tract occur in women who have gynecologic cancer of ovarian cancer. • Approximately 12 of every 1000 women in the US older than 40 years will develop ovarian cancer, but only 2 or 3 of the 12 will be cured.

  7. Incidence, Epidemiology, and Etiology • Malignant germ cell tumors are most commonly seen in females younger than 20 years, whereas epithelial cancers of the ovary are primarily seen in women older than 50 years. • Incidence rate of ovarian cancer related to age : • 40-44 yr : 15.7/100000. • 50-60 yr : 35/100000. • 75-79 yr : 54/100000. • More than one third of the cases occur in patients 65 yrs or older

  8. Primary ovarian neoplasm related to age Type Up to 20 yr 20-50 yr Over 50 yr Coelomic epithelium 29% 71% 81% Germ cell 59% 14% 6% Specialized gonadal 8% 5% 4% stroma Nonspecific mesenchyme 4% 10% 9%

  9. Familial Ovarian Cancer • Several reports describe families in which girls and women of the same or succeeding generations develop similar neoplasms of the ovaries. • Most of these neoplasms were serous carcinomas. • Cancers of the breasts, colon,and other sites were also found more commonly in female members of these afflicted families. • NCI studies disclosed the number of relatives with ovarian cancer was significantly higher ( relative risk : 2.61) than the control.

  10. Familial Ovarian Cancer • The lifetime risk for ovarian cancer in the population as a whole is approximately 1.4% ; with one first-degree relative, it is 5% ; with two or more first-degree relatives, it rises to 7%. • Among the later group, there is 3% chance of having hereditary ovarian cancer syndrome; in those families, the lifetime risk of ovarian cancer is at least 40%. • Firm guidelines for prophylactic oophorectomy have not been established.

  11. Lifetime probability of ovarian cancer by age in women with one relative with ovarian cancer Lifetime probability lifetime probability of Age(year) of ovarian Ca (%) ovarian ca with one relative(%) 30 1.6 5 35 1.6 5 40 1.6 4.8 45 1.5 4.5 50 1.4 4.4 55 1.3 4.1 60 1.2 3.6

  12. Familial Ovarian Cancer • Three different hereditary syndromes of cancer have been identified : All three syndrome have a pattern of early-onset cancer and vertical transmission consistent with autosomal dominant inheritance. • The first is a site-specific familial ovarian cancer syndrome : women are at high risk for the development of ovarian carcinoma only. • The second is a breast-ovarian cancer syndrome : 50% risk of ovarian carcinoma if their mothers or sisters had breast and/ or ovarian carcinoma. The syndrome have been associated with the BRCA-1 and BRCA-2 gene.

  13. Familial Ovarian Cancer • The third is the cancer family syndrome in which both males and females are at increased risk of acquiring colon cancer, and to a lesser extent other cancers, including gastric carcinoma, thyroid carcinoma, and sarcoma. • Most of the colon cancers are in the proximal colon and not easily diagnosed. • Women in these families are at increased risk for carcinoam of the ovary, endometrium, and breast.

  14. Familial Ovarian Cancer • Because of the AD inheritance pattern, 50 % risk can be predicted in all offspring and siblings of inflicted individuals. • Prophylactic oophorectomy as soon as childbearing is completed ? • Most of the cancers have been detected in women between 35 to 45 yrs; thus, if oophorectomy not done, biannual sonogram with PV plus CA-125 should be advised. • Even the prophylactic oophorectomy was done; safety?

  15. Familial Ovarian Cancer • It is important to distinguish women in families with hereditary ovarian cancer syndromes from those who have family members with ovarian cancer. • Thorough medical history : a woman’s family history of ovarian cancer, breast cancer, endometrial cancer, and non- polyposis colorectal cancer. • Determining the age of occurrence of these cancers in the family members. • Family pedigree by a physician to identify the AD inheritance pattern.

  16. Familial Ovarian Cancer • Suggest for these patients: • Should be maintain by oral pills until such time that they desire childbearing. • Patients less than 35 yrs with a history of hereditary ovarian cancer syndrome should be monitored with a PV + sonogram + CA-125 every 6 months. • At the age of 35, prophylactic oophorectomy may be elective.

  17. How oral pills use affects the risk of ovarian cancer Duration of oral No. of women who Relative pills use developed ovarian Ca Controls risk Never 242 1532 1.0 3-6 months 26 280 0.6 7-11 months 14 134 0.7 1-2 years 65 602 0.7 3-4 years 40 397 0.6 5-9 years 39 594 0.4 >10 years 13 328 0.2

  18. Etiology of Ovarian Cancer • Environmental factors : physical and chemical products of industry are major causes of epithelial neoplasms. • Theory of “ incessant ovulation” suggests that the epithelial lining of the ovary may be sensitive to the constant trauma of ovulation, which in turn can act as a promoting factor in the carcinogenic process. • Prolonged use of fertility drugs such as Clomid may increase the risk of borderline and invasive ovarian cancer.

  19. Etiology of Ovarian Cancer • Others have suggested that ovarian cancer may be initiated by a chemical carcinogen via the vagina, uterus, and fallopian tubes, and the substances promoting cancer may even be the steroid- rich antral fluid from ruptured follicles. • Genital exposure to Talc : 42% Vs 28%. • No evidence exists to incriminate viruses in the development of neoplasms of the human ovary.

  20. Most frequent presenting symptoms of ovarian cancer Symptom Relative frequency Abdominal swelling XXXX Abdominal pain XXX Dyspepsia XX Urinary frequency XX Weight change X

  21. Nonovarian etiology of adnexal mass • Frequently encountered nonovarian causes of apparent adnexal masses : • Diverticulitis. • TOA. • Carcinoma of cecum or sigmoid. • Pelvic kidney. • Uterine or intraligamentous myomas

  22. Ovarian Cancer Screening • Periodic pelvic examination, ultrasonography, CA-125. • 10000 PV would be required to pick up one early ovarian cancer in an asymptomatic patient population. • CA-125 as a screening technique has not been rewarding especially in premenopausal women. • Many conditions of a benign nature as well as most GI malignancies, may elevated the CA-125. • Ultrasonography, especially the TVS ( color doppler ).

  23. Scroing System for Ovarian Tumor- Morphologic Index DePriest PD, Shenson D, Fried A, Hunter J, Andrews S, Gallion H, et al. A morphology index based on sonographic findings in ovarian cancer. Gynecol Oncol 1993;51:7-11.

  24. Scroing System for Ovarian Tumor-Morphologic Index

  25. Doppler Study • In Doppler velocimetry, the flow velocity waveform obtained from a target vessel is evaluated according to standard parameters, pulsatility index (PI) and resistant index (RI). • The vessels supplying benign ovarian tumors generally were peripheral in location, had high systolic flow, and a high PI (>1.0) and RI (>0.4). In contrast, vessels supplying ovarian malignancies generally had significant diastolic flow, were centrally located, and had a low PI (<1.0) and RI (<0.4). • It is difficult to clearly identify ovarian malignancies on the basis of pulsed Doppler findings alone.

  26. CA-125 • An ideal marker should have high sensitivity (few false-negative results), high specificity (few false-positive results), and high accuracy. Serum levels of CA 125 are elevated (>35 u/mL) in approximately 50% of patients with stage I epithelial ovarian cancer and in more than 90% of those with advanced disease. • Generally, serum CA 125 values rise over time in patients with ovarian cancer, whereas they remain stable or decrease in patients with benign ovarian tumors. • Therefore, serial CA 125 determinations at 2 to 4-week intervals can be helpful in deciding whether a sonographically confirmed ovarian tumor can be monitored safely or should be removed surgically.

  27. CA-125 • With advances in molecular technology, a number of candidate tumor markers for ovarian cancer have been identified including CA 15.3, CA 72.4, CA 19.9, and soluble epidermal growth factor. • At present, however, there is little evidence to suggest that their use in a multimodality screening panel is superior to CA 125 alone in differentiating benign from malignant ovarian tumors.

  28. Proteomics • Proteomic profiling of serum using mass spectroscopy (surface-enhanced laser desorption and ionization) has been proposed recently as a method to detect ovarian cancer. • Basically, a population of proteins can be profiled according to the size and net electrical charge of the individual proteins. • The discriminating proteomic pattern formed by a subset of proteins is defined by peak amplitude at key mass/charge positions along the spectrum.

  29. Ovarian Cancer Screening • Improve the effectiveness of ovarian cancer screening would be to target populations at increased risk of the development of the disease, such as individuals, with a positive family history of ovarian cancer. • Another strategy to improve sensitivity and specificity in screening for ovarian cancer involves the use of multiple serum tumor markers. Because less than 50% of patients with stage I ovarian cancer will have an elevated CA-125.

  30. Management Guideline

  31. Gynecologic Acute PID Adenomyosis Benign ovarian neoplasm Endometriosis Functional ovarian cyst Meig’s syndrome Menstruation OHSS Unexplained infertility Uterine myoma Nongynecologic Active hepatitis Acute pancreatitis Cirrhosis Congestive heart failure DM(poor control) Diverticulitis Mesothelioma Nonmalignant ascites pericarditis Pneumonia Post-op period SLE Non-malignant conditions that may elevate CA-125 concentrations

  32. Pattern of Spread • Transcelomic : The most common and earliest mode of dissemination is by exfoliation of cells than implant along the surfaces of the peritoneal cavity. • Lymphatic : retroperitoneal ( pelvic and paraaortic ) LN spreading is common in advanced- stage disease. 78% with stage III disease had positive pelvic LN. And the rate of the positive paraaortic LNs was 18% in stage I , 20% in stage II, 42% in stage III, and 67% in stage IV. • Hematogenous : is uncommon at the time of diagnosis, lungs and liver is the most common sites

  33. Diagnostic Techniques • Pelvic examination remains the most practical means of detecting early disease. • Pain is usually a late complication. • Any ovary palpated in a patient 3 or more years after menopause should raise a high index of suspicious of an early ovarian neoplasm. • Diagnostic paracentesis is a patients with ascites and a pelvic-abdominal mass is unnecessary and dangerous.

  34. Diagnostic Techniques • Ovarian cancer is classically a serosal spreading disease, and thus all peritoneal surfaces must be carefully inspected, especially when disease is thought to limited to the pelvis. • Washing cytology : 1. subdiaphragm, bil . 2. Paracolic gutter, bil. 3. Cul-de-sac . • Care should be taken to visualize and palpate all peritoneal surfaces including the underside of the daiphragm, the surface of the liver and the small and large bowel mesentary.

  35. Complete Workup For Ovarian Cancer • Careful history • Physical examination • Pelvic examination and Pap’s smear • Proctosigmoidoscopy, where indicated • CBC and urinalysis • Blood chemistries, including CA-125 • Chest film, IVP, Barium enema, or CT scan • Pelvic sonogram.

  36. Surgical Therapy in Ovarian Cancer • Peritoneal cytologic examination • Determination of extent of disease • Pelvis • Peritoneal surface • Diaphragms • Omentum • Lymph node • Removal of all tumor possible

  37. Guidelines For Staging in Epithelial Ovarian Cancer • 4 peritoneal washings ( diaphragm, bil paracolic gutter and cul-de-sac ). • Careful inspection and palpation of all peritoneal surfaces • Biopsy of smear from undersurface of bil diaphragm. • Biopsy of all suspicious lesions . • Infracolic omentectomy. • Biopsy or resection of any adhesions • Random biopsy of normal peritoneum of bladder reflection cul-de-sac, Rt and Lt paracolic gutters and both pelvic side walls. • Selected lymphadenectomy of pelvic and para-aortic nodes. • ATH,BSO, and excision of all masses where prudent

  38. Stage and 5-year Survival Stage Ia 84% Stage Ib 79% Stage Ic 73% Stage IIa 65% Stage IIb 54% Stage IIc 61% Stage IIIa 52% Stage IIIb 29% Stage IIIc 18% Stage IV 14% Overall 31%

  39. Early-Stage Ovarian Cancer • Early-stage ovarian cancer: I-IIa • The primary treatment for early stage epithelial ovarian cancer is surgical, that is, a ATH+BSO+ complete surgical staging. (24% will be upstaging to stage III) • Based on the prognostic variables, early stage epithelial ovarian cancer can be subdivided into low-risk and high-risk disease. • The uterus and the contralateral ovary can be preserved in women with stage IA , low-risk disease who wish to preserve fertility. Zanetta et al. BJOG,1997; Favalli et al. Int J Gyn Cancer, 2001

  40. Low risk Low grade Non-clear cell histologic type Intact capsule No surface excrescences No ascites Negative peritoneal washing Unruptured or intraoperative rupture No dense adhesion Diploid tumor High risk High grade Clear cell type Tumor growth through capsule Surface excrescences Ascites Malignant cells in fluid Preoperative rupture Dense adhesion Aneuploid tumor Prognostic Variables in Early-stage Epithelial Ovarian Cancer

  41. Early-Stage Low-Risk Ovarian Cancer • Stage IA, IB, Grade 1 and 2. • GOG randomized trial of observation versus melphalan in this group of patients and the 5-year survival for each group were 94% and 96%. • No further adjuvant treatment is needed for such patients.

  42. Early-Stage High-Risk Ovarian Cancer • In patients whose disease is high risk ( e.g., more poorly differentiated or in whom there are malignant cells either in ascitic fluid or in peritoneal washings ) . Additional therapy in indicated. • Treatment options include chemotherapy or whole-abdominal radiation

  43. Randomized Trials in Stage I Epithelial Ovarian Cancer ( since 1995) Author Patients Stages Treatment Best Arm Young et al GOG7601 81 I(Low) Observation Vs. Melphalan NP GOG7602 141 I(High), II P32 Vs melphalan NP Bolis et al. 47 I(Low) Observation Vs cisplatinx6 NP 104 I(High) P32 Vs cisplatinx6 Cisplatin 79 Vs 69% Young et al. 205 I(High), II Cisplatin75mg/m2/ cyclo Cis/cyclo GOG95 750mg/m2 Vs P32 77 Vs 66% Trope et al 134 I(High) Carboplatin vs. observation NP Closed/maturing GOG172 331 I(High), II Taxol 175 mg/m2/ carbo AUC 7.5 (3 vs 6 courses) Ongoing Trial GOG175 I(high), II Taxol 175mg/m2/carbo AUC 6 followed by observation vs. Taxol 40mg/m2/weeklyx26wks

  44. Early-Stage High-Risk Ovarian Cancer • Patients with high-risk stage I epithelial ovarian cancer be given adjuvant chemotherapy. The type depends on the patient’s overall health and status. • Treatment with carboplatin and Taxol chemotherapy for 3 to 6 cycles seem desirable in most patients, whereas a short course of a single agent, either carboplatin or Taxol, may be preferable for older women.

  45. Advanced-Stage Ovarian Cancer • After the introduction of cisplatin in the latter half of the 1970s, platinum-based combination chemotherapy became the most frequently used regimen in USA. • Taxol become available in the 1980s, and this drug was incorporated into the combination chemotherapy in the 1990s.

  46. Cisplatin Combination Chemotherapy • Combination chemotherapy has been shown to be superior to single-agent therapy. • After cisplatin became available for the treatment of ovarian cancer showed that cisplatin was better than an alkylating agent , cyclophosphamide, as a single agent. • Several studies recommended the platinum-based chemotherapy were shown to be superior. • Most studies using the PC or PAC regimen, disclosed the same survival rates.

  47. Taxol-based Combination Chemotherapy • The next major advance in the treatment of advanced stage disease was the incorporation of taxol into the chemotherapeutic regimen. • Several prospective randomized trial with taxol-based arms have defined the current recommended protocol in advanced epithelial ovarian cancer. • Based on the GOG111,1996 and OV10,1998 studies, Taxol should be included in the primary treatment of all women with advanced-stage epithelial ovarian cancer

  48. Platinum and Taxol Chemotherapy randomized Trials in Advanced-Stage epithelial Ovarian Cancer Author Year Group Status Drugs/doses Best McGuire 1996 GOG 111 Subopt T:135(3)/cis75 Taxol/cis vs ctx750/cis75 Stuart 1998 EORTC Opt/Subopt T:175/cis75 Taxol/cis OV10 vs ctx750/cis75 Muggia 1997 GOG132 Subopt Cis100 vs T200(24) Taxol/cis vs cis75/T135(24) Ozols 1999 GOG158 Opt Carbo7.5/T175(3) Taxol/carbo vs cis75/T135(24) Bois 1999 AGO Opt/subopt Carbo6/T185(3) Taxol/carbo vs cis75/T185(3) Albert 1996 GOG104 Opt Ipcis100/ctx750 Ip cis/ctx vs Iv cis75/ctx750 Markman 1998 GOG114 Opt Carbox2-9/Ip cis100 Ip cis/carbo /T135(24) vs Iv cis / Taxol 75/T135(24)

  49. Platinum and Taxol Chemotherapy randomized Trials in Advanced-Stage epithelial Ovarian Cancer-Ongoing Author Group(Protocol) Status Drugs/Doses/(hrs) Harper ICON3 Opt/Subopt T135(24)/cis75 vs Carbo vs cis/ctx/doxo GOG162 Subopt T135(24)/cis75 vs T120(96)/cis75 GOG172 Opt Iv T135(24)/Ipcis100 (D2)/Ip T60(D8) vs Iv T135(24)/Iv cis75

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