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

Epithelial Ovarian Carcinoma

高雄榮總婦產科高雄榮總婦產科劉文雄醫師劉文雄醫師

Introduction

Malignant neoplasms of the ovary present an increasing Malignant neoplasms of the ovary present an increasing challenge to the physician. They are the cause of more challenge to the physician. They are the cause of more deaths than any other female genital tract cancer.deaths than any other female genital tract cancer.

It accounts for 5% of all cancers among women.It accounts for 5% of all cancers among women. In U.S, deaths from this cause occur at a rate of one In U.S, deaths from this cause occur at a rate of one

every 45 min, and one in every 56 women will develop every 45 min, and one in every 56 women will develop this disease.this disease.

Classification The early development of the ovary may be divided into four major The early development of the ovary may be divided into four major

stages :stages : During the first stage, undifferentiated germ cells (primordial During the first stage, undifferentiated germ cells (primordial

germ cells) become segregated and migrate from their sites of germ cells) become segregated and migrate from their sites of origin to settle in the genital ridges.origin to settle in the genital ridges.

The second stage occurs after arrival of the germ cells in the The second stage occurs after arrival of the germ cells in the genital ridges and consists of proliferation of the coelomic genital ridges and consists of proliferation of the coelomic epithelial and the underlying mesenchyme.epithelial and the underlying mesenchyme.

During the third stage, the ovary becomes divided into a During the third stage, the ovary becomes divided into a peripheral cortex and a central medulla.peripheral cortex and a central medulla.

The fourth stage is characterized by the development of the cortex The fourth stage is characterized by the development of the cortex and involution of the medulla.and involution of the medulla.

Relative Frequency of Ovarian neoplasms

TypeType %%Coelomic epithelialCoelomic epithelial 50-7050-70Germ cellGerm cell 15-2015-20Specialized gonadal stromaSpecialized gonadal stroma 5-105-10Nonspecific mesenchymeNonspecific mesenchyme 5-105-10Metastatic tumorMetastatic tumor 5-105-10

Classification

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

Incidence, Epidemiology, and Etiology

Approximately 23 % of gynecologic cancers are of Approximately 23 % of gynecologic cancers are of ovarian origin, but 47% of all deaths from cancer of the ovarian origin, but 47% of all deaths from cancer of the female genital tract occur in women who have female genital tract occur in women who have gynecologic cancer of ovarian cancer.gynecologic cancer of ovarian cancer.

Approximately 12 of every 1000 women in the US older Approximately 12 of every 1000 women in the US older than 40 years will develop ovarian cancer, but only 2 or 3 than 40 years will develop ovarian cancer, but only 2 or 3 of the 12 will be cured.of the 12 will be cured.

Incidence, Epidemiology, and Etiology

Malignant germ cell tumors are most commonly seen in Malignant germ cell tumors are most commonly seen in females younger than 20 years, whereas epithelial cancers females younger than 20 years, whereas epithelial cancers of the ovary are primarily seen in women older than 50 of the ovary are primarily seen in women older than 50 years.years.

Incidence rate of ovarian cancer related to age :Incidence rate of ovarian cancer related to age : 40-44 yr : 15.7/100000.40-44 yr : 15.7/100000. 50-60 yr : 35/100000.50-60 yr : 35/100000. 75-79 yr : 54/100000.75-79 yr : 54/100000. More than one third of the cases occur in patients 65 yrs More than one third of the cases occur in patients 65 yrs

or olderor older

Primary ovarian neoplasm related to age

TypeType Up to 20 yrUp to 20 yr 20-50 yr20-50 yr Over 50 Over 50 yryr

Coelomic epitheliumCoelomic epithelium29%29% 71%71%81%81% Germ cellGerm cell 59%59% 14%14%6%6% Specialized gonadal Specialized gonadal 8%8% 5%5%4%4% stromastroma

Nonspecific mesenchymeNonspecific mesenchyme4%4% 10%10% 9%9%

Familial Ovarian Cancer

Several reports describe families in which girls and Several reports describe families in which girls and women of the same or succeeding generations develop women of the same or succeeding generations develop similar neoplasms of the ovaries.similar neoplasms of the ovaries.

Most of these neoplasms were Most of these neoplasms were serous carcinomas.serous carcinomas. Cancers of the breasts, colon,and other sites were also Cancers of the breasts, colon,and other sites were also

found more commonly in female members of these found more commonly in female members of these afflicted families.afflicted families.

NCI studies disclosed the number of relatives with NCI studies disclosed the number of relatives with ovarian cancer was significantly higher ovarian cancer was significantly higher ( relative risk : ( relative risk : 2.61)2.61) than the control. than the control.


The lifetime risk for ovarian cancer in the population as a The lifetime risk for ovarian cancer in the population as a whole is approximately whole is approximately 1.4%1.4% ; with one first-degree ; with one first-degree relative, it is relative, it is 5% 5% ; with two or more first-degree relatives, ; with two or more first-degree relatives, it rises to it rises to 7%.7%.

Among the later group, there is Among the later group, there is 3%3% chance of having chance of having hereditary ovarian cancer syndromehereditary ovarian cancer syndrome; in those families, ; in those families, the lifetime risk of ovarian cancer is at least the lifetime risk of ovarian cancer is at least 40%.40%.

Firm guidelines for prophylactic oophorectomy Firm guidelines for prophylactic oophorectomy have not have not been established.been established.

Lifetime probability of ovarian cancer by age in women with one relative with ovarian cancer

Lifetime probabilityLifetime probability lifetime probability of lifetime probability of Age(year)Age(year) of ovarian Ca (%)of ovarian Ca (%) ovarian ca with one relative(%)ovarian ca with one relative(%)

3030 1.61.6 553535 1.61.6 554040 1.61.6 4.84.84545 1.51.5 4.54.55050 1.41.4 4.44.45555 1.31.3 4.14.16060 1.21.2 3.63.6


Three different hereditary syndromes of cancer have been Three different hereditary syndromes of cancer have been identified : All three syndrome have a pattern of early-onset identified : All three syndrome have a pattern of early-onset cancer and vertical transmission consistent with autosomal cancer and vertical transmission consistent with autosomal dominant inheritance.dominant inheritance. The first is a The first is a site-specific familial ovarian cancer site-specific familial ovarian cancer

syndromesyndrome : women are at high risk for the development of : women are at high risk for the development of ovarian carcinoma only.ovarian carcinoma only.

The second is a The second is a breast-ovarian cancer syndromebreast-ovarian cancer syndrome : : 50%50% risk risk of ovarian carcinoma if their mothers or sisters had breast of ovarian carcinoma if their mothers or sisters had breast and/ or ovarian carcinoma. The syndrome have been and/ or ovarian carcinoma. The syndrome have been associated with the associated with the BRCA-1 and BRCA-2 gene.BRCA-1 and BRCA-2 gene.


The third is the The third is the cancer family syndromecancer family syndrome in which both in which both males and females are at increased risk of acquiring males and females are at increased risk of acquiring colon cancercolon cancer, and to a lesser extent other cancers, , and to a lesser extent other cancers, including gastric carcinoma, thyroid carcinoma, and including gastric carcinoma, thyroid carcinoma, and sarcoma.sarcoma. Most of the colon cancers are in the Most of the colon cancers are in the proximal colonproximal colon

and not easily diagnosed.and not easily diagnosed. Women in these families are at increased risk for Women in these families are at increased risk for

carcinoam of the carcinoam of the ovary, endometrium, and breast.ovary, endometrium, and breast.


Because of the AD inheritance pattern, Because of the AD inheritance pattern, 50 % risk50 % risk can be can be predicted in all offspring and siblings of inflicted predicted in all offspring and siblings of inflicted individuals.individuals.

Prophylactic oophorectomyProphylactic oophorectomy as soon as childbearing is as soon as childbearing is completed ?completed ?

Most of the cancers have been detected in women Most of the cancers have been detected in women between 35 to 45 yrs; thus, if oophorectomy not done, between 35 to 45 yrs; thus, if oophorectomy not done, biannual sonogram with PV plus CA-125 should be biannual sonogram with PV plus CA-125 should be advised.advised.

Even the prophylactic oophorectomy was done; Even the prophylactic oophorectomy was done; safety?safety?


It is important to It is important to distinguishdistinguish women in families with women in families with hereditary ovarian cancer syndromes from those who hereditary ovarian cancer syndromes from those who have family members with ovarian cancer.have family members with ovarian cancer. Thorough medical history : a woman’s family history Thorough medical history : a woman’s family history

of ovarian cancer, breast cancer, endometrial cancer, of ovarian cancer, breast cancer, endometrial cancer, and non- polyposis colorectal cancer.and non- polyposis colorectal cancer.

Determining the age of occurrence of these cancers in Determining the age of occurrence of these cancers in the family members.the family members.

Family pedigree by a physician to identify the AD Family pedigree by a physician to identify the AD inheritance pattern.inheritance pattern.


Suggest for these patientsSuggest for these patients :: Should be maintain by Should be maintain by oral pillsoral pills until such time that until such time that

they desire childbearing.they desire childbearing. Patients less than 35 yrs with a history of hereditary Patients less than 35 yrs with a history of hereditary

ovarian cancer syndrome should be monitored with a ovarian cancer syndrome should be monitored with a PV + sonogram + CA-125 every 6 monthsPV + sonogram + CA-125 every 6 months..

At the age of 35, At the age of 35, prophylactic oophorectomyprophylactic oophorectomy may be may be elective.elective.

How oral pills use affects the risk of ovarian cancer

Duration of oralDuration of oral No. of women whoNo. of women who RelativeRelativepills usepills use developed ovarian Cadeveloped ovarian Ca ControlsControls riskrisk

NeverNever 242242 15321532 1.01.03-6 months3-6 months 2626 280280 0.60.67-11 months7-11 months 1414 134134 0.70.71-2 years 1-2 years 6565 602602 0.70.73-4 years 3-4 years 4040 397397 0.60.65-9 years 5-9 years 3939 594594 0.40.4>10 years>10 years 1313 328328 0.20.2

Etiology of Ovarian Cancer

Environmental factors : physical and chemical products Environmental factors : physical and chemical products of industry are major causes of epithelial neoplasms.of industry are major causes of epithelial neoplasms.

Theory of “ Theory of “ incessant ovulationincessant ovulation” suggests that the ” suggests that the epithelial lining of the ovary may be sensitive to the epithelial lining of the ovary may be sensitive to the constant trauma of ovulation, which in turn can act as a constant trauma of ovulation, which in turn can act as a promoting factor in the carcinogenic processpromoting factor in the carcinogenic process..

Prolonged use of fertility drugs such as Clomid may Prolonged use of fertility drugs such as Clomid may increase the risk of borderline and invasive ovarian increase the risk of borderline and invasive ovarian cancer.cancer.

Etiology of Ovarian Cancer

Others have suggested that ovarian cancer may be Others have suggested that ovarian cancer may be initiated by a chemical carcinogen via the vagina, uterus, initiated by a chemical carcinogen via the vagina, uterus, and fallopian tubes, and the substances promoting cancer and fallopian tubes, and the substances promoting cancer may even be the steroid- rich antral fluid from ruptured may even be the steroid- rich antral fluid from ruptured follicles.follicles.

Genital exposure to Genital exposure to TalcTalc : 42% Vs 28%. : 42% Vs 28%. No evidence exists to incriminate viruses in the No evidence exists to incriminate viruses in the

development of neoplasms of the human ovary.development of neoplasms of the human ovary.

Most frequent presenting symptoms of ovarian cancer

SymptomSymptom Relative frequencyRelative frequency

Abdominal swellingAbdominal swellingXXXXXXXX Abdominal Abdominal

painpain XXXXXX DyspepsiaDyspepsiaXXXX Urinary Urinary

frequencyfrequency XXXXWeight changeWeight change XX

Nonovarian etiology of adnexal mass

Frequently encountered nonovarian causes of Frequently encountered nonovarian causes of apparent adnexal masses :apparent adnexal masses : Diverticulitis.Diverticulitis. TOA.TOA. Carcinoma of cecum or sigmoid.Carcinoma of cecum or sigmoid. Pelvic kidney.Pelvic kidney. Uterine or intraligamentous myomasUterine or intraligamentous myomas

Ovarian Cancer Screening Periodic pelvic examination, ultrasonography, CA-125.Periodic pelvic examination, ultrasonography, CA-125.

10000 PV would be required to pick up one early 10000 PV would be required to pick up one early ovarian cancer in an asymptomatic patient population.ovarian cancer in an asymptomatic patient population.

CA-125 as a screening technique has not been CA-125 as a screening technique has not been rewarding especially in premenopausal women.rewarding especially in premenopausal women.

Many conditions of a benign nature as well as most GI Many conditions of a benign nature as well as most GI malignancies, may elevated the CA-125.malignancies, may elevated the CA-125.

Ultrasonography, especially the TVS ( color doppler ).Ultrasonography, especially the TVS ( color doppler ).

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.

Scroing System for Ovarian Tumor-Morphologic Index

Scroing System for Ovarian Tumor-Morphologic Index

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.

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.

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.

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.

Ovarian Cancer Screening

Improve the effectiveness of ovarian cancer screening Improve the effectiveness of ovarian cancer screening would be to would be to target populations at increased risktarget populations at increased risk of the of the development of the disease, such as individuals, with a development of the disease, such as individuals, with a positive family history of ovarian cancer.positive family history of ovarian cancer.

Another strategy to improve sensitivity and specificity in Another strategy to improve sensitivity and specificity in screening for ovarian cancer involves the use of multiple screening for ovarian cancer involves the use of multiple serum tumor markers. Because less than 50% of patients serum tumor markers. Because less than 50% of patients with stage I ovarian cancer will have an elevated CA-with stage I ovarian cancer will have an elevated CA-125.125.

Management Guideline

Non-malignant conditions that may elevate CA-125 concentrations

GynecologicGynecologic Acute PIDAcute PID AdenomyosisAdenomyosis Benign ovarian neoplasmBenign ovarian neoplasm EndometriosisEndometriosis Functional ovarian cystFunctional ovarian cyst Meig’s syndromeMeig’s syndrome MenstruationMenstruation OHSSOHSS Unexplained infertilityUnexplained infertility Uterine myomaUterine myoma

NongynecologicNongynecologic Active hepatitisActive hepatitis Acute pancreatitisAcute pancreatitis CirrhosisCirrhosis Congestive heart failure Congestive heart failure DM(poor control)DM(poor control) DiverticulitisDiverticulitis MesotheliomaMesothelioma Nonmalignant ascitesNonmalignant ascites pericarditispericarditis PneumoniaPneumonia Post-op periodPost-op period SLESLE

Pattern of Spread

Transcelomic : The most common and earliest mode of Transcelomic : The most common and earliest mode of dissemination is by dissemination is by exfoliation of cells than implant along the exfoliation of cells than implant along the surfaces of the peritoneal cavitysurfaces of the peritoneal cavity..

Lymphatic : retroperitoneal ( pelvic and paraaortic ) LN Lymphatic : retroperitoneal ( pelvic and paraaortic ) LN spreading is common in advanced- stage disease. spreading is common in advanced- stage disease. 78% with 78% with stage III disease had positive pelvic LN. And the rate of the stage III disease had positive pelvic LN. And the rate of the positive paraaortic LNs was 18% in stage I , 20% in stage II, positive paraaortic LNs was 18% in stage I , 20% in stage II, 42% in stage III, and 67% in stage IV42% in stage III, and 67% in stage IV..

Hematogenous : is uncommon at the time of diagnosis, Hematogenous : is uncommon at the time of diagnosis, lungs lungs and liverand liver is the most common sites is the most common sites

Diagnostic Techniques

Pelvic examination remains the most practical means of Pelvic examination remains the most practical means of detecting early disease.detecting early disease.

Pain is usually a late complication.Pain is usually a late complication. Any ovary palpated in a patient 3 or more years after Any ovary palpated in a patient 3 or more years after

menopause should raise a high index of suspicious of an menopause should raise a high index of suspicious of an early ovarian neoplasm.early ovarian neoplasm.

Diagnostic paracentesis is a patients with ascites and a Diagnostic paracentesis is a patients with ascites and a pelvic-abdominal mass is pelvic-abdominal mass is unnecessary and dangerous.unnecessary and dangerous.

Diagnostic Techniques

Ovarian cancer is classically a serosal spreading disease, Ovarian cancer is classically a serosal spreading disease, and thus all peritoneal surfaces must be carefully and thus all peritoneal surfaces must be carefully inspected, especially when disease is thought to limited inspected, especially when disease is thought to limited to the pelvis.to the pelvis.

Washing cytology : 1. subdiaphragm, bil . 2. Paracolic Washing cytology : 1. subdiaphragm, bil . 2. Paracolic gutter, bil. 3. Cul-de-sac .gutter, bil. 3. Cul-de-sac .

Care should be taken to visualize and palpate all Care should be taken to visualize and palpate all peritoneal surfaces including the underside of the peritoneal surfaces including the underside of the daiphragm, the surface of the liver and the small and daiphragm, the surface of the liver and the small and large bowel mesentary.large bowel mesentary.

Complete Workup For Ovarian Cancer

Careful historyCareful history Physical examinationPhysical examination Pelvic examination and Pap’s smearPelvic examination and Pap’s smear Proctosigmoidoscopy, where indicatedProctosigmoidoscopy, where indicated CBC and urinalysisCBC and urinalysis Blood chemistries, including CA-125Blood chemistries, including CA-125 Chest film, IVP, Barium enema, or CT scanChest film, IVP, Barium enema, or CT scan Pelvic sonogram.Pelvic sonogram.

Surgical Therapy in Ovarian Cancer

Peritoneal cytologic examinationPeritoneal cytologic examination Determination of extent of diseaseDetermination of extent of disease

PelvisPelvis Peritoneal surfacePeritoneal surface DiaphragmsDiaphragms OmentumOmentum Lymph nodeLymph node

Removal of all tumor possibleRemoval of all tumor possible

Guidelines For Staging in Epithelial Ovarian Cancer 4 4 peritoneal washings ( diaphragm, bil paracolic gutter and cul-peritoneal washings ( diaphragm, bil paracolic gutter and cul-

de-sac ).de-sac ). Careful inspection and palpation of all peritoneal surfacesCareful inspection and palpation of all peritoneal surfaces Biopsy of smear from undersurface of bil diaphragm.Biopsy of smear from undersurface of bil diaphragm. Biopsy of all suspicious lesions .Biopsy of all suspicious lesions . Infracolic omentectomy.Infracolic omentectomy. Biopsy or resection of any adhesionsBiopsy or resection of any adhesions Random biopsy of normal peritoneum of bladder reflection cul-Random biopsy of normal peritoneum of bladder reflection cul-

de-sac, Rt and Lt paracolic gutters and both pelvic side walls.de-sac, Rt and Lt paracolic gutters and both pelvic side walls. Selected lymphadenectomy of pelvic and para-aortic nodes.Selected lymphadenectomy of pelvic and para-aortic nodes. ATH,BSO, and excision of all masses where prudentATH,BSO, and excision of all masses where prudent

Stage and 5-year Survival

Stage IaStage Ia 84%84% Stage IbStage Ib79%79% Stage IcStage Ic 73%73%

Stage IIaStage IIa 65%65%Stage IIbStage IIb 54%54% Stage IIcStage IIc

61%61% Stage IIIaStage IIIa 52%52%Stage IIIbStage IIIb 29%29%

Stage IIIcStage IIIc 18%18% Stage IVStage IV14%14% Overall Overall 31%31%

Early-Stage Ovarian Cancer

Early-stage ovarian cancer: I-IIaEarly-stage ovarian cancer: I-IIa The primary treatment for early stage epithelial ovarian The primary treatment for early stage epithelial ovarian

cancer is surgical, that is, a ATH+BSO+ complete surgical cancer is surgical, that is, a ATH+BSO+ complete surgical staging. (24% will be upstaging to stage III)staging. (24% will be upstaging to stage III)

Based on the prognostic variables, early stage epithelial Based on the prognostic variables, early stage epithelial ovarian cancer can be subdivided into ovarian cancer can be subdivided into low-risk and high-low-risk and high-riskrisk disease. disease.

The uterus and the contralateral ovary can be preserved in The uterus and the contralateral ovary can be preserved in women with stage IA , low-risk disease who wish to women with stage IA , low-risk disease who wish to preserve fertility. preserve fertility. Zanetta et al. BJOG,1997; Favalli et al. Int J Gyn Cancer, Zanetta et al. BJOG,1997; Favalli et al. Int J Gyn Cancer, 20012001

Prognostic Variables in Early-stage Epithelial Ovarian Cancer

Low riskLow risk Low gradeLow grade Non-clear cell histologic Non-clear cell histologic

typetype Intact capsuleIntact capsule No surface excrescencesNo surface excrescences No ascitesNo ascites Negative peritoneal washingNegative peritoneal washing Unruptured or Unruptured or

intraoperative ruptureintraoperative rupture No dense adhesionNo dense adhesion Diploid tumorDiploid tumor

High riskHigh risk High gradeHigh grade Clear cell typeClear cell type Tumor growth through Tumor growth through

capsulecapsule Surface excrescencesSurface excrescences AscitesAscites Malignant cells in fluidMalignant cells in fluid Preoperative rupturePreoperative rupture Dense adhesionDense adhesion Aneuploid tumor Aneuploid tumor

Early-Stage Low-Risk Ovarian Cancer

Stage IA, IB, Grade 1 and 2.Stage IA, IB, Grade 1 and 2. GOG randomized trial of observation versus melphalan GOG randomized trial of observation versus melphalan

in this group of patients and the 5-year survival for each in this group of patients and the 5-year survival for each group were group were 94% and 96%.94% and 96%.

No further adjuvant treatment is needed for such patients.No further adjuvant treatment is needed for such patients.

Early-Stage High-Risk Ovarian Cancer

In patients whose disease is high risk ( e.g., more poorly In patients whose disease is high risk ( e.g., more poorly differentiated or in whom there are malignant cells either differentiated or in whom there are malignant cells either in ascitic fluid or in peritoneal washings ) . in ascitic fluid or in peritoneal washings ) . Additional Additional therapy in indicated.therapy in indicated.

Treatment options include chemotherapy or whole-Treatment options include chemotherapy or whole-abdominal radiationabdominal radiation

Randomized Trials in Stage I Epithelial Ovarian Cancer ( since 1995)

AuthorAuthor PatientsPatients StagesStages TreatmentTreatment Best ArmBest Arm Young et alYoung et alGOG7601GOG7601 8181 I(Low)I(Low) Observation Vs. MelphalanObservation Vs. Melphalan NPNP GOG7602GOG7602

141141 I(High), II I(High), II P32 Vs melphalanP32 Vs melphalan NPNP Bolis et al.Bolis et al. 4747I(Low)I(Low) Observation Vs cisplatinx6Observation Vs cisplatinx6 NPNP 104104I(High)I(High) P32 Vs cisplatinx6P32 Vs cisplatinx6 CisplatinCisplatin 79 Vs 69%79 Vs 69%

Young et al.Young et al. 205205 I(High), III(High), II Cisplatin75mg/m2/ cycloCisplatin75mg/m2/ cyclo Cis/cycloCis/cyclo GOG95GOG95750mg/m2 Vs P32750mg/m2 Vs P3277 Vs 66%77 Vs 66% Trope et al Trope et al 134134

I(High)I(High) Carboplatin vs. observationCarboplatin vs. observation NPNP Closed/maturingClosed/maturingGOG172GOG172 331331 I(High), III(High), II Taxol 175 mg/m2/ carboTaxol 175 mg/m2/ carbo AUC 7.5 (3 AUC 7.5 (3

vs 6 courses)vs 6 courses) Ongoing Trial Ongoing Trial GOG175GOG175 I(high), III(high), II Taxol 175mg/m2/carbo AUCTaxol 175mg/m2/carbo AUC 6 followed by 6 followed by

observation vs.observation vs. Taxol Taxol 40mg/m2/weeklyx26wks40mg/m2/weeklyx26wks

Early-Stage High-Risk Ovarian Cancer

Patients with high-risk stage I epithelial ovarian cancer Patients with high-risk stage I epithelial ovarian cancer be given adjuvant chemotherapy. The type depends on be given adjuvant chemotherapy. The type depends on the patient’s overall health and status.the patient’s overall health and status.

Treatment with carboplatin and Taxol chemotherapy for Treatment with carboplatin and Taxol chemotherapy for 3 to 6 cycles seem desirable in most patients, whereas a 3 to 6 cycles seem desirable in most patients, whereas a short course of a single agent, either carboplatin or short course of a single agent, either carboplatin or Taxol, may be preferable for older women.Taxol, may be preferable for older women.

Advanced-Stage Ovarian Cancer

After the introduction of cisplatin in the latter half of the After the introduction of cisplatin in the latter half of the 1970s, platinum-based combination chemotherapy 1970s, platinum-based combination chemotherapy became the most frequently used regimen in USA. became the most frequently used regimen in USA.

Taxol become available in the 1980s, and this drug was Taxol become available in the 1980s, and this drug was incorporated into the combination chemotherapy in the incorporated into the combination chemotherapy in the 1990s.1990s.

Cisplatin Combination Chemotherapy

Combination chemotherapy has been shown to be Combination chemotherapy has been shown to be superior to single-agent therapy.superior to single-agent therapy.

After cisplatin became available for the treatment of After cisplatin became available for the treatment of ovarian cancer showed that ovarian cancer showed that cisplatin was better than an cisplatin was better than an alkylating agent , cyclophosphamide, as a single agentalkylating agent , cyclophosphamide, as a single agent..

Several studies recommended the Several studies recommended the platinum-based platinum-based chemotherapy were shown to be superiorchemotherapy were shown to be superior..

Most studies using the PC or PAC regimen, disclosed the Most studies using the PC or PAC regimen, disclosed the same survival ratessame survival rates..

Taxol-based Combination Chemotherapy

The next major advance in the treatment of advanced The next major advance in the treatment of advanced stage disease was the incorporation of taxol into the stage disease was the incorporation of taxol into the chemotherapeutic regimen.chemotherapeutic regimen.

Several prospective randomized trial with taxol-based Several prospective randomized trial with taxol-based arms have defined the current recommended protocol in arms have defined the current recommended protocol in advanced epithelial ovarian cancer.advanced epithelial ovarian cancer.

Based on the GOG111,1996 and OV10,1998 studies, Based on the GOG111,1996 and OV10,1998 studies, Taxol should be included in the primary treatment of all Taxol should be included in the primary treatment of all women with advanced-stage epithelial ovarian cancerwomen with advanced-stage epithelial ovarian cancer

Platinum and Taxol Chemotherapy randomized Trials in Advanced-Stage epithelial Ovarian Cancer

AuthorAuthor YearYear GroupGroup StatusStatus Drugs/dosesDrugs/doses BestBestMcGuireMcGuire 19961996 GOG 111GOG 111 SuboptSubopt T:135(3)/cis75T:135(3)/cis75 Taxol/cisTaxol/cis

vs ctx750/cis75 vs ctx750/cis75 StuartStuart 19981998EORTC EORTC Opt/SuboptOpt/Subopt T:175/cis75T:175/cis75 Taxol/cisTaxol/cis OV10OV10vs ctx750/cis75vs ctx750/cis75 MuggiaMuggia 19971997 GOG132GOG132

SuboptSubopt Cis100 vs T200(24)Cis100 vs T200(24) Taxol/cisTaxol/cis vs cis75/T135(24)vs cis75/T135(24)OzolsOzols 19991999 GOG158GOG158 OptOpt Carbo7.5/T175(3)Carbo7.5/T175(3) Taxol/carboTaxol/carbovs cis75/T135(24)vs cis75/T135(24) BoisBois 19991999

AGOAGO Opt/suboptOpt/subopt Carbo6/T185(3)Carbo6/T185(3) Taxol/carboTaxol/carbovs cis75/T185(3)vs cis75/T185(3) AlbertAlbert 19961996

GOG104GOG104 OptOpt Ipcis100/ctx750Ipcis100/ctx750 Ip cis/ctxIp cis/ctx vs Iv cis75/ctx750vs Iv cis75/ctx750MarkmanMarkman 19981998 GOG114GOG114 OptOpt Carbox2-9/Ip cis100Carbox2-9/Ip cis100 Ip cis/carboIp cis/carbo/T135(24) vs Iv cis/T135(24) vs Iv cis / / TaxolTaxol 75/T135(24)75/T135(24)

Platinum and Taxol Chemotherapy randomized Trials in Advanced-Stage epithelial Ovarian Cancer-Ongoing

AuthorAuthor Group(Protocol)Group(Protocol) StatusStatus Drugs/Doses/(hrs)Drugs/Doses/(hrs)HarperHarper ICON3ICON3 Opt/SuboptOpt/Subopt

T135(24)/cis75 vsT135(24)/cis75 vs Carbo Carbo vs cis/ctx/doxovs cis/ctx/doxo GOG162GOG162SuboptSubopt T135(24)/cis75 vsT135(24)/cis75 vsT120(96)/cis75T120(96)/cis75 GOG172GOG172

OptOpt Iv T135(24)/Ipcis100Iv T135(24)/Ipcis100(D2)/Ip T60(D8) vs (D2)/Ip T60(D8) vs Iv Iv

T135(24)/Iv cis75T135(24)/Iv cis75

Chemotherapeutic Recommendation in Advanced Ovarian Cancer

Combination chemotherapy with carboplatin and Taxol. The Combination chemotherapy with carboplatin and Taxol. The recommended doses and schedule are recommended doses and schedule are carboplatin ( AUC 5 to 6) carboplatin ( AUC 5 to 6) and Taxol 175 mg/m2(3hrs) Q3W for 6 cycles.and Taxol 175 mg/m2(3hrs) Q3W for 6 cycles.

In patients who cannot tolerate the combination, single- agent In patients who cannot tolerate the combination, single- agent carboplatin (AUC 5 to 6 ) can be given.carboplatin (AUC 5 to 6 ) can be given.

In those who have a hypersensitivity to Taxol, an alternative In those who have a hypersensitivity to Taxol, an alternative active drug can be substituted ( e.g., cyclophosphamide or active drug can be substituted ( e.g., cyclophosphamide or topotecan).topotecan).

In patients who cannot tolerate IV chemotherapy, an oral In patients who cannot tolerate IV chemotherapy, an oral alkylating agent can be substituted.alkylating agent can be substituted.

Combination Chemotherapy for Advanced Epithelial Ovarian Cancer : Recommended Regimens

DrugsDrugs DoseDose InfusionInfusion Interval Interval No. of cyclesNo. of cyclestime(hr)time(hr) Standard RegimenStandard RegimenTaxolTaxol 175mg/m2175mg/m2 2424 Q3WQ3W 6 cycles6 cycles

CarboplatinCarboplatin AUC 5-6AUC 5-6 Q3WQ3W 6 cycles6 cyclesTaxolTaxol 135 mg/m2135 mg/m2 33 Q3WQ3W 6 cycles6 cycles

CisplatinCisplatin 75 mg/m275 mg/m2 Q3WQ3W 6 cycles6 cyclesAlternative Drugs( can be given with platinum )Alternative Drugs( can be given with platinum )

CyclophosphamideCyclophosphamide 600-750 mg/m2600-750 mg/m2 Q3WQ3WTopotecanTopotecan 1.0-1.25 mg/m21.0-1.25 mg/m2 Daily x 5 DDaily x 5 D

Q3WQ3W GemcitabinGemcitabin 800-800-1000 mg/m21000 mg/m2 Q3WQ3W

Administration of Chemotherapy and Amelioration of Toxicity

Taxol :Taxol : The principal concern of Taxol + Carboplatin is the The principal concern of Taxol + Carboplatin is the

patential for enhanced patential for enhanced bone marrow toxicity.bone marrow toxicity. In general, In general, 3 hrs infusion tend to reduce the likehood 3 hrs infusion tend to reduce the likehood

of bone marrow depression than 24 hrs infusion.of bone marrow depression than 24 hrs infusion. The principal concern of Taxol + cisplatin is the The principal concern of Taxol + cisplatin is the

potential for potential for neurotoxicity. neurotoxicity.


Carboplatin :Carboplatin : The renal and GI toxicities of carboplatin are modest The renal and GI toxicities of carboplatin are modest

compared with cisplatin, and therefore do not require compared with cisplatin, and therefore do not require prehydration and outpatient administration is more prehydration and outpatient administration is more feasible.feasible.

Carboplatin does tend to have appreciable bone Carboplatin does tend to have appreciable bone marrow toxicity.marrow toxicity.

G-CSF 250 ug/m2 given sc. From D2-14 may be G-CSF 250 ug/m2 given sc. From D2-14 may be protective .protective .


Cisplatin :Cisplatin : Is given Q3W by IV infusion not over 1mg/min .Is given Q3W by IV infusion not over 1mg/min . Required prehydration, 1/2 saline given iv at a rate of Required prehydration, 1/2 saline given iv at a rate of

300-500 ml/hr for 2-4 hours until the urine output is 300-500 ml/hr for 2-4 hours until the urine output is greater than 100 ml/hr .greater than 100 ml/hr .

The principal toxicities of Taxol + cisplatin are renal, The principal toxicities of Taxol + cisplatin are renal, GI, hematologic, and neurologic. The renal and GI, hematologic, and neurologic. The renal and neurologic toxicities usually limit the duration of neurologic toxicities usually limit the duration of treatment to six cycles.treatment to six cycles.

Radiation Therapy

An alternative to combination chemotherapy for selected An alternative to combination chemotherapy for selected patients with metastatic ovarian cancer is the use of whole-patients with metastatic ovarian cancer is the use of whole-abdomimal radiation therapy.abdomimal radiation therapy.

The treatment involves a radiation field that extends from The treatment involves a radiation field that extends from 1 1 to 2 cm above the level of the diaphragm to include the to 2 cm above the level of the diaphragm to include the entire pelvisentire pelvis..

Whole-abdominal radiation appears useful in patients whose Whole-abdominal radiation appears useful in patients whose metastatic disease is microscopic or completely resected.metastatic disease is microscopic or completely resected.

No definite roleNo definite role in the treatment of ovarian cancer. in the treatment of ovarian cancer.

Hormonal Therapy

There is no evidence that hormonal therapy alone is There is no evidence that hormonal therapy alone is appropriate primary therapy for advanced ovarian cancer.appropriate primary therapy for advanced ovarian cancer.

The us of progestational agents in the treatment of The us of progestational agents in the treatment of recurrent, well-differentiated endometrioid cancer is recurrent, well-differentiated endometrioid cancer is supported by the current datasupported by the current data..

The reported response rates by Rendina et al, is The reported response rates by Rendina et al, is 57%57% (17/30) in recurrent epithelial cancer, with (17/30) in recurrent epithelial cancer, with 10%10% (3/30) (3/30) complete response, complete response, all responding patients had well all responding patients had well differentiated , estrogen recepor-positive tumorsdifferentiated , estrogen recepor-positive tumors..

Immunotherapy

Various trials using nonspecific immunostimulants to treat Various trials using nonspecific immunostimulants to treat patients with ovarian cancers.patients with ovarian cancers.

Most frequently, agents such as Most frequently, agents such as corynebacterium parvum and corynebacterium parvum and bacillus Calmette-Guerin (BCG)bacillus Calmette-Guerin (BCG) have been used have been used systemically in conjunction with cytotoxic chemotherapy.systemically in conjunction with cytotoxic chemotherapy.

None as yet has demonstrated efficacy as primary treatment.None as yet has demonstrated efficacy as primary treatment. The use of cytokines has been tested in a second-line setting, The use of cytokines has been tested in a second-line setting,

and the activity of and the activity of interferon-a, interferon-r, and interleukin- interferon-a, interferon-r, and interleukin- 22 has been demonstrated has been demonstrated

Immunotherapy Trials of Trials of monoclonal antibodies directed toward ovarian monoclonal antibodies directed toward ovarian

cancer- associated antigenscancer- associated antigens are being conducted. are being conducted. Antibodies directed toward CA125 and the human milk fat Antibodies directed toward CA125 and the human milk fat

globulin (HMFG) tumor- associated antigens are underway.globulin (HMFG) tumor- associated antigens are underway. Herceptin, an antibody directed toward the extracellular Herceptin, an antibody directed toward the extracellular

protein produced when the HER-2/neu oncogene is protein produced when the HER-2/neu oncogene is overexpressedoverexpressed, has been used extensivelly in breast cancer., has been used extensivelly in breast cancer.

Trials of Herceptin in HER-2/neu overexpressing ovarian Trials of Herceptin in HER-2/neu overexpressing ovarian cancer are ongoing.cancer are ongoing.

Antibodies against the Antibodies against the protein produced by the mutated P53 protein produced by the mutated P53 tumor suppressor genetumor suppressor gene are also undergoing clinical studies. are also undergoing clinical studies.

Treatment Assessment Tumor Markers :Tumor Markers :

CA-125 : a surface glycoprotein associated with mullerian CA-125 : a surface glycoprotein associated with mullerian epithelial tissue, epithelial tissue, is elevated in approximately 80% of is elevated in approximately 80% of patients with epithelial ovarian cancerpatients with epithelial ovarian cancer, particularly those , particularly those withwith nonmucinous nonmucinous tumors.tumors.

The level of CA-125 have been correlated with the The level of CA-125 have been correlated with the findings at second-look operations. findings at second-look operations. Positive levels are Positive levels are useful in predicting the presence of disease, but negative useful in predicting the presence of disease, but negative levels are an insensitive determinant of the absence of levels are an insensitive determinant of the absence of disease.disease.

Treatment Assessment

Tumor markers :Tumor markers : Positive predictive value : 100%Positive predictive value : 100% Negative predictive value : 56%Negative predictive value : 56% The change in level usually correlates with response. Those The change in level usually correlates with response. Those

patients with persistently patients with persistently elevated titers after three cycleselevated titers after three cycles of of treatment most likely have resistant clones.treatment most likely have resistant clones.

Radiologic Assessment :Radiologic Assessment : The false-negative rate of a CT scan is approximately The false-negative rate of a CT scan is approximately 45%.45%.

Treatment Assessment Second-look Operations :Second-look Operations :

Is performed to determined the response to therapy on a patient who has Is performed to determined the response to therapy on a patient who has clinical complete responseclinical complete response after a prescribed course of chemotherapy. after a prescribed course of chemotherapy.

5 sites (cul-de-sac, bil paracolic gutter & bil subdiaphragm ) cytology5 sites (cul-de-sac, bil paracolic gutter & bil subdiaphragm ) cytology and biopsies of the peritoneal surface, particularly in any areas of and biopsies of the peritoneal surface, particularly in any areas of previously documented tumor.previously documented tumor.

Any Any adhesions or surface irregularitiesadhesions or surface irregularities should be sampled. should be sampled. Biopsy specimens should be taken from the Biopsy specimens should be taken from the pelvic sidewalls, the pelvic pelvic sidewalls, the pelvic

cul-de-sac, the bladder, the paracolic gutters, the residual omentum, and cul-de-sac, the bladder, the paracolic gutters, the residual omentum, and the diaphragm.the diaphragm.

Treatment Assessment

Second-look operation :Second-look operation : A pelvic and paraaortic lymph node dissection should be A pelvic and paraaortic lymph node dissection should be

performed in those patients whose nodal tissue have not been performed in those patients whose nodal tissue have not been previously removed.previously removed.

Approximately, Approximately, 30%30% of patients with no evidence of of patients with no evidence of macroscopic disease have microscopic metastases.macroscopic disease have microscopic metastases.

Also, in many patients with microscopic disease, it is Also, in many patients with microscopic disease, it is detected only in the detected only in the occasional biopsy or cytologic specimen.occasional biopsy or cytologic specimen.

If gross tumor is disclosed at second-look operation, resected If gross tumor is disclosed at second-look operation, resected all the tumor tissue may be performed to faciliate response to all the tumor tissue may be performed to faciliate response to salvage therapies.salvage therapies.

Second-Look Operation

Has not been shown to influence patient survivalHas not been shown to influence patient survival, , although the information obtained at second look is although the information obtained at second look is highly prognostic.highly prognostic.

The reported relapse rates after negative second-look The reported relapse rates after negative second-look operation is around operation is around 30-50 % at 5 years30-50 % at 5 years..

Initial Stage : Patients whose tumors are initially stage Initial Stage : Patients whose tumors are initially stage II & & IIII have negative second-look rates of have negative second-look rates of 85-95%85-95% and and 70-70-80%.80%. Whereas the rates for patients with stage Whereas the rates for patients with stage III or IVIII or IV disease is disease is 30-45%.30-45%.

Second-Look Operation

Tumor gradeTumor grade : The likelihood of a negative second look : The likelihood of a negative second look in patients at all stages is about in patients at all stages is about 60%-70%60%-70% for those with for those with grade Igrade I tumors, tumors, 40-50%40-50% for those with for those with grade IIgrade II, and only , and only 20%20% for those with for those with grade IIIgrade III..

Type of chemotherapyType of chemotherapy : In patients with optimally : In patients with optimally resected stage III disease treated with the resected stage III disease treated with the taxol + taxol + platinumplatinum, the negative second look rate is about , the negative second look rate is about 45-50%.45-50%.

Second-look laparoscopy ? role Second-look laparoscopy ? role

Second-Line Chemotherapy

The response rates for second-line chemotherapies have The response rates for second-line chemotherapies have been been 15 to 35%15 to 35% for most drugs tested by the oral or IV for most drugs tested by the oral or IV route.route.

Single-agent drugs are sometimes used for second-line Single-agent drugs are sometimes used for second-line chemotherapy because of their relative ease of chemotherapy because of their relative ease of administration and low toxicity. administration and low toxicity.

Second-Line Chemotherapy in Recurrent/Persistant Epithelial Ovarian Cancer

DrugDrug Platinum ResponsePlatinum Response % Response% Response Response/PatientsResponse/PatientsCisplatinCisplatin SensitiveSensitive 77%77% 17/2217/22ResistantResistant 28%28% 14/5014/50 CarboplatinCarboplatinSensitiveSensitive 33%33% 24/7224/72ResistantResistant 19%19% 38/20238/202 TaxolTaxolSensitiveSensitive 22%22% 28/12728/127ResistantResistant 13%13% 33/25533/255 TopotecanTopotecanSensitiveSensitive 26%26% 35/13435/134ResistantResistant 13%13% 34/26334/263 EtoposideEtoposideSensitiveSensitive 36%36% 16/4416/44ResistantResistant 27%27% 25/9425/94 Liposomal Liposomal Doxo-Doxo- SensitiveSensitive 26%26% 9/359/35rubicinrubicin ResistantResistant 15%15% 15/10315/103GemcitabineGemcitabine SensitiveSensitive 20%20% 7/357/35ResistantResistant 13%13% 8/608/60 HoloxanHoloxan BothBoth

17%17% 5/295/29 HexamethylmelamineHexamethylmelamineBothBoth 27%27% 13/4913/49

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