Ovarian Cancer

Ovarian Cancer

• Epithelial Tumor, postmenopausal women• Germ cell, younger women• Sex cord-stromal origin, any age

• Approximately 90% of ovarian cancer is epithelial • significant therapeutic challenges (Epithelial Tumor)• other types of ovarian cancer are often

localized ,more amenable to surgical resection, more favorable px

• peritoneal serous carcinoma and fallopian tube carcinoma (their clinical and management considerations are similar to those of epithelial ovarian cancer)

Epidemiology

• leading cause of gynecologic cancer mortality• The lifetime risk :1.7%, • familial predisposition :of 10% to 40%• The median age at diagnosis for sporadic disease

is 60 years, • improvement in 5-year survival• A higher risk for nulliparous women• lower risk for those who have had children, who

have breastfed, who have undergone tubal ligation, or who have taken oral contraceptives

Pathogenesis and Patterns of Metastases

• arise from the surface epithelium covering the ovary, which is contiguous with peritoneal mesothelium. It is thought that malignant transformation preferentially occurs within epithelium that becomes trapped within ovarian inclusion cysts during ovulation, where it can develop into a variety of mullerian-type histologies. Thus, ovarian serous carcinomas can resemble the fallopian tube, ovarian mucinous tumors may resemble the endocervix, and ovarian endometrioid carcinomas may resemble the endometrium.

Pathogenesis and Patterns of Metastases

• Germ cell tumors most likely originate in cells derived from the primitive streak that ultimately migrated to the gonads.

• The ovarian stroma consists of granulosa cells, theca cells, and fibroblasts, which give rise to the sex cord- stromal tumors.

• Several molecular abnormalities in patients with epithelial ovarian cancer,

• Cytogenetic analysis may reveal complex abnormalities

• Mutation in the p53 proto-oncogene occurs in over 50% of cases,

• Mutations in the K-ras proto-oncogene are more common in ovarian borderline tumors (which typically do not undergo p53 mutation).

• Amplification of the Her-2/neu gene , 8% • Overexpression of proapoptotic genes such as

BAX(Px good)• Expression of (VEGF) (high serum :Px poor)

• exfoliate from the ovarian surface• The tumor typically spreads to the omentum and to

peritoneal surfaces • The lymphatic drainage

para-aortic region, pelvic sidewall lymphatics, (external iliac, obturator,

and hypogastric chains) inguinal lymph nodes.• 10% to 15% appears to be localized to the ovaries

have metastases to para-aortic lymph nodes• retroperitoneal lymph node involvement is found in

over 50% of patients with advanced disease.

• The most common site of extra-abdominal spread is the pleural space (thought to occur via transdiaphragmatic lymphatics), where it causes a malignant pleural effusion in some patients.

• Hematogenous metastases to the liver, spleen, or lung

• Bone or central nervous system metastases

Histologic Classification of Epithelial Tumors

• The nomenclature for these tumors reflects the cell type, location of the tumor, and degree of malignancy, ranging from benign lesions to tumors of low malignant potential (LMP) to invasive carcinomas

Tumors of LMP (borderline tumors)

• epithelial papillae with atypical cell clusters• excellent prognosis • increased mitotic activity• lack stromal invasion

Epithelial carcinomas• characterized by histologic cell type and

degree of differentiation (tumor grade)• The histologic cell type has limited prognostic

significance independent of clinical stage• High tumor grade ,especially in patients with

early stage epithelial tumors.

• papillary serous variety of epithelial ovarian cancer: psammoma bodies

• clear cell histology may also be associated with endometriosis, hypercalcemia , relatively resistant to chemotherapy

• mucinous ovarian cancers are chemoresistant, sometimes associated with pseudomyxoma peritonei, and may not be associated with dramatic elevations of (CA 125)

COMMON EPITHELIAL TUMORS

• Malignant serous tumor• Malignant mucinous tumor• Malignant endometrioid tumor

SEX CORD - STROMAL TUMORS

• Granulosa - stromal cell tumor• Androblastoma: Sertoli-Leydig cell tumor• Germ cell tumor

DDx

• Gastric, breast (especially ILC), mesothelioma, and colorectal cancers may occasionally present with diffuse peritoneal implants, ascites, and ovarian metastases that mimic primary ovarian cancer.

• routine light microscopic histologic evaluation, IHC• cytokeratin CK7 +and CK20 - in most cases of

primary serous ovarian cancer, • Staining for gross cystic disease fluid protein

(GCDFP) may be positive in up to 50% of patients with breast cancer, whereas this marker should be negative in patients with gastric, colorectal, or ovarian cancer.

Common Histologic Types of Epithelial Ovarian Cancer

• Papillary serous• Endometrioid• Mucinous• Clear cell

Papillary serous

• The most common type of epithelial ovarian cancer.

• May contain psammoma bodies • often associated with CA 125 elevation. • Identical histology is observed for primary

peritoneal serous cancer (PPSC).

Endometrioid

• Sometimes associated with endometriosis or an independent uterine cancer of similar histology. May occur with early stage disease in younger patients, although advanced disease is also possible.

Mucinous

• May rarely be associated with pseudomyxoma peritoneii. CA 125 levels may not be markedly elevated. Relatively chemoresistant. Differential diagnosis of a mucinous ovarian tumor includes metastatic disease from an appendiceal primary.

Clear cell

• The most chemoresistant type of ovarian cancer. Often contains hobnail cells with cleared out cytoplasm due to glycogen. Sometimes associated with endometriosis or humorally mediated hypercalcemia.

Diagnosis• asymptomatic• Symptomatic of spreads to the upper abdomen• Approximately 70% with stage III or IV whereas the

majority of patients with borderline, germ cell, and sex cord -stromal tumors present with early stage disease limited to the pelvis

• mass on routine pelvic examination or because of pelvic pain caused by ovarian torsion.

• ovarian germ cell malignancies tend to stretch and twist the infundibulopelvic ligament, causing severe pain

• Abdominal discomfort, bloating, and early satiety (ascites and a pelvic mass on physical examination)

• (Sister Mary Joseph's node) or a pleural effusion

• The mass on pelvic examination is frequently firm and fixed, with multiple nodularities palpable in the cul-de-sac.

• The CA 125 serum level is elevated in more than 80% of serous epithelial ovarian cancers.

• not a reliable diagnostic test, since it can also be elevated in a variety of benign gynecologic conditions (such as endometriosis, pelvic inflammatory disease, or pregnancy) and nongynecologic malignancies (such as breast, lung, and GI).

• the CA 125 level is elevated in 50% of patients with early stage epithelial ovarian cancer,

• CA 19-9, which is elevated in some mucinous ovarian carcinomas, and carcinoembryonic antigen (CEA) are less frequently useful.

• It is typical for a patient with epithelial ovarian cancer to have a normal CEA level in the setting of a significantly elevated CA 125 level.

• Postoperatively, the CA 125 level provides a sensitive way to monitor treatment response and development of disease recurrence. Because relapsed epithelial ovarian cancer is usually incurable, however, there is currently no evidence that early detection of recurrence through CA 125 levels confers a survival advantage in this disease.

International Federation of Gynecology and Obstetrics Staging System for Epithelial

Ovarian Cancer

STAGE I Tumor limited to ovary or ovariesa

IA One ovary, without ascites, positive peritoneal washings, surface involvement, or rupture.

IB Both ovaries, without ascites, positive peritoneal washings, surface involvement, or rupture.

IC Ascites, positive peritoneal washings, surface involvement, or rupture present.

STAGE IIOvarian tumor with pelvic extensiona

IIAInvolvement of the uterus or fallopian tubes.IIBInvolvement of other pelvic organs (e.g.,

bladder, rectum, or pelvic sidewall).IICPelvic extension, plus findings indicated for IC.

STAGE IIITumor involving the upper abdomen or lymph nodesIIIAMicroscopic disease outside of the pelvis, typically

involving the omentum.IIIBGross deposits less than or equal to 2 cm in

diameter.b

IIICGross deposits greater than 2 cm in diameter, or

nodal involvement.b

STAGE IVDistant organ involvement, including pleural

spacec or hepatic/splenic parenchyma.

• aPatients with disease that appears to be confined to the ovaries or pelvis require nodal biopsy for complete staging, in order to exclude the possibility of occult stage IIIC.

• bDisease measurements for staging purposes are made before debulking has been attempted.

• cPleural effusion must be cytologically proven to be malignant if used to define stage IV disease.

TVU

• diagnostic tool • TVU is more sensitive (CTS)• The classic sonographic finding of malignancy is a complex

cyst, defined as containing both solid and cystic components, sometimes with septations and internal echogenicity .

• Finding a complex cyst on sonography, especially in the presence of signs and symptoms consistent with ovarian cancer, often requires surgery for further evaluation. It is best to avoid percutaneous biopsy during the initial evaluation, which can result in cyst rupture and spillage of malignant cells into the peritoneal cavity. Bilateral ovarian involvement and ascites are sometimes detected by sonography as well.

• Color Doppler imaging

Simple cysts

• Simple cysts in asymptomatic postmenopausal do not always require surgical evaluation if they are associated with normal CA 125 levels,

• Postmenopausal women with simple cysts in association with elevated serum CA 125 levels, simple cysts that exceed 5 to 10 cm in diameter, or simple cysts in association with abnormal color Doppler flow studies are often referred for surgery.

Simple cysts In premenopausal

• may be functional (i.e., a corpus luteum cyst) • a benign process such as a serous cystadenoma. • simple cysts that are persistent or enlarging, especially in

the setting of a rising CA 125 level, are reasonable candidates for surgical evaluation to exclude malignancy.

• several benign conditions in premenopausal women may also be associated with elevated CA 125 levels, such as pregnancy or endometriosis, and there is no absolute CA 125 cutoff to distinguish benign from malignant pathologies

• CT or (MRI) in defining the extent of peritoneal disease

• However, for the patient with a complex ovarian cyst and clinical signs and symptoms to suggest ovarian cancer, these studies generally do not obviate the need for surgical exploration.

• CT may sometimes be helpful in distinguishing a gynecologic malignancy from a metastatic pancreatic neoplasm, for instance, for which an exploratory laparotomy may not be warranted. In selected patients, CT may also assist in surgical planning by locating the site of suspected bowel obstruction.

• MRI has not been shown to have a clear advantage over CT in patients with an ovarian mass, except for pregnant patients when ultrasonography is inconclusive and there is a desire to avoid radiation exposure.

• PET:there is currently no proven role for PET in the diagnosis or subsequent follow-up of patients with ovarian cancer.

• CXR may sometimes be performed to evaluate the presence of pleural effusions, which occur in 10% of patients with epithelial ovarian cancer at diagnosis.

Screening and Early Detection

1. identifying the majority of patients with precancerous lesions or early disease

2. major surgery 3. Costs4. mortality5. the false-positive rate 6. positive predictive value (PPV)

screening procedure

• serum tumor marker levels • ultrasonography • both

CA 125 serum level• alone, is not a useful • not specific for ovarian cancer cirrhosis, peritonitis, pleuritis, pancreatitis, endometriosis,

uterine leiomyomata, benign ovarian cysts, and pelvic inflammatory disease

• elevated in other malignancies such as breast, lung, colorectal, pancreatic, and gastric

cancers. • CA 125 level is elevated in the majority of patients with

advanced epithelial ovarian cancer, it is abnormal in only 50 % of patients with early stage disease.

candidate markers

show promise for enhancing the accuracy of CA 125 levels,

1. HE4 (human epididymis 4)2. osteopontin3. mesothelin4. osteoblast-stimulating factor-2. 5. OVX-16. Lysophosphatidic acid

these markers may be complementary to CA 125

None of these tests has been proven to have sufficient sensitivity and specificity for routine screening at the current time.

CA 125+ TVU

• an attempt to improve screening.

• TVU suggested a sensitivity of close to 100% but a specificity of 98%, which is insufficient to achieve a PPV of 10%.

• color Doppler imaging improves the specificity of TVU ,PPV?

• using a morphologic index?

• Two randomized controlled trials measurement of CA 125 level (single threshold

elevation of more than 35 U/mL) and TVU together, performed annually, as a first-line screen

will require an average of 10 years of follow-up

• The second randomized screening trial is currently being conducted in the United Kingdom and uses CA 125 levels (or rate of rise of CA 125) as a trigger for performing TVU.

Hereditary Ovarian Carcinoma

• 5% to 10% epithelial ovarian carcinoma carry a germline mutation

• The breast -ovarian cancer syndrome 90% of hereditary ovarian cancer and is often suspected whenever the pedigree reveals multiple affected family members with ovarian cancer, bilateral or early onset breast cancer, both breast and ovarian cancer in the same individual, or a male relative with breast cancer.Fallopian tube cancer and primary peritoneal serous cancer (PPSC)

Breast and ovarian cancers

• inherited germline mutations in the BRCA1 or BRCA2 genes,

• transferred by either parent, • these genes act as tumor suppressors and play

a critical role in the repair of double-stranded DNA breaks.32

• The lifetime risk of ovarian cancer is 20% to 60% for patients with BRCA1 mutations, and 10% to 35% for BRCA2 mutation carriers.

• Ovarian cancer with germline mutations of BRCA1 appears to present with distinct clinical and pathologic features compared with sporadic ovarian cancer.

• The majority of BRCA1-associated cancers are serous adenocarcinomas, with an average age at diagnosis of 48 years, whereas the mean age for BRCA2-associated ovarian cancers is 60 years.

Furthermore, BRCA-associated cancers may have a more favorable course than sporadic ovarian cancer.

• chemosensitivity may be partly due to the inability of tumor cells to repair platinum-induced DNA damage in the setting of a BRCA1 or BRCA2 mutation.

• The more favorable survival of patients with BRCA1 or BRCA2 mutations when compared to their sporadic counterparts is not necessarily related to a higher rate of cure, but may also be related to a longer duration of responsiveness to chemotherapy agents used in the relapsed setting.

Hereditary nonpolyposis colorectal cancer

• 5% to 10% of all hereditary ovarian cancer • autosomal dominant • right colon, as well as an increased risk of

developing endometrial, ovarian, hepatobiliary, upper gastrointestinal, and Gyn cancers.

• Colorectal and uterine cancers comprise the majority of tumors developing in affected families.

• A germline mutation in one of five genes involved in DNA mismatch repair is responsible for the HNPCC phenotype: hMSH2 (chromosome arm 2p), hMLH1 (chromosome arm 3p), hPMS1 (chromosome arm 2q), hPMS2 (chromosome arm 7p),

• The majority of affected patients are found to have defects in either hMSH2 or hMLH1

• Patients with HNPCC due to germline mutation of hMSH6 may be particularly predisposed to uterine cancer. In addition, HNPCC may account for approximately 7% of cases with synchronous uterine and ovarian cancers, which are often low grade and of endometrioid histology

Patients at high risk of having a hereditary cancer

• genetic counseling• Multidisciplinary services available in such a

setting often include pretest and posttest counseling, screening, treatment, and psychosocial counseling.

Test results

• an identifiable mutation, • no identifiable mutation• a polymorphism of indeterminate clinical

significance.

Management of patients with an inherited genetic predisposition to ovarian cancer

• complex • variable penetrance of genetic alterations • lack of effective early detection methods for ovarian

cancer• Although annual pelvic examinations, serum CA 125

determinations, and TVU are sometimes considered in affected individuals, there is currently no conclusive evidence that ovarian cancer mortality is reduced as a result of these interventions

• efficacy of prophylactic, risk reduction bilateral salpingo-oophorectomy (RRSO) for patients with the hereditary breast-ovarian cancer syndrome has been more convincingly demonstrated.

• RRSO• Chemoprophylaxis• Other risk-reducing strategies

Management of patients with an inherited genetic predisposition to ovarian cancer

• Even after RRSO, BRCA mutation carriers are still at small risk for developing primary peritoneal serous cancer, which is histologically and clinically similar to epithelial ovarian cancer. Such cancers represent malignant transformation of the peritoneal mesothelium, which is contiguous with ovarian surface epithelium.

RRSO

• most effective preventative strategy• at high risk for developing ovarian cancer and

who have completed childbearing, especially if they are at least 35 years of age

• A laparoscopic approach

• The surgical pathologist must perform a careful examination of the surgical specimens, as occult ovarian and tubal carcinoma have been found in 2% to 10% of RRSO specimens.

• Some patients with occult disease discovered after careful pathological evaluation may require a second operation to complete surgical staging in order to determine the need for postoperative treatment .

• Significant issues regarding RRSO remain unresolved, such as the physiologic adjustments to premature surgical menopause and the safety of hormone replacement therapy in this group, especially in those at high risk for breast cancer.

• chemoprophylaxis with oral contraceptives for 5 years might decrease ovarian cancer risk by 50% in both the general population and in high-risk women.

• Other risk-reducing strategies such as tubal ligation and hysterectomy have also been associated with a reduced incidence of ovarian cancer among high-risk women.

Staging

1. laparotomy permits histologic confirmation of disease,

2. Surgery is also necessary to determine the extent of disease (staging), post opTX ,Px

3. debulking optimally cytoreduced (defined as having less

than or equal to 1-cm diameter residual tumor)

• midline incision • ascitic fluid • If intraperitoneal carcinomatosis is absent, first

resect the ovarian tumor• The grossly normal, opposite ovary may

undergo biopsy, or any visible benign-appearing cysts may be excised.

• Pelvic and para-aortic retroperitoneal lymph nodes

• Any enlarged pelvic retroperitoneal lymph nodes should be removed

The staging system for ovarian cancer is defined by FIGO based on the findings at exploratory laparotomy

Staging

• fertility• endometrioid ovarian cancer

incomplete surgy

• completing the surgical staging if the findings would alter postoperative management(stage IA, grade 1 or 2 )

• ( at least stage IC or stage II )or (tumor is grade 3),less importent

• Laparoscopic techniques • CT scan?

Prognostic Factors for Epithelial Ovarian Cancer

• FIGO stage,• volume of residual disease after cytoreductive

surgery• histologic subtype, • histologic grade,• age, • malignant ascites.

• 5ys stage IA disease and grade 1 or 2 >90% after surgery alone( or +stage IB, grade 1 or 2 )

• relapse rate without postop adj treatment is 30% to 40% for patients with stage IC , stage I, grade 3 , or stage II

a 5-ys 80% after postop adj therapy• Controversial: some investigators report that

rupture alone does not appear to confer a worse prognosis if it occurred intraoperatively, as opposed to preoperatively.

advanced-stage disease

• 5ys 20% to 30% After postoperative treatment stage III optimally debulked, and this decreases to less than 10% for patients with suboptimally debulked stage III disease or those with stage IV tumors.

• stage IIIA disease survivals in the range of 50% after postoperative adjuvant therapy.

• mucinous or clear cell histologic have worse Px

CA 125• Preoperative serum CA 125 levels frequently reflect the

volume of disease and do not appear to have an independent effect on survival, after correcting for stage and debulking status.

• postoperative CA 125 levels, both during and after completion of first-line chemotherapy, have prognostic value.

• normalization of the serum CA 125 levels after three cycles of cht is associated with more favorable outcome, as well as achievement of a CA 125 nadir of less than or equal to 10 U/mL upon completion of treatment. Although this information has prognostic significance, it has limited therapeutic value in the absence of effective salvage regimens with curative potential.

The prognostic significance

• DNA ploidy and S-phase fraction aneuploidy?relationship between histologic grade and the

degree of aneuploidy?

molecular prognostic factors

• markers of proliferation • drug resistance• levels of serum cytokines • growth factor receptors• expression of genes associated with

metastases.

Management of Early Stage Disease

• Postoperative Chemotherapy• Postoperative Radiation Therapy

Postoperative Chemotherapy

• can improve both progression-free and overall survival in patients with high-risk, early stage ovarian cancer. Such patients include those with stage I, grade 3, stage IC, or any stage II disease.

• six cycles of adjuvant carboplatin plus paclitaxel chemotherapy for high-risk, early stage patients,

Postoperative Radiation Therapy

• different chemotherapy regimens • whole abdominal radiotherapy (WAR) • intraperitoneal (IP) administration of

radioactive phosphorus (32P).

In summary

• these randomized trials generally found WAR or IP 32P was less effective or more toxic than platinum-containing regimens. Hence, adjuvant radiation therapy has fallen out of use as the primary treatment for patients with high-risk, early stage ovarian cancer

Management of Advanced-Stage Disease

• Primary Cytoreductive Surgery• Postoperative Chemotherapy for Epithelial

Ovarian Cancer• Intraperitoneal Chemotherapy• Interval Cytoreductive Surgery• Radiotherapy After First-Line Chemotherapy• Maintenance Therapy

Primary Cytoreductive Surgery• The theoretical benefits of cytoreductive surgery

include removal of large, necrotic tumors with poor blood supply that might lead to impaired chemotherapy delivery.

• tumor debulking may permit residual tumor to proliferate more rapidly and thereby enhance sensitivity to postoperative chemotherapy.

• Although neither of these mechanisms has been proven, the association between successful cytoreduction and more favorable outcome has been demonstrated in many surgical series.

optimal cytoreduction

• residual disease of 1 cm or smaller in maximum individual diameter

• Primery cytoreduction refers to performance of debulking surgery prior to administration of first-line chemotherapy and is the standard approach for managing most patients with suspected epithelial ovarian cancer.

neoadjuvant chemotherapy and an interval cytoreduction

• patients with a poor performance status initiating neoadjuvant CHT →surgical cytoreduction in responding patients after three cycles of chemotherapy

• stage IV disease

neoadjuvant chemotherapy

• Potential advantages of neoadjuvant chemotherapy are

1. a more rapid improvement in quality of life2. a technically more feasible operation 3. shorter hospitalization 4. less morbidity.

Postoperative Chemotherapy for Advanced-stage epithelial ovarian cancer

• It is a chemoresponsive disease in the majority of cases, although relapse often occurs and resistance eventually develops to most forms of treatment.

• The platinum compounds remain the single most active drugs in the treatment of this disease.

• the use of carboplatin instead of cisplatin conferred an equivalent survival advantage, but with less myelosuppression, neuropathy, nephropathy, and emesis

P base + a taxane such as paclitaxel

• is now accepted as an appropriate first-line,• The response rate as high as 70% for patients

with suboptimally debulked disease, • over 80% for patients who are optimally

cytoreduced. • nonoverlapping mechanisms of action,

Combination or sequential single agents

• For individuals who may have difficulty tolerating a combination regimen (e.g., those with marginal performance status or significant comorbid medical conditions), it is reasonable to initiate treatment with intravenous single-agent carboplatin and later add intravenous paclitaxel to the regimen or deliver the drugs as sequential single agents.

• For appropriate patients with stage III disease who are optimally cytoreduced, intraperitoneal chemotherapy is an important new option

• carboplatin (AUC = 5) plus paclitaxel (175 mg/m2) • icarboplatin (AUC = 5) and docetaxel (75 mg/m2) has shown equivalent response rates, progression-free, and

overall survival, although their toxicity profiles differed. More grade 4 neutropenia occurred with the docetaxel-containing regimen, and a greater incidence of grade 2 or 3 neuropathy was observed with the paclitaxel-containing program.

• These data indicate that a carboplatin and docetaxel combination is an acceptable first-line regimen for patients with advanced ovarian cancer, especially in the setting of pre-existing neuropathy (where paclitaxel may be difficult to tolerate).

How many cycles

• There appears to be no value in extending platinum-based first-line therapy beyond five or six cycles to ten or 12 cycles.

• there is no convincing evidence to suggest a benefit to the addition of cytotoxic drugs such as liposomal doxorubicin, epirubicin, topotecan, or gemcitabine to the platinum and taxane doublet

• Bevacizumab ?

Intraperitoneal Chemotherapy• The rationale for this approach is based on the

observation that many active drugs such as cisplatin and paclitaxel have favorable peritoneal to plasma concentrations, on the order of 20 to 1 and 1,000 to 1, respectively.

• generally acceptable systemic side effects, • limited penetration

1. receive either a control arm of IV paclitaxel (135 mg/m2 administered over 24 hours) and IV cisplatin (75 mg/m2) for six cycles,

2. IV paclitaxel on day 1 (135 mg/m2 administered over 24 hours), IP cisplatin on day 2 (100 mg/m2), and IP paclitaxel on day 8 (60 mg/m2), for six cycles.

The median overall-survival was 65.6 months for the IP arm and 49.7 months for the IV arm (HR 0.75; 95% CI 0.58 to 0.97; P = .03).

This significant prolongation of median overall survival was associated with several toxicities, including a higher incidence of neutropenia, infection, catheter blockage, neuropathy, abdominal pain, renal dysfunction, and electrolyte abnormalities

• Although some investigators still feel that IP chemotherapy should remain experimental, others feel that these data offer strong support for the IP approach.

IP therapy no superior to IV treatment in

1. stage IV disease, 2. suboptimally debulked residual disease3. relapsed disease.• It should also be avoided in patients with

comorbid conditions such as renal insufficiency, significant baseline neuropathy, or extensive intra-abdominal adhesions.

Improve the tolerability of IP therapy

• reduction of the day-2 IP cisplatin dose,• administration of day-1 IV paclitaxel over 3 hours instead

of 24 hours, • and/or omitting day-8 IP paclitaxel until patient tolerance

to the first cycle of IP cisplatin can be assessed. • reduce toxicity while still preserve the benefits of the IP

approach?• use of IP carboplatin instead of IP cisplatin it is not yet known whether carboplatin is as effective as

cisplatin when administered via the IP route.

Technical Aspects of Intraperitoneal Chemotherapy Administration

• either cisplatin or paclitaxel • a catheter with a subcutaneous access port in

the anterior chest wall region, just below the breast, which then tunnels subcutaneously downward to the midabdomen, where it enters the peritoneal cavity. IP catheter insertion can be performed at the time of primary cytoreductive surgery, or afterward by laparoscopy.

• Based on the available data, colon resection with fecal contamination or left colon resection would appear to represent relative contraindications to placement of an IP catheter at the time of primary cytoreduction

1. Tenckhoff catheter adhesion formation within the peritoneal catheter

related to the development of a fibrous sheath surrounding the catheter fenestrations, and intestinal obstruction due to the Dacron sheath migrating into the peritoneal cavity

2. a single-lumen silicone catheter with an implantable port designed for IV injection may be preferable,

Catheter insertion typically involves the following steps1. A separate 5 to 6 cm transverse incision is made two to three

fingerbreadths above the left inferior costal margin in the midclavicular line and is carried down to the fascia.

2. A subcutaneous pocket is created to house the implantable port3. The port is sutured to the fascia at the four corners4. A tonsil clamp or similar instrument is tunneled subcutaneously above

the fascia for approximately 10 cm from the port. At a point about 6 cm lateral to the umbilicus, a small aperture is made in the peritoneum.

5. The proximal end of the catheter is grasped with the clamp and brought through from the peritoneal cavity, through the subcutaneous tunnel, to the port.

6. The catheter is connected to the port, and it is trimmed to allow approximately 10 cm of catheter within the peritoneal cavity

7. The catheter is flushed with heparinized saline to check patency.8. The transverse skin incision is closed

• Intraperitoneal instillation • If the infusion rate is slow, repositioning the

patient may be beneficial in an attempt to move the catheter tip away from bowel loops or a pocket caused by adhesions.

• a second prewarmed liter of fluid• Standard premedications

Interval Cytoreductive Surgery

• Interval cytoreduction is defined as a debulking procedure performed after several cycles of chemotherapy have been administered, typically in those patients who had a suboptimal cyto-reduction at the time of initial surgery.

• a randomized trial : improvement in median overall survival (P = .01), suggesting a role for this strategy in suboptimally debulked patients who are responding to first-line chemotherapy.

• the negative results of the GOG study than in the EORTC trial, are partly due to

1. definition of suboptimally debulked disease2. performance of initial surgery by a gynecologic

oncologist, 3. more effective paclitaxel and cisplatin regimen in

the GOG trial (compared to cyclophosphamide and cisplatin in the EORTC trial) may have negated any added value of interval cytoreduction.

• Thus, patients who are deemed to be suboptimally debulked after a cytoreductive effort performed by a surgeon skilled in this procedure, who then receive first-line paclitaxel- and platinum-based chemotherapy, are not likely to benefit from interval cytoreduction.

• For those patients who did not adequate attempt at initial cytoreduction (due to being a poor operative candidate or due to lack of surgical expertise), the EORTC study suggests that an attempt at interval cytoreduction is reasonable if disease control can be achieved during the first three cycles of chemotherapy.

Radiotherapy After First-Line Chemotherapy

Cht+ :1. WAR2. Pelvis +para aort3. IP 32P4. observe

In conclusion ?

• the value of radiation therapy as consolidation therapy following chemotherapy for patients with ovarian cancer is uncertain.

• Routine use of consolidation radiotherapy after chemotherapy is not generally recommended.

Maintenance Therapy

• There is no evidence that continuing first-line platinum-based chemotherapy beyond five to six cycles confers added benefit for patients with advanced ovarian cancer

• There is currently great interest in studying the value of antiangiogenic agents such as bevacizumab, which is a humanized monoclonal antibody that neutralizes vascular endothelial growth factor in the maintenance setting.

Surveillance After First-Line Chemotherapy

• Over 50% of newly diagnosed patients with advanced-stage epithelial ovarian cancer will achieve a clinical complete remission after platinum and taxane induction chemotherapy.

• Clinical complete remission is defined as no evidence of disease on physical examination, a normal CA 125 level, and normal radiographic studies such as CT.

• Patients with advanced-stage disease who achieve a clinical complete remission have a high chance of relapse

• follow1. pelvic examinations 2. CA 125 determinations

CTS

• Routine performance of CT in the absence of symptoms, findings on physical examination, or an elevated CA 125 level has no proven value in the management of patients with this disease. This is partly due to the lack of sensitivity of CT compared to serologic testing with CA 125, which is currently the most sensitive method for detection of early relapse

• There is currently no proven benefit for routine surveillance with other radiographic tests such as PET scans in the posttreatment setting

second-look laparotomy

• Although performance of a second-look laparotomy after completion of first-line therapy will reveal residual disease in over half of all patients with advanced ovarian cancer who have achieved a complete clinical remission, this procedure does not appear to confer a survival advantage. This is due to the current lack of curative treatment options for patients with disease that persists after platinum-based, first-line therapy.

• In addition, a negative second-look laparotomy does not guarantee against the development of disease relapse, which occurs in 50% of patients with advanced stage disease who have a negative second-look procedure.

• For these reasons, second-look laparotomy is no longer considered a standard procedure in the assessment of patients after completion of first-line therapy, although it is sometimes used as an investigation tool in the context of clinical trials.

Management of Recurrent Disease

• Hormonal Therapy• Chemotherapy• Surgery• Radiation Therapy

Hormonal Therapy• (marker-only relapse)• Unfortunately, the majority of patients with

recurrent ovarian cancer are destined to die of their tumors, regardless of the second-line treatment modality used. Patients who demonstrate marker-only evidence of relapse, are often initially managed with a drug like tamoxifen or an aromatase inhibitor. These drugs are potentially active in ovarian cancer and are generally well tolerated.

• The response to hormonal agents is typically slow and may require approximately 2 to 3 months before a reduction in the CA 125 level is evident

Chemotherapy• Chemotherapy for recurrent disease is usually

indicated for the development of tumor-related symptoms, objective evidence of significant disease on examination or CT, or failure of hormonal therapy.

• Platinum is the most active agent in the management of patients with epithelial ovarian cancer, and retreatment with this drug may produce valuable responses that translate into improvement in quality of life.

• However, the likelihood of benefit depends on the interval between the last dose of platinum and the time of relapse (i.e., the platinum-free interval, PFI).

In patients with PFI:

• less than 6 months are less likely to respond to second-line platinum and are often managed with an alternative agent, (platinum resistant)

• between 6 and 24 months have an approximately 30% chance of benefit from second-line platinum used at the time of relapse.

• very prolonged PFI (e.g., greater than 2 years), the response rate with second-line platinum may be as high as 60% to 70%.

• Patients with a PFI of greater than 6 months are referred to as potentially platinum sensitive and are often treated with either single-agent platinum or a combination of platinum with another agent such as paclitaxel or gemcitabine.

• combination chemotherapy compared to single-agent platinum in the setting of potentially platinum-sensitive relapse (PFI greater than 6 months)?

• combination second-line chemotherapy with regimens like paclitaxel and carboplatin or gemcitabine and carboplatin are a reasonable consideration in selected patients who are potentially platinum sensitive, based on their PFI.

• since the primary goal of relapse management is palliation of symptoms, the decision to use combinations in this setting should be based on patient age, amount of disease, kinetics of relapse, and patient preference after a discussion of the issues

• For older patients who require chemotherapy for asymptomatic, minimal volume, potentially platinum-sensitive relapse, it is reasonable to use single-agent carboplatin as a first step.

• liposomal doxorubicin is a generally well-tolerated alternative if there is a contraindication to the use of carboplatin, if carboplatin fails to induce a response, or if an allergic reaction develops to carboplatin that precludes further administration.

• With either single-agent carboplatin or liposomal doxorubicin, patients have minimal problems with alopecia or myelosuppression, and their quality of life is generally well preserved.

• For younger patients who wish to adopt an aggressive approach to the management of potentially platinum-sensitive relapse, combination chemotherapy with either paclitaxel and carboplatin or gemcitabine and carboplatin is reasonable.

aggressive approach

• This is especially the case for the symptomatic patient with kinetically brisk relapse, or the patient who has undergone a successful secondary cytoreduction after a very long PFI.

• Some physicians prefer the use of gemcitabine and carboplatin in this setting if there is persistent peripheral neuropathy related to first-line therapy.

• Given concerns over toxicity, the decision to use combination chemotherapy for patients with potentially platinum-sensitive relapse should be individualized.

• There are currently no data supporting a role for combination chemotherapy regimens in the management of patients with platinum-resistant relapse.

• Patients who are platinum resistant, as defined by a short PFI of less than 6 months or progression during platinum-based chemotherapy, or those who tolerate second-line platinum poorly are typically treated with a variety of single agents. Potentially non “cross-resistant drugs with activity in the platinum-resistant setting include liposomal doxorubicin, paclitaxel, docetaxel, topotecan, gemcitabine, or oral etoposide.

• Liposomal doxorubicin is often well tolerated in doses of 40 mg/m2 given every 4 weeks, although the development of palmer-planar erythrodysesthesia (hand-foot syndrome) or mucositis may require dose reductions and treatment delays.

• Topotecan may cause significant myelosuppression and fatigue, although this agent is generally well tolerated through the use of weekly dosing schedules

• Unfortunately, the likelihood of obtaining a response to any of these agents in the platinum-resistant setting is less than 20%, responses are generally short lived (median PFS in the range of 4 to 6 months), and they tend to become progressively shorter with each subsequent regimen.

• Bevacizumab • Randomized data in metastatic colorectal, breast, and

lung cancers have shown a survival advantage for the use of this drug in combination with chemotherapy.

• As a single agent, bevacizumab has been shown by the GOG to induce responses in 18% of patients with relapsed ovarian cancer (either platinum sensitive or platinum resistant, treated with less than or equal to two prior regimens), with 39% of patients progression-free at 6 months.

• the risk of bowel perforation with bevacizumab in the recurrent ovarian cancer setting might be related to a higher number of prior treatment regimens, radiographic evidence of bowel wall involvement , or bowel obstruction These and other possible risk factors for this complication will require further evaluation.

No approved

• ET743 (trabectedin)• halichondrin B• pertuzumab• Epothilones

Secondary cytoreductive surgery• an attempt at surgical debulking of disease at the time

of relapse and is performed in selected patients prior to the administration of second-line chemotherapy.

• a successful secondary cytoreduction: no gross residual disease greater than 1 cm in diameter,

• However, it is possible that the ability to perform a successful secondary cytoreduction may simply identify those patients with biologically less aggressive disease or those with a lower tumor burden at the time of relapse.

Secondary cytoreductive surgery• relapse within 12 months after completion of

first-line therapy, especially if they have ascites, are generally not candidates for this procedure.

1. late relapses (i.e., greater than 2 to 3 years after finishing chemotherapy)

2. apparently isolated relapses may experience a prolonged disease-free interval

after successful secondary cytoreduction followed by additional chemotherapy.

Combination Chemotherapy1519cervix 4b• Most reports of combination chemotherapy for carcinoma of the cervix

have described small, uncontrolled phase II trials of drug combinations. However, the results of two phase III randomized trials, published in 2004 and 2005, have provided the first solid evidence that combination chemotherapy can improve both progression-free survival (cisplatin plus paclitaxel vs. single-agent cisplatin,272 cisplatin plus topotecan vs. single-agent cisplatin273) and overall survival (cisplatin plus topotecan273) when it is administered as treatment for recurrent or metastatic carcinoma of the cervix. In the cisplatin-topotecan trial, the combination regimen (cisplatin 50 mg/m2 day 1 and topotecan 0.75 mg/m2 days 1 to 3 every 3 weeks) was associated with a median overall survival of 9.4 months, compared with 6.5 months (P = .17) for single-agent cisplatin.273 An ongoing GOG phase 3 trial is directly comparing several platinum-based combination chemotherapy regimens in this clinical setting.

Management of Recurrent Disease1582ovary relapse

• Two randomized trials have investigated the value of combination

chemotherapy compared to single-agent platinum in the setting of potentially platinum-sensitive relapse (PFI greater than 6 months). The ICON-4 trial compared combination chemotherapy with paclitaxel and platinum to single-agent platinum in patients with potentially platinum-sensitive disease, with most patients having a PFI of 12 months or greater.111 This study demonstrated a statistically significant improvement in overall survival for the combination regimen, with an absolute difference at 2 years of 7% (P = .023). However, 58% of patients in the single-agent platinum arm never received a taxane as part of first-line therapy, and 69% of patients in the single-agent platinum arm never received a taxane as part of relapse management (i.e., after progression on single-agent platinum). Thus, 40% of patients in the single-agent platinum arm never received a taxane at any point during the course of their disease. Given the proven survival benefit of taxanes in this disease, the imbalance in the use of taxanes between these two treatment arms makes the results of ICON-4 difficult to interpret.

Palliative surgery

• colostomy • lysis of adhesions• management of small bowel obstructionsurgerygastrostomy tube

• Surgery generally plays no role in management of patients with a pseudo-obstructive pattern due to intra-abdominal carcinomatosis, with infiltration of the myoenteric plexus of the small bowel.

TX :Metoclopramide

Radiation Therapy

• A minority of patients with localized recurrences may experience prolonged survival after WAR or limited-field irradiation.

RT?

• The small number of highly selected patients in these series and the use of multiple concurrent treatment modalities make it difficult to adequately assess whether radiation therapy truly improves long-term outcome in this setting.

palliation

• Symptoms from a growing pelvic mass can cause pain, bleeding, and rectal narrowing.

• Palliative pelvic radiotherapy can provide rapid relief and, in some cases, may prevent or delay the need for diverting colostomy. Doses of 8 to 10 Gy in a single fraction, 20 Gy in five fractions, 30 Gy in ten fractions, or higher total doses given in smaller fractions have produced acceptable short-term results, with serious complications in 5% or fewer patients.

• Finally, patients with epithelial ovarian cancer may rarely develop isolated cerebral or bone metastases that can sometimes be successfully palliated with radiotherapy.

Borderline TumorsDefinition and Clinical Features

• absence of stromal invasion• low malignant potential (LMP• serosal implants • majority of patients present with early stage

disease

• The median age : 40 years, 20 years younger than the median age for women with epithelial ovarian cancer.

• asymptomatic mass • pelvic pain• Nonspecific GI symptoms

• serous feature:more common bilateral in 10% to 20%

• mucinous featurelarger than their serous counterpartsinfrequently bilateral, pseudomyxoma peritonei

• pseudomyxoma peritonei1. mucinous borderline ovarian tumor2. mucinous ovarian carcinoma3. gastrointestinal tumors such as appendiceal

mucinous cystadenocarcinoma.The mainstay of treatment for pseudomyxoma

peritonei is intermittent surgery

• careful examination of the tissue blocks • The presence of microinvasion • Mucinous borderline tumors are characterized

by multiloculated cystic masses, with smooth outer surfaces and areas of papulations and solid thickening on the inner surface

• Greater than 90% of patients with early stage borderline tumors are alive at 10 years

• more than 50% of patients with advanced disease experience long-term survival.

• survival does not appear to be improved by postoperative adjuvant treatment with either chemotherapy or radiation

• borderline serous tumors may behave more aggressively if they are associated with micropapillary features, and/or invasive implants elsewhere in the peritoneal cavity.

• Patients with serous borderline tumors without invasive implants have expected 10-year survival rates of greater than 95%, whereas those with serous borderline tumors and invasive implants have survival rates of approximately 60% to 70% at 10 years.

• Thus, it is possible that micropapillary features portend a poorer prognosis because of their association with invasive implants, although this is still an area of controversy.

Surgical Management

• TAH, BSO, tumor debulking, and full staging• Conservative surgery

An appendectomy is considered in patients with suspected mucinous borderline tumors because of its occasional association with a primary appendiceal carcinoma.

Conservative surgery• with preservation of the uterus, the contralateral

ovary and fallopian tube, and in some cases the ipsilateral ovary (i.e., cystectomy)

One of the largest studies found a 12% recurrence rate for patients treated conservatively compared to 2.5% for TAH, BSO.

Recurrences or progression to carcinoma (1.5%) were more common among patients with invasive implants or advanced-stage disease.

• Borderline ovarian tumors during pregnancy.

Postoperative Management

• Without adjuvant therapy, long-term survival is generally excellent

• simple observation with serial examinations, with radiographic studies as needed to investigate new symptoms or findings on examination.

• long-term follow-up• Surgery is the mainstay of treating recurrent disease • Tx multiple recurrences : HT(as tamoxifen )• CHT

Germ Cell Tumors of the OvaryDefinition and Clinical Features

• 2% to 3% of all ovarian cancers • in younger women( early 20s)• It is often possible to cure these malignancies

while preserving fertility,

WHO classification for germ cell tumors of the ovary

• Dysgerminoma(male seminoma )

• Nondysgerminoma Endodermal sinus tumor (AFP)

Embryonal carcinoma(both AFP and HCG elevation)PolyembryomaChoriocarcinoma(HCG)Immature teratomaMature dermoid cyst with malignant transformationMonodermal and highly specializedStruma ovariiCarcinoidStruma ovarii and carcinoidOthersMixed forms

• Abdominal pain, abdominal pain can be severe(hemorrhage,

rupture, or ovarian torsion)• distension,• pelvic fullness, • urinary symptoms

rapid growthpalpable adnexal massTVU, which may show a complex cyst

comprised of solid and cystic region(AFP)(HCG)

• Pure immature teratoma : normal levels of AFP and HCG, although the AFP may be elevated in 30% of cases.

• Mature cystic teratoma (dermoid cyst), a benign germ cell tumor, usually have normal levels of AFP and HCG.

• choriocarcinoma hyperthyroidism • mature cystic teratoma hyperthyroidism a Coomb's positive hemolytic anemia

Germ cell tumors

• 60% to 70% are stage I at diagnosis• Stages II and IV tumors are relatively

uncommon• stage III disease accounts for about 25% to

30% of tumors.

• Bilateral ovarian involvement dysgerminoma and mature cystic teratoma may

be bilateral in 10% to 15% of cases• More advanced disease may involve

retroperitoneal lymph nodes and multiple peritoneal surfaces, although ascites is infrequent.

• Hematogenous spread to the liver, lung, and brain can be observed, especially with choriocarcinoma

Surgical Management

1. تخمدان یک برداشتبیوپسی. 2 یا سیستکتومی و تخمدان یک برداشت

دیگر تخمدانروتین. 3 درمان

second-look operations In some patients whose tumor contains teratomatous elements, however, a second-look procedure may be beneficial

Postoperative Management of Dysgerminoma

• stage IA disease can be observed without further postoperative treatment.

Approximately 15% to 25% of such patients will experience recurrence, although salvage chemotherapy is almost always successful

• Dysgerminoma in patients with higher than stage IA disease is typically treated with platinum-based chemotherapy

PVB ,BEP

Postoperative Management of Nondysgerminoma

Tx:Surgery followed by combination chemotherapy,

as even patients with early stage nondysgerminomas have a significant risk of relapse that can be reduced by postoperative adjuvant therapy

Current regimen of choice is BEP

Toxicities bleomycin-induced pulmonary damage etoposide-induced leukemia, platinum-induced neuropathy and nephropathy. Many patients will regain fertility after

completion of treatmentHowever, patients are known to be at increased

risk for development of premature menopause following chemotherapy.

• In pure immature teratoma with stage IA, grade 1 (5-ys :90%), there is no evidence to suggest that CHT improves outcome

• Patients with stage IA, grade 2 and 3 immature teratoma have a higher relapse rate that generally warrants consideration of postoperative chemotherapy

• The Children's Oncology Group (COG) is currently studying the approach of surgery followed by surveillance in patients with stage I germ cell tumors of the ovary. Although this strategy appears to be potentially promising, further study, particularly in adult patients, is warranted to ensure its safety and efficacy

Sex Cord-Stromal TumorsDefinition and Clinical Features

• Patients often present with stage I disease• long-term follow-up• Granulosa cell tumors are the most common

type

Sex cord-stromal tumors such as granulosa cell tumors may secrete:

• Estradiol• inhibin • mullerian inhibitory substance

• The hormonal manifestations :1. precocious puberty2. amenorrhea or abnormal menses, intra-

abdominal hemorrhage that mimics an ectopic pregnancy

3. postmenopausal bleeding due to endometrial hyperplasia (or a separate uterine carcinoma)

• Surgical staging of sex cord-stromal tumors is the same as that for epithelial ovarian cancer.

• Surgical management of sex cord-stromal tumors is based on the stage of the tumor as well as the age of the patient.

1. premenarchal women or patients presenting in the reproductive years with stage I disease

2. In women who have completed childbearing,

Postoperative Management

Stage is the most important prognostic factor, • 10-year survivals of over 85% for stage I • 50% to 65% for stage II disease• 17% to 33% for stages III and IV.

Tx• stages II to IV sex cord-stromal tumors are

reasonable candidates for additional therapy after initial surgery,

• although the survival benefit of such therapy has not been proven

• Approximately 30% to 50% of patients will respond to platinum-based chemotherapy,

• cyclophosphamide, doxorubicin, and cisplatin (CAP)

• PVB, • BEP• paclitaxel and carboplatin

BEP• bleomycin-induced lung damage, • etoposide-induced leukemia• , renal dysfunction, hypertension• Raynaud's phenomenon

• in the older patientEP (without bleomycin)• in the young patient paclitaxel and carboplatin

(S1)Who has higher risk?

• large tumor size (greater than 10 to 15 cm in diameter)

• high mitotic count (greater than 4 to 10 mitoses per 10 high-power fields).

• Rupture• surface involvement• Age

Relapse

• may recur several years after the original diagnosis

• abdominal or pelvic discomfort, a mass on pelvic examination, or an asymptomatic rise in serum tumor markers such as estradiol or inhibin

• hematogenous spread to the liver, lung, or bone

Tx Relapse :S-CHT or RT

1. surgical resection 2. postoperative therapy such as platinum-based

treatment ,resistant to platinum-based chemotherapy, in which case single-agent paclitaxel, or the use of progestational agents or leuprolide, may be considered.

3. radiotherapy. In cases in which the recurrence is isolated and can be

encompassed in a radiation field, older literature suggests that radiation therapy may be of value for granulosa cell histology.

Primary Peritoneal Serous Carcinoma

• PPSC is a distinct clinical entity that resembles ovarian cancer histologically, clinically, and in its response to treatment

• multifocal fashion• PPSC occurs at a higher incidence in patients

with germline mutations in BRCA1 and BRCA2,

differential diagnosis

1. epithelial ovarian carcinoma2. metastatic breast cancer(expression of

GCDFP)3. peritoneal mesothelioma4. gastric or pancreatic cancers, and

hepatobiliary tumors.

• Dx an exploratory laparotomy is usually necessary to establish the histologic diagnosis and to perform tumor cytoreduction.

• almost all patients with PPSC present with stages III or IV disease.

• Tx are the same as those for epithelial ovarian cancer.

• Px is likely to be the same, as for epithelial ovarian cancer.

• There is currently no effective screening procedure that enables early detection of PPSC in this clinical setting.

Fallopian Tube Cancer

• papillary serous adenocarcinoma or other mullerian histologies such as endometrioid tumors

• A minority are bilateral • the majority are confined to the tubes and

pelvic structures. • a higher propensity for retroperitoneal lymph

node spread • Advanced stage disease may occur with a

pattern of intraperitoneal dissemination

• Postmenopausal vaginal bleeding

• colicky lower abdominal pain

• intermittent abdominal pain and leucorrhea are common presentations.

• Occasionally, a Papanicolaou smear revealing abnormal glandular cells with negative cervical or endometrial findings

DDX• metastatic ovarian carcinoma

• the main criterion used to establish the diagnosis of a primary fallopian tube carcinoma is histologic evidence of a transition between in situ carcinoma and invasive malignancy within the fallopian tube epithelium.

• tubo-ovarian carcinoma.

• Survival is partly dependent on the depth of invasion of the primary lesion.

• For intramucosal lesions, the 5-year survival is 91%, compared with 53% for tumors that invade the muscular wall, and less than 25% for tumors that have penetrated the tubal serosa.

• Histologic differentiation and lymphatic capillary space involvement may also have prognostic significance.

surgical management

• identical to that of patients with epithelial ovarian cancer.

• Postoperatively : paclitaxel and carboplatin in patients with fallopian tube carcinoma that has spread beyond the tube.

• reasonable candidates for postoperative adjuvant treatment, based on features :

muscle wall invasion, serosal extension, high-grade histology