Ovarian Cancer

GYN TUMORS
Sheilaine Mabanta

EPITHELIAL OVARIAN CARCINOMA

Epidemiology:

  • Fourth most common type of female cancer
  • 26,000 cases/year diagnosed in U.S.
  • 14,500 cases/year die of disease
  • Lifetime risk is 1.9% (1 in 70)
  • Median age at presentation: 63 years

**Risk Factors: **

  • Relation to Endocrine Function: risk increases with the number of ovulatory cycles in a women\’s lifespan.

## There is increased risk with nulliparity, infertility, or use of fertility drugs.
## There is decreased risk with multiple pregnancies, long term use of oral
contraceptives, or early age of first pregnancy.

  • Environmental Factors:
  1. There is increased risk with residence in North America or Northern Europe, use of talc powder, or asbestos exposure.
  2. Familial and Genetic Associations: Family history is the single most important risk factor.

** 5% risk with one first degree relative with ovarian ca.
** Familial ovarian cancer syndromes (Autosomal Dominant, \~50% lifetime risk):

  1. Hereditary breast/ovarian cancer syndrome

BRCA 1 mutation – a tumor suppressor gene at 17q21

  1. Lynch II syndrome: (ovarian ca, nonpolyposis colorectal ca, and endometrial ca)
  2. Hereditary site-specific ovarian carcinoma syndrome

Anatomy

Ovary:

  • The postmenopausal ovary is 1.5x1x0.5cm and is typically not palpable on physical exam if normal.
  • The ovary is composed of the outer cortex and the inner medulla.
  • The ovary is attached to the posterior lateral wall by the infundibulopelvic ligament, to the lateral pelvic wall by the broad ligament, and to the uterus by the utero-ovarian (round) ligament.

Blood Supply:

  • The arterial supply is from the ovarian artery and the ovarian branch of the uterine artery.
  • The venous drainage is to the inferior vena cava on the right and the renal vein on the left.

Lymphatic Drainage:

  • Along the ovarian vessels in the infundibulopelvic ligament to the para-aortic lymph nodes at level of the renal vessels
  • Along the broad ligament to the external iliac and hypogastric nodes.
  • Rarely, along the round ligaments to the external iliac and inguinal nodes

Histopathology

80% of all ovarian tumors are epithelial which are further subdivided as follows:

** Epithelial Ovarian Cancer
*** serous 40%

  • mucinous 10%
  • endometroid 15%
  • undifferentiated 15%
  • clear cell <1
  • Germ cell (10%): Dysgerminoma, endodermal sinus, choriocarcinoma, embryonal
  • Stromal (5%): Granulosa cell, Sertoli-Leydig cell
  • Indeterminate 5%

Molecular Pathology:

  • Her-2/neu over-expression
  • Mutation of P53 gene
  • DNA Ploidy

Presentation

  • Early stage disease usually causes few symptoms so most present with advanced disease (75-85%).
  • Symptoms: nausea, abdominal discomfort, bloating, vaginal bleeding, dyspepsia, and constipation
  • Signs: Ascites, abdominal/pelvic mass, increasing abdominal girth, lymphadenopathy, and pleural effusion

Diagnosis

  • H&P including pelvic with bimanual and rectovaginal exam
  • Palpation of adnexal mass/ovary in a symptomatic woman warrants trans-vaginal ultrasound (TVUS) with color-flow Doppler
  • Ovarian mass in premenopausal usually requires exploratory laparotomy because functional cysts do not occur in premenopausal women.
  • Small cysts (1.5-3cm) in postmenopausal women can be normal and do not need removal if unilocular and CA 125 level is normal. Laparoscopy may be used if malignancy is not thought likely.
  • CT scan abdomen and pelvis – eval PAN and pelvic nodes, tumor implants, and the primary mass.
  • Barium enema if any lower GI complaints
  • Cystography if indicated
  • Staging Laparotomy (see below)

**Markers: **

  • CA 125 – normal level is 30-35 U/ml or less in postmenopausal women. Premenopausal women may have levels up to 65 – 200 when menstruating. It is elevated in approximately 85% of patients with ovarian cancer. It is useful in monitoring relapse after treatment.
  • CEA - It is elevated in 2/3 of patients with advanced ovarian cancer.

Patterns of Spread:

  • Local: Tumor can spread to adjacent organs such as the uterus, fallopian tubes, or other ovary.
  • Transcoelomic: Most common mode of metastatic spread. Tumor cells exfoliate and implant the omentum, paracolic gutters, diaphragm, and other regions of the peritoneum. Once the cells reach the diaphragm, they are trapped into the submesothelial lymphatic channels and drain to the internal mammary chain and to the thoracic duct.
  • Lymphatic: In surgical series, incidence of para-aortic and pelvic nodal involvement was:
Stage

(Pelvis or PAN)||

I 25%
II 50%
III,IV 65 –75%

The PAN are typically not involved unless the pelvic nodes are positive.

  • Hematologic: Occurs in 2-3% and is more likely in patients with malignant ascites, peritoneal carcinomatosis, and large adenopathy at initial surgery.

Site of DM Incidence

Pleural Effusion 25%
Lung 7%
Subcutaneous nodules 3%
Pericardial Effusion 2%
CNS 2%
Bone 1%

Staging
Note: Stage I tumors that are densely adherent to adjacent structures are generally considered as Stage II(1).

FIGO STAGING 1987
Stage Description
+ I + Ovaries only
Ia One ovary
Ib Both ovaries
Ic Ruptured capsule, pos. washings, or ascites
+ II + Pelvic Extension
IIa Uterus or tubes
IIb Other pelvic involvement
IIc Ruptured capsule, pos. washings, or ascites
III Beyond pelvis, pos. RP or inguinal nodes, bowel
IIIa Microscopic implants
IIIb Gross implants <2cm
IIIc Gross implants >2cm or pos. RP or inguinal nodes
IV Distant mets (including parenchymal liver mets)

Prognostic factors

Age: Five-year survival for patients of all stages

  • <50 years is 40%
  • >50 years is 15%.

Performance Status:

  • Better if KPS is >70-80

Stage of Disease: 5-year survival by stage (2)

Stage 5 yr Survival
Ia 92%
Ib 85%
Ic 82%
IIa 69%
IIb 56%
IIc 51%
IIIa 39%
IIIb 25%
IIIc 17%
IV 12%

Pathology:

  • Clear cell is possibly worse than other subtypes.
  • Diploid is better than aneuploid.
  • Five year survival according to Grade:

Grade 1 (40%) Grade 2 (20%) Grade 3 (5%)
Ascites: Poor prognosis if fluid collected is greater than 250ml
Presence of dense adhesions between tumor and pelvic organs:

  • Dense adhesions are raw areas left after sharp dissection required to remove the tumor from an adhered organ or cystic rupture as a result of dissecting tumor from adhesions.

Initial tumor volume:

  • If there is extensive tumor burden, then it is difficult to achieve optimal cytoreduction.

Diameter of Largest Met Median Survival
< 1.5 cm 25 mo.
1.5 – 10 cm 15 mo.

10 cm 9 mo.

CA 125 Level post-op and after Chemotherapy

  • If CA 125 is elevated, then it predicts a positive second look laporatomy in 97% of the cases.

Low residual tumor volume:

  • Multiple studies report that survival is influenced by amount of residual tumor after

cytoreduction. Mean survival with < 2 cm is 36-29 mo. and 16-13 mo. for > 2 cm (3).

Treatment

Surgery:

  • Surgery is the mainstay of treatment for epithelial tumors and goals are diagnosis, staging, and maximum cytoreduction (residual tumor <2cm).
  • Guidelines for surgery are:

Vertical incision
Inspect/palpate the entire abdominal content for tumor deposits
Peritoneal washings (gutters, pelvis, diaphragm)
Extrafascial TAH/BSO
Resection of omentum and gross visible and palpable disease
Biopsies of the cul de sac, pelvic side walls, paracolic gutters, and diaphragm
Sampling/lymphadenectomy of the pelvic and para-aortic nodes
Appendectomy
External Beam Radiotherapy:

  • Dose: microscopic disease (25-30 Gy), tumors < 2 cm (45-50 Gy), > 2cm (50-60 Gy).
  1. Schray (4)suggested that disease relapse is related to size after 50-60 Gy to the pelvis; 16% relapse if < 2cm residual and 45% if > 2 cm.
  2. Dembo (5) (6)showed 5- year survival with < 2cm residual at 78% and 20% with larger residual lesions with WART ( 45 Gy pelvic RT and 2250 cGy to upper abdomen).
  • Normal Tissue Tolerance: The probability of control is based on the feasibility of delivery of tumorcidal doses without significantly injuring normal organs such as the kidney, liver, spinal cord, and intestines. Based on normal tolerance doses of these organs, only patients with minimal or microscopic residua would be candidates for cure by radiotherapy.
  • Treatment fields: WART is supported based on the risk for metastatic disease in the entire peritoneal cavity.
  1. The open field technique uses AP and PA fields extending from the above the diaphragm to the below the obturator foramen. At some institutions, total dose is 30 Gy/20 fractions at 120-150 cGy/day with kidney blocks placed (PA and AP) after 20 Gy and partial liver block at 25 Gy. The lower abdomen is then boosted an additional 20-25 Gy. At UF, the total dose 3040 cGy at 80 cGy BID with kidney blocks placed at 960cgy in the PA field only (total kidney dose: \~2000 cGy max).
  2. The moving strip technique was popularized to avoid dose uncertainties at field junctions when using multiple fields and to produce maximum biologic effect by delivering the total dose in 10-12 fractions to each segment. The technique divides the cavity into 2.5-cm horizontal strips. Treatment starts by irradiating the four lowest strips and then moving upward one strip at a time until the whole abdomen is treated, so that each strip receives a total dose of 25-30 Gy/10-12 fractions.
  3. Dembo(7) compared the two techniques and found that relapse free survival, overall survival rates, and acute toxicities were the same. Although, the late toxicities were 5x more frequent in the moving strip technique, so the open field technique is the standard method for WART.
  4. Complications of WART(5): small bowel obstruction (3%), hepatitis (1%).

Intraperitoneal Radioisotopes:

  • P32 is a pure beta emitter with T½ of 14.3 days. Mean energy of 0.69 MeV and penetrates 3-5mm. The standard doses given are 15-20 mCi.
  • P32 is in the form of a chromic phosphate colloid that is taken up by macrophages and mesothelial peritoneal cells which decreases systemic absorption.
  • Extreme care/expertise must be used to avoid increased late complications (SBO):
  1. Boye(8) estimated the surface dose to the peritoneum from 10 mCi to be approximately 30 Gy.
  2. Separate catheters placed in R and L gutters at laparotomy.
  3. Verify no adhesions by infusing Tc-99m and doing nuclear medicine scan.
  4. To optimize dose, mix colloid in 1 L NS. Infuse into R and L gutters within 12 hours of surgery. Infuse NS before and after P32 and change position of patient.
  • GOG \#93 was closed in 1996 but not yet published. It compares P32 with no further tx for III dz with a negative 2nd look lap.
  • GOG \#95 (9), Norwegian Radium Hospital (1992)(10): GICOG (Bolis 1995)(11): UF (Condra 1997)(12) are studies that show similar disease control but increased late complications for P32 in early stage pt\’s with no residual dz (see below).

2nd Look Laparotomy:

  • Reserved for assymptomatic pts who have
  1. Advanced stage disease (III or IV)
  2. had initial cytoreductive surgery
  3. a complete course of chemotherapy
  4. negative CT
  5. negative CA-125
  • Exploration of entire abdominal contents, biopsies of sites of initial dz, and completion of TAH/BSO and lymphadenectomy.

Guidelines Summarized

Risk groups for pts with optimal cytoreductive surgery (<2cm residuum)(1)

Stage Residium Grade 1 Grade 2 Grade 3
I 0 Low risk
<2cm
II 0 Intermediate Risk
<2cm
III 0 High Risk
<2cm

Stage Ia and Ib, grade 1 with no residual disease (low risk)

  • GOG (Young 1990)(9) randomized stage Ia and Ib patients with favorable prognosis to observation or 12 cycles of oral melphalan. 10 year RFS for observation group was 88% and 93% for those who received chemotherapy. There were increased toxicities with melphalan including myelosuppression and leukemia.
  • Dembo (PMH 1984)(6): Study randomized stage Ia patients to observation or pelvic RT (45Gy/20). 4/27 patients relapsed in the observation group and 5/27 patients in the RT group (3/5 relapsing in the upper abdomen). There were no relapses if tumor was well differentiated.
  • Based on these observations, stage Ia and Ib patients, grade 1 do not require adjuvant therapy after laporatomy.

Stage Ia/Ib, grade 2 or 3 and Ic with no residual disease (intermediate risk)

  • GOG (Young 1990)(9): Prospective randomized trial (stage Ib, G3; Ic; II with no residual) compares 12 cycles of melphalan to P32. There was no survival difference at 10 years, 65% for chemotherapy and 69% for P32. 20% of the patients treated with melphalan had severe myelosuppression. Therefore, P32 was superior to melphalan due to toxicity profile.
  • GOG-95 (Young 1990)(9): Randomized trial (Ia/b, grade 3or clear cell or II) compared P32 and cyclophosphamide + cisplatinum. The number of recurrences was the same in each group.
  • Norwegian Radium Hospital (1992)(10): Randomized patients to cisplatinum versus P32 in early stage I, II, and III patients. DFS were similar between the 2 groups but there was increased GI toxicity with P32.
  • GICOG (Bolis 1995)(11):
  1. Trial 1: Patients with Ia/b, grade 2 or 3 were randomized to cisplatinum versus observation and 5 year DFS was 83% and 65% respectively. There was no difference in OS due to salvage with chemotherapy in the observation group.
  2. Trial 2: FIGO stage Ic pts were randomized to cisplatinum versus P32 and 5 year DFS was 85% and 65% respectively. Again, there was no difference in OS.
  • UF (Condra 1997)(12): 25 patients with Ia, grade 3, Ib, grade 2-3, and Ic received P32 and 10 year CSS was 82%. 5/25 patients had significant GI toxicity with P32.
  • Final treatment recommendations in this group of patients are still controversial. Both P32 and cisplatinum based treatment are both effective but P32 has a higher toxicity profile.

Stage I, II, III with Minimal Residual Disease or Intermediate Group

  • WART vs. Pelvic RT
  1. Dembo (PMH 1979)(13): Prospective randomized trial (Ib; II, and III)

comparing pelvic RT alone +/- oral chlorambucil vs. WART (moving strip
technique). Survival difference was noted in those patients with complete
resection. In this group, the 10-year survival was either 64% (WART)
or 40% (pelvic RT +/- chlorambucil). The study demonstrated the
superiority of WART over pelvic RT due to decreased upper abdomen relapses.

  1. Fuller(14): Retrospective review compared pelvic RT (64pts) to open field WART

(42pts). 10/62 patients receiving pelvic RT also received P32. 10 year RFS (stage I-
IIIA with < 2cm residual) was 71% in WART group and 40% in the pelvic RT
group. There was increased bowl complications with addition of P32 to pelvic RT.

  • WART vs. Chemotherapy
  1. Smith (MDAH 1975)(15): Randomized study comparing melphalan to WART (moving strip with pelvic boost) in patients with I, II, and III. 5-year survival was equivalent with patients with < 2cm residual. The problems with the trial include: 1) patients not stratified according to stage, grade, and residual disease 2) more early stage patients were placed in chemotherapy arm 3) WART technique was poor with inadequate coverage of diaphragm.
  2. NCI-Canada (Klaussen 1988)(16): Prospective randomized trial comparing pelvic RT +

melphalan vs. WART vs. pelvic RT + P32 (discontinued due to toxicity). There was
no difference in OS at 60% and DFS was slightly better with melphalan. There was
poor protocol compliance and RT field errors.

  1. Redman 1993(17) compared WART with cisplatinum alone in 40 patients (IC-III with minimal residual) with 5-year survival at 58% and 64% respectively.
  • A number of studies show that WART can cure patents with minimal residual disease and also show that residual disease >2cm should not be treated with RT alone.

Study Residuum Endpoint
<2cm >2cm
PMH 38% 6% 10 y RFS
Stanford 50% 14% 15 y RFS
Salt Lake City 62% 0% 10 y RFS
Walter Reid 42% 10% 10 y survival
Yale 41% — 6 y surviving fraction
Adapted from Dembo(1)

  • The new protocols are emphasizing the use of chemotherapy as an adjuvant treatment in this group of patients with I/II/III + minimal residual disease, so current treatment options include either WART or cisplatinum based chemotherapy.

Stage II-IV with Macroscopic Residual or High Risk Group

  • These patients should not receive RT alone. Cisplatin based chemotherapy alone is recommended although the latest trend is carbo/taxol (see below).
  • Consolidative WART for advanced disease:
  1. WART should probably considered only for patients with
  • microscopic positive second-look laparotomy with well-diff tumors
  • Stage III dz with negative second-look who had large residuum after 1st lap
  • Grade 3 tumors
  1. Consolidative RT after chemo causes higher bowel complications which is increased with dose (pelvic dose > 45 Gy or WA dose > 22.5-25 Gy with standard fractionation) and multiple laps.
  2. Hyperfractionated WART:
  • UF/Fein(18) reviewed 28 stage III patients with either microscopic residual or gross residual < 2cm after chemotherapy. They received WART BID to 3040cgy and pelvic boost of \~15 Gy. AS at 5 years for the entire group was 21%. There were 22/23 failures in the abdomen or pelvis. Complications included 4 undergoing surgery for SBO (14%), 1 death due to myelosuppression, and 1 death after lap for suspected recurrence.
  • Chemotherapy for advanced disease:
  1. Platinum based chemo obtains \~70-80% response rates
  • For pts with optimal cytoreductive surgery \~50% get a CR
  • For suboptimal cytoreductive surgery, 20-30% get a CR
  • Unfortunately, many CR pts develop drug-resistant recurrences
  1. Recent studies have shown that cisplatin/paclitaxel (Taxol) is now the standard of care.
  • GOG \#111 – survival advantage for cisplatin/taxol (C/T) over cisplatin/cytoxan (C/C) for advanced stage, high volume dz(19).
  • Canadian/European collaborative trial – improved CR and progression-free survival for C/T over C/C in advanced low and high volume disease(20)
  • Carboplatin may used with Taxol in order to reduce neurotoxicity but may increase myelosuppression (usually to acceptable levels).
  • 3-hour infusion of Taxol causes more neurotoxicity so should be used with carbo instead of cis.
  • 24-hour infusion of Taxol is safer to use with cisplatin.
  • Current thinking is that outcomes are the same for carbo or cisplatin but that toxicity is lower with Carboplatin. GOG \#158 is an ongoing trial that compares carbo/taxol to cis/taxol head-to-head. This is expected to confirm equivalency, which will make carbo/taxol the standard of care.
  • Standard therapy is 6 cycles of standard carbo (or cis)/Taxol.
  • New protocols include multiple cycles of high-dose chemo followed by stem cell rescue.
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-Share Alike 2.5 License.