Epithelial ovarian cancer is a disease that occurs in women between 50 and 80 years
old. The incidence increases with age and peaks in the 75- to 79-year-old
age group. In the United States, the age-adjusted rate
of ovarian cancer for whites is significantly higher than for African-American
women. The course of epithelial ovarian cancer remains unknown. Data on dietary
and environmental factors are conflicting. Evidence suggests that the
more ovulatory cycles a woman experiences, the greater her risk of ovarian
cancer. In addition, 5% to 10% of ovarian cancers result from inherited defects
in the BRCA1, BRCA2, and nonpolyposis colorectal cancer (HNPCC) genes. Lynch and colleagues2 describe the hereditary breast-ovarian cancer syndrome, site-specific
ovarian cancer syndrome, and breast-ovarian-endometrial-nonpolyposis colorectal
cancer syndrome. Most patients with early stage epithelial ovarian cancer often lack specific
symptoms. Up to 75% of women with newly diagnosed ovarian cancer
have stage III or IV disease. There is no proven method of screening
for ovarian cancers. A sensitive and specific biologic marker in conjunction
with rectovaginal examination and transvaginal ultrasound could
improve the detection of early stage epithelial ovarian cancer.3,4 Serum CA-125, which is elevated in about 50% of patients with early ovarian
cancer with transvaginal ultrasound, seems to be reasonable for periodic
surveillance of high-risk patients. The use of oral contraceptives until childbearing is complete followed
by prophylactic oophorectomy is recommended in women with a hereditary
predisposition to ovarian cancer.5 Although epithelial ovarian cancer can spread through lymphatic or hematogenous
dissemination, it most commonly spreads by local shedding and
implantation and growth on peritoneal surfaces. A laparotomy is necessary for definitive staging of ovarian cancer (Table 1). If disease appears confined to the ovaries, it is essential to perform
a complete evaluation of all visceral and peritoneal surfaces within
the peritoneal cavity, as well as omentectomy and biopsy of the aortic
and pelvic lymph nodes. TABLE 1. FIGO Staging System for Primary Carcinoma of the Ovary
Stage | Description |
I | Growth limited to ovaries |
IA | Growth limited to one ovary; no ascites. No tumor on the external surface; capsule
intact |
IB | Growth limited to both ovaries; no ascites. No tumor on the external surfaces; capsule
intact |
IC* | Tumor either stage IA or IB, but with tumor on surface of one or both ovaries; or
with capsule ruptured; or with ascites present containing malignant
cells or with positive peritoneal washings |
II | Growth involving one or both ovaries with pelvic extension |
IIA | Extension or metastases to the uterus, tubes, or both |
IIB | Extension to other pelvic tissues |
IIC* | Tumor either stage IIA or IIB, but with tumor or surface of one or both
ovaries; or with capsules ruptured; or with ascites present containing
malignant cells or with positive peritoneal washings |
III | Tumor involving one or both ovaries with peritoneal implants outside the
pelvis or positive retroperitoneal or inguinal nodes. Superficial liver
metastasis equals stage III. Tumor is limited to the true pelvis but
with histologically proven malignant extension to small bowel or omentum |
IIIA | Tumor grossly limited to the true pelvis with negative nodes but with histologically
confirmed microscopic seeding of abdominal peritoneal surfaces |
IIIB | Tumor of one or both ovaries with histologically confirmed implants of
abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Nodes
are negative |
IIIC | Abdominal Implants greater than 2 cm in diameter or positive retroperitoneal
or inguinal nodes |
IV | Growth involving one or both ovaries with distant metastasis. If pleural
effusion is present, there must be positive cytologic findings to allot
a case to stage IV. Parenchymal liver metastasis equals stage IV |
FIGO, International Federation of Gynecology and Obstetrics.
*To evaluate the impact on prognosis of the different criteria for allotting
cases to stage IC or IIC, it would be of value to know (1) if rupture
of the capsule was spontaneous or caused by the surgeon, or (2) if
the source of malignant cells detected was peritoneal washings or ascites.
The prognosis of epithelial ovarian cancer depends on stage, histologic
grade and type, volume of disease, age, performance status, and ploidy. Work
continues in the identification of molecular markers of prognosis
in ovarian cancer. The goals of initial surgery are to establish the diagnosis, to stage the
patient's cancer, and to debulk the tumor. After surgical debulking, the
patient's disease is categorized as optimally debulked (less
than 1 cm of postoperative residual disease) or suboptimally debulked (more
than 1 cm postoperative residual disease. Retrospective analysis demonstrates that optimal resection of metastatic
epithelial ovarian cancer is increasing the effectiveness of chemotherapy
and survival.6,7 Prospective studies are needed to determine the role of neoadjuvant chemotherapy
and“interval” cytoreductive surgery, and the applicability
of CA-125 and laparoscopy to predict resectability.8–11 Chemotherapy of Early Stage Epithelial Ovarian Cancer Only approximately 25% of women are diagnosed with stage I or II disease. Careful
surgical staging determines the patient's risk of recurrence (Table 2). Low-risk patients have a 5-year survival rate greater than 90% and do
not require postsurgical treatment. The 5-year mortality rate of high-risk
patients is 25% to 30%. Additional postsurgical therapy appears
to lower the significant risk of recurrence in this group of patients.12,13 TABLE 2. Risk Factors for Patients With Early-Stage Epithelial Ovarian
Cancer
Low risk | Well or moderately differentiated and intact capsule |
| No tumor or external surface |
| No ascites |
| Negative peritoneal cytologic findings |
| No dense adhesions |
| No extraovarian disease |
High risk | Poorly differentiated or ruptured capsule |
| Tumor on external surface |
| Ascites |
| Positive peritoneal cytologic findings |
| Dense adhesions |
| Extraovarian disease | Many different adjuvant treatments, including whole-abdominal radiation,14 intraperitoneal radioactive isotopes, and single alkylating agents,15 have been effective. Gynecologic Oncology Group Protocol 9516 and the Italian studies17 show the effectiveness of platinum-based adjuvant chemotherapy. Whether adjuvant therapy is better for patients with high-risk early stage
epithelial ovarian cancers than continued observation with chemotherapy
only for those who relapse depends on the outcome of current ongoing
trials (Table 3). The results of a recently completed GOG trial evaluating three versus
six cycles of paclitaxel and carboplatin are pending. The GOG replacement
protocol is evaluating IV carboplatin (AUC 6) and paclitaxel, 175 mg/m2 every 21 days for three courses, plus low-dose paclitaxel, 40 mg/m2/week given 24 times, versus IV carboplatin (AUC 6) and paclitaxel, 175 mg/m2 every 21 days for three courses, plus observation in patients with early
stage epithelial ovarian cancer. The standard approach for nonprotocol
patients with high-risk early stage epithelial ovarian cancer should
be taxane and platinum-based chemotherapy. TABLE 3. Phase III Studies in Early-Stage Epithelial Ovarian Cancer
EORTC | Randomized comparison of adjuvant platinum containing chemotherapy (cisplatinum
with or without other agents) vs no adjuvant therapy |
GOG | Randomized study of carboplatin and paclitaxel with or without low-dose
paclitaxel |
EORTC, European Organization; GOG, Gynecologic Oncology Group.
Chemotherapy of Advanced Epithelial Ovarian Cancer Systemic chemotherapy after cytoreductive surgery is indicated for all
women with advanced epithelial ovarian cancer (stages III and IV). Before
the 1980s, standard chemotherapy consisted of a single alkylating
agent with response rates of about 50% and clinical complete response
of 20%. The introduction of the platinum drugs led to overall response rates of 70% to 80% and
clinical complete response rates of 40% to 50%. Platinum-based
combination chemotherapy was considered by most investigators
to be superior to single-agent platinum in overall response and progression-free
survival but not in overall survival.18 In the United States, the initial postoperative chemotherapy for patients
with advanced epithelial ovarian cancer has been a platinum-based
combination. Anthracyclines (doxorubicin) have been added to initial platinum-based
chemotherapy with questionable benefit.13 In the 1980s, it was demonstrated that a new class of compounds, the taxanes, were
active in platinum-resistant epithelial ovarian cancer. Based on these observation, large randomized trials, which included cisplatin
in combination with paclitaxel, were initiated.19–22 The paclitaxel-cisplatin combination resulted in higher overall response
rates, higher clinical complete remission rates, and improved median
survival. Carboplatin was developed as an alternative to cisplatin. It is easier
to administer with less gastrointestinal, neurologic, and renal toxicity. Cisplatin
and carboplatin appear to achieve similar response rates
when combined with paclitaxel. The final results of a recently completed GOG study, which compares cisplatin (75 mg/m2) plus paclitaxel (135 mg/m2, 24-hour infusion) with carboplatin (AUC 7.5) and paclitaxel (175 mg/m2, 3-hour infusion) in patients with optimally debulked epithelial ovarian
cancer, are pending. The carboplatin-paclitaxel combination appears
to be better tolerated (less nausea, vomiting, peripheral neuropathy) and
can be administered on an inpatient basis. The number of platinum-paclitaxel
treatment cycles needed is unknown. Second-look laparotomy in patients who achieved a clinical and radiographic
complete response and normalization of tumor markers (CA-125) after
six cycles of platinum-paclitaxel therapy remains controversial. There
appears to be no impact on time to progression or overall survival
for patients selected for a second-look laparotomy.23 About half of patients found to have a pathologic complete response ultimately
relapse. Currently, there is no evidence that continuation of
chemotherapy or consolidation therapy, including whole-abdominal radiation, high-dose
chemotherapy with hematologic support, or intraperitoneal
chemotherapy, prolongs disease-free or overall survival in patients
who are in complete clinical remission after six cycles of platinum-taxol
therapy. The current recommended chemotherapy of choice for patients with stage
III and IV epithelial ovarian cancer consists of carboplatin together
with paclitaxel. No data from randomized trials demonstrate that high-dose
systemic chemotherapy with bone marrow transplantation, peripheral
progenitor cell support, or intraperitoneal chemotherapy results in
improved therapeutic outcomes. Second-Line Chemotherapy Most patients with stage III and IV epithelial ovarian cancer experience
recurrence some time in the course of their disease and become candidates
for salvage chemotherapy. The goal of second-line chemotherapy is
optimization of quality of life. Cure is an unrealistic expectation. The role of secondary surgical cytoreduction remains controversial. Patients
who relapse more than 2 years after completion of initial chemotherapy
sometimes gain some benefit from repeat surgical resection. The
response to second-line therapy depends on several factors (treatment-free
interval, toxicity from prior therapy, volume of disease, ascites, performance
status). Patients are considered “platinum-sensitive” when recurrence
occurs 6 months or more after the completion of platinum-based therapy. They
are classified as“platinum resistant” if disease
progresses during platinum-based therapy or within 6 months after completion. The
platinum-free interval also predicts sensitivity to other
drugs. The longer the interval between previous chemotherapy and subsequent
recurrence, the more likely is the response to subsequent chemotherapy. Most
patients with recurrent epithelial ovarian cancer require
therapy for the remainder of their lives. Because avoidance of toxicity
and palliation of symptoms is paramount, single-agent treatment with
crossover to other drugs on progression is preferable to using combination
therapy. In addition to retreatment with initially active drugs, several new active
agents in platinum- and taxane-resistant epithelial ovarian cancer
are available (Table 4). No data suggest that any of the second-line regimens are superior to
any of the others. The choice of second-line chemotherapy depends on
patient preference, administration schedules, and toxicities. TABLE 4. Second-Line Chemotherapy in Recurrent Epithelial Ovarian Cancer
Agent | Dose | Dosage |
Cisplatin | 75 mg/m2 | IV every 3---4 wk |
Carboplatin | AUC 4---6 | IV every 3---4 wk |
Docetaxel | 60---75 mg/m2 | IV every 3 wk |
Oral etoposide | 50 mg/m2 | 14---21 days, every 4 wk |
Topotecan | 1.25---1.5 mg/m2 | IV daily X 5 d, every 3 wk |
Ifosfamide (with MESNA) | 1.5 gm/m2 | IV daily X 3---5 d, every 4 wk |
Liposomal doxorubicin | 40---50 mg/m2 | IV every 4 wk |
Gemcitabine | 800---1000 mg/m2 | IV d 1, 8, 15, every 4 wk |
Vinorelbine | 25---30 mg/m2 | IV weekly |
Oral altretamine | 260 mg/m2 | PO daily X 14 d, every 4 wk |
Paclitaxel | 175 mg/m2 | IV over 3 h, every 3 wk |
| 40---75 mg/m2 | Over 1 h weekly | Response rates ranging from 19% to 40% have been accomplished with platinum,24 paclitaxel,25 topotecan,26 liposomal doxorubicin,27 oral etoposide,28 gemcitabine,29 vinorelbine,30 ifosfamide,31 altretamine,32 and docetaxel33 in patients with recurrent epithelial ovarian cancer. Responses generally
are brief (3 to 6 months), but meaningful palliation of symptoms and
prolongation of survival has been shown. Objective responses with tamoxifen
in platinum-resistant epithelial ovarian cancer have been reported.34 Experimental Chemotherapy The identification of new active salvage chemotherapeutic agents may allow
incorporation of these drugs into front-line chemotherapy with the
goal of overcoming resistance and interacting synergistically with other
active agents. Developing three- or four-drug combinations is difficult because of overlapping
toxicities and possible use of inadequate doses of each of the
drugs. A different approach is under investigation, that is, the use
of doublets alternating with one or more other doublets while allowing
the administration of a full dose of all of them (i.e., three to four cycles of paclitaxel-platinum followed by three to four
cycles of topotecan-oral etoposide or topotecan-germcitabine).35 Novel noncytotoxic drugs targeting specific signaling molecules or the
tumor microenvironment include the antibody to HER 2/neu, the p53 gene, matrix metalloproteinase inhibitors, and agents targeting protein
kinase C alpha. It is unknown how to best use such agents together with
chemotherapy.36 Twenty-one patients with advanced ovarian cancer in complete remission
after conventional therapy treated with intraperitoneal radioimmunotherapy
using HMFG1-labeled with 90y achieved a survival rate of 78% at more
than 10 years.37 Multinational trials are defining the value of intraperitoneal radioimmunotherapy
in the management of epithelial ovarian cancer. Although intraperitoneal chemotherapy in epithelial ovarian cancer as salvage
treatment or for consolidation is theoretically attractive, its
use should be restricted to research trials.38 Several new treatment strategies are investigating the cause of resistance
to cytotoxic agents in ovarian cancer.39 Epithelial ovarian cancer is an active field of investigation. All possible
patients should be included in clinical trials to quickly answer
the open questions. Low Malignant Potential Ovarian Tumors Low malignant potential ovarian tumors represent approximately 10% to 15% of
all epithelial ovarian malignancies. The epidemiologic features
of women with low malignant potential ovarian tumors are similar to those
of women with epithelial ovarian cancer, with the exception of an
earlier age onset.40 Management is primarily surgical. Platinum-based chemotherapy can cause tumor regression.41 Prognostic factors that define women most likely to benefit from adjuvant
chemotherapy are unknown. Response to chemotherapy has not shown a
survival benefit.41,42 Chemotherapy for Malignant Ovarian Germ Cell Tumors Malignant ovarian germ cell tumors represent approximately 5% of all ovarian
neoplasms. Histologically, they can be divided into dysgerminomatous
and nondysgerminomatous ovarian germ cell tumors. The latter group
consists of immature teratoma, endodermal sinus tumor, embryonal carcinoma, choriocarcinoma, polyembryoma, and mixed tumors. Known characteristics
of these tumors are their presentation at a young age, rapid
growth, frequent production of tumor markers (β-human chorionic gonadotropin, α-fetoprotein, lactate dehydrogenase), predilection for
hematogenous and lymphatic spread, and, with the exception of dysgerminomas, a
predominantly unilateral involvement. The potential for preservation of the reproductive organs is the result
of the development of effective chemotherapy. Current management consists
of conservative surgery with adequate surgical staging and surgical
cytoreduction of advanced disease followed by adjuvant or primary chemotherapy
in most patients. Nondysgerminomatous Ovarian Germ Cell Malignancies Postoperative chemotherapy is indicated for all nondysgerminatous malignant
ovarian germ cell tumors except those with an adequate surgically
staged IA, grade I pure immature teratoma. Various regimens have been
used worldwide43,44 (Table 5). TABLE 5. Chemotherapy Regimens for Malignant Ovarian Germ Cell Tumors
Regimen | Dosage |
VAC (repeated at 28-day intervals) | |
Vincristine | 1---1.5 mg/m2 IV day 1 |
Dactinomycin | 350 μ/m2 IV days 1---5 |
Cyclophosphamide | 150 mg/m2 IV days 1---5 |
PVB (repeated at 21- to 28-day intervals) | |
Cisplatin | 100 mg/m2 IV on day 1 |
Vinblastine | 0.3 mg/kg in divided doses on days 1 and 2 |
Bleomycin | 15 mg/day for 5 days by continuous infusion |
BEP (repeated at 21- to 28-day intervals) | |
Bleomycin | 10---15 mg/day IV for 3 days by continuous infusion |
Etoposide | 100 mg/m2/day IV for 3 days |
Cisplatin | 100 mg/m2 IV on day 1 | Because of the rarity of these tumors, no randomized clinical trials have
been conducted to compare the different regimens. Gershenson and coworkers
accomplished a sustained remission in 25 of 26 patients with the
bleomycin, etoposide, and cisplatin (BEP) regimen.45 In a GOG study, three courses of adjuvant BEP were administered to patients
with completely resected stage I-III tumors. Eighty-nine of 93 patients
achieved disease-free survival with a median follow-up of 38.6 months.46 A combination of cisplatin, vincristine, methotrexate, bleomycin, actinomycin
D, cyclophosphamide, and etoposide was administered to 59 newly
diagnosed patients. Disease-free and overall survival at 3 years were 86% and 88%, respectively, with acceptable toxicity.47 There is no clear advantage of this regimen over BEP, the current optimal
therapy for malignant germ cell tumors. After tumor removal and thorough surgical staging, three to four courses
of BEP is the standard for adjuvant treatment. Patients with higher
stages should receive five to six cycles. Patients positive for tumor
markers are being treated with two more cycles until after they achieve
a status negative for tumor markers. Platinum-sensitive patients who relapse can be treated with cisplatin and
ifosfamide plus either etoposide or vinblastine.48 Platinum-resistant patients can be considered for high-dose chemotherapy (ifosfamide, carboplatin, and etoposide) with autologous bone marrow
transplantation or hematopoietic progenitor cell support.49,50 Dysgerminoma Dysgerminomas of the ovary are the female counterpart of male seminoma. They
are among the most radiosensitive and chemosensitive gynecologic
malignancies. Preliminary evidence suggests that the fertility potential
of patients treated with chemotherapy may be preserved. In 1991, Williams and associates reported the GOG experience with combination
chemotherapy in 20 patients with advanced incompletely resected
dysgerminomas. The investigators conclude that probably three to four
courses of BEP (see Table 5) is adequate for most women with incompletely resected dysgerminoma, with
the possible exception of patients with advanced visceral metastases.51 The GOG is investigating the combination of carboplatin and etoposide in
patients with completely resected dysgerminoma. The standard postoperative
therapy for dysgerminomas, even with bulky residual disease, is
three to four courses of BEP. Radiation can be used as salvage therapy. Sex Cord Stromal Tumors Sex cord stromal tumors constitute less than 5% of all ovarian malignancies. The
World Health Organization (WHO) classification is shown in Table 6. The most common histologic type (about 70%) is granulosa cell tumor. The
mean age at diagnosis is approximately 53 years. Ninety-five percent
of cases are diagnosed as stage I. They are low-grade malignancies
with a relapse rate of 10% to 30% some 5 to 20 years after the initial
diagnosis. TABLE 6. World Health Organization Classification of Sex Cord Stromal Tumors
Granulosa stromal cell
Granulosa cell
Thecoma---fibroma
Androblastomas: Sertoli-Leydig cell tumors
Well-differentiated (Pick adenoma, Sertoli cell tumor)
Moderately differentiated
Poorly differentiated with heterologous elements
Lipid cell tumors
Gynandroblastoma
Unclassified
Patients with stage III diseases have a 5-year survival rate of only 0% to 22%.52 Potentially useful tumor markers are serum levels of estradiol, testosterone, CA-125, inhibin, and follicle regulatory protein. Cytotoxic chemotherapy
usually is administered only to patients with postsurgical
residual disease or with recurrent and metastatic disease. The value of
adjuvant chemotherapy for stage IA granulosa cell tumors with poor prognostic
factors is uncertain. For women with stage IA Sertoli-Leydig
cell tumors with poor differentiation or heterologous elements, adjuvant
chemotherapy is needed. Optimal chemotherapy of patients with advanced
or recurrent ovarian sex cord stromal tumors is uncertain. Table 7 lists active chemotherapy regimens for advanced ovarian sex cord stromal
tumors. A platinum and etoposide combination with or without bleomycin
is the current regimen of choice.52,55 There is a need for defining the role of other agents like paclitaxel
with the goal of improving response and lowering toxicity. TABLE 7. Active Chemotherapy Regimens for Advanced Ovarian Sex Cord Stromal
Tumors
Regimen | No. of Patients Treated | CR/PR | Reference |
Cisplatin | | | |
Doxorubicin | 8 | 3/2 | Gershenson et al, 198753 |
Cyclophos- | | | |
phamide | | | |
Bleomycin | | | |
Cisplatin | 11 | 6/3 | Colombo et al, 198654 |
Vinblastine | | | |
Bleomycin | | | |
Etoposide | 24 | 6/4 | Homesley et al, 199955 |
Cisplatin | | | |
CR, complete response; PR, partial response
| 
3 schedule of intravenous vinorelbine for refractory epithelial ovarian
cancer. Gynecol Oncol 70: 404, 1998