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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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Epithelial Ovarian Cancer

, MD and , MD.

Ovarian cancer is one of the most treatable solid tumors, as the majority will respond temporarily to surgery and cytotoxic agents. The disease, however, frequently persists and recurs, having the highest fatality-to-case ratio of all the gynecologic cancers. Ovarian cancer represents one fourth of the malignancies of the female genital tract, but it is the most common cause of death among women who develop cancers of gynecologic origin. Ovarian carcinomas account for 4% of the total cancers in women in the United States, ranked behind malignant neoplasms of the lung, breast, colon and uterus. In 2003, over 24,400 new cases and 14,300 deaths are expected. 1 Despite these discouraging statistics, improvement in 5-year survival has occurred steadily over the last three decades with more aggressive surgical management and the development of more effective chemotherapy. Five-year survival in the United States has improved significantly (p < .05) from 37% in 1974-76 to 52% in 1992-1998. 1

Ovarian cancer is a disease of postmenopausal women, with only 10% to 15% discovered in premenopausal patients. 2 The median age for diagnosis of epithelial ovarian cancer, the most common histologic type, is between 60 and 65 years. 2 Less than 1% of epithelial ovarian cancers are found in women less than 30 years of age, and most ovarian malignancies in these younger patients are germ cell tumors. 2–4 Ovarian cancer occurs sporadically in the population. A strong hereditary component contributes to development of the disease in 10% of cases, but 90% are sporadic. Ovarian cancer is neither a common nor a rare disease. The prevalence of ovarian cancer among postmenopausal women in the United States is 40 per 100,000 or 1 in 2,500. The lifetime risk for a woman to develop ovarian cancer is approximately 1 in 70 (1.4%), compared to 1 in 8 or 9 for breast cancer. 5 The prevalence of ovarian cancer in the general population impacts substantially on strategies for prevention and early detection. In the absence of better markers for increased risk, strategies for prevention must have few serious side effects and screening strategies must be highly specific.

Epidemiologic studies suggest that ovulation is an important co-factor in the development of ovarian cancer. Use of oral contraceptives that suppress ovulation and induce apoptosis in ovarian epithelial cells can reduce the risk of developing ovarian cancer in later life by as much as 50%. In patients with hereditary ovarian cancer who carry mutations of BRCA1 or BRCA2, prophylactic oophorectomy can be considered.

As there are few specific symptoms for early stage disease and there is no generally accepted screening strategy, carcinoma has metastasized beyond the ovary in more than three fourths of patients when epithelial cancer is finally diagnosed. 4 If ovarian cancer is still confined to the ovary, 90% of patients can be cured with conventional surgery and chemotherapy. Many cancers are detected as pelvic masses, although even small tumors confined to the pelvis may have metastasized by the time that they are palpated. About 20% to 30% of ovarian masses found in postmenopausal women are malignant, whereas only 7% of ovarian masses in premenopausal women are malignant. Intense investigation is underway to develop an effective strategy for early detection of ovarian cancer using pelvic ultrasonography and serum/plasma assays that include CA125 and other novel markers. Development of more effective strategies for detection, prevention and treatment has been accelerated by a more and more rapid increase in understanding ovarian cancer at a cellular and molecular level.

Etiology and Epidemiology

The cause of ovarian cancer is unknown. 5 Some have speculated that an etiologic agent or a potentiator of oncogenesis could enter the peritoneal cavity through the lower genital canal and spread through the uterus and the fallopian tubes. 3 Possible carcinogens, such as infectious agents and chemical carcinogens have been studied, and while case-control studies have failed to document a specific agent, some studies have linked environmental exposure to asbestos-contaminated talc in douches and contraceptives with the development of epithelial tumors. 5, 4 Case control studies have also pointed to an association of white race, high-fat diet and galactose consumption with a higher incidence of the disease. 8, 5

Among the epidemiological variables, however, prior reproductive history and the number of ovulatory cycles appear to have the greatest impact on development of the disease, with low parity, infertility, early menarche and late menopause increasing the risk. 6, 7 Fertility enhancing drugs, such as clomiphene citrate and gonadotropins used for ovulation induction have been thought to increase the risk of ovarian cancer, but the data have not been consistent and have not adequately distinguished the influence of infertility per se from the use of fertility stimulating agents. 12- 8 A pooled analysis of eight case-control studies that included 5,207 cases and 7,705 controls found an association of fertility stimulating drugs with serous borderline tumors, but not with invasive ovarian cancers. 9 The increased incidence of ovarian cancer in single women, nuns, and nulliparous women suggests that continual ovulation, uninterrupted by pregnancy, may predispose women to develop this malignancy. 7, 10, 10 Over many cycles of ovulation, the ovarian surface epithelium undergoes repetitive disruption and repair. Epithelial cells covering the ovarian surface are stimulated to proliferate, increasing the probability of spontaneous mutations in tumor suppressor or proto-oncogenes that might contribute to oncogenesis. Alternatively, trapping of epithelial cells within the stroma following ovulation can lead to the formation of inclusion cysts where epithelial cells are subjected to a unique microenvironment.

Most case control and cohort studies have failed to link hormone replacement therapy to an increased risk of epithelial ovarian cancer. 11 One large cohort study has recently re-opened controversy regarding this issue. 12 Among 44,241 postmenopausal women in the Breast Cancer Detection Demonstration Project, 329 developed ovarian cancer. Women who had received estrogen replacement therapy only, without progestin, for more than 10 years were at increased risk of developing ovarian cancer. By 20 years the relative risk was 3.2 fold.

The incidence of ovarian cancer varies in different geographic locations throughout the world. Western countries, including the United States and the United Kingdom, have an incidence of ovarian cancer that is three to seven times greater than in Japan, where epithelial ovarian tumors are considered rare. 2 In Asia, the incidence of germ cell tumors of the ovary appears to be somewhat higher than in the West. Japanese immigrants to the United States, however, have a significant increase in the incidence of epithelial ovarian cancer at a rate approaching that of white women from the United States. The incidence of epithelial tumors is about one and one half times greater in whites than in blacks.

Prevention

As parity is inversely related to the risk of ovarian cancer, having at least one child is protective of the disease with a risk reduction of 0.3to 0.4. Remarkably, use of oral contraceptives for 5 or more years reduces their relative risk to 0.5, ie (there is a 50% reduction in the likelihood of developing ovarian cancer). 13, 14 Women who have had two children and have used oral contraceptives for 5 or more years have a relative risk of ovarian cancer as low as 0.3, or a 70% reduction. Therefore, the oral contraceptive pill is the only documented method of chemoprevention for ovarian cancer, and it should be recommended to women for this purpose. When counseling patients regarding birth control options, this important benefit of oral contraceptive use should be emphasized. This is also important for women with a strong family history of ovarian cancer.

Fenretinide

Fenretinide (4-hydroxyphenyl-all-trans-retinoic acid amide), a vitamin A derivative, has been given to women with unilateral breast cancer in an effort to reduce the risk of contralateral breast cancer. In a prospective, randomized, placebo-controlled trial conducted in Italy, women with unilateral breast cancer were given either oral fenretinide or a placebo for five years. 21 In the treatment group, no ovarian cancers developed during the five years on study, whereas there were 6 cases of ovarian cancer in the control group (p < .01). When participants were followed long-term, however, the protective effect disappeared after discontinuing the drug. 15 In cell culture, fenretinide can induce apoptosis in ovarian cancer cells and in normal ovarian surface epithelial cells. 16 Trials are planned in the United States to determine the effect of fenretinide on the ovaries of women at high risk for developing ovarian cancer who will receive the drug prior to prophylactic oophorectomy.

Oophorectomy

The performance of a prophylactic oophorectomy will reduce, but not eliminate, the excess risk of cancer in women at high risk for developing ovarian cancer. 17–29 Because the entire peritoneum is at risk, peritoneal carcinomas can occur even after prophylactic oophorectomy in less than 5% of cases. Because the ovaries provide protection from cardiovascular disease and osteoporosis, prophylactic oophorectomy should not be routinely performed in premenopausal women at average risk for ovarian cancer.

Genetic Risk for Epithelial Ovarian Cancer

Most epithelial ovarian cancer is sporadic, with familial or hereditary patterns accounting for 5% 10% of all malignancies. 18 The risk of ovarian cancer is higher than that of the general population in women with certain family histories. 19–36 Most familial ovarian cancer is associated with mutations in BRCA1, BRCA2 or DNA mismatch repair genes in the human nonpolyposis colon cancer (HNPCC, Lynch Type II) syndrome. 31–36, 20, 21 There have also been reportable cases of ovarian cancer associated with Li-Fraumini syndrome that occurs due to p53 mutations in the germ line. 22 In the past, it had been thought that there were two distinct syndromes associated with a genetic risk, site-specific hereditary ovarian cancer, and hereditary breast/ovarian cancer syndrome. However, it is now believed that these groups essentially represent a continuum of mutations with different degrees of penetrance within a given family.

BRCA1 and BRCA2

The majority of ovarian cancer families have mutations in the BRCA1 gene that is located on chromosome 17. 23, 24 A small fraction of inherited disease has been traced to another gene, BRCA2, located on chromosome 13. 25 Discovered through linkage analyses, these two genes are associated with the genetic predisposition to both ovarian and breast cancer.

BRCA1/2 mutations are passed via autosomal dominant inheritance, and a full pedigree analysis (ie, both maternal and paternal sides of the family) must be carefully evaluated. There are numerous distinct mutations that have been identified on each of these genes, and the mutations have different degrees of penetrance which may account for the preponderance of either breast cancer, ovarian cancer, or both, in any given family. Based on analysis of women who have a mutation in the BRCA1 gene and are from high-risk families, the lifetime risk of ovarian cancer may be as high as 28% to 44% and the risk has been calculated to be as high as 27% for those women with a BRCA2 mutation. 35, 26 The risk of breast cancer in women with a BRCA1 or BRCA2 mutation may be as high as 56% to 87%.

Hereditary ovarian cancers generally occur in women about 10 years younger than those with nonhereditary tumors. 41 As the median age of epithelial ovarian cancer is in the mid- to late 50s, a woman with a first- or second-degree relative who had premenopausal ovarian cancer may have a higher probability of carrying an affected gene.

Within a given family, a combination of epithelial ovarian and breast cancers can affect a mixture of first- and second-degree relatives. Women with this syndrome tend to develop cancers at a young age, and breast cancers may be bilateral. If two first-degree relatives are affected, this pedigree is consistent with an autosomal dominant mode of inheritance. 32

Founder Effect

More than 100 different mutations of BRCA1 and BRCA2 have been cataloged in different families with ovarian and breast cancer. A particularly high carrier rate of BRCA1 and BRCA2 mutations has been found in women of Ashkenazi Jewish descent and in Islandic women. 33, 42 Three specific mutations occur repeatedly in the Ashkenazi population and are associated with many of the breast and ovarian cancer families: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. One in 40 or 2.5% of all Ashkenazi Jewish women carry at least one of these three mutations. The prevalence of these specific mutations in the Ashkenazi population is thought to have resulted from a “founder effect”, where the mutations can be traced to particular families within a defined geographic area.

Pedigree Analysis

The risk of ovarian cancer depends on the number of first- and/or second-degree relatives with a history of epithelial ovarian carcinoma and/or breast cancer, and on the number of malignancies that occur at an early age. The degree of risk is difficult to determine precisely unless one performs a full pedigree analysis.

In families with two first-degree relatives (ie, mother, sister, or daughter) with documented premenopausal epithelial ovarian cancer, the risk that a female first-degree relative will have an affected gene could be as high as 35% - 40%. 32 In families with a single first-degree relative and a single second-degree relative (ie, grandmother, aunt, first cousin, or granddaughter) with epithelial ovarian cancer, the risk that a woman will have an affected gene also may be increased. The risk may be two- to tenfold higher than in those without a familial history of the disease. 32 In families with a single post-menopausal first-degree relative with epithelial ovarian carcinoma, a woman may not have an increased risk of having an affected gene because the case is most likely to be sporadic. However, if the ovarian cancer occurred in a premenopausal relative, this could be significant, and a full pedigree analysis should be undertaken. Women with a primary history of breast cancer have twice the expected incidence of subsequent ovarian cancer.

Lynch Type II Syndrome

The hereditary nonpolyposis colorectal cancer (HNPCC) syndrome includes multiple adenocarcinomas, including familial colon, ovarian, endometrial, and breast cancers, as well as other malignancies of the gastrointestinal and genitourinary systems. 38 Mutations of DNA mismatch repair genes have been associated with this syndrome including mutations of MSH2, MLH1, PMS1 and PMS2. The risk that a woman who is a member of a Lynch type II family will develop epithelial ovarian cancer depends on the frequency of this disease in her first- and second-degree relatives, although these women appear to have at least three times the relative risk of the general population.

Management of Women at High-Risk for Ovarian Cancer

The management of a woman with a strong family history of epithelial ovarian cancer must be individualized and depends on her age, her reproductive plans, and the extent of risk. In all of these syndromes, women at risk benefit from a thorough pedigree analysis. A geneticist should evaluate the family pedigree for at least three generations. Decisions about management are best made after careful study and, whenever possible, verification of the histologic diagnosis of the family members' ovarian cancer.

The value of testing for BRCA1 and BRCA2 has yet to be clearly established, although some guidelines for testing now exist. 30, 34 The importance of genetic counseling cannot be overemphasized, as decisions surrounding genetic testing are complex. The American Society of Clinical Oncologists has offered guidelines that emphasize careful evaluation by geneticists, careful maintenance of medical records, as well as a clear understanding in a genetic screening clinic of how to counsel and manage these patients. 27 Concerns remain regarding how the information will be used, the impact on insurability, how the results will be interpreted and how the information will be applied within a specific family (eg, to counsel children). Although there are conflicting data, the behavior of breast cancers arising in women with germ-line mutations in BRCA1 or BRCA2 is comparable to that of sporadic breast cancers. 36 Women with breast cancer who carry these mutations are, however, at a greatly increased risk of ovarian cancer as well as a second breast cancer.

Although recommended by the NIH Consensus Conference on Ovarian Cancer, 28 the value of screening with transvaginal ultrasonography, CA 125 levels, or other procedures has not been clearly established in women at high risk. Bourne and colleagues have shown that this approach can detect tumors about ten times more often than in the general population, and thus they recommend screening in high-risk women. 46

Data derived from a multi-institutional consortium of genetic screening centers indicate that the use of the oral contraceptive pill is associated with a lower risk of developing ovarian cancer in women who have a mutation in either BRCA1 or BRCA2. 29 The risk reduction is significant: in women who have taken the oral contraceptive pill for 5 or more years, the relative risk of ovarian cancer is 0.4, or a 60% reduction in the incidence of the disease.

The value of prophylactic oophorectomy in women with BRCA1/2 mutations has been clearly documented. 28, 29 The risk of ovarian cancer is substantially diminished, but there remains the low risk of primary peritoneal carcinoma, a tumor that may also have a higher incidence in women who have mutations in the BRCA1 and BRCA2. Women at high risk for ovarian cancer who undergo prophylactic oophorectomy can harbor occult neoplasia. In one series of 42 such operations, 4 (9.5%) of patients had a malignancy, one was detected at surgery and 3 were found only on microscopic examination. 24 Performance of a prophylactic oophorectomy also appears to lower the risk of breast cancer by about 54%. Women who carry these germ-line mutations are at higher risk for fallopian tube cancer; a complete bilateral salpingo-oophorectomy should be performed when they undergo prophylactic surgery. 30

Current recommendations for management of women with high-risk for ovarian cancer have been summarized. 45 Women who appear to be at high-risk for ovarian and or breast cancer should undergo genetic counseling and, if the risk appears to be substantial, may be offered genetic testing for BRCA1 and BRCA2. Women who wish to preserve their reproductive capacity can undergo periodic screening by transvaginal ultrasonography every 6 months, although the efficacy of this approach is not clearly established. Prophylactic surgery (bilateral salpingo-oophorectomy with or without a hysterectomy) is the treatment of choice for women who have completed their childbearing. Oral contraceptives should be recommended to young women before a planned family. Women who do not wish to maintain their fertility or who have completed their family may undergo prophylactic bilateral salpingo-oophorectomy. The risk should be clearly documented, preferably established by BRCA1 and BRCA2 testing, before salpingo-oophorectomy. These women should be counseled that this operation does not offer absolute protection, as peritoneal carcinomas occasionally can occur after bilateral oophorectomy. In women who also have a strong family history of breast cancer, annual mammographic screening should be performed commencing at age 30 years. Women with a documented HNPCC syndrome should be treated as above, and in addition, should undergo periodic screening mammography, colonoscopy, and endometrial biopsy. 31

In a recent study, Markov modeling was performed in a simulated cohort of 30-year-old women who tested positive for BRCA1/2 mutations. 32 Quality adjustment of survival estimates were obtained from a survey of women aged 33 to 50 years. A 30-year-old woman could prolong her survival beyond that associated with surveillance alone by 1.8 years with tamoxifen, 2.6 years with prophylactic oophorectomy, 4.6 years with both tamoxifen and prophylactic oophorectomy, 3.5 years with prophylactic mastectomy and 4.9 years with both surgeries. Quality adjusted survival could be prolonged by 2.8 years with tamoxifen, 4.4 years with prophylactic oophorectomy, 6.3 years with tamoxifen and oophorectomy and 2.6 years with mastectomy or both operations. Benefits would decrease if institution of these preventive measures were delayed beyond age 30.

Embryology

In the human embryo, the ovary appears as a genital ridge about 1 month after fertilization. 2 The primitive mesoderm gives rise to the mesothelial covering of the ovary and of the peritoneum, the so-called germinal epithelium from which epithelial ovarian cancers and primary peritoneal cancers are thought to arise. These cells arise along the medial and ventral borders of the mesonephros from which the mesenchymal tissues of the ovary are derived. The mesenchymal tissues give rise to the ovarian stroma. The germ cells originate from the primitive streak and migrate from the yolk sac endoderm toward the developing ovary. The primitive ovary is histologically unique and distinguishable from the primitive testis by 6 weeks after fertilization. The ovarian cortex develops by 8 to 9 weeks.

Biology and Prognosis of Ovarian Neoplasms

The prognosis of ovarian cancer can be correlated with numerous clinical and biologic factors. Tumor stage, grade, and size of metastatic disease after resection correlate best with outcome. 33, 34, 35 As discussed below, among patients with low stage disease, tumor grade correlates with prognosis (ie, patients with stage I high-grade lesions have a shorter survival than those of low-grade). 52 In patients with advanced stage disease, the size of residual disease after surgery correlates most clearly with survival. 36 The rapidity with which disease regresses during chemotherapy also correlates with survival. A short apparent half-life of the serum tumor marker CA 125 has correlated with improved survival in more than a dozen studies. 37 Normalization of CA 125 by the third course of chemotherapy has been associated with a favorable prognosis. 38

Several biologic factors have been correlated with prognosis in epithelial ovarian cancer. Using flow cytometry, Friedlander and others have shown that ovarian cancers are commonly aneuploid and that a correlation exists between FIGO stage and ploidy, (low-stage cancers tend to be diploid and high-stage tumors tend to be aneuploid). 57–67 Patients with diploid tumors have a significantly longer median survival than those with aneuploid tumors: 5 years versus 1 year, respectively. 66 Multivariate analyses have demonstrated that ploidy is an independent prognostic variable and one of the most significant predictors of survival. 67 Flow cytometric analysis also provides data on the cell cycle, and the proliferation fraction (S phase) determined by this technique has correlated with prognosis in some studies. 57, 63, 39 More recent reports utilizing comparative genomic hybridization suggest that copy number abnormalities for chromosome segments also have prognostic significance. 40

Most sporadic ovarian carcinomas evolve from a single clone of cells. When primary cancers and metastases have been compared, more than 90% share the same patterns of loss of heterozygosity, inactivation of the same X chromosome and, when present, the same mutations in p53. 41–42 Ovarian cancers can metastasize by multiple routes. Like other epithelial neoplasms, ovarian cancers can spread through lymphatics to the level of the renal hylus and can also spread hematogenously. Most frequently, however, ovarian cancer spreads over the surface of the peritoneum, studding the serosal surface of the bowel and abdominal wall and ultimately producing intestinal obstruction. Ascites formation results from increased leakage of proteinaceous fluid from capillaries under the influence of VEGF/VPF produced by ovarian cancers and from inhibition of fluid outflow through diaphragmatic lymphatics that have been blocked by metastatic disease. 73, 43 Studies of the immunobiology of the peritoneal cavity suggest that it may function as an immunoprivileged site, with elevated levels of suppressive molecules and growth factors.

Epithelial ovarian cancers are thought to arise from a single layer of cells that covers the ovary or that lines cysts immediately beneath the ovarian surface. These cells are generally quiescent, but proliferate following ovulation to repair the defect created by rupture of a follicle. A distinctive profile of genetic and epigenetic alterations has been observed in early and late stage ovarian cancers. 44 A number of oncogenes have been overexpressed and/or activated (Table 118-1) and the function of several tumor suppressor genes has been lost (Table 118-2). Among the oncogenes activated, particular attention has been given to the HER family of transmembrane tyrosine kinase growth factor receptors, including the epidermal growth factor receptor (EGFR) and c-erbB-2 (HER-2). EGFR is expressed by normal ovarian surface epithelial cells and EGFR expression is lost in approximately 30% of ovarian cancers, associated with an improved prognosis. 45 HER-2 is overexpressed in approximately 15%to 30% of ovarian cancers and, in some studies, has been associated with a poor prognosis. 46, 47 The ras oncogene is mutated and activated in less than 20% of serous ovarian cancers, but is more frequently mutated in mucinous and borderline neoplasms. 79- 48 In addition, ras may be physiologically activated in a larger fraction of cancers. 49 Myc is amplified and overexpressed in approximately 33% of cases. 50 More frequent and consistent abnormalities have been found in the PI3 kinase signaling pathway. The p110 catalytic subunit of the PI3 kinase is amplified, overexpressed and activated in more than half of ovarian cancers. 51 Downstream within the PI3 kinase signaling pathway, AKT is also amplified, overexpressed and activated in 20% of cases. 52 PTEN is mutated in endometrioid ovarian cancers. 53 Overall, abnormalities of the PI3 kinase pathway have been found in more than 70% of ovarian cancers. 86

Table 118-1. Oncogenes in Epithelial Ovarian Cancer.

Table 118-1

Oncogenes in Epithelial Ovarian Cancer.

Table 118-2. Putative Tumor Suppressor Genes In Epithelial Ovarian Cancer.

Table 118-2

Putative Tumor Suppressor Genes In Epithelial Ovarian Cancer.

Recently, a murine model has been developed that mimics human ovarian cancer and that permits the introduction of multiple genes using an avian retroviral gene delivery technique. 54 When the ovarian target cells were derived from transgenic mice deficient for p53, the addition of any two of the oncogenes c-myc, k-ras and AKT were sufficient to induce ovarian tumor formation when infected cells were injected at intraperitoneal, subcutaneous or ovarian sites. Another model has been developed from normal human ovarian surface epithelial cells that have also been immortalized with telomerase and with viral T antigen which neutralizes p53 and RB function. Introduction of activated human H-ras or K-ras genes transforms these immortalized cells and permits them to grow in immunosuppressed mice with a nodular or papillary histology that resembles human ovarian cancer. 55

A number of tumor suppressor genes have been studied in ovarian cancers. The RB and VHL genes can be downregulated in a fraction of ovarian cancers, but their function remains intact. 56–57 P53 is mutated and consequently overexpressed in 50& to 60% of advanced ovarian cancers, but in only 15% of stage I disease. 58 p53 Is rarely mutated in borderline cancers, but when this occurs, it is associated with a poor prognosis. 59, 60 The pattern of p53 abnormalities is most consistent with spontaneous mutation rather than the activity of chemical carcinogens. 61 . Novel tumor suppressor genes have been discovered in recent years. 86, 62–63 ARHI and Lot-1 are imprinted genes with only one functioning allele in adult cells. 98, 99 As the “first hit” has already occurred during imprinting, loss of function can occur with a single genetic or epigenetic event. Loss of the functional allele of ARHI can occur through loss of heterozygosity, methylation and transcriptional downregulation. ARHI is homologous to the oncogenes ras and rap, but has the opposite function, inhibiting cell proliferation, motility and invasion. Overexpression of ARHI induces apoptosis and may prove useful, as may other suppressor genes, for gene therapy alone or in combination with standard cytotoxic agents. 64

Several autocrine or paracrine factors affect the growth of normal and transformed ovarian epithelial cells including epidermal growth factor (EGF) transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, interleukin-1 (IL-1), interleukin-6 (IL-6), macrophage colony stimulating factor (M-CSF, CSF-1) and lysophosphatidic acid (LPA). 102- 65 Different ovarian cancers exhibit abnormal production of these factors, altered receptor function and/or altered signaling. A fraction of ovarian cancers have lost expression of EGFR and consequently the ability to be stimulated by EGF and TGF-α, and this loss is associated with an improved prognosis. 103, 104 In contrast to normal epithelium, the proliferation of many ovarian cancer cells from different patients may lose the ability to express TGF-β and may be only partially inhibited by exogenous TGF-β. Thus, the inhibitory effect that TGF-β exerts in normal epithelium may be lost during transformation. 66, 67 Interestingly, TGF-β can produce apoptosis in malignant cells, but not in normal cells. 68 TNF can stimulate, fail to affect or inhibit growth of different cell lines. 106, 69 As ovarian cancers transform, receptors for M-CSF (fms) and for LPA (edg-7) are upregulated resulting in greater proliferation, invasiveness, and resistance to apoptosis in the presence of the ligands. 109, 110

Several additional molecular alterations contribute to the ability of ovarian cancers to metastasize. Alteration in integrins and expression of altered CD44 promote adhesion to mesothelial cells lining the peritoneum, 115–117 Upregulation of proteases enhances invasion. 70–71 . Several angiogenic factors are secreted including IL-8, β FGF and VEGF. 72 The VEGF molecule is also known as vascular permeability factor that increases leakage of proteinacious material from capillaries and the formation of ascites.

Upregulation and aberrant glycosylation of extracellular mucins have provided targets for therapy and markers for monitoring disease. MUC-1 is a mucin expressed by more than 80% of ovarian cancers. 73 In transformed cells, aberrant glycosylation exposes peptide determinants recognized by murine monoclonal antibodies that have been used for serotherapy. CA 125 is also a mucin (MUC-16) associated with cells that line the coelomic cavity during embryonic development. CA125 is shed from 80% of epithelial ovarian cancers 124 and can be measured using the murine monoclonal antibody OC125. 124- 74 Regression and progression of disease tend to correlate well with falling or rising CA125 levels. 124 The precise function of the glycoprotein is unknown.

Classification and Pathology

Primary ovarian cancers are classified according to the structures of the ovary from which they are derived. 2, 75 Most develop from the epithelial cells that cover the ovarian surface or that line inclusion cysts. These cells are ultimately derived from the coelomic epithelium of mesodermal origin and share cytologic markers with mesothelium. Germ cell malignancies constitute the next most common group and the least common tumors are derived from ovarian stromal cells.

Epithelial malignancies account for 85% to 90% of ovarian cancers. The majority of epithelial lesions are seen in patients who are 40 years or older. Under the age of 40 years, epithelial malignancies are uncommon, and most malignancies seen in women under the age of 30 years are of germ cell origin. 2 The histologic types of the epithelial tumors are listed in Table 118-3. The majority of lesions, about 75%, are of the serous type, followed by the mucinous, endometrioid, clear cell, mixed, Brenner, and undifferentiated histologies. 2, 76 The cellular patterns of different histotypes resemble different derivatives of the Müllerian duct in different portions of the female reproductive tract. For example, serous epithelial cells resemble cells that line the Fallopian tube, endometrioid epithelial cells resemble the endometrium, and mucinous epithelial cells resemble the uterine endocervix.

Table 118-3. Epithelial Ovarian Tumors.

Table 118-3

Epithelial Ovarian Tumors.

Invasive Histologies

Serous carcinomas may have a complex admixture of cystic and solid areas with extensive papillations, or they may contain a predominantly solid mass with areas of necrosis and hemorrhage (Figure 118-1). The poorly differentiated tumors may have some areas with a papillary pattern, but other portions may be indistinguishable from the other histologic patterns described below (Figure 118-2). Stage I or II lesions are most frequently unilateral, with about 10% to 20% involving both ovaries. Conversely, about 50% to 70% of stage III serous carcinomas are bilateral. 2

Figure 118-1. Serous cystadenocarcinoma gross with omentum.

Figure 118-1

Serous cystadenocarcinoma gross with omentum. (Four-color version of figure on CD-ROM)

Figure 118-2. Poorly differentiated papillary carcinoma of ovary.

Figure 118-2

Poorly differentiated papillary carcinoma of ovary. (Four-color version of figure on CD-ROM)

Mucinous tumors tend to be large, with many masses over 20 cm in diameter (Figure 118-3). The histologic pattern resembles uterine endocervical glands. The lesions frequently contain areas of hemorrhage, necrosis, and various quantities of mucin. These tumors are bilateral in 10% to 20% of cases. 2 Occasionally, mucin is secreted into the peritoneal cavity and produces a condition known as pseudomyxoma or myxoma peritonei. A mucocoele of the appendix may also be seen in conjunction with this tumor.

Figure 118-3. Mucinous cystadenocarcinoma.

Figure 118-3

Mucinous cystadenocarcinoma. (Four-color version of figure on CD-ROM)

Endometrioid carcinomas of the ovary resemble typical carcinomas of the endometrium. These tumors may be seen with synchronous endometrial carcinoma, and when they are, both lesions may be of low stage. 2 Rarely, endometrioid carcinomas arise in conjunction with pelvic endometriosis, resulting from malignant transformation of a benign process (Figure 118-4). Bilaterality is seen in 10% - 15% of stage I and II disease, and in about 30% of stage III. 2

Figure 118-4. Endometrioid carcinoma.

Figure 118-4

Endometrioid carcinoma. (Four-color version of figure on CD-ROM)

Clear cell carcinomas were formerly called mesonephromas, a term that has been abandoned because clear cell tumors are derived from tissues that are embryologically distinct from mesonephros. About one fourth of clear cell tumors are associated with endometriosis. Clear cell tumors are only rarely bilateral. 2

Brenner tumors are uncommon, representing less than 1% of all epithelial malignancies. Mixed epithelial tumors may contain small areas of Brenner tumor histology, which have a histologic pattern similar to that of transitional cell. Malignant Brenner tumors are unilateral. 2

Borderline Tumors

Borderline tumors, or those of low malignant potential, are important to differentiate from those that are frankly invasive. The treatment and prognosis for borderline lesions are considerably different from those for invasive malignancies. Borderline tumors tend to remain confined to a single ovary at the time of diagnosis, and also tend to occur in younger, premenopausal women (Figure 118-5). They may be confused with a well-differentiated invasive ovarian cancer, and the treatment for the two may be different. Thus, in a young patient who has a lesion confined to the ovary that is suspected of having an epithelial ovarian cystadenocarcinoma, a borderline tumor must be excluded, because bilateral oophorectomy, hysterectomy, and chemotherapy are unnecessary in these patients. In women under the age of 40 years, about 60% to 70% of non-benign ovarian neoplasms are borderline, whereas in women over 40 years, only 10% are borderline. 2, 77

Figure 118-5. Borderline papillary serous tumor.

Figure 118-5

Borderline papillary serous tumor. (Four-color version of figure on CD-ROM)

Histologic criteria for borderline tumors include (1) the presence of epithelial cell proliferation with a “piling up” of cells, so-called pseudostratification; (2) cytologic atypia, but with rare mitoses; and (3) no evidence of stromal invasion. Borderline tumors tend to remain confined to the ovary, but may be associated with peritoneal disease, which represents either dissemination or the multifocal evolution of the disease. In those rare patients with peritoneal involvement, death can occur by progressive intestinal obstruction. 2, 78, 79

Primary Peritoneal Carcinomas

Malignancy that arises primarily from the peritoneal cells is referred to as peritoneal carcinoma or primary peritoneal (papillary) adenocarcinoma. 80 There is some debate as to whether these should all be classified as peritoneal mesotheliomas, or whether this latter group is a specialized variety of a poorly differentiated peritoneal tumor. 2, 81 Some of the lesions appear identical to those tumors that arise from the surface epithelium of the ovaries, and the cells of the peritoneum have the ability to recapitulate any of the histologic patterns seen in ovarian cancer. Thus, the most common pattern of a peritoneal carcinoma is a papillary serous carcinoma.

Knowledge of primary peritoneal carcinomas is important. This lesion explains many instances of unknown primary when no clear explanation for peritoneal carcinomatosis can be documented. Also, the existence of this phenomenon explains the occurrence of ovarian cancer after oophorectomy. 82 In these patients, the presence of carcinomatosis that involves the surface of the ovaries but without ovarian enlargement, probably represents peritoneal carcinoma with secondary or concomitant involvement of the ovarian surfaces. In this manner, the ovaries are the “innocent bystanders” of the process. Therapeutically, primary peritoneal malignancy should be treated as one would manage an epithelial ovarian cancer.

Patterns of Spread

Ovarian epithelial tumors spread primarily by direct exfoliation of cells throughout the peritoneal cavity, but they also spread via the lymphatic and hematogenous routes. Germ cell tumors have a greater predilection for spread via the retroperitoneal lymphatics, which must be evaluated carefully when staging those tumors that appear to be confined to the ovary. 2, 83, 84

The most common and earliest mode of dissemination of epithelial tumors is by the exfoliation of cells along the peritoneal surfaces. 85 The cells spread directly to the pelvic and abdominal peritoneal surfaces, and tend to follow the path of circulation of peritoneal fluid from the right pericolic gutter cephalad to the right hemidiaphragm. 86 The intestinal mesenteries become involved by peritoneal metastases. Adhesions form between loops of intestine producing mechanical obstruction, even though involvement of the lumen of the intestine by direct extension is uncommon. The intestinal dysfunction can also result from involvement by tumor of the myenteric plexus, the autonomic innervation of the intestine that is found in the mesentery. This condition has been referred to as carcinomatous ileus 2 .

Spread via the lymphatics is common in epithelial ovarian cancer. Apparent stage I and II tumors have retroperitoneal lymphatic dissemination in about 5% to 10% in most series, whereas lymphatic dissemination in stage III has been reported to be as high as 42% to 78% in carefully explored patients. 52, 137, 87–88 Most of these lymph nodes are not enlarged, but are microscopically positive for malignant cells. Spread through the retroperitoneal and diaphragmatic lymphatics can result in metastasis to the supraclavicular lymph nodes.

Blood-borne metastasis of ovarian cancer is uncommon at diagnosis and is often a late finding in the disease. Hematogenous dissemination at the time of diagnosis to the parenchyma of the liver or lung is seen in only 2% to 3% of patients. Indeed, most patients who have disease dissemination cephalad to the diaphragm at the time of presentation have a right pleural effusion. Metastasis to the central nervous system is rare and spread to the bone is very rare, except for the clear cell histologic type. 143, 144 However, in patients who survive many months and years with their disease, involvement of distant sites is more common. In one report by Dauplat and colleagues, distant metastases consistent with stage IV findings were documented in almost two fifths of patients who died of ovarian cancer originally thought confined to the peritoneal cavity. 143

Clinical Features

Traditionally, ovarian cancer has been considered a “silent killer” that does not produce symptoms until far advanced. Some patients with ovarian cancers confined to the ovary are asymptomatic, but the majority will have nonspecific symptoms that do not necessarily suggest an origin in the ovary. In one survey of 1,725 women with ovarian cancer, 95% recalled symptoms prior to diagnosis, including 89% with Stage I/II disease and 97% with Stage III/IV disease. 89 Some 70% had abdominal or gastrointestinal symptoms, 58% pain, 34% urinary symptoms, and 26% pelvic discomfort. At least some of these symptoms could have reflected pressure on the pelvic viscera from the enlarging ovary.

Metastatic ovarian cancer is rarely asymptomatic. In addition to the gastrointestinal and urinary symptoms noted in early stage disease, formation of ascites can produce an increase in abdominal girth. Pleural effusion may lead to dyspnea as the first complaint. Acute symptoms, such as those of adnexal rupture or torsion, are uncommon. Vaginal bleeding is also an uncommon symptom in postmenopausal women, although premenopausal patients may present with irregular or heavy menses. 52

Detection of an adnexal mass by pelvic examination can permit the early diagnosis of ovarian cancer. Since malignancy is rare and the majority of palpable adnexal masses are benign, an enlarged ovary discovered on pelvic examination is not likely to be an ovarian malignancy. In premenopausal women, ovarian cancer is uncommon and represents less than 7% of all adnexal masses. Even in postmenopausal women, 70% to 80% of adnexal tumors are benign. In some patients who complain primarily of abdominal symptoms, a pelvic examination frequently is omitted and the tumor missed. Signs of advanced disease include abdominal distension and a fluid wave consistent with ascites. These signs are nonspecific and can be associated with many conditions arising in the abdominal cavity, especially malignancies of other primary sites or carcinomatosis from metastatic tumors of the gastrointestinal tract and breast.

Diagnosis

The diagnosis of ovarian cancer is usually made at laparotomy, but occasionally at laparoscopy. If a pelvic mass is suspicious and the most likely diagnosis is ovarian cancer, surgery should not be unnecessarily delayed. In premenopausal patients, however, predominantly cystic pelvic masses can be observed over a period of 1 to 2 months. Lesions that are essentially mobile, are unilateral, and have a smooth contour are much less likely to be neoplastic, and are unlikely to be malignant. In premenopausal patients with cystic lesions of less than 8 cm, attempted suppression with oral contraceptives is indicated. In women who are definitely postmenopausal, cystic masses larger than 5 cm should be removed unless they represent a chronic finding. Those masses that regress in size can be managed with continued observation, whereas those that persist or enlarge must be evaluated surgically. Conversely, patients whose lesions are irregular, predominantly solid, and somewhat immobile should undergo an exploratory laparotomy. 51

The preoperative evaluation of patients can be aided by the use of CA125. Elevated CA125 levels are most frequently associated with malignant adnexal masses in postmenopausal women. In women over 50 years of age whose serum CA125 level is greater than 35 U/mL the adnexal mass is malignant in about 80% of cases. A CA125 of more than 95 U/mL is associated with a positive predictive value of 96% in this setting. Conversely, the majority of premenopausal women with serum CA125 levels greater than 35 U/mL have benign conditions, such as uterine myomata, endometriosis, and benign ovarian tumors. 3, 90 Elevation of serum CA 125 in a postmenopausal patient with a pelvic mass should prompt exploration by surgeons prepared to undertake complete staging and, if necessary, cytoreductive operations.

Ultrasonographic signs of malignancy include an adnexal pelvic mass with areas of complexity, such as irregular borders; multiple echogenic patterns within the mass; and dense, multiple irregular septae. Bilateral tumors are more likely to be malignant, although the individual characteristics of the lesions are of greater significance. Transvaginal ultrasonography may have a somewhat better resolution than transabdominal ultrasonography for adnexal neoplasms. 91 Newer techniques using Doppler color flow imaging may enhance the specificity of ultrasonography for demonstrating findings consistent with malignancy. 92

Radiographic techniques, including abdominal radiographs, computed tomography (CT) scans, and nuclear magnetic resonance imaging (MRI), are not useful prior to the surgical diagnosis of ovarian cancer. 93 The preoperative evaluation of patients who have a suspicious pelvic mass can omit these studies when blood chemistries and enzymes suggest normal hepatic and pancreatic function. 52 In patients with ascites and no pelvic mass, however, a CT or MRI may be useful in identifying other potential sites of origin. Paracentesis is not recommended because of the frequency of metastatic implantation and growth in the needle tract. Liver-spleen scans, brain scans, and bone scans are unnecessary unless specific symptoms suggest metastasis to these sites.

In premenopausal women, radiographic studies of the intestines are not required unless there is the finding of occult blood in the rectum or there are symptoms indicating upper or lower intestinal obstruction. A barium enema or endoscopy is appropriate in postmenopausal patients. Mammography should be performed to exclude primary breast cancer, which can coexist with ovarian cancer or spread to the ovaries. Cervical cytology should be performed, although ovarian cancer cells are unlikely to exfoliate through the uterus to the cervix. In patients with irregular or heavy menses, an endometrial biopsy should be performed to exclude primary endometrial pathology. 52

The differential diagnosis of an adnexal mass includes a variety of functional changes of the ovary, benign neoplasms of the reproductive tract, and inflammatory lesions of these organs. A hydrosalpinx, endometriosis, and pedunculated uterine leiomyomata can simulate an ovarian neoplasm. Nongynecologic diseases, such as inflammatory processes of the colon and rectum, must be excluded.

Screening

There is no well-established strategy for early detection of ovarian cancer. Discovery of a pelvic mass on routine physical examination can lead to surgery prior to the dissemination of a malignancy, but conventional diagnosis detects only 20% of patients in Stage I. Given the prevalence of ovarian cancer in the postmenopausal population, any screening strategy must be highly specific (> 99.6%) as well as highly sensitive for early stage disease (> 75%) to achieve a positive predictive value of 10% (ie, 10 laparotomies for each case of ovarian cancer detected). Two approaches have been evaluated for early detection of ovarian cancer: ultrasonography and serum tests such as CA 125.

Ultrasound

Transvaginal sonography (TVS) has proven superior to transabdominal sonography (TAU) for the detection of a pelvic mass. In three large studies that screened 66,620 women, 565 operations were performed to detect 45 ovarian cancers, 34 of which were invasive. 150–154 Overall, the sensitivity for early stage disease was 78%, but the specificity fell just short of that required for a positive predictive value of 10% with 12 operations per case of ovarian cancer detected. The most promising single study achieved a positive predictive value of 9.9%. 153 Confirmatory tests with Doppler ultrasound have not proven consistent, but additional studies with 3-D power Doppler are underway to improve specificity in distinguishing malignant from benign ovarian abnormalities.

CA 125

CA 125 is elevated in 50% – 60% of patients with stage I and in 90% with stage II ovarian cancer. 94–95 CA 125 levels can rise 10 to 60 months prior to diagnosis with an average estimated lead time of 1.9 years prior to diagnosis of disease in all stages. 158–162 Specificity for a single determination of CA 125 is not adequate to screen a population at average risk, but specificity can be improved with a two-stage strategy that utilizes CA 125 followed by ultrasound in a subset of women with elevated CA 125. Use of CA 125 to trigger ultrasound has been evaluated in trials in Sweden and in the United Kingdom. 160, 161, 96 The latter randomized 22,000 women to conventional surveillance or to annual CA 125 with TAU if the value were elevated. 163 When TAU was abnormal, surgery was undertaken. Among 10,985 women screened, 29 operations were performed to detect 6 cancers, providing a positive predictive value of 21%. During 7 years follow-up, 10 more cancers were diagnosed in the screened group. Over the same intervals, 21 ovarian cancers were diagnosed in the control group. Median survival in the screened group (72.9 months) was significantly greater (p = .0112) than that in the control group (41.8 months).

Risk of Ovarian Cancer (ROC) Algorithm

Analyzing serum samples stored from screening studies in Stockholm and in the United Kingdom with an improved CA 125II assay, it has been possible to improve the specificity of CA 125 as a screening tool by following the values of an individual over time. 97 Elevated CA 125 levels in women without ovarian cancer remain static or decrease with time, whereas levels associated with ovarian malignancy tend to rise. This finding has been incorporated into an algorithm that uses age, rate of change of CA 125 and absolute levels of CA 125 to calculate an individual's “risk of ovarian cancer” (ROC). Patients at sufficient risk undergo TVS. Some 10,000 volunteers greater than 50 years of age have been randomized in the United Kingdom to a screening group (5,046) or to a control group (4,954). 98 Using the ROC algorithm, 101 patients were found to be at sufficiently high risk to undergo TVS. Seventeen patients had abnormal findings prompting operations that detected 4 cases of ovarian cancer, yielding a positive predictive value of 20%.

Currently, a trial has begun in the United Kingdom that will include 200,000 post menopausal women who will be randomized to a control group (100,000) who will be followed with conventional pelvic examinations; a second group (50,000) who will have annual TVS; and a third group (50,000) who will have CA125 determined at least annually. Based on the ROC algorithm, patients in the third group will be referred for TVS and/or surgery. Women will be screened for 3 years and followed for 7 years. This trial may demonstrate more definitively the feasibility of screening for ovarian cancer as well as the impact of early detection on survival.

Complementary Markers

Whatever the outcome of the current trial in the United Kingdom or of the Prostate, Lung, Colon and Ovary (PLCO) screening trial with CA 125 and TVS in the United States, strategies based on CA 125 alone are not likely to exceed a sensitivity of 80%, as CA 125 is not expressed by 20% of epithelial ovarian cancers. Greater sensitivity might be attained through the use of multiple serum markers in combination, provided that specificity were not compromised. From a recent review, some 27 serum markers have been evaluated for their ability to complement CA 125 and to improve sensitivity for detection of ovarian cancer. 150 Use of markers 2 to 3 at a time increased sensitivity 5% to 15%, generally at the expense of a substantial decrease in specificity. For example, use of CA 125 in combination with OVX1, a Lewis X determinant on mucin, and M-CSF, a cytokine, increased sensitivity for Stage I disease from 69% with CA 125 alone to 84% with the combination, but specificity declined from 99% to 84%. 150, 156, 157

A number of novel markers for ovarian cancer have been identified in recent years including mesothelin, a 110 kD fragment of EGFR, lysophosphatidic acid, HE4, prostasin, osteopontin, and human kallikreins 6 and 10. 166–173 Use of surface laser desorption and ionization (SELDI) with subsequent resolution by mass spectroscopy has demonstrated a pattern of low molecular weight moieties that has been reported to distinguish sera from ovarian cancer patients from those of healthy individuals with 100% sensitivity and 95% specificity. 99 Prospective replication of these results and determination of sensitivity for stage I disease should be available in the near future. SELDI may also identify a limited number of protein peaks that could be assayed by more conventional techniques. 100 Mathematical techniques to combine markers, enhancing their sensitivity without sacrificing specificity, have also been developed. Both artificial neural networks and mixtures of multivariate normal distributions have been used to combine values for four serum markers (CA125 II, CA72-4, CA15-3 and M-CSF) from patients with stage I ovarian cancer and from healthy individuals. 176, 177 Using either technique, sensitivity could be increased from 48% using CA 125II alone to 72% to 75% using the combination, while maintaining specificity at 98%. In a two-stage strategy, an initial stage with 98% specificity would require ultrasounds to be performed in only 2% of women screened.

Current Recommendations for Women at Average Risk

The application of screening techniques other than pelvic examination for ovarian cancer in the entire female population is unwarranted at this time. The sensitivity and specificity of ultrasound and CA125 are low in premenopausal women, making it unlikely that this approach will be useful in this group. However, with refinements of the transvaginal and flow techniques, as well as the addition of other serum markers, screening could become a reality in the future. There is a need for critical studies to define the potential of different screening startegies and to determine whether their application can decrease mortality from the disease.

Current Recommendations for Screening Women at High-Risk

In women with strong evidence of a hereditary predisposition for ovarian cancer, screening has been frequently advocated, although the efficacy of such surveillance to reduce risk is unknown. Screening can be problematic because this high-risk population often includes premenopausal women who have a higher incidence of false positive CA 125 elevations and ultrasound abnormalities. In these high-risk populations, initial screening trials using ultrasound alone or in combination with color-flow Doppler and were associated with high false-positive rates (2.5% to 4.9%). The current trend is to combine ultrasound with CA 125. 178

There are now 5 prospective studies where combined screening has been undertaken in high-risk populations. 101–102 In three screening programs involving a total of 1,228 women with a family history of ovarian cancer, no invasive ovarian cancer was detected and false-positive rates have ranged from 0.4% to 3.9%. In one of the remaining two studies, one case of ovarian cancer was detected on screening 137 high risk women with a false positive rate of 0.7%; in the other study 9 ovarian cancers were detected in screening 180 women with a false positive rate of 3.9%. 182, 183

Women in the high-risk population who request screening should be counseled about the current lack of evidence for the efficacy for either CA 125 or for sonography as well as the associated false-positive rates. Many will still opt for screening despite the risks and limitations of the available strategies. Screening is best carried out in clinical trials such as those conducted by the Cancer Genetics Network or by several university centers. Screening with TVS every 6 to 12 months and with CA 125 every 3 to 6 months is currently being evaluated.

Staging of Ovarian Cancer

Ovarian malignancies are staged according to the International Federation of Gynecology and Obstetrics (FIGO) system. The FIGO staging system of 1987 (Table 118-4) is based on the findings at surgical exploration. A preoperative evaluation should exclude the presence of extraperitoneal metastases. A thorough surgical exploration is important because subsequent treatment will be determined by the stage of disease. In patients whose exploratory laparotomy does not reveal any macroscopic evidence of disease by inspection and palpation of the entire intraabdominal space, a careful search for microscopic spread must be undertaken. 52, 137, 140, 103–104 In an earlier series in which patients did not undergo careful surgical staging, the overall 5-year survival for patients with apparent stage I epithelial ovarian cancer was only about 60%. 10 Survival rates of 90% to 100% have been reported for properly staged patients found to have stage IA or IB disease. 137, 185

Table 118-4. FIGO Stages for Primary Carcinoma of the Ovary.

Table 118-4

FIGO Stages for Primary Carcinoma of the Ovary.

Metastases in apparent stage I or II epithelial ovarian cancer are common. About 30% of patients whose ovarian epithelial cancers appear to be confined to the pelvis have occult metastatic disease in the upper abdomen or in the retroperitoneal lymph nodes. 137, 138, 141, 142, 185, 105–106 The importance of a comprehensive initial surgical staging is emphasized by the findings of a cooperative national study in which 100 patients with apparent stage I or II disease who were referred for subsequent therapy underwent additional surgical staging. 185, 107 In this series, 28% of patients initially thought to have stage I disease were upstaged, and 43% of patients thought to have stage II disease had more advanced disease. Thus, 31% of patients were upstaged as a result of additional surgery, and 77% were reclassified as stage III. Histologic grade was a significant predictor of occult metastasis, that is, 16% of patients with grade 1 lesions were upstaged, compared to 34% with grade 2 and to 46% with grade 3 disease.

Although the literature has emphasized the importance of thorough surgical exploration in patients with disease apparently localized to the ovaries, scant recognition is made of the semantic difficulty presented by the concept of extension to other pelvic (ie, stage II) or abdominal (ie, stage III) organs. No problem exists when the surgeon encounters discrete implants, or seeds, separate from the primary tumor, or when solid tumor is found growing into adjacent structures. A more common situation, however, is the apparently benign adherence of the tumor to adjacent structures in the absence of metastatic implants or obvious direct tumor extension. There is a considerable body of evidence that such benign adherence, when it is dense, is associated with a relapse risk equivalent to stage II, and that these patients should not be included in stage I, but rather in stage II. 108 Adherence is considered dense when sharp dissection is required to mobilize the tumor, when a raw area is left at the site of adherence, or when cyst rupture results from dissecting free the adhesions. It is the practice at most North American centers to advance the stage of densely adherent tumors to stage II, and this was done in a recent multicenter study of stage I and II disease. 185

After a comprehensive staging laparotomy, only a minority of women have local or regional disease (FIGO stages I and II). Of the 26,600 women diagnosed yearly with epithelial ovarian cancer in the United States, approximately 2,000 to 3,000 have the disease confined to pelvic structures. 185 The prognosis for these patients depends on clinical-pathologic features, as summarized below. 52, 185

Although accounting for only 15% to 20% of all cases, approximately one third to one half of all cured patients are derived from stage I, highlighting its importance. 186 An indepth understanding of the management of stage I is hampered by the small fraction of patients with limited disease, as well as by their excellent long-term prognosis (over an 80% 5-year relapse-free rate). Consequently, Phase III randomized trials are difficult to conduct with this group due to their small numbers and low rate of recurrence and death. No controlled study to date has been able to establish a curative advantage to postoperative adjuvant therapy.

The most recent FIGO staging classification of stage I is, in practice, descriptive rather than prognostic. The classification recognizes nine subcategories of stage I. Subclasses A (unilateral), B (bilateral), and C (capsular penetration, tumor spillage, or positive peritoneal cytology) are each further subdivided according to differentiation into three grades. 53

Within each grade, it is incorrect to assume that the factors which assign patients to substages B and C necessarily carry a worse prognosis than substage A, or that rupture, capsular penetration, and positive peritoneal cytology all worsen prognosis to the same degree, or that ascites in the absence of positive cytology is not prognostic. Indeed, several studies have failed to show that bilaterality or iatrogenic intraoperative rupture had any influence on outcome. 192–195 Data on the prognostic significance of positive peritoneal cytology in ovarian cancer are scarce and inadequate.

Treatment of Early Stage Ovarian Cancer

The treatment of early stage epithelial ovarian cancer must be individualized. Thorough surgical exploration and staging are indicated for all patients with early stage disease. Adjuvant treatment with chemotherapy or radiotherapy is appropriate for those women at highest risk of recurrence.

Surgery

Properly staged early disease can be managed conservatively. The primary treatment for invasive stage I epithelial ovarian cancer is surgical, that is, the performance of a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging. 52 In certain circumstances, a unilateral oophorectomy may suffice, as discussed below.

Radiotherapy

There have been two randomized studies of external beam radiotherapy in stage I epithelial ovarian cancer. 109, 110 Both compared pelvic radiotherapy with no postoperative treatment. These trials suggested that pelvic irradiation reduced the rate of pelvic relapses, but because relapses occurred throughout the peritoneal cavity, this was of no therapeutic benefit. Abdominopelvic radiotherapy has not been studied in a Phase III trial in stage I, but was compared with pelvic radiotherapy or to no treatment. No benefit was found in grade 1, where the risk of relapse was under 5% overall. In grades 2 and 3, a nonsignificant reduction in relapse risk was observed. A significant reduction in relapse risk was seen in patients whose tumors were densely adherent, but these patients are more correctly classified in stage II.

Chemotherapy

Some researchers have questioned the wisdom of chemotherapy in women with early stage disease, suggesting that the evidence for a durable impact on survival is marginal. Furthermore, the risks of leukemia with alkylating agents and cisplatin argue against the administration of adjuvant therapy unless there is a significant benefit. Two major prospective randomized clinical trials were conducted over a 10-year period that evaluated the efficacy of adjuvant therapy for localized ovarian cancer in patients with favorable and unfavorable prognoses. 201, 202 In the first trial, patients with favorable prognostic features were randomized either to no adjuvant therapy or to intermittent oral melphalan (0.2 mg/kg daily for 5 days every 4 to 6 weeks for up to 12 cycles). The second trial compared adjuvant melphalan (as described above) with a single intraperitoneal dose of 15 mCi of 32P in patients with unfavorable prognostic features. Both trials were performed by the Gynecologic Oncology Group (GOG), required a comprehensive staging laparotomy, and were reported at a time when median follow-up was greater than 6 years. In these studies, conclusions were weakened by the exclusion of nearly half of the randomized patients from the analysis, but a nonsignificant advantage for the melphalan-treated patients was claimed. Two follow-up studies of comprehensively staged patients were subsequently performed. 202 In the first study, 81 of 92 randomized patients were evaluable who had stage I cancers of grades 1 and 2, without ascites, tumor rupture, or excrescences. When observation was compared with melphalan, a small, nonsignificant benefit for melphalan was observed (a 93% versus an 88% 10-year relapse-free rate). In the second study, 143 patients were randomized, including all the remaining classes of stage I and stage II with small or no residual tumor. In assessing these patients, 141 were evaluable for the comparison of melphalan and intraperitoneal radiocolloid. 202 No significant differences were observed (10-year survival rates were 65% and 69%, respectively), and two leukemic deaths occurred in the melphalan arm. The overall survival for all 222 patients entered on this study is shown in Figure 118-6. There were no significant differences in 5-year survival for patients with a favorable prognosis who received no adjuvant therapy (94%) or melphalan (98%). In patients with unfavorable clinicopathologic features, overall survival was substantially worse. There were no differences, however, in 5-year survival for patients treated with intermittent melphalan or intraperitoneal 32 P: 81% vs 78%, respectively.

Figure 118-6. Treatment scheme for patients with advanced-stage ovarian cancer.

Figure 118-6

Treatment scheme for patients with advanced-stage ovarian cancer.* Do in a research setting where treatment will be based on outcome. Reprinted with permission from Berek JS, Hacker NF. Practical gynecologic oncology. 3rd ed. Baltimore, MD: Lippincott (more...)

In recent years, based upon experience in treating patients with advanced ovarian cancer, cisplatin, carboplatin, cyclophosphamide and paclitaxel have been administered, individually and in combination, to patients with early stage disease. Several series reported outcomes when cisplatin and/or cyclophosphamide have been used to treat patients with stage I disease. 111–112 In a GOG trial that compared 3 cycles of cisplatin and cyclophosphamide to intraperitoneal 32P in patients with Stage Ib and Ic disease, the progression-free survival of women receiving the platinum-based chemotherapy was 31% higher than that of women who received the radiocolloid. 200 The Gruppo Italiano Collaborativo Oncologica Ginecologica (GICOG) has reported two studies that evaluated treatment with cisplatin for women with early stage disease. The first study included patients who had stage I cancers of grades 1 and 2, without ascites, positive cytology, rupture, or capsular penetration. When observation was compared to six cycles of cisplatin, the 4-year disease-free rates were 70% and 71% respectively. In the second study, patients with all other classes of stage I were randomized to intraperitoneal 32P or six cycles of cisplatin. The 4-year disease-free survival rate with cisplatin was 79% compared to 69% with i.p. radiocolloid, but this difference did not achieve statistical significance. The GOG has subsequently completed an additional trial in which high-risk patients were randomized to three or six cycles of carboplatin and paclitaxel. The results of this trial are currently not available. The current GOG trial provides all patients at high risk of recurrence with 3 cycles of carboplatin and paclitaxel and participants are then randomized to observation or 6 months of weekly low-dose (40 mg/m2) paclitaxel.

Outcomes of the randomized studies reported to date do not permit definitive treatment recommendations for stage I patients. Failure to prove a benefit for treatment may be the result of methodologic problems rather than ineffective treatment. None of the studies, for example, contained a sample size large enough to detect a 10% improvement in survival or freedom from relapse, despite durations of accrual that often exceeded 5 years. An improvement of 10% would, however, halve the number of treatment failures. In addition, several early studies included grade 1, stage I patients, whose relapse risk after surgery alone is about 5%. Most of these lesions are diploid, and tend to have an excellent prognosis. At present, it is possible to identify patients with borderline and well-differentiated lesions who do not require additional treatment. In the future, identification of these individuals might be made more precise by analysis of genomic and expression profiles, as well as by measurement of individual prognostic molecular markers. Patients with moderately and poorly differentiated lesions require further treatment, but optimal therapy remains to be defined.

Management of Early Stage Borderline Tumors

The principal treatment for borderline ovarian tumors is the surgical resection of the primary tumor. There is no evidence that either subsequent chemotherapy or radiation therapy improves survival. After performing a frozen section and determining that the histology is borderline, premenopausal patients who desire preservation of ovarian function may be managed with a conservative operation, such as a unilateral salpingo-oophorectomy. 52, 202 Thus, hormonal function and fertility can be maintained. In patients in whom an ovarian cystectomy has been performed and a borderline tumor is documented in the permanent pathology, no additional surgery is warranted.

There has been considerable controversy regarding the optimum treatment of patients with localized borderline ovarian tumors. This has been due, in part, to lack of unanimity regarding the histopathologic criteria for borderline tumors. For all stages of ovarian cancer, borderline tumors have a more favorable natural history than have invasive tumors. 201 There have been conflicting reports regarding the efficacy and necessity of adjuvant chemotherapy for patients with localized stage I or stage II borderline tumors. In the large GOG trial described above, a total of 51 patients were reclassified as having borderline tumors. 113 In these carefully staged patients, there have been no deaths directly attributable to cancer. While a substantial number of patients did receive adjuvant chemotherapy in these trials, there is no evidence that it was necessary or beneficial. If, after careful histologic review of multiple slides sectioned at 1-cm intervals, no evidence of stromal invasion is found, patients with localized borderline tumors should not routinely receive adjuvant therapy.

Management of Invasive Early Stage Low Risk Disease (Stage IA and IB, Low Grade)

In patients who have undergone a thorough staging laparotomy where there is no evidence of spread beyond the ovary, the performance of an abdominal hysterectomy and bilateral salpingo-oophorectomy is appropriate therapy. The uterus and contralateral ovary can be preserved in women with stage IA diploid lesions who wish to preserve fertility. These women should be followed carefully with periodic pelvic examinations and CA125 titers. Generally, the other ovary and uterus are removed at the completion of childbearing. In a recent report by Guthrie and colleagues, the outcome of 656 patients with early-stage epithelial ovarian cancer was studied. 114 No patients who had a properly documented stage I, grade 1 cancer died of their disease; that is, there was a 100% survival in this condition when patients were surgically staged, and thus adjuvant radiation and chemotherapy appeared to be unnecessary.

Management of Invasive Early Stage High-Risk Disease (Stage IA and IB, High Grade, Stage IC and Stage II)

In patients whose disease is more poorly differentiated or in whom there are malignant cells either in ascitic fluid or peritoneal washings, additional therapy is indicated. Patients with grade 2 and grade 3 tumors, with densely adherent tumors, with large-volume ascites, and/or with positive peritoneal cytology, have a relapse risk of 20% to 45%, and postoperative treatment is warranted. Regrettably, it would appear that thorough staging with negative findings, including random peritoneal biopsies and lymph node sampling, does not eliminate the risk of relapse in patients with these characteristics. 202 Although the optimal therapy for these patients is not known, treatment options include platinum based chemotherapy or abdominopelvic radiation therapy. Chemotherapy for patients with early stage high-risk epithelial ovarian cancer can be either single agent carboplatin or a combination of carboplatin and a taxane for 3 to 6 courses. Melphalan is not recommended due to its leukemogenic properties, its long-term compromise of marrow reserve, and its variable oral absorption, despite its ease of administration. 115

In the absence of definitive studies, the recommendation of adjuvant therapy is based on the assumption that chemotherapy or radiotherapy will cure a fraction of patients and that management of recurrent disease will not be as effective. In a recent report from the United Kingdom, 194 women with early stage disease were treated with surgery alone and received chemotherapy only at relapse. 116 Among 44 assessable patients treated at recurrence with platinum based therapy, the response rate was 47%. Progression free and overall survival rates 5 years after salvage chemotherapy were 24% and 46% respectively.

Treatment of Advanced Stage Epithelial Ovarian Cancer

A scheme for the management of patients with advanced-stage epithelial ovarian cancer is presented in Figure 118-6. The components of this approach are discussed below.

Cytoreductive Surgery in Ovarian Cancer

Patients who have advanced-stage epithelial ovarian cancer documented at initial exploratory laparotomy should undergo cytoreductive surgery to remove as much of the tumor and its metastases as possible in order to facilitate the effectiveness of subsequent therapies. 117–118 The operation usually includes the performance of a total abdominal hysterectomy and bilateral salpingo-oophorectomy, a complete omentectomy, and resection of metastatic lesions on the peritoneal surfaces or from the intestines. In addition, the pelvic tumor may directly involve the rectosigmoid colon, the terminal ileum, and the cecum. In some patients, most or all of their disease is confined to the pelvic viscera and the omentum, so that removal of these organs results in the extirpation of all gross tumor, a situation that is associated with a reasonable chance of complete response.

The rationale for cytoreductive surgery relates to three general theoretical considerations: (1) potential physiologic benefits from excising the tumor; (2) improved tumor perfusion and increased growth fraction, that may increase the likelihood of a response to chemotherapy or radiation therapy; and (3) enhanced immunologic competence of the patient. 208, 210–212

The principal goal of cytoreductive surgery is to remove all of the primary cancer and, if possible, its metastases. If resection of all metastases is not feasible, the goal is to reduce the tumor burden by resection of all individual tumors to an optimal status. 54, 119, 120 The definition of “optimal” was initially proposed by Griffiths, who found that the survival of patients whose metastatic disease was resected to less than 1.5 cm in maximum dimension was significantly longer than the survival of those whose residual lesions were larger than 1.5 cm. 206 The optimal category of patients had a higher subsequent response rate to chemotherapy and longer disease-progression-free interval. Subsequently, Hacker and colleagues 207 showed that patients whose largest residual lesions were less than 5 mm (defined as minimal residual disease, MRD) survived much longer than did those with larger non-resectable tumor deposits, and this finding has been confirmed by Van Lindert. 211 The median survival of patients in this category was 40 months, compared with 18 months for patients whose disease was greater than 1.5 cm. It has been suggested that the performance of a complete retroperitoneal lymphadenectomy might also improve the survival of patients with advanced stage disease. 215, 216 Resectability of the metastatic tumor is often determined by the size of nodules, the extent of carcinomatosis, and the location of the disease. 217

The ability of cytoreductive surgery to influence survival is limited by the size, extent, and location of metastases prior to cytoreduction, and presumably by the presence of drug-resistant cells. 214 For example, in patients whose metastatic disease was very large (ie, greater than 10 cm before cytoreductive surgery), survival was shorter than when less bulky disease was resected. Thus, the value of cytoreductive surgery seems to be more limited in patients with very large metastases, regardless of the extent of tumor removal. 207 This may result from the presence of resistant clones among large masses of tumor cells. 213, 218 Patients with gross ascites also seem to do less well, regardless of the extent of surgical resection. 209, 210, 219 In some patients, very extensive upper abdominal masses, particularly on the diaphragm or in the parenchyma of the liver, will preclude an adequate surgical excision of metastatic disease. Extensive disease involving the base of the small bowel mesentery, the large bowel mesentery, the lesser omentum, and the porta hepatis, as well as diffuse extraperitoneal metastasis, may prevent the optimal resection of tumor. 220, 221 Thus, the efficacy of cytoreductive surgery is limited. From these and other data, definitions of the patients' status based on the extent of residual disease are presented in Table 118-5.

Table 118-5. Nomenclature for Patient Status -Residual Ovarian Cancer.

Table 118-5

Nomenclature for Patient Status -Residual Ovarian Cancer.

An analysis of the retrospective data available suggests that these operations are feasible in 70 to 90% of patients when performed by gynecologic oncologists 209, 210, 222, 223 Major morbidity is in the range of 5% and operative mortality is 1%. 209, 224 Intestinal resection in these patients does not appear to increase the overall morbidity of the operation 225, 226 The median survival and progression-free interval of patients after cytoreductive surgery relate to the extent of residual disease at the completion of the laparotomy. A meta-analysis has been performed with 81 cohorts of patients that included 6,885 women with stage III or stage IV disease. 227 A statistically significant positive correlation was found between percent maximal cytoreduction and log median survival time that remained significant after controlling for all other variables (p < .001). Each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time. Cohorts with 25% or less maximal cytoreduction had a median survival time of 22.7 months compared to 33.9 months in cohorts with greater than 75% maximal cytoreduction.

In a study by Van der Burg and colleagues, a prospective randomized trial of “interval” debulking operations was performed on patients with advanced-stage epithelial ovarian cancer. 228 The patients were referred after having undergone an exploratory laparotomy during which the patient's tumor was not debulked. The patients were then randomized to receive either (1) chemotherapy for three cycles followed by another operation, then an interval debulking operation, followed by more chemotherapy; or (2) chemotherapy with no interval debulking. The patients who underwent the interval debulking had a longer disease-free and overall survival as compared with those patients who did not. These data support the role of debulking surgery in advanced-stage epithelial ovarian cancer and suggest that the sooner the operation can be performed during the course of treatment, the more likely it is that the surgery will improve the survival. 229 Therefore, primary cytoreductive or interval surgery should be the standard of care in patients with advanced epithelial ovarian cancer. If the primary operation either was not done or was unsuccessful, interval debulking should be performed.

Chemotherapy for Advanced Stage Epithelial Ovarian Cancer

Systemic chemotherapy is the standard treatment for metastatic epithelial ovarian cancer. 121, 230–260 Early studies utilized single alkylating agents such as melphalan or combinations of alkylating agents and antimetabolites. After the introduction of cisplatin in the latter half of the 1970s, platinum-based combination chemotherapy became the most frequently used treatment regimen in the United States. Cisplatin was initially used in combination with cyclophosphamide and doxorubicin, but the modest contribution of doxorubicin to the efficacy of the combination prompted simplification of the standard regimen to cyclophosphamide and cisplatin. By the early 1990s a combination of carboplatin and cyclophosphamide was found to be as effective as cisplatin and cyclophosphamide, but substantially less toxic, with less nausea, renal toxicity and neurotoxicity. Paclitaxel was incorporated into combination chemotherapy in the 1990s. 231–237, 240 Over the last decade, a substantial amount of clinical investigation has centered on (1) whether a combination of a platinum compound and a taxane is superior to an optimal dose of a platinum compound alone, (2) the choice of the optimal platinum compound and taxane, and (3) the most convenient and effective schedule for taxane administration. Recent studies have focused on the introduction of a other compounds into a “triplet” or a “sequential doublet” to eliminate drug resistant cancer cells.

Single Alkylating Agents

For many years, oral single-agent alkylating therapy was used. The standard dose for the single alkylating agent, melphalan, is 0.2 mg/kg/day given orally for 5 consecutive days every 28 days. In three separate GOG studies of suboptimal stage III ovarian cancer, 193 patients were treated with this regimen. Sixty-two patients (33%) had a clinical response; with a 16% complete response rate and a 17% partial response rate. 237 However, the median duration of response was only 7 months and median survival was 12 months. The use of single-agent chemotherapy for metastatic epithelial ovarian cancer is generally reserved for patients whose overall physical condition precludes the use of more toxic therapy.

A variety of regimens containing combinations of cytotoxic drugs have been tested in the treatment of advanced epithelial ovarian cancer. Combination chemotherapy has been shown to be superior to single-agent therapy in most patients with advanced epithelial ovarian cancer. 242

Platinum Compounds

For the last two decades, platinum compounds have been the most active agents against ovarian cancer. In early studies from England, cisplatin was found superior to cyclophosphamide as a single agent. 243 Concurrently, cisplatin was tested in combination with a variety of different drugs. Platinum-containing regimens have proven superior to regimens that lacked platinum compounds. 247 In a meta-analysis performed on 37 randomized studies involving 5,667 patients with advanced-stage disease, those patients given cisplatin-containing combination chemotherapy were compared with those treated with regimens that did not include cisplatin. 242, 251, 122 Platinum based chemotherapy was superior to non-platinum based chemotherapy. A trend favored platinum combinations over single agent platinum. In studies of cisplatinum containing regimens, several trials have compared cyclophosphamide and cisplatin (CP) with cisplatin, doxorubicin and cyclophosphamide (PAC). 244–249–253 No study showed a significant difference in survival between treatment arms. The GOG's randomized prospective comparison of equitoxic doses of PAC versus PC showed no benefit to the inclusion of doxorubicin in the combination. 249 While a meta-analysis of the combined data from these four trials showed a 7% survival advantage at 6 years for those patients treated with the doxorubicin-containing regimen, the survival curves converge at 8 years. Consequently, in recent years doxorubicin has not been incorporated in regimens for epithelial ovarian cancer in the United States. It is, however, possible that a small subset of ovarian cancer patients benefit substantially from treatment with anthracyclines. In the future, new technologies may permit the identification of those patients and permit individualization of their treatment. 253

In the 1980s, the second-generation platinum analog carboplatin became available, exhibiting greater myelotoxicity, but substantially less nephrotoxicity, ototoxicity, peripheral neurotoxicity, and emetogenic potential than did cisplatin. Initial studies showed that carboplatin and cisplatin had approximately a 4:1 ratio of potency. Thus a standard single-agent dose of about 400 mg/M2 has been used in most Phase II trials. The dose is best calculated by using the probable area under the curve (AUC) based on the glomerular filtration rate (GFR) according to the Calvert formula. 263 When used as a single agent, a target AUC of 7 may be appropriate for untreated patients with ovarian cancer. When used in combination with other myelotoxic drugs, AUCs of 5 to 6 have been used more frequently.

Meta-analysis has suggested that cisplatin and carboplatin are equally effective against epithelial ovarian cancer. 264 Direct comparison of cisplatin and cyclophosphamide to carboplatin and cyclophosphamide demonstrated comparable response rates and survival, but significantly less toxicity for the carboplatin containing regimen. 242

Paclitaxel

Paclitaxel was shown to be a very active agent against ovarian cancer. 234–238, 255 The overall response rates for paclitaxel in phase II trials was 36% in previously treated patients, which is a higher rate than was seen for cisplatin when it was first tested. 236

Three large concurrently controlled randomized trials in previously untreated patients with ovarian cancer have compared paclitaxel and a platinum compound to different platinum containing regimens that did not contain paclitaxel. 238, 239, 265 The Gynecologic Oncology Group randomized 410 women with suboptimally cytoreduced stage III-IV ovarian cancer to six cycles of chemotherapy with a combination of cisplatin (75 mg/M2) and paclitaxel (135 mg/M2 over 24 hr) or with cisplatin (75 mg/M2) and cyclophosphamide (750 mg/M2) (GOG-111). 238 Patients who received the paclitaxel combination had a superior overall response rate (73% vs 60%), clinical complete response rate (51% vs 31%), prolongation of disease-free survival (18 months vs 14 months), and prolongation of overall survival (36 months vs. 24 months).

The superiority of paclitaxel-cisplatinum was confirmed in a trial (OV-10) conducted jointly by the European Organization for the Research and Treatment of Cancer (EORTC), the Nordic Ovarian Cancer Study Group (NOCOVA), and the National Cancer Institute of Canada (NCIC) in which 680 women with both optimal and suboptimal disease in stages IIB-IV were treated. 239 Patients were randomized to to six cycles of cisplatin (75 mg/M2) and cyclophosphamide (750 mg/M2) or to six cycles of cisplatin (75 mg/M2) with a slightly higher dose of paclitaxel (175 mg/M2) over a shorter interval (3 h) than in GOG-111. In this study, the paclitaxel-containing arm produced a significant improvement in median progression-free interval (15.5 vs 11.5 months) and overall median overall survival (35.6 vs 25.8 months) that extended to both optimal and suboptimal groups. Greater neurotoxicity was observed with the combination of paclitaxel and cisplatin when the paclitaxel was infused over 3 hours in OV-10 compared to infusion over 24 h in GOG-111.

A third study, the International Collaborative Ovarian Neoplasm-3 (ICON-3), was conducted as 4 parallel trials across 130 centers in eight countries in Europe to compare carboplatin (AUC 5) and paclitaxel (175 mg/M2 over 3 h) to regimens that did not contain paclitaxel. 262 Prior to randomization, each patient and physician could choose a control arm that included either carboplatin (AUC 5) alone or a combination of cisplatin (50 mg/M2), doxorubicin (50 mg/M2) and cyclophosphamide (500 mg/M2). Of the women on the control arm, 69% received carboplatin. Dose escalation was permitted and occurred in approximately half of patients. 263 Overall, 2,074 women participated with ovarian cancer of all stages, including 20% of women with stage I-II disease. A central review of pathology, surgical staging, cytoreduction or protocol adherence was not performed. 264 No significant difference was found in overall median survival between the paclitaxel-carboplatin group (36.1 months) and the control group (35.4 months). In comparing the three trials, the outcome was no worse in the paclitaxel-carboplatin arm of ICON-3 than in the paclitaxel-cisplatin arms of GOG-111 and OV-10, but the control group in ICON-3 enjoyed a better outcome. The better survival of controls in ICON-3 might relate to the fraction of early stage patients or possibly to the optimization of carboplatin dosage permitted by dose escalation. 263 A trend (p = .22) was noted toward a benefit of paclitaxel-carboplatin in patients who had > 2cm residual disease, patients comparable to those entered in GOG-111. 264

The GOG had undertaken a comparison of sequential and simultaneous paclitaxel-cisplatin (GOG-132). 237 A three-arm comparison of equitoxic doses of paclitaxel (200 mg/M2 over 24 h) versus cisplatin (100 mg/M2) versus a combination of paclitaxel (135 mg/M2 over 24 h) and cisplatin (75 mg/M2) was carried out in 648 suboptimal stage III and IV patients. Crossover was permitted and the three groups exhibited similar median overall survival of 26 to 30 months. The simultaneous regimen was better tolerated than the sequential use of agents at these optimized doses. The overall response rate to cisplatin alone or to the paclitaxel-cisplatin combination was 67%, whereas the response to paclitaxel alone was 42% (p < .001). This observation suggests that more than half of patients who are treated arbitrarily with the combination of paclitaxel and a platinum derivative may not benefit from the taxane. To date, laboratory studies do not support any super-additive interaction of platinum compounds and taxanes, arguing against synergy in the clinic. In the future, using molecular markers it may be possible to identify those patients who would respond or not respond to paclitaxel, providing another opportunity to individualize therapy.

Two randomized, prospective clinical studies have compared the combination of paclitaxel and carboplatin to that of paclitaxel and cisplatin. 254, 255 In both studies, response rates and duration of survival are similar, but the carboplatin-containing regimens have more acceptable toxicity. In the first trial conducted by the GOG (GOG-158), patients were randomized to carboplatin (AUC 7.5) and paclitaxel (175 mg/M2 over 3 h versus the previous standard of cisplatin (75 mg/M2) and paclitaxel (135 mg/M2 over 24 h). Progression-free survival of the carboplatin-containing arm was 22 months versus 21.7 months for the control arm. The gastrointestinal and neurotoxicity of the carboplatin arm were appreciably lower than that of the cisplatin arm. In addition, paclitaxel administration over 3 h is substantially more convenient than administration over 24 h. A similar result was obtained in a large randomized trial in Germany, in which carboplatin (AUC 6) and paclitaxel (185 mg/M2 over 3 h) were compared to paclitaxel (135 mg/M2 over 24 h) and cisplatin (75 mg/M2). 258 Thus, the best established regimen in patients with advanced stage disease is a combination of carboplatin and paclitaxel over 3 h.

Docetaxel

Docetaxel is a semi-synthetic second generation taxane with properties that differ from paclitaxel. Docetaxel is a more potent promoter of microtubule assembly and stabilization than paclitaxel. 266 Docetaxel is taken up, bound and retained more effectively by cancer cells than paclitaxel. Docetaxel has produced a 23% to 28% overall response rate in platinum resistant ovarian cancer. 265 A combination of docetaxel and cisplatin or carboplatin has achieved a 66% to 81% overall response rate in Phase II trials. 268 Consequently, a combination of docetaxel (75 mg/M2 over 1 h) and carboplatin (AUC 5) has been compared to paclitaxel (175 mg/M2) and carboplatin (AUC 5) in the SCOTROC trial.266 Similar efficacy was observed, but docetaxel-carboplatin was associated with significantly less neurotoxicity.

Other Doublets and Triplets

Use of platinum compounds and taxanes has improved median and overall survival, but the outcome in patients with advanced ovarian cancer is still disappointing. Drug resistance ultimately develops in the majority. A number of drugs have exhibited activity against recurrent disease including liposomal doxorubicin, topotecan and gemcitabine. The GOG has conducted a series of Phase I pilot studies in previously untreated patients to define combinations that are suitable for a group wide Phase III trial. 123 A five arm study has now been initiated, administering 8 cycles of chemotherapy to women with newly diagnosed stage III/IV ovarian cancer. The control arm consists of paclitaxel (175 mg/M2 over 3h on day 1) and carboplatin (AUC 6 on day 1). Two additonal arms contain triplets. The gemcitabine triplet includes paclitaxel (175 mg/M2 over 3 h on day 1), carboplatin (AUC 5 on day 1) and gemcitabine (800 mg/M2 / day on day 1 and 8). The doxil triplet administers paclitaxel (175 mg/M2 over 3 h on day 1), carboplatin (AUC 5 on d1) and doxil (30 mg/M2 on day 1 every other cycle). Two arms contain sequential doublets. The topocetan doublet includes 4 cycles of carboplatin (AUC 5 on day 3) with topotecan (1.25 mg/M2/ day on day 1 to 3) followed by 4 cycles of paclitaxel and carboplatin. Finally, a gemcitabine doublet includes 4 cycles of carboplatin (AUC 6 on day 8) with gemcitabine (1000 mg/M2/day on days 1 and 8) followed by 4 cycles of paclitaxel and carboplatin.

Dose Intensification with Intravenous Chemotherapy

Higher or more frequent doses of chemotherapy might be more effective, if tolerated. The issue of dose-intensification of cisplatin was examined in a prospective trial conducted by the GOG. In this study, 243 patients with suboptimal ovarian cancer were randomized to receive either 50 mg/M2 or 100 mg/M2 cisplatin plus 500 mg/M2 cyclophosphamide. There was no difference in response rates in those patients with measurable disease and the overall survival was identical. As one might anticipate, there was greater toxicity associated with the high-dose regimen. A group in Scotland performed a similar study and found that patients who received 100 mg/M2 cisplatin plus 750 mg/M2 cyclophosphamide had a significantly longer median survival compared with those who received 50 mg/M2 cisplatin plus the same dose of cyclophosphamide. The overall median survival time was 114 weeks in the high-dose group and 69 weeks in the low-dose group (p = .0008), but this difference disappeared with longer follow-up. 262 Thus, doubling the dose of cisplatin does not improve long term survival. Dose escalation of paclitaxel and carboplatin require G-CSF due to their combined myelosuppressive effects, but there is no evidence to support more intensive administration of either agent. 253, 256

Intraperitoneal Chemotherapy

As ovarian cancer spreads over the surface of the peritoneum and often recurs at this site, investigators have evaluated intraperitoneal (IP) administration of chemotherapy that can achieve high local concentrations of drug. A randomized, prospective trial performed by the Southwest Oncology Group (SWOG) and the GOG compared IP cisplatin (100 mg/M2) to IV cisplatin (100 mg/M2), each given with II cyclophosphamide (600mg/M2), in patients with disease less than 2 cm in diameter. 267 The intraperitoneal cisplatin arm had a significantly longer overall median survival than the intravenous arm, 49 versus 41 months (p = .03). In the patients with the least residual disease (< 0.5 cm maximum residual), however, there was not a statistically significant difference in median survival between the two treatments, 51 versus 46 months (p = .08).

Results of this randomized trial became available as paclitaxel was being incorporated into clinical practice. In a follow-up trial conducted by the GOG, a standard regimen of IV cisplatin (75 mg/M2) and IV paclitaxel (135 mg/M over 24 h) was compared to a dose-intense regimen that was initiated by giving moderately high-dose carboplatin (AUC=9) for two induction cycles followed by IP cisplatin 100 mg/M2 and IV paclitaxel (135 mg/M2 over 24 h). 269 The dose-intense arm produced slightly better progression-free median survival (27.6 months vs 22.5 months, p = .02), but there was not a statistically significant difference in overall survival (52.9 months vs 47.6 months, p = .056).

A randomized prospective GOG study is comparing IP cisplatin and paclitaxel to IP cisplatin and paclitaxel. Based on results of currently available studies, the value of intraperitoneal chemotherapy in the primary treatment of optimally resected stage III ovarian cancer remains unclear.

Neoadjuvant Chemotherapy

Some authors have suggested that, for patients with suboptimal stage III and stage IV disease, chemotherapy may be given in lieu of cytoreductive surgery. A series performed at Yale by Schwartz and colleagues suggested that the survival of patients treated with “neoadjuvant” or cytoreductive chemotherapy was comparable to those patients historically treated with cytoreductive surgery followed by conventional chemotherapy in the same institution. 270 As other authors have shown a benefit to debulking patients prior to chemotherapy, the issue would need to be resolved by a prospective clinical trial. However, two or three cycles of chemotherapy prior to cytoreductive surgery may be helpful in patients with massive ascites or large pleural effusions. Chemotherapy may eliminate the effusions, improve the patient's performance status, and decrease postoperative morbidity, particularly within the chest.

Radiotherapy in Advanced Invasive Disease

In the past decade, several studies have refined our knowledge of the possible benefits of radiation therapy in ovarian cancer. In particular, subgroups of patients have been identified who are most likely to have a curative benefit when radiation therapy is used as the sole postoperative treatment. In addition, the technical aspects of whole abdominal radiation (WAR) have been worked out, permitting therapy to be delivered with acceptable late toxicity (Table 118-6). Despite this knowledge, WAR is not used widely. Table 118-7 summarizes long term survival or relapse free rates from six published studies of whole abdominal radiation therapy for patients with advanced ovarian cancer. 271–276 The results of these studies are concordant in showing long-term failure-free survivors determined both by the stage at presentation and by the volume of residual disease, as expressed by the largest diameter of the largest remaining lesion. Between 38% and 62% of patients with identified residual disease less than 2 cm in diameter were cured after whole abdominal and pelvic irradiation. Most of the long term survivors had stage II disease, in which the postoperative tumor residuum was confined to the pelvis and was encompassed in the boost volume, where radiation doses are significantly higher than can be delivered to the upper abdomen. For patients with larger residual lesions, the probability of cure is small, in the neighborhood of 5% to 15%. These studies provide strong evidence that whole abdominal irradiation is therapeutic for patients with small-volume residual ovarian cancer, but questions have been raised about the interpretation of these results in the context of more modern surgical techniques and more effective chemotherapy. These studies were performed in an era when aggressive cytoreductive surgery and comprehensive surgical exploration of the abdominal contents were not uniformly performed.

Table 118-6. Technical Principles of Curative Radiotherapy.

Table 118-6

Technical Principles of Curative Radiotherapy.

Table 118-7. Whole Abdominal Radiation in Patients with Residual Disease.

Table 118-7

Whole Abdominal Radiation in Patients with Residual Disease.

Management of Advanced Invasive Ovarian Cancer

At present, the treatment of choice for patients with advanced invasive epithelial ovarian cancer is cytoreductive surgery followed by six cycles of chemotherapy with a combination of carboplatin (AUC 5-6) and paclitaxel (175 mg/M2 over 3 h) every 3 weeks (Table 118-8). Paclitaxel is administered before the carboplatin. In patients at risk for severe neuropathy, for example, diabetics, a combination of docetaxel (75 mg/M2) and carboplatin (AUC 5) provides an alternative that is less neurotoxic. As data confirming the SCOTROC trial are obtained, the latter regimen may become a standard option for all patients. In women who cannot tolerate the toxicity of taxanes, carboplatin alone (AUC 6-7) can be given. For the rare patient who cannot tolerate IV chemotherapy, an oral alkylating agent can be used for palliation.

Table 118-8. Combination Chemotherapy for Advanced Epithelial Ovarian Cancer: Recommended Regimens.

Table 118-8

Combination Chemotherapy for Advanced Epithelial Ovarian Cancer: Recommended Regimens.

Management of Advanced Borderline Tumors

The effectiveness of chemotherapy in patients with advanced-stage borderline tumors has not been established. The GOG is evaluating the use of chemotherapy in patients with advanced-stage borderline tumors who have recurrent disease after initial surgery. Until the results of this trial are known, the current approach to treatment is primarily surgical. Patients should undergo cytoreductive surgery and observation. Borderline tumors, even in advanced stage, have a favorable prognosis. The first symptomatic recurrence may be several years after diagnosis. In contrast to the 20% to 25% survival rates for advanced epithelial invasive carcinoma of the ovary, the survival rate for patients with stage III borderline tumors is over 60%.277 Consequently, secondary cytoreductive surgery frequently will lead to another prolonged interval of symptom free survival. Chemotherapy can be administered to the patients in whom cytoreductive surgery is no longer feasible, although its efficacy is uncertain.

Assessment of Response in Patients Who are Clinically Free of Disease

Many patients who have undergone optimal cytoreductive surgery and subsequent therapy for epithelial ovarian cancer will have no evidence of disease at the completion of treatment. Tumor markers and radiologic assessments have proven to be too insensitive to exclude accurately the presence of subclinical disease. 278 Therefore, a common technique used to evaluate residual disease has been the second-look operation. 279–281 A second-look operation is one performed on a patient who has no clinical evidence of disease after a prescribed course of chemotherapy, in order to determine the response to therapy. Most often, patients have undergone a formal reassessment laparotomy. The laparoscope also has been used in some of these cases but there is a 35% false-negative rate if laparoscopy is used as a second-look procedure. 282, 283

If a second-look operation is performed, the proper surgery should be carried out to maximize the likelihood of detecting any microscopic residual disease. The technique of the second-look laparotomy is essentially identical to that of the staging laparotomy. 52, 137 The operation should be performed through a vertical abdominal incision. The incision may be initiated below the level of the umbilicus, so that if pelvic disease is detected in the absence of any palpable upper abdominal disease, a smaller incision might suffice. The incision can be extended cranially as needed. After first obtaining multiple cytologies, biopsies of the peritoneal surfaces should be performed, particularly from any areas of previously documented tumor. 137 These are the most important areas to biopsy because they are most likely to contain residual cancer. Any adhesions or surface irregularities should be sampled. A pelvic and periaortic lymph node dissection below the level of the inferior mesenteric artery should be carried out in those patients whose nodal tissues were not previously removed, which is the case for most patients with stage III disease.

The ability to obtain a complete remission with a platinum-based therapy is dependent on the extent of residual disease at the time chemotherapy is initiated. Clinical trials have uniformly demonstrated that patients who have bulky disease (any tumor nodule greater than 2 to 3 cm in diameter) have less than a 10% likelihood of achieving a complete remission with induction chemotherapy with a platinum-based regimen. In contrast, patients who have small-volume disease after the initial laparotomy have a three to four times higher likelihood of achieving a complete remission. 284 There is no evidence that prolonging the number of cycles of induction chemotherapy will increase the complete remission rate. In a prospective randomized trial of five versus 10 cycles of the PAC regimen, there was no statistically significant difference in overall survival and only 1 of 12 patients who were not in complete remission after five cycles of PAC achieved a complete remission with an additional five cycles of therapy. 285, 286 It appears that the maximum benefit from a platinum-based regimen is obtained with five to six cycles of chemotherapy.

The levels of CA125 have been correlated with the findings at second-look surgery. Positive titers are useful in predicting the presence of disease, but negative titers are an insensitive marker for the absence of disease. In studies performed to date, the predictive value of a positive test has been 96%, that is, if the level of CA125 was positive (> 35 U/mL), disease was almost always detectable in patients at the second-look. In one such prospective analysis, the predictive value of a negative test was only 56%, that is, if the level was less than 35 U/mL, disease was present in 44% of the patients at the time of the second-look. 287 Therefore, the CA125 is not sensitive enough to exclude subclinical disease in many patients. Serum CA125 titers can be used to follow those patients during chemotherapy whose titer was positive at the initiation of therapy. 288 Changes in antigen level (ie, falling, rising, or plateauing) generally correlates with response. 288 Those patients with persistently elevated levels of CA125 after 3 months of treatment most likely have resistant tumors. Persistently elevated or rising titers on treatment usually indicate treatment failure and suggest that continuation of the current regimen is unlikely to be of value.

Because second-look laparotomies have not been shown to influence patient survival, they should be done only in a research setting, as second-line or salvage therapies in patients with persistent cancer have not yet demonstrated a clear improvement in the overall survival. 186, 289 The findings at a second-look procedure do, however, correlate with subsequent outcome and survival. 137, 279 Patients who have no histologic evidence of disease have a significantly longer survival compared with those who have microscopic or macroscopic disease documented at laparotomy. 290, 291 About 50% to 70% of patients with negative second look examinations remain free of disease at 5 years, whereas the median survival of patients with any disease (microscopic and macroscopic) is 12 to 18 months. 52, 137 The extent of residual disease documented at the second-look procedure also correlates with patient survival. 298 Patients with microscopic disease only have a 5-year survival of 40% to 50% (median of more than 36 months), compared with 12 months for patients with any evidence of macroscopic disease. 52 Clearly, it is not possible to sample every potential site of disease. In addition, disease can become clinically apparent at sites that are impossible to examine, such as the liver parenchyma. The majority of recurrences after a negative second-look procedure are in patients with poorly differentiated cancers.

Consolidation Chemotherapy and Immuno-therapy

The optimal management of patients who do achieve a clinical complete remission after induction chemotherapy remains to be determined. Even patients who achieve a surgically confirmed complete remission have a 30% to 50% recurrence rate. 293, 294 Some investigators have suggested that second-look laparotomy should be performed to identify patients who may be candidates for intraperitoneal therapy. There is, however, currently no evidence that the routine sequential administration of intraperitoneal chemotherapy after intravenous induction chemotherapy leads to a prolongation of survival.

Clinical trials are in progress to determine whether consolidation therapies are of benefit in patients who achieve a surgically confirmed clinical complete remission. A recent study conducted by the GOG and SWOG compared 3 and 12 monthly cycles of “consolidation” chemotherapy with paclitaxel (135–175 mg/m2 IV over 3 h) for patients who had achieved a clinical remission following primary paclitaxel and carboplatin chemotherapy. 293 Progression free survival was 21 and 28 months in the 3-cycle and 12-cycle paclitaxel arms (p = .035). Consequently, 9 months of additional chemotherapy provided an additional 7 months of progression free survival. To date, there is no difference in overall survival between the two arms.

A number of experimental regimens are being tested including IP chemotherapy, high dose IV chemotherapy with stem cell support, immunotherapy with interferon, the IP administration of 90Y-labelled anti-MUC1 antibody, and the IP administration of 32P. Vaccine trials are about to begin with Ovarex‚ in an attempt to utilize anti-idiotypic immunity against antibodies reactive with CA 125. Outside of a clinical research setting, a standard approach is to follow patients carefully after the achievement of a clinical complete remission until recurrence.

Consolidation or Salvage Radiotherapy

Just as whole abdominal radiation therapy is used as primary postoperative therapy for some patients with ovarian cancer, it has also been used as consolidation or salvage therapy following combination chemotherapy. Fuksand collegues.were among the first to propose the use of sequential cisplatin-based chemotherapy, secondary cytoreductive surgery, followed by whole abdominal radiation therapy, in patients with advanced disease. 295 Since that time, numerous reports of sequential multimodality therapy have appeared. 296–313–319 A review of this subject 297 examined the published results. Unfortunately, definitive conclusions about the value of such a strategy cannot be reached since most of the reported studies are single-arm trials without appropriate controls, and, in many situations, patients selected for the sequential therapy were inappropriate since they had large-volume residual disease following chemotherapy. Radiation therapy is not of benefit even as the initial postoperative therapy if residual disease measures more than 1 cm in the pelvis, or if there is any macroscopic disease in the upper abdomen. Salvage radiotherapy is inappropriate for most patients with any macroscopic disease after chemotherapy. 305 When consolidative radiotherapy has been used, there does not appear to be any curative benefit.

Follow-up Examinations

The optimal frequency of follow-up examinations is unknown, but in those patients who have completed chemotherapy and who are in clinical remission it is reasonable to perform a pelvic examination and to obtain a CA125 every-3-months for 1 to 2 years. An elevated CA 125 (> 35 U/mL) can provide lead time of approximately 3 months in detecting recurrent disease. A rising CA 125 can prompt the performance of a CT scan. The role of PET scanning in this setting has not been defined. A rising CA 125 in the absence of changes on physical examination or CT scan in a patient in initial remission poses a dilemma. At present, additional cytotoxic therapy is not recommended based on a rising CA 125 alone. As more effective salvage therapy becomes available, serum markers such as CA 125 may have greater utility. In patients whose disease was never found to be metastatic to the chest or who never had a pleural effusion, chest radiograph surveillance is not mandatory. In the absence of a rising CA125, follow-up CT or MRI scans should be used with discretion, perhaps 6 to 12 months after the completion of chemotherapy, and then again a year later.

Intravenous Second-line Therapy in Patients With Recurrent or Persistent Advanced Epithelial Ovarian Cancer

The overall prognosis is unfavorable for patients who do not achieve a complete remission with induction chemotherapy or who relapse after an initial response. Responses to second-line therapy can, however, be clinically beneficial. The frequency of a response to second-line therapy depends on both the nature of the prior response to initial therapy and the duration of remission. In patients who achieve a complete remission on a platinum-based induction regimen and have a disease-free interval of greater than 6 months, second-line treatment with a platinum complex has approximately a 30% response rate. -314–316 Patients can be retreated with either cisplatin or carboplatin. However, because of its more favorable toxicity profile, carboplatin is the drug of choice for patients who relapse after responding to a platinum-based induction regimen. In contrast, if patients do not achieve a remission on a platinum-based regimen or have a very short response duration, retreatment with a platinum-based regimen is unlikely to be beneficial, and such patients should be encouraged to enter experimental clinical trials.

As noted above, the current treatment of choice for patients with previously untreated ovarian cancer is the combination of carboplatin plus paclitaxel. Successful retreatment with paclitaxel is similar to that described above for platinum compounds. Patients who have responded to initial paclitaxel-based chemotherapy have a significant probability of responding to paclitaxel, that is dependent upon the length of response. There is no evidence that retreatment with a combination of paclitaxel plus carboplatin is superior to using these agents sequentially in patients with recurrent disease. However, many investigators do recommend that combination chemotherapy be used as part of reinduction for patients who have a disease-free interval that extends beyond 18 months. 317 In patients who become resistant to paclitaxel and platinum compounds, a wide variety of second-line agents have been shown to have activity, including topotecan, gemcitabine, liposome-encapsulated doxorubicin, oral etoposide, and vinorelbine. 318–323 All of these second-line agents have a comparable degree of activity with partial response rates of approximately 20%. Few formal comparisons have been performed among these drugs. Pegylated liposomal doxorubicin (PLD) has been compared to topotecan in a Phase III study. 324 Similar response rates (19.7% vs 17.0%) and overall survival times (60 weeks vs 57 weeks) were observed for the entire group of patients with recurrent disease. PLD was more active than topotecan in the subset of women with platinum-sensitive disease, producing improved progression-free survival (29 weeks vs 23 weeks, p = .037) and overall survival (108 vs 71 weeks, p = .008). Selection of the appropriate agent for an individual patient is based upon prior toxicity, expected toxicities of the second-line agent, patient preference for intravenous versus oral administration, and quality of life considerations. 325 It appears the older second-line agents, such as ifosfamide and hexamethylmelamine, have less clinical activity than do newer agents in patients whose tumors have become resistant to paclitaxel and platinum-based chemotherapy. Traditionally, second line agents have been used individually and sequentially, but two recent studies suggest that a combination of cisplatin and gemcitabine may exert synergistic effects, producing response rates of 38% and 70% with responses that have been maintained for 3-5 months. 326, 327

High-dose Chemotherapy and Stem Cell Transplantation

The use of high-dose chemotherapy and either autologous bone marrow transplantation (ABMT) or peripheral stem cell support is being tested in patients with advanced ovarian cancer. 328–330, 335 In one trial of high-dose mitoxantrone, carboplatin and cyclophosphamide with stem cell support, 89% of patients responded with clinical complete responses in 88% of platinum-sensitive and 47% of platinum-resistant cases. 329 Median progression free survival was 10.1 months for platinum sensitive disease and 5.1 months for platinum resistant disease. In another retrospective analysis of 35 patients treated with high-dose melphalan and stem cell support, 9 of 12 patients with evaluable residual disease had a measurable response. The morbidity of this approach is high, and the survival after this approach in a Phase II trial has been similar to the survival following second-line paclitaxel. A prospective randomized clinical trial of a combination very high-dose chemotherapy supported with autologous bone marrow transplantation versus standard-dose chemotherapy with paclitaxel and carboplatin was initiated by the GOG, but the trial was discontinued because of poor accrual. Transplantation earlier in the course of disease may have a greater impact. One recent study of 96 patients, many of whom were in clinical CR (43%) or PR (34%), produced 6-year survival of 37%. For patients who received transplantation for remission consolidation, the 6-year survival was 53% and the progression free survival was 29%. 330

Immunotherapy

The use of intravenous or subcutaneous immunostimulants in addition to chemotherapy has not improved the response rate or survival of ovarian cancer patients. The GOG used melphalan with or without subcutaneous administration of Corynebacterium parvum in a randomized trial, and there was no difference between the two groups. 331 Another trial used combination chemotherapy with cisplatin, doxorubicin, and cyclophosphamide with or without BCG (Bacillus Calmette-Guerin) by scarification in patients with suboptimal ovarian cancer, and there was no difference between the two groups. This finding was confirmed in a study by SWOG. 332 The intraperitoneal administration of C. parvum did produce complete responses in some patients with minimal residual disease at second-look laparotomy, suggesting that the regional administration of an immunostimulant, similar to the intralesional injection of melanoma with BCG, might be an effective way to control small amounts of residual cancer confined to the peritoneal cavity. 333, 334

Based on the response seen with regional nonspecific immunotherapy, several trials of intraperitoneal cytokines have been performed. 333- 3385 In a GOG study, recombinant human IFN-α exhibited activity when administered i.p. to patients with minimal residual ovarian cancer. Administration of 25-50 million units three times a week was not tolerated because of persistent general malaise, fever, and gastrointestinal toxicity. 335 Treatment with the same dose once a week was tolerated for 8-16 consecutive weeks. Notably, there was an absence of significant neurotoxicity and renal toxicity. While most of the side effects of single agent recombinant IFN-α seem to complement those of cisplatin, the general malaise and gastrointestinal toxicity produced by both could potentially be additive when these agents are combined. Similar results were reported in another trial of IP IFN-α in the Netherlands. 333, 334 . The toxicity encountered in this trial was similar to that seen in the Phase I GOG trial. 335 In a follow-up Phase II trial conducted by the GOG, there was a 28% surgically-documented response rate in 25 patients with platinum-sensitive minimal residual tumors. 124 Overall, 53 surgically evaluated patients have been treated in three trials, with 40% responses and 25% complete responses. 335, 338 All of the responding patients had microscopic or small macroscopic residual disease. Thus, the use of high-dose IP recombinant IFN-α given frequently can result in the regional control of very small-volume disease confined to the peritoneal cavity. Whether survival is affected is not known. Other cytokines have been evaluated. A Phase I-II trial of intraperitoneal interferon-γ also yielded a 30% response rate. 341 Another phase I trial with intraperitoneal IL-2 has been performed, and the optimal dose was defined. 342, 343

Preclinical studies have examined the interaction of cytokines, such as IFN-a, tumor necrosis factor, and IL-2, with various cytotoxic agents, including cisplatin and doxorubicin 344, 345 Even low doses of cytokines can induce synergistic activity with standard cytotoxic drugs against fresh ovarian cancer cells in vitro. Italian investigators 346 reported a surgically-documented complete response rate of 50% when ovarian cancer patients received weekly treatment IP with cisplatin, alternating with human IFN-α (50 × 106 units). Responses were confined to those patients who started their treatment with minimum residual disease. Toxicity was similar to that seen with IFN-α alone. Therefore, the combination of IP cisplatin and IFN-α appeared to be tolerated and resulted in an appreciable response rate. Since response rates were similar to those reported in other studies of single-agent IP cisplatin, it was unclear whether the addition of IFN-α to the cisplatin had any significant benefit. When the GOG conducted a study of combined IP IFN-α and cisplatin, a very low partial response rate of 7% was seen, contrary to the results of other Phase I-II trials of IP cisplatin and IFN-α in patients with residual small-volume ovarian cancer, in which response rates of 20% to 40% have been noted. 347 In the GOG study, however, most evaluable patients had extensive carcinomatosis that was cisplatin-resistant and the maximum tumor diameters were > 1 cm. In a follow-up Phase II study of IFN-α alternating with cisplatin in patients with platinum-sensitive minimal residual disease, the surgically-documented response rate was 28%. 340 In a randomized Phase III trial, Windbichler and colleagues have demonstrated that the use of subcutaneous interferon-γ in women receiving first-line platinum-based chemotherapy in ovarian cancer was well-tolerated. 348 A higher complete clinical response rate (68% vs 56%) and longer disease progression-free survival (48 months vs 17 months, p = .031) was observed in women receiving the interferon-γ plus chemotherapy than in women who were treated with chemotherapy alone. Improved progression-free survival was seen in patients with residual disease greater than 2 cm, as well as in those with optimal resection.

There has been interest in the use of adoptive immunotherapy in ovarian cancer. 345, 349, 125 In a Phase I/II trial performed at the National Cancer Institute, IL-2 and lymphokine-activated killer (LAK) cells were administered intraperitoneally to 22 patients with ovarian cancer, many of whom had minimal residual disease confined to the peritoneal cavity. 350, 351 In this trial, the toxicity was high, especially with the development of extensive peritoneal fibrosis. There were, however, eight surgically documented partial responses (27%). Improvements in the specificity of this therapy, as well as the development of methods to reduce regional toxicity, could make adoptive immunotherapy an applicable technique in these patients. 228

Monoclonal antibodies raised against antigens on the surface of the epithelial ovarian cells have been used in clinical trials. Most of these antibodies have been linked to radiolabeled agents, such as 125I or 186Rh, and have been used for radioimmunoscintigraphy. Epenetos and colleagues and others, have used the intraperitoneal injection of 131I-labeled monoclonal antibody directed toward placental alkaline phosphatase labeled and human milk fat globulin protein (HMFG). 189, 352, 353, Intraperitoneal administration of 90Y-labeled anti-HMFG protein significantly prolonged survival relative to historical controls. 354 A multicenter randomized controlled study has compared IP treatment with 90Y-labeled antibodies to no additional therapy in patients without evidence of disease following second-look laparoscopy. Accrual has been completed, but results have not yet been analyzed. Other investigators have evaluated 125I-labeled OC125 antibody directed toward the CA125 antigen, and have shown good radiolocalization in patients with advanced bulky disease. 355, 356 Herceptin (trastuzumab) is an antibody that reacts with the tyrosine kinase growth factor receptor HER-2, a receptor that is overexpressed in 30% of breast cancers. In patients with recurrent breast cancer, trastuzumab has been shown to improve the response rate to paclitaxel and doxorubicin. Trials of this antibody in ovarian cancers that overexpress HER-2 are ongoing. Only 15% to 30% of ovarian cancers overexpress HER-2 and a response of 12% has been observed in a Phase II trial of trastuzumab. Consequently, relatively few ovarian cancer patients may benefit from this approach.

The therapeutic potential of an anti-idiotypic response to an anti-CA125 antibody was discovered in a retrospective analysis of a diagnostic study with MAb-B43.13, where a large group of patients who had been imaged enjoyed unexpectedly long survival. 357–359- When the clinical and immunologic profiles of 60 patients exposed to labeled MAb-B43.13 were compared to those of a contemporaneous historical cohort of 247 patients, those in the immunoscintigraphy group were 2.7 times less likely to die from ovarian cancer than were controls who had not been imaged (p < .001). Median survival time was doubled from 30 months in controls to 59 months in the immunoscintigraphy group. A randomized multicenter study compared vaccination with MAb-B43.13 (Ovarex) to placebo in 342 women with stage III/IV ovarian cancer who were disease free at the conclusion of frontline treatment. 360, 361 Overall, there was no difference in time to relapse, but in a subpopulation of 99 women defined by more successful response to frontline surgery and chemotherapy, time to relapse was extended from 10.3 months in the placebo group to 20.2 months in those who received MAb-B43.3 (p = .029). A prospective study has been planned to confirm the efficacy of MAb-B43.3 in this more optimal population.

Hormonal Therapy

Epithelial ovarian tumors frequently contain elevated levels of estrogen and androgen receptors. Some patients with epithelial ovarian tumors have had responses to endocrine therapy, although it appears that the overall response rate is approximately 10% to 20%. Progestational agents and estrogen antagonists, such as tamoxifen, have been used either singly or in combination with cytotoxic chemotherapy in patients with advanced disease. 362 Other studies have used gonadotropin agonists,for example. leuprolide acetate alone or with tamoxifen, or aromatase inhibitors. 363–366 In a Gynecologic Oncology Group study, patients with advanced epithelial ovarian cancer were treated with tamoxifen and a 13% partial response rate was reported. 226 There is a lack of correlative studies comparing the response to endocrine manipulations and the presence of hormone receptors. Hormonal therapy for patients with advanced ovarian cancer should primarily be reserved for those who have failed chemotherapeutic regimens and who are not candidates for aggressive salvage drug regimens or investigative approaches. These agents are well tolerated and in circumstances where quality of life issues are paramount, such therapies can be employed.

Palliative Radiotherapy in Ovarian Cancer

Unfortunately, recurrent or persistent ovarian cancer following adjuvant chemotherapy is relatively common and incurable. Usually, second-, third- or fourth-line chemotherapy is used in attempts to prolong life and palliate symptoms. Little specific data are available to judge the degree of symptom relief provided. Response rates range between 10% and 43% and are associated with various toxicities. 367–369- 126 Radiotherapy as a palliative modality in ovarian cancer is often neglected but may be very useful if the sole dominant symptomatic problem for the patient is localized to a site and volume that may be safely encompassed in a limited radiation field. For example, a fixed pelvic mass eroding the vaginal mucosa causing bleeding, pain or bowel or bladder dysfunction may occur without obvious disseminated symptomatic peritoneal disease. Localized masses in the retroperitoneal nodes or in extra abdominal sites such as the supraclavicular or inguinal node regions or bony or brain metastases may benefit from palliative irradiation as would painful hepatomegaly from hepatic capsular distention.

Recently a number of reports have documented the high objective and subjective response rate of patients treated with radiation for recurrent ovarian cancer after resistance to available chemotherapeutic agents has developed. Large single fraction irradiation, usually one to three fractions of 10 Gy has been investigated. 370 A 55% response rate for palliation of pain and 71% of bleeding was reported although severe bowel complications occurred in six of 42 patients, probably related to the high dose per fraction employed. Another report of palliative radiotherapy used after initial management with cisplatin-containing regimens documented that radiotherapy produced a mean symptom-free interval of 8.5 months and the median survival was 19.5 months using fractionated palliative irradiation. They reported a complete palliative response in 51% of 33 patients and overall palliative responses in 79%. 371 The median duration of palliation was four months which reflected palliation until death in 90% of cases. Vaginal or rectal bleeding was controlled in 90% and 85% respectively and pain relief occurred in 83%. A study from Memorial Sloan-Kettering Cancer Center documented subjective or objective responses in 70% of patients who had platinum-refractory disease who had not previously received paclitaxel. 372 While the optimal dose for palliation has not been established, it is clear that durable palliation may be achieved with local radiotherapy for ovarian cancer recurring after chemotherapy even in the presence of chemoresistant disease.

Palliative whole brain irradiation is indicated for documented cerebral metastases in those whose life expectancy is several weeks to months. Corn and collegues reported symptomatic response in 23 of 32 patients which was maintained until death in 71% 373 At the present time, CNS relapse remains sufficiently uncommon that prophylactic cranial irradiation is not recommended.

Survival of Patients with Advanced Ovarian Cancer

Cisplatin-based combination chemo-therapy regimens have clearly produced higher response rates, complete remission rates, and an improvement in the median survival of patients with advanced ovarian cancer. The impact on long term survival has been modest, and the majority of patients with advanced ovarian cancer still die of their disease. Five-year survival rates for patients treated with cisplatin-based regimens are approximately 20% to 25%. While this is a substantial improvement over the 5% to 10% survival rate reported for patients with advanced disease in the pre-platinum era, it is obvious that ovarian cancer still remains a formidable challenge and that new treatment approaches are needed.

The prognosis for patients with epithelial ovarian cancer is related to several clinical variables. Survival analyses based on the most commonly used prognostic variables are presented below. 374–377 , Including patients at all stages, patients less than 50 years of age have a 5-year survival rate of about 40%, compared with about 15% for patients older than 50 years. 53, 74, 77, 386

The 5-year survival rate for carefully and properly staged patients with stage I disease is 76% to 93%, depending on the tumor grade. 195 The 5-year survival for stage II is 60% to 74%. The 5-year survival rate for stage IIIa is 41%, for stage IIIb about 25%, for stage IIIc 23% and for stage IV disease 11%. 3 An analysis of the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database reveals a trend toward improved survival for ovarian cancer in the U.S. during the last period of analysis (1988-1994). In this cohort, the survival for stage I was 93%, for stage II 70%, for stage III 37% and for stage IV 25%. 378 Compared with the interval 1983-1987, there was a statistically significant improvement in survival for stages I, III and IV disease.

Survival of patients with borderline tumors is excellent, with stage I lesions having a 98% 15-year survival. 129 When all stages of borderline tumors are included, the 5-year survival rate is about 86% to 90%. 53, 129

For invasive cancers grade affects the prognosis. For invasive stage I disease, the 5-year survival rate for grade 1 epithelial ovarian cancers is about 91%, compared with about 74% for grade 2 and 75% for grade 3. 53 For stage II disease, the survivals are 69%, 60% and 51%, respectively, for grades 1, 2 and 3. Examining stage III–IV patients, the 5-year survivals for grades 1, 2 and 3, respectively, are 38%, 25%, and 19%. Patients with stage III disease with microscopic residual disease at the start of treatment have a 5-year survival rate of about 40% to 75%, compared with about 30% to 40% for those with optimal disease and only 5% for those with non-optimal disease. 138 Patients whose Karnofsky index (KI) is low (<less than> 70) have a significantly shorter survival than those with a KI <more than> 70. 375

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