Ovarian cancer is the sixth most common cancer, with 26,600 new cases expected in 1995. It is the fourth most common cause of cancer-related deaths in American women of all ages and the most frequent cause of death from gynecologic malignancies in the United States. It accounts for 14,500 deaths annually. The median age at diagnosis is about 62 years, and incidence rises rapidly after age 60 .
Ovarian cancer is the sixth most common cancer, with 26,600 new cases expected in 1995. It is the fourth most common cause of cancer-related deaths in American women of all ages and the most frequent cause of death from gynecologic malignancies in the United States. It accounts for 14,500 deaths annually. The median age at diagnosis is about 62 years, and incidence rises rapidly after age 60 .
In the United States, the lifetime risk of developing ovarian cancer is 1 in 70 . Internationally, the lifetime risk of developing ovarian cancer is highest in Sweden (1.73%), followed by the United States (1.53%), the United Kingdom (1.25%), South Europe (1.11%), South America (0.87%), India (0.75%), and Japan, with the lowest incidence (0.47%).
The etiology of ovarian cancer is unknown. Numerous studies have sought any possible link between environmental, dietary, reproductive, endocrine, viral, and hereditary factors and the risk of developing ovarian cancer.
The strongest risk factor for ovarian cancer identified to date is a familial pattern of ovarian cancer, which is reported in about 7% of women with the disease . There are two types of familial patterns: hereditary syndromes and familial history.
Hereditary ovarian cancer syndromes refer to (a) site-specific ovarian cancer syndromes; (b) ovarian and breast cancer (breast/ovarian cancer syndrome); and (c) nonpolyposis colorectal cancer, endometrial cancer, and ovarian cancer (Lynch II syndrome) within two or more generations of a kindred . The hereditary ovarian cancer syndrome accounts for less than 1% of ovarian cancers and less than 3% of cancers among women with familial evidence of ovarian cancer . In some families, an autosomal dominant mode of inheritance has been shown and may increase one's lifetime risk of developing ovarian cancer up to 50% [4-9].
The family history pattern of ovarian cancer, which is much more common than the hereditary syndrome, applies to families with isolated cases of ovarian cancer. Often, this is only one relative, with no evidence of hereditary disease. Of women with ovarian cancer, 7% report a family history of the disease [3,5]. The lifetime risk of ovarian cancer ranges from 1.2% to 3.7% in a 50-year-old woman with a family history of ovarian cancer in a first-degree relative and up to 5.5% in a woman with two or three first-degree relatives with ovarian cancer (Table 1) [5,10,11].
|Risk factor||Relative risk||Lifetime risk for ovarian cancer (%)ª|
|No risk factors||1.0||1.2|
|Familial ovarain cancer syndrome||Unknown||50 or less|
|One first- or second-degree relative with ovarian cancer||3.1*||3.7|
|Two or three relatives with ovarian cancer||4.6*||5.5|
|Oral contraceptibe pill use||0.65^||0.8|
Two other reported risk factors for ovarian cancer have been consistently shown to reduce the risk for this cancer: the use of oral contraceptives [10,11] and increasing number of pregnancies (Table 1). Though there is no definite explanation for the correlation between risk and either of these factors [10,11], two theories have been offered: the excess gonadotropin secretion theory by Cramer and Welch  and the incessant ovulation theory by Fathala .
Other risk factors have also been studied: asbestos-talc powder absorption through the vagina or cervix, increased dietary galactose consumption and low serum levels of galactose-1-phosphatase uridyltransferase, increased fat consumption, menstrual history, age at first pregnancy, infertility, and hormonal replacement treatment [14-16]. None, however, has shown a consistent and significant effect on ovarian cancer risk [16,17]. No association has been found between ovarian cancer and the use of coffee, alcohol, or tobacco .
The main purpose of a screening test is to increase survival by allowing diagnosis of disease at a more localized and curable stage (Table 2)[19-24]. However, there is no evidence to date that treatment of ovarian cancer detected in its early stages by currently available screening methods lowers the cause-specific mortality .
|Stage||Definition||Patients in stage at clinical detection (%)ª||Five-year survival (%)*|
|I||Confined to ovaries||25||73|
|II||Extension within pelvis||8||45|
|III||Intraperitoneal metastases outside pelvis or positive retroperitoneal nodes||52||21|
Available Screening Techniques
Physical Examination: Pelvic examination is of limited value in screening asymptomatic women for ovarian cancer. Its sensitivity and specificity in detection of adnexal masses have not been well established. Sensitivity increases with the size of the mass. In about two thirds of patients, disease is disseminated by the time it is palpable. Yet, pelvic examination is still too insensitive to serve as the sole screening test . However, some studies suggest that a pelvic examination by a highly skilled examiner may reveal early-stage ovarian cancer.
Abdominal/Transvaginal Ultrasound: In diagnosing ovarian cancer, the morphology and size of the mass are the most important factors. Uniform hypoechogenic or entirely cystic patterns are usually of no concern, as opposed to complex or solid patterns [27,28]. Also important to consider is that cyclic changes in ovary size during the menstrual cycle can give an abnormal transvaginal ultrasound (TVUS); therefore, an abnormal TVUS always needs to be repeated. Screening studies have shown specificities as high as 97.6% with TVUS and between 76% and 97% with abdominal ultrasound (US) and sensitivities between 80% and 100% for either method. Although TVUS and, to a lesser degree, abdominal US can detect diseases at early stages, more extended studies of larger populations are needed to confirm the exact sensitivity and specificity .
CA125: CA125 is an antigenic determinant on a glycoprotein shed into the bloodstream by malignant cells derived from coelomic epithelium . Serum levels of CA125 are increased in about 80% of patients with epithelial ovarian cancers, more frequently in patients with nonmucinous histologic types. Levels of CA125 are also increased in patients with endometrial and pancreatic cancer. They may be increased in patients with some benign conditions, including endometriosis and uterine leiomyoma; in patients with pelvic inflammatory disease (PID), in early pregnancy, and with benign ovarian cysts; and in patients with cirrhosis and pericarditis .
The serum level of CA125 fluctuates during the menstrual cycle . Consequently, screening with CA125 in premenopausal women has been little studied. At a reference level of 35 µ/mL, the sensitivity of CA125 as a marker of clinically diagnosed ovarian cancer ranges from 61% to 96%: 25% to 75% for stage I and 67% to 100% for stage II . The reported specificity is 98.6% to 99.2% . In about one third of women who ultimately develop cancer, CA125 levels rise above 35 µ/mL 18 months before the disease is clinically detected .
Combined Ultrasound and CA125: The positive predictive value of an abnormal US test is less than 1% for women at average risk and 2% for women with a history of ovarian cancer in one relative. For CA125, the positive predictive value is 3% for women at average risk and 10% for women with one or more relatives with ovarian cancer (Table 3) [2,33]. In a large British study whose primary screen was CA125 followed by US, CA125 levels achieved a positive predictive value of 27% . However, even though the combined specificity of US and CA125 is high, only one of every two early-stage ovarian cancers can be so detected.
|Screening method||Women at average risk||Women with one relative with ovarian cancer|
A recent study showed that combined screening with CA125 and the tumor-associated antigens M-CSF and OVX1 increases the sensitivity of the screening in patients with stage I ovarian cancer: At least one of the serum markers was elevated in 98% of patients with stage I ovarian cancer, yet the true specificity in the study was moderate. Elevations of one or more serum tumor markers should be further evaluated by TVUS to increase the specificity in apparently healthy women . Having recognized the need to determine whether the available screening can decrease the mortality of ovarian cancer by early detection, the US National Cancer Institute (NCI) has instituted a trial of screening for ovarian cancer in women aged 60 to 74 years using CA125, TVUS, and pelvic examination . To date, 17,000 women have been accrued to this study. Results of this trial are eagerly awaited .
The benefits of screening a woman who has one or no first-degree relatives with ovarian cancer are unproven. There is currently no evidence to support routine screening in these women. However, participation in clinical trials is an appropriate option. There are inconclusive data that screening benefits women with two or more first-degree relatives who have ovarian cancer; however, women with two or more affected family members have a 3% chance of having a hereditary ovarian cancer syndrome. Though there are no data showing that screening these high-risk women reduces their mortality, rectovaginal and pelvic examination at least annually is recommended. The Consensus Panel further recommends measurement of CA 125 levels, TVUS, and consideration of prophylactic bilateral oopherectomy at age 35 or completion of childbearing. These recommendations are of uproven value and controversial .
Biology, Immunology,Tumor Markers, and Pathogenesis
Steroid Hormones: Many ovarian cancers have histologic characteristics of classic endocrine-responsive tissues. This alone suggests a role for hormones in the etiology and progression of such cancers . Many studies show the presence of estrogen receptors in a high percentage of ovarian tumor specimens; estrogen has been shown to stimulate the growth of ovarian cancer cell lines. Progesterone and androgen receptors have also been reported in ovarian cancer specimens . As for gonadotropin, there are conflicting reports as to the presence of its receptors in ovarian cancer . Finally, experimental data indicate a role for peptide hormones in the regulation of growth or function of normal or neoplastic ovarian surface epithelial cells.
Growth Factors and Cytokines: Because it localizes to the peritoneal cavity, ovarian cancer is amenable to immune analysis and experimental immunotherapy. It has even been suggested that the intraperitoneal growth of ovarian cancer may be related to the local deficiency of antitumor immune effector mechanisms [38,39].
Several cytokines and growth factors have been studied in this respect. For instance, levels of interleukin-10 (IL-10) and interleukin-6 (IL-6) are particularly elevated in ovarian cancer ascites [40,41]. Also, preliminary studies have shown that on one hand, endogenously produced IL-6 can protect tumor cells from natural killer cell-mediated killing  and that on the other hand, high levels of IL-10 may play a role in immune responsiveness and the promotion of tumor growth [40,42-44].
Epidermal growth factor (EGF) receptors have been detected in a high percentage of ovarian cancer specimens, and overexpression of the receptor has been correlated with poor prognosis . The effects of tumor growth factor (TGF)-beta, which is closely related to epidermal growth factor (EGF), are mediated through the EGF receptor, and TGF-beta has been shown to inhibit the growth of normal surface epithelium and some ovarian cancer cell lines . Furthermore, fibroblast growth factor (FGF) was shown in one study to be mitogenic in one of four ovarian cancer cell lines . Receptors for two other factors, c-Erb-2 and c-Fms, have been identified, and increased levels of their oncogenes have been correlated with poor prognosis [45,46].
Oncogenes: Recent efforts have focused on the role of oncogenes in ovarian cancer. HER-2/neu is the most studied. Normal ovarian epithelium expresses low to moderate levels of HER-2/neu ; however, as studies have shown, overexpression of this oncogene may impart a biologic advantage to tumor cells by enhancing their resistance to cytotoxicity . HER-2/neu is overexpressed in about 30% of ovarian malignancies and appears to indicate poor clinical prognosis and poor survival. HER-2/neu thus has the potential to be clinically useful as both a prognostic marker and a potential therapeutic target for ovarian cancer [47,49,50].
Antioncogenes have also been studied, notably the tumor suppressor gene p53. The loss of normal p53 function, due to mutation and overexpression or to deletion of the normal p53 gene, is often associated with a malignant phenotype. The p53 gene is located on chromosome 17p and has been seen to be overexpressed and mutated in about 30% to 50% of ovarian cancers [51-53]. Another antioncogene, MDR-1, is specifically stimulated by mutant p53 and repressed by wild-type p53, implying an increased drug resistance and a growth advantage in cells that express a mutated p53 gene .
Tumor necrosis factor (TNF)-alpha, levels of which are also increased in ascites, has been shown to upregulate p53 mRNA expression and to induce apoptosis in an ovarian cancer cell line . TNF-alpha also was recently found to follow a distinct pathway in inducing apoptosis . Upregulation by TNF-alpha of the mutated oncogene p53 could induce the proliferation of ovarian cancer cells, whereas its upregulation of wild-type p53 would induce apoptosis [57,58].
The prognostic value of the preoperative CA125 level in epithelial ovarian cancer is debatable [59,60]. Most aggressive tumors are not necessarily those with the highest CA125 levels. Although the highest CA125 levels are seen in the most poorly differentiated tumors, there is no big difference in the percentages of patients with low-grade and high-grade tumors who have elevated CA125 level [61,62]. This suggests that the absolute level of CA125 does not relate to the volume of ovarian tumor; furthermore, the expression of CA125 in tissue shows no association with tumor grade, DNA ploidy, or S-phase fraction .
DNA Ploidy Analysis: DNA ploidy, which is the expression of a cell's nuclear DNA content, is an independent prognostic factor . Aneuploidy increases with age, stage, histology other than serous and mucinous, and degree of atypia and in the presence of Pseudomyxoma peritonei. In patients with invasive cancer, most tumors are aneuploid; most borderline tumors are diploid. To establish an individual tumor's ploidy, at least two biopsies from the solid tumor are required. S-phase fraction is currently not a reliable prognostic factor .
Other Prognostic Factors: Prognostic factors are tumor-related characteristics that determine the biologic behavior and risk of death from the disease and whose predictive value may change during the course of treatment and thereafter. The main prognostic factors in early ovarian cancer (stage I to IIA) are International Federation of Obstetricians and Gynecologists (FIGO) stage, histologic grade, histologic type, and age [65,66]. Ovarian cancer is discovered early in fewer than 30% of patients; in such cases, the 5-year survival is good, ranging from 51% to 98% [65,67,68]. Unfortunately, however, the histologic grading of ovarian tumors is based on subjective criteria and varies widely between and among observers [69-71]. To improve on this shortcoming, DNA flow-cytometric analysis has been introduced in recent years as a tool for assessing prognosis.
All studies agree that most borderline malignant tumors are diploid and that the few patients with aneuploid tumors have a worse prognosis [72-74]. Among stage I (early ovarian cancer) patients, diploid tumors are associated with an extremely good survival, independent of adjuvant treatment. The 5-year disease-free survival for patients with diploid tumors is 90% vs 64% for those with aneuploid tumors [75,76].
Factors associated with a poor prognosis in advanced ovarian cancer (stage III or IV) fall into two subgroups (as determined by multivariate analysis in clinical trials):
Postoperative residual tumor volume may simply reflect the natural biology and history of the disease. Tumors that are more advanced are more difficult to resect and therefore associated with larger residual disease. Therefore, how advanced the tumor was before debulking may be more important than how much disease was left behind . Other features, such as the type of chemotherapy, the intrinsic chemosensitivity of the tumor, and the presence of other biologic variables, may be as important as or even more important than the extent of the surgery [81-86]. Indeed, Heintz et al found that factors influencing the ability to perform optimal cytoreductive surgery were the same as those influencing disease-free and overall survival .
The literature on second-look surgery in ovarian cancer covers its diagnostic, prognostic, and therapeutic aspects. The earlier assumption that a negative second-look surgery is associated with excellent survival is clearly not true [87,88], since it is now quite clear that at least 30% to 50% of patients with no pathologic evidence of disease will experience a relapse [88-91]. Furthermore, patients with grade 3 tumors or grossly visible disease at completion of initial surgery also are at high risk. The question then remains whether additional treatment will affect outcome in these high-risk patients (survival difference) [89-91].
Some investigators have attempted to quantify the impact of pretreatment prognostic factors on survival and to construct from these factors a prognostic index (PI). Five pretreatment characteristics so far used in calculating the PI are performance status, FIGO stage, residual tumor size, tumor grade, and presence of ascites [85,92,93]. Future prognostic factors under study and which have produced promising results include p53 immunostaining of epithelial ovarian cancers. It has been shown that those individuals whose tumors express excessive amounts of mutated p53 experience shorter overall survival. However, those same studies failed to show that p53 expression is an independent prognostic factor .
The ovarian stroma and epithelium are of the same mesodermal origin . The epithelium lining the ovary and the peritoneum is similar to the coelomic epithelium that gives rise to the fallopian tube, uterus, cervix, and mllerian duct and from which approximately 75% of all primary ovarian neoplasms arise.
“Epithelial” ovarian tumors contain varying amounts and activities of the gonadal mesenchyma and are all potentially hormone producing. They are classified according to cell type and behavior as benign, borderline malignant or of low malignant potential, or malignant.
Criteria for the diagnosis of borderline malignant tumors are as follows: (1) epithelial proliferation with papillary formation and pseudostratification; (2) nuclear atypia and increased mitotic activity; and (3) absence of true stromal invasion (20% to 25% of borderline malignant tumors have truly spread beyond the ovary, although rare examples of microinvasion have been reported; the prognosis of these tumors is determined by the nature of metastatic implants).
The major cell types of epithelial tumors are serous, mucinous, endometrioid, clear cell, transitional, and undifferentiated. The importance of distinguishing among different epithelial subtypes lies in their different biologic behaviors, likelihood of spread, and consequent variation in prognosis and treatment. For the invasive epithelial carcinomas, however, the current consensus is that histologic type has limited prognostic significance independent of clinical stage, extent of residual disease, and histologic grade.
Serous Tumors: Serous tumors represent 50% of epithelial ovarian tumors. Of these, 10% are borderline malignant serous tumors and 50% occur before the age of 40. The 5-year survival is 80% to 90%. Malignant calcified psammoma bodies are found in 80% of serous carcinomas.
Mucinous Tumors: Mucinous tumors make up 8% to 10% of epithelial ovarian tumors. These tumors may reach enormous size, filling the entire abdominal cavity. The tumors are bilateral in 8% to 10% of cases, and the mucinous lesions are intraovarian in 95% to 98% of cases. Pseudomyxoma peritonei is most commonly secondary to an ovarian mucinous carcinoma.
Endometrioid Tumors: Overall, 6% to 8% of epithelial ovarian tumors resemble endometrial adenocarcinoma, and both types occur simultaneously as synchronous primary tumors in 30% of cases. Identification of multifocal disease is important because patients with disease metastatic from the uterus to the ovaries have a 5-year survival rate of 30% to 40%. Those with synchronous multifocal disease have a 5-year survival rate of 75% to 80%. Concurrent endometriosis is present in 10% of cases. The malignant potential of endometriosis is very low, although a transition from benign to malignant epithelium may be seen.
Adenocarcinoma with benign-appearing squamous metaplasia has an excellent prognosis. Conversely, mixed adenosquamous carcinoma (malignant glandular and squamous epithelial) has a very poor one.
Clear-Cell Carcinomas: Clear-cell carcinomas occur in 5% of cases and may also be associated with endometriosis or endometrial cancer. Often the clear-cell type coexists with other cell types. It is sometimes associated with hypercalcemia or hyperpyrexia and metastatic disease. These tumors have a worse prognosis than others.
Small-Cell Carcinomas: Small-cell carcinomas are rare, occasionally associated with neuroendocrine features, and usually have a poor prognosis.
Brenner Tumors: Brenner tumors can be malignant, borderline, or benign; they are very rare.
Transitional-Cell Tumors: Some primary ovarian carcinomas resemble transitional-cell carcinoma of the urinary bladder without a recognizable Brenner tumor. Ovarian carcinomas that are more than 50% transitional-cell tumors are more sensitive to chemotherapy and have a more favorable prognosis .
Undifferentiated Carcinomas: Undifferentiated carcinomas make up 17% of epithelial ovarian tumors, and the prognosis for patients with these tumors is poor.
Peritoneal Mesotheliomas: Peritoneal mesotheliomas are characterized by carcinomatosis with peritoneal epithelium as the primary source. The ovaries are not involved with tumor, or only their surfaces are involved. Women with such tumors may have a remote history of oophorectomy.
Two histologic grading systems are in common use. The pattern system considers the general microscopic appearance of a lesion. Lesions range from grade 1 (well differentiated) to grade 2 (moderately differentiated and predominantly glandular) to grade 3 (poorly differentiated and predominantly solid). Broder's grading system classifies lesions from grade 1 to 4, depending on the lesions' cytologic and nuclear characteristics. This system assumes grade 4 to be an undifferentiated lesion. Pathologists usually use a combination of both systems.
The value of grade as an independent prognostic variable has not been fully clarified. A number of reports state that tumor grade may be of value in early-stage ovarian cancer but that its value falls off in patients with advanced-stage disease.
Objective signs of ovarian carcinoma are nonspecific and include a pelvic mass, ascites, pleural effusion, and occasionally supraclavicular lymphadenopathy. Patients with ovarian cancer may occasionally present with various types of paraneoplastic conditions, such as humorally mediated hypercalcemia (clear-cell, small-cell), cerebellar degeneration (associated with antibodies to Purkinje's cells), the sudden appearance of seborrheic keratosis (a sign of Leser-Trelat syndrome), or chronic intravascular coagulation (Trousseau's syndrome). Preoperative evaluation should include a barium enema, an abdominal/pelvic computed tomography (CT) scan, blood chemistries, chest x-ray, and CA125 measurement. If symptoms of obstruction are present, an upper gastrointestinal (GI) series may be indicated. Mammograms may be helpful in ruling out metastatic breast cancer. Ascitic or pleural fluid should be tapped and examined.
A full staging laparotomy should be performed, the essential steps of which are listed in Table 4. Meticulous surgical staging for early-stage ovarian cancer is very important and should include the following: peritoneal washing; palpation of all peritoneal surfaces, including the diaphragm; bilateral salpingo-oophorectomy and total abdominal hysterectomy (although a unilateral salpingo-oophorectomy without hysterectomy may be considered for those patients with low-risk early-stage disease who wish to maintain fertility); biopsy of suspicious nodules; infracolic omentectomy; multiple peritoneal biopsies including paracolic gutters, pouch of Douglas, and diaphragm; and ipsilateral pelvic lymph nodes .
Evaucation and cytologoic analysis of ascites
If ascites absent, cytologic washing of pelvis and paracolonic gutters
Inspection and palpation of the subdiaphragmatic areas, intraperitoneal contents, and retroperitoneal areas, including pancreas
Frozen section of ovarian mass (unilateral or bilateral)
If carcinoma on frozen section, hysterectomy and bilateral salpingo-oophorectomy
Omentectomy with optimal bulk reduction of remaining tumor masses
Relief of intestinal obstruciton by resection or colostomy
If disease limited to ovaries, multiple biopsies including the paracolonic gutters, cul-de-sac, lateral pelvic walls, vesicouterine reflection, subdiaphragmatic sites, and intra-abdominal areas
Ipsilateral and para-aortic lymph-node sampling if conservative therapy planned
Repeat surgery for staging may be indicated in patients who have been inadequately staged and in whom this will provide further information that will affect treatment. After surgery is completed, the patient's histologic grade, stage, and residual disease should be characterized.
FIGO staging criteria, whose prognostic value is well established, are used to stage these tumors (Table 5). According to FIGO, stage I has a 5-year survival rate of 80% to 90%; stage II has a 5-year survival rate of 40% to 60%; stage III has a 5-year survival rate of 10% to 15%; and stage IV has a 5-year survival rate of less than 5%. Differences in survival among patients with the same FIGO stage of disease may indicate incomplete staging. This may limit stage as a prognostic factor. Frequently unrecognized sites of disease include the pelvic lymph nodes, cul-de-sac peritoneum, para-aortic nodes, omentum, and diaphragm.
|I||Growth limited to the ovaries|
|IA||Growth limited to one ovary; no ascites; no tumor on the external surfaces, capsule intact|
|IB||Growth limited to both ovaries; no ascites; no tumor on the external surfaces, capsules intact|
|IC||Stage IA or IB tumor, but with tumor on the surface of one or both ovaries or with ruptured capsule; or ascites present containing malignant cells or positive peritoneal washings|
|II||Growth involving one or both ovaries with pelvic extension|
|IIA||Extension and/or metastases to the uterus and/or fallopian tubes|
|IIB||Extension to other pelvic tissues|
|IIC||Tumor either stage IIa or IIb but with tumor on the surface of one or both ovaries; capsule(s) ruptured; ascites present containing malignant cells; or positive peritoneal washings|
|III||Tumor involving one or both ovaries with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastases; tumor limited to true pelvis but with histologically proven malignant extension to small bowel or omentum|
|IIIA||Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces|
|IIIB||Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative|
|IIIC||Abdominal implants greater than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes|
|IV||Growth involving one or both ovaries with distant metastases; if pleural effusion is present, there must be positive cytologic test results to allot a case to stage IV; parenchymal liver metastases indicates stage IV|
The rationale for cytoreductive surgery is based on kinetic as well as retrospective studies, which have shown that patients with small-volume residual disease following initial surgery respond better to subsequent chemotherapy and survive longer. Cytoreductive surgery in properly selected patients probably helps palliate intestinal obstruction and abdominal discomfort. However, there are no prospective, randomized studies to prove the survival benefit of cytoreductive surgery . In fact, several retrospective studies recently have questioned the value of initial cytoreductive surgery in the long-term prognosis of patients with advanced disease .
One recent meta-analysis  of patients with advanced disease treated with platinum-based chemotherapy shows that patients who had maximum cytoreductive surgery had only a small increase in mean survival time. Two large retrospective trials [89,90], one that included patients with stage III disease and one that included patients with stage IV disease, failed to show that initial cytoreductive surgery prolonged survival. Some studies have advocated extensive debulking procedures, including bowel resection and peritoneal stripping [99,100]. However, in a study of 302 patients with advanced epithelial ovarian cancer, Potter found that patients who had extensive debulking surgery showed no improved survival over those who did not .
Together, these studies suggest that survival in patients with advanced bulky ovarian carcinoma is influenced by many factors other than the surgeon's technical ability to cytoreduce tumor bulk. Instead, tumor biology probably plays an important but undefined role in the natural history of the disease.
Nevertheless, in the absence of a prospective randomized trial, the standard practice remains cytoreductive surgery when it can be accomplished with acceptable morbidity. The importance of secondary cytoreduction following chemotherapy, however, remains controversial, since there is no evidence to suggest that second-look laparotomy prolongs survival [91,102].
The information obtained at a second look is primarily prognostic. However, information from a negative second look is of limited clinical benefit: in 30% to 50% of patients who obtain a surgically confirmed complete response (CR), disease will recur [88-91]. Nevertheless, as one randomized study reports, patients with recurrent or progressive ovarian cancer who had optimal (less than 2 cm) secondary cytoreduction survived longer (mean, 27.1 months) than those who had unsuccessful surgery (mean, 9 months) .
In a large European study, patients who had undergone primary surgery and had residual tumors larger than 1 cm received three cycles of cisplatin chemotherapy. Then the patients with responding disease were randomly assigned to have either interval debulking surgery (IDS) and chemotherapy or no surgery followed by further chemotherapy. In both groups, 84% of patients received at least six cycles of chemotherapy. Median survival for the IDS patients was 26 months vs 19 months for the chemotherapy patients . This finding suggests that further studies are needed to determine the role of secondary debulking surgery. Berek et al  have even gone so far as to suggest that the focus should be on whether any intervention during or after secondary surgery can improve survival, since salvage therapies may have an even greater negative impact on quality of life than second-look surgery.
The standard present practice of following cytoreductive surgery with platinum-based chemotherapy fails to cure the vast majority of patients with advanced disease. Chemotherapy's role at present is largely palliative. However, at a recent consensus meeting on the treatment of advanced ovarian cancer, there was agreement that after appropriate cytoreductive surgery, platinum-based chemotherapy yields superior response rates, progression-free survival, and superior survival rates . The meeting participants also concluded that carboplatin (Paraplatin) is an acceptable option in patients with suboptimal disease (stage III or IV) but should not replace cisplatin in patients with potentially curable small-volume disease. Investigators at a recent symposium came to the same conclusion .
The above statements raise one of the most common concerns in treating ovarian cancer: the issue of carboplatin vs cisplatin. A recent meta-analysis  that incorporated data from two trials, including survival data from over 2,000 patients, compared carboplatin and cisplatin treatment groups; it failed to demonstrate any significant differences in overall survival between the two groups. A similar conclusion came from two large North American trials: a trial by the Southwest Oncology Group  (342 patients with stage III or IV disease randomized to receive cisplatin, 100 mg/m², plus cyclophosphamide, 600 mg/m², or carboplatin, 300 mg/m², plus cyclophosphamide, 600 mg/m²) and a trial by the National Cancer Institute of Canada  (447 patients randomized to cisplatin 75 mg/m², plus cyclophosphamide vs carboplatin/cyclophosphamide). All three of these trials failed to demonstrate a significant difference in overall survival, though the carboplatin regimen was found to have a better therapeutic index and to produce a better quality of life [109,110]. In contrast, a recent French trial  involving 144 patients with stage III or IV disease who received either cisplatin or carboplatin demonstrated very different results, as seen in Table 6 [109-115]. The doses of cyclophosphamide (500 mg/m²) and doxorubicin (40 mg/m²) were the same in both groups. The pathologic complete remission and overall response rates were significantly higher in the cisplatin arm than in the carboplatin arm (33% vs 15% and 73% vs 47%, respectively). The median survival time was 27.9 months for the cisplatin arm and 20.6 months for the carboplatin arm. The actual delivered dose intensity of the drugs in the two arms was not reported .
|Group||Number of patients||Carb/cis dose (mg/m²)||Carb/cis PDI (mg/m²/wk)||Combine with drug||SOD %||Carb/cis PCR||Carb/cis median PFS (mo)||Carb/cis median survival (mo)|
|EORTC ||342||350/100||70/20||DOX CTX HMM||63*||23/27||13.1/16.8||22.7/24.6|
|GONO ||164||200/50||50/12.5||DOX CTX||66ª||14/20||15.5/13.2||23.1/22.6|
|ARTAC ||144||300/75||75/18.75||DOX CTX||NA||10/25||NA||20.6/27.9|
Another issue is the addition of doxorubicin to cisplatin or cyclophosphamide regimens. The recent consensus  is that either cyclophosphamide (750 mg/m²) plus cisplatin (75 mg/m²) every 3 weeks or cyclophosphamide (500 mg/m²) plus doxorubicin (50 mg/m²) plus cisplatin (50 mg/m²) every 3 weeks (CAP) is acceptable standard therapy. However, four prospective randomized trials [116-119] comparing cisplatin and cyclophosphamide with the CAP regimen failed to show statistically significant differences in overall survival.
The largest of the above trials was that of the Italian Cooperative Gynecologic Oncology Group (GICOG), which randomized 529 patients to receive CAP, cisplatin/cyclophosphamide, or single-agent cisplatin . No statistical difference was seen in overall survival (minimum follow-up, 5 years) among the three groups. Meta-analysis of the above four trials  revealed a 6-year survival advantage of 7% in patients receiving the doxorubicin-containing regimen, but it remains unclear whether the benefit was a result of doxorubicin or the greater dose intensity reached by adding it.
A third and still controversial issue is the number of cycles of chemotherapy to be given. Most studies report 5 to 10 courses of treatment, and it is generally agreed that most responses occur within four courses of chemotherapy. Two prospective randomized trials failed to demonstrate any significant benefit for more prolonged treatment [121,122]. The current recommendation is to give at least six courses of treatment. There is no evidence so far to show that additional treatment produces any benefit.
The importance of dose intensity (DI)(mg/m²/time period) in relation to clinical outcome in ovarian cancer has been analyzed by several investigators. In particular, three large prospective randomized trials have failed to consistently demonstrate a clinically significant improvement with high-dose chemotherapy [123-125]. The Hong Kong trial included stage III to IV patients who showed improved survival with high-dose regimens, but the patient population was small and staging criteria were not uniform . The large Scottish trial  also showed a difference in survival but included in its population optimally debulked patients with stage IC to IV disease. However, a separate analysis by the Scottish investigators of patients with advanced ovarian cancer still showed a difference favoring the high-dose arm with respect to progression-free and overall survival. Patients on the high-dose arm received the same number of treatment cycles as those in the low-dose arm, and as a result the total dose of cisplatin was 67% higher.
The Gynecologic Oncology Group (GOG) trial of patients with suboptimal stage III or IV disease failed to demonstrate any survival advantage for the high-dose chemotherapy arm . However, it is important to note that the final assessment of clinical response was based on a relatively small subset of patients with measurable disease (34%), and that in this study the high-intensity arm consisted of only four courses of chemotherapy (Table 7)[116,122-125]. It is possible that a greater increase in dose intensity was required to produce clinically meaningful improvement in patients with advanced disease. A central problem, however, with evaluation of dose intensity in ovarian cancer is that multiple chemotherapy-related toxicities preclude marked increases in dose intensity for prolonged periods.
|Group||Disease stage||Number of patients||Drug regimens||Dose intensity||Cumulative dose||Assigned increase in dose intensity in the intensified arm||Results|
|Hong Kong ||Stage III/IV||60||Cisplatin 100 mg/m² + CTX 1,000 mg/m² vs cisplatin 50 mg/m² + CTX 1,000 mg/m² × 6 cycles||+||+||× 2||+3-year survival rates: higher dose = 60%, lower dose = 30%|
|GOG ||Untreated, suboptimal stage III/IV||458||Cisplatin 100 mg/m² + CTX 1,000 mg/m² × 4 vs cisplatin 50 mg/m² + CTX 500 mg/m² × 8||+||-||× 2||Median survival duration: higher dose = 21.9 mo, lower dose = 18.9 mo|
|Scottish ||Stage I-IV||165||Cisplatin 100 mg/m² + CTX 750 mg/m² vs cisplatin 50 mg/m² + CTX 750 mg/m² × 6 cycles||+||-||× 2||Median survival duration: higher dose = 28.5 mo, lower dose = 17.2 mo|
|Italian ||Stage III/IV||296||Cisplatin 75 mg/m² every 3 wk × 6 vs cisplatin 50 mg/m² every wk × 9 cycles||+||-||× 2||Median survival duration: higher dose = 36 mo, lower dose = 33 mo|
|Danish ||Stage II-IV||78||AUC escalation from 3-8 mg/ml/min||+||+||AUC × 4 vs AUC × 8||Higher PCR; survival too early for analysis|
Single-Agent Therapy: Three phase II trials with paclitaxel (Taxol) as a single agent without cytokine support have been completed (Table 8)[126-134]. A total of 110 patients with advanced ovarian cancer were involved [126-128,131,135-137]. The paclitaxel dose ranged from 100 mg/m² to 250 mg/m² infused over 24 hours every 3 weeks. Overall, in 20% to 37% of patients tumor regressed partially, and in seven patients regression was complete. Responses were 40% to 50% in platinum-sensitive tumors and 24% to 30% in platinum-resistant tumors. At least two patients with platinum-resistant disease achieved a CR. The median duration of response was 6 months. The overall median survival was 11 months (17 months in patients with platinum-sensitive tumors and 9 months in those with platinum-resistant tumors) . The major toxic effect was granulocytopenia.
|Institution||Number of patients||Dose (mg/m²)||Overall response||CR % (number)||Median survival (mo)|
|JHOC ||40||135 (110-170)||30%||2.5 (1)||8.2|
|GOG ||41||170 (decreasing)||37%||12 (5)||15.9|
|Einstein ||30||180-250||20%||3 (1)||6.5|
|European/Canadian ||195 187||135 175||15% 20%||1 (2) 2 (4)||11 11.5|
|M.D. Anderson [133,134]||48||250||48%||4||12|
Patients With Multiple Prior Regimens: The NCI-designated Comprehensive Cancer Centers provide paclitaxel (135 mg/m²) in a 24-hour infusion to patients with ovarian cancer who have failed at least three prior treatments . In a study of response rates, Trimble et al found that 22% of patients had objective responses to this regimen (4% CR, 18% PR) and that the median survival was 9 months.
Dose Intensification With Cytokines: The effect of dose intensification of paclitaxel on outcome is suggestive in ovarian cancer ; efforts have been made to better define dose intensification with paclitaxel in this disease [132-134,138]. Paclitaxel was given as a single agent at 250 mg/m² over 24 hours to patients with platinum-resistant ovarian carcinoma. Granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) also was administered starting 24 hours after completion of paclitaxel infusion. Objective tumor response was seen in 48% of patients. The duration of response was 6 months and the median survival was 12 months.
Dose and Schedule Study: A joint European-Canadian trial coordinated by the NCI of Canada prospectively randomized patients to two dose levels of paclitaxel (135 mg/m² or 175 mg/m²) and two different infusion schedules (3 or 24 hours). Responses were more frequent at larger doses (20% vs 15%) and with longer infusion (19% vs 16%). Though neither of these differences in response was statistically significant, paclitaxel at 175 mg/m² given over 3 hours was recommended in that study.
Combinations in Primary Treatment: In 1993, the GOG presented in abstract form the preliminary results of a trial using paclitaxel in combination with other agents as front-line chemotherapy in suboptimally debulked stage III/IV disease . At the 1995 meeting of the American Society of Clinical Oncology, the same group  presented the 5-year follow-up data from this trial comparing paclitaxel plus cisplatin with cisplatin plus cyclophosphamide as first-line therapy in advanced-stage III/IV ovarian cancer. Patients were randomized to receive either 750 mg/m² cyclophosphamide and 75 mg/m² cisplatin or 135 mg/m² of paclitaxel and 75 mg/m² of cisplatin. The reported toxicity was lower for the paclitaxel/cisplatin arm. Clinical response was 64% in the cisplatin/cyclophosphamide (CP) group and 77% in the paclitaxel/cisplatin (TP) group. The median progression-free survival was 12.9 months for the CP group and 18 months for the TP group. The median overall survival was 24.4 months for the CP group and 37.5 for the TP group. Only approximately one third of the patients in the cyclophosphamide study arm were treated with paclitaxel on relapse. The overall survival of this subgroup has not been reported. Of further interest is the observation that the cisplatin dose was higher in the paclitaxel arm . The European Organization for Research and Treatment of Cancer (EORTC) and NCI of Canada Clinical Trials Group plan to confirm and possibly extend these findings in both optimal and suboptimal patients, including those with early disease who are at high risk of relapse.
Intraperitoneal Chemotherapy: The rationale for intraperitoneal (IP) chemotherapy is based primarily on patterns of spread of epithelial ovarian cancer. It has been shown that IP platinum produces objective responses in patients with small-volume residual ovarian cancer. In a phase III Southwest Oncology Group (SWOG)-GOG-ECOG study, the results of which were presented at the 1995 ASCO meeting, patients with optimal (less than 2 cm) residual stage III disease were randomized to receive either six courses of IP platinum (100 mg/m²) and IV cyclophosphamide (600 mg/m²) or IV platinum (100 mg/m²) and IV cyclophosphamide (600 mg/m²). Median follow-up was 47 months in the IP arm and 44 months in the IV arm. Survival in the IP arm was 49 months, and in the IV arm, 41 months . The IP platinum approach is also under study in patients who have achieved a surgically confirmed CR to determine whether disease recurrences can be prevented or delayed . Intraperitoneal administration of paclitaxel appears promising, but first, a prospective randomized trial of IP vs IV paclitaxel is required to determine the relative efficacy of the different routes of administration .
It is very important to point out that IP chemotherapy should be used in patients with small-volume disease or no residual disease in light of poor penetration of IP tumor nodules by most antineoplastic agents. Moreover, IP therapy in patients with ovarian cancer may be limited by the frequent presence of extraperitoneal disease.
Other Chemotherapeutic Agents
Docetaxel (Taxotere) is a semisynthetic compound structurally related to paclitaxel. The toxicity of docetaxel is in many ways similar to that of paclitaxel. However, prolonged treatment with docetaxel increases skin toxicity and produces significant edema. When used as a single agent in advanced (stage IV) platinum-refractory ovarian cancer, the rate of response to docetaxel is 25% to 32% .
Etoposide (VePesid) has produced reported response rates of up to 30%, but more typically 10% to 20%. In patients with platinum-refractory disease who were given 100 mg doses of etoposide orally for 14 days every 21 days, the response rate was about 26% . Immediately after failing paclitaxel therapy, patients show a minimal response rate to etoposide .
Altretamine (Hexalen): In patients with platinum-resistant measurable disease who were administered 600-mg/m²/d doses of altretamine for 5 days every 4 weeks, no objective responses were noted .
Gemcitabine is a primary antimetabolite that closely resembles cytarabine. In patients with platinum-refractory disease who received 800-mg/m² doses weekly for 3 weeks, 19% had a partial response . We plan to study this drug at higher doses.
Topoisomerase I Inhibitors: Topotecan, a semisynthetic camptothecin derivative [150-152], has shown activity in both preclinical and phase I studies. For example, 30 women with ovarian cancer refractory to cisplatin or carboplatin and no prior taxane therapy were treated with a starting dose of 1.5 mg/m²/d for 5 days every 21 days. The result was a 14% partial response rate with a median duration response of 9 months and a median survival of all treated patients of 10 months .
CPT-11: This drug produced an 18% to 28% objective response rate and a 23% response rate in patients who received prior platinum therapy [154-157].
Ifosfamide (Ifex): The response rate of platinum-refractory ovarian cancer to ifosfamide is 13% .
Hormones: There has been relatively little prospective evaluation of hormonal therapy in ovarian cancer. Nevertheless, there are several reports of responses to various hormonal treatments (eg, progestational agents, antiandrogens, gonadotropin agonists, and tamoxifen [Nolvadex]) ranging from 10% to 20% and an additional 10% to 20% stabilization of disease in patients treated with prior chemotherapy and platinum-resistant tumors [159-161].
Radiation therapy has been used to treat ovarian carcinoma in two situations: (1) as adjuvant therapy for stages I to III disease without residual tumor after surgery and (2) as consolidation after chemotherapy in advanced disease with minimal residual tumor at second-look laparotomy . Whole abdominal radiation (WAR) and IP isotopes have been used in the adjuvant setting. Review of the randomized and nonrandomized data for WAR suggest that it can help prolong disease-free survival in early-stage ovarian cancer . Unfortunately, no prospective randomized trial has compared WAR with a cisplatin-containing regimen.
However, three papers concerning the use of intraperitoneal phosphorus-32 have been published. After conducting a study that included patients with FIGO stage I or II disease, Soper et al  concluded that phosphorus-32 is not effective in the adjuvant setting. Spanos et al  gave no information about survival. Vergote et al studied patients with stage I ovarian cancer who were randomly assigned to receive either six courses of cisplatin or intraperitoneal phosphorus-32 . There was no difference in response between the two groups, but complications (ie, bowel obstruction) were more frequent in the phosphorus-32-treated group.
To date, there is no proof that adjuvant radiation therapy is superior to other treatment modalities. However, it is clear from two studies of consolidation radiation therapy that the related complications are significant. Hoskins et al evaluated patients with stage III or IV disease and found a 10-year overall survival of 4% . Whelan et al evaluated 105 patients and found no survival advantage and an increased risk (8.6%) of complications (bowel obstruction). Overall, the complication rate of radiation therapy as consolidation treatment is considerable and the effect on survival unremarkable.
Ovarian cancer is a good model in which to investigate chemotherapeutic resistance because both intrinsic and acquired resistance are apparent. Approximately 50% of ovarian carcinomas are intrinsically resistant to conventional chemotherapy. The natural history of the disease after relapse is characterized by the eventual development of broad cross-resistance to various treatments. Patients with relapses within 6 months of a complete response have only a 10% to 20% chance of responding to platinum retreatment, whereas those with treatment-free intervals of 21 months or longer have a 90% response rate . In general, drug resistance may result from alterations in host-drug metabolism, from the spread of tumor cells to sites poorly accessible to chemotherapy, and/or from biochemical changes at the cellular or subcellular level.
To date, there is no modulator of drug resistance that benefits refractory ovarian cancer patients. However, general mechanisms of resistance that may be able to be manipulated are currently under investigation. They include efflux by multidrug resistance (MDR) pumps and other transport proteins, intracellular drug inactivation either by enzymatic detoxification (by glutathione transferases) or by binding to thiol-rich proteins (eg, metallothionein) or glutathione, repair of cytotoxic DNA adducts, alterations in tubulin structure, and enhancement of signal transduction pathways that include growth factors .
ABMT and PBSC Support
High-Dose Chemotherapy Approaches That Require Cytokines: Two such approaches are autologous bone marrow transplant (ABMT) and peripheral blood stem cell (PBSC) support. Patients with drug-sensitive, small-volume disease are good candidates for high-dose chemotherapy approaches that require cytokines. To date, however, there is no conclusive evidence that high-dose therapy with ABMT benefits any subset of patients with epithelial ovarian cancer.
The major obstacle is that giving such high-dose chemotherapy in a single course produces a dose-dependent antitumor effect; this, in turn, can induce a high but not durable response rate in patients with advanced disease [170,171]. A single intensification course is inadequate because of the low-growth fraction of tumor cells, which comprises a significant number of clonogenic tumor cells, and is unaffected by most chemotherapeutic agents. Since dose intensity is important in achieving responses in ovarian cancer, a viable alternative to ABMT is to administer repeated courses of dose-intensified therapy with PBSC support [172-174].
The first phase I and II trials with ABMT included patients with refractory ovarian carcinoma [175,176]. Most of the regimens included high doses of alkylating agents; some used carboplatin and/or mitoxantrone (Novantrone) [177-180]. However, patients with responsive residual disease are more likely to respond to high-dose chemotherapy since they are not too heavily pretreated and their likelihood of drug resistance is less. With this in mind, French investigators evaluated high-dose melphalan (Alkeran) treatment with ABMT as salvage or consolidation treatment in 35 patients. After a median follow-up of 23 months, 19 patients were alive, and projected survival at 54 months was 47% .
In another French study, Dauplat et al evaluated 14 patients who received similar treatment . All patients were treated with high-dose melphalan and autologous bone marrow support after a second-look operation. The median follow-up after the second-look operation was 43 months. Five patients (35.7%) remain disease free at 30 to 60 months. The actuarial 3-year survival rate was 64% .
Later, Legros et al evaluated patents who had received high-dose melphalan chemotherapy following induction therapy. They reported a median survival of 47 months with 69% alive at 3 years and 33% at 5 years . Further clinical trials now underway are examining the efficacy and feasibility of high-dose chemotherapy with PBSC as front-line therapy .
Interferon is the most studied biological used against ovarian carcinoma. When administered intraperitoneally, it has produced response rates of 30% to 50% in patients with minimal residual disease. Other studies are underway with different combinations of biological agents, including retinoids, interleukins, and interferons, but results are preliminary [184-186].
Ovarian cancer has a number of clinical features that make it well suited for monoclonal antibody (MoAb)-directed therapy. Because it remains primarily within the peritoneal cavity, ovarian cancer is a possible target for the IP use of MoAbs . In the past, radioactive MoAbs have been used to deliver therapeutic doses of radiation to malignant tumors. The most studied of these are rhenium-186 and yttrium-90 . Radioactive MoAbs have already been used to palliate ascites, and delivery of meaningful radiation doses for this purpose is now possible with 40 mCi of yttrium-90 . Relief of ascites was reported in two studies using AB263I131 or H MFGY90 [190,191].
MoAb-directed therapy also might be possible through the use of immunotoxins. Indeed, the therapeutic activity of immunotoxins has already been demonstrated in studies of human ovarian cancers in mice . The most frequently used immunotoxins are plant toxins (ricin and abrin) and bacterial toxins (Pseudomonas and diphtheria). However, clinical trials of immunotoxins have been hampered by several features of these agents. In particular, immunotoxins are only cytotoxic to cells that express the appropriate antigen and that internalize the MoAb toxin.
One other promising approach to immunotherapy of ovarian cancers involves tumor-infiltrating lymphocytes. Such cells have been expanded from malignant lesions and reinfused intraperitoneally with low-dose interleukin-2 (aldesleukin [Proleukin]) to reduce ascites .
A recent and powerful approach to treating ovarian cancers is gene therapy, especially that involving the MDR gene. The rationale behind MDR gene transduction into hematopoietic stem cells is to protect against the toxic effects of high-intensity chemotherapy and to overcome tumor drug resistance.
At M.D. Anderson, we introduce MDR gene into marrow cells to protect them from paclitaxel. Once the marrow is returned to the patient, continued intensive therapy can then be given cyclically. With each therapy cycle, the marrow should become increasingly enriched with chemotherapy-resistant stem cells, because cells not transduced with MDR gene should die, while those containing chemotherapy resistance factors continue to grow. This, in turn, should permit more intensive therapy with paclitaxel . A study of MDR gene therapy is underway at M. . Anderson Cancer Center. Ten patients have already been enrolled.
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