Despite the fact that it is highly curable if diagnosed early, cancer of the ovary kills more American women each year than all other gynecologic malignancies combined. An estimated 23,400 new cases of this cancer will be diagnosed in the United States in 2001, and about 13,900 women will succumb to the disease.
Although the number of deaths from ovarian cancer continues to increase, notable advances in chemotherapy and surgery over the last several decades have begun to translate into improved survival. Long-term survival data reflecting these recent advances are expected to show further increases.According to American Cancer Society data, the overall 5-year survival rate from ovarian cancer has increased significantly from 36% in the mid 1970s to 50% in the late ?0s to mid ?0s. Recent data from the National Cancer Institute show a similar increase in stage-specific survival.
This chapter will focus on epithelial cancers of the ovary, which account for about 90% of ovarian malignancies.
Age Ovarian cancer is primarily a disease of postmenopausal women, with the large majority of cases occurring in women between 50 and 75 years old. The incidence of ovarian cancer increases with age and peaks at a rate of 54 per 100,000 in the 75- to 79-year-old age group.
Race The incidence of ovarian cancer appears to vary by race, altough the effects of race are difficult to separate from those of environment related to culture, geography, and socioeconomic status. In the US, the age-adjusted rate of ovarian cancer for Caucasians is estimated to be 14.2 per 100,000, which is significantly higher than 9.3 per 100,000 for the African-American population.
Geography There are distinct geographic variations in the incidence of ovarian cancer, with the highest rates found in the industrialized countries and the lowest rates seen in underdeveloped nations. Japan, with an incidence of only about 3.0 per 100,000, is a notable exception to this observation. It has been postulated that geographic variations in the incidence of ovarian cancer are related, in part, to differences in family size.
Some of the highest rates are seen in European-born Jews, who have an estimated incidence of 17.2 per 100,000, a probable result of the relatively high frequency of BRCA1 and BRCA2 mutations in this population.
The cause of epithelial ovarian cancer remains unknown. Although it now appears likely that, at the cellular level, ovarian cancer results from the accumulation of multiple discrete genetic defects, the mechanism or mechanisms by which these defects develop have yet to be determined. Epidemiologic studies have identified a number of factors that may increase or decrease the risk of the disease. In addition, a small proportion of ovarian cancers, perhaps 5%-10%, result from inherited defects in the BRCA1 gene or other genes, including BRCA2 and the hereditary nonpolyposis colorectal cancer (HNPCC) genes.
Diet It has been suggested that numerous dietary factors increase the risk of ovarian cancer.
Fat Countries with a higher per capita consumption of animal fat tend to have higher rates of ovarian cancer.
Lactose Populations with a high dietary intake of lactose who lack the enzyme galactose-1-phosphate uridyltransferase have been reported to be at increased risk.
Coffee Conflicting reports have been published regarding the role of coffee consumption and the risk of ovarian cancer.
Environmental factors Various environmental risk factors also have been suggested.
Talc Exposure to talc (hydrous magnesium trisilicate) used as dusting powder on diaphragms and sanitary napkins has been reported in some studies to increase the risk of ovarian cancer, although other studies have failed to find an association.
Radiation Data on the association between exposure to ionizing radiation and the risk of ovarian cancer are also conflicting.
Viruses Several studies have examined the effect of viral agents, including mumps, rubella, and influenza viruses, on the risk of ovarian cancer. No clear relationship has been demonstrated.
Hormonal and reproductive factors In contrast to the conflicting data on dietary and environmental factors, some clear associations have been drawn between certain hormonal and reproductive factors and the risk of developing ovarian cancer.
Low parity and infertility Several analyses have documented that women with a history of low parity or involuntary infertility are at increased risk of ovarian cancer.
Ovulation-inducing drugs Recent evidence suggests that treatment with ovulation-inducing drugs, particularly for prolonged periods, may be a risk factor.
Hormone replacement therapy No association has been uncovered between the use of postmenopausal hormone replacement and the development of ovarian cancer.
Oral contraceptives Importantly, several large case-control studies have documented a marked protective effect of oral contraceptives against ovarian cancer. Women who have used oral contraceptives have approximately half the risk of ovarian cancer as do nonusers, and the protective effect of oral contraceptives appears to persist for years after their discontinuation. It is estimated that the routine use of oral contraceptives may prevent nearly 2,000 cases of ovarian cancer yearly in the United States.
Hereditary cancer syndromes There has been a fascinating evolution in our understanding of the role of hereditary factors in the development of ovarian cancer. It has been recognized for many years that women with a family history of cancer, particularly cancer of the ovary or breast, are themselves at increased risk of ovarian cancer. More recently Lynch and colleagues have refined these observations by delineating several apparently distinct syndromes of hereditary cancer involving the ovaries, including breast-ovarian cancer syndrome, site-specific ovarian cancer syndrome, and Lynch II syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]).
Epidemiologically, these syndromes appear to be inherited as an autosomal-dominant trait with variable penetrance. During the last several years, the specific genes responsible for HNPCC and for most cases of hereditary ovarian cancer have been identified, allowing fundamental observations to be made regarding their molecular pathophysiology.
BRCA mutations The BRCA1 gene is classified as a tumor suppressor, since mutations in this gene increase the risk of breast and ovarian cancer. Definitive identification of the function of the protein translated from this gene remains to be elucidated, although recent evidence suggests that it plays a role in the repair of oxidative damage to DNA. Part of the protein appears to contain a DNA-binding domain, suggesting that it also functions as a transcriptional regulator.
The frequency of BRCA1 mutations in the general population is estimated at approximately 1 in 800 and, in Jewish women of eastern European descent, 1 in 100.
Women carrying a germline mutation of BRCA1 have a significantly elevated risk of both breast and ovarian cancers compared to the general population. The average population risk of developing breast cancer is about 12.5% (1 in 8) and for developing ovarian cancer, 1.5%. However, in the presence of a germline BRCA1 mutation and a strong family history of cancer, these risks rise to about 90% and 65% for breast and ovarian cancer, respectively.
It is important to recognize that these risk estimates are derived from families identified with multiple cases of breast and/or ovarian cancer. The risk for women with BRCA1 mutations from families with less impressive family histories is probably lower, perhaps in the range of 15%-20% for ovarian cancer.
Although the presence of germline mutations in BRCA1 is not limited to women with a strong family history of breast cancer, data from several laboratories suggest that BRCA1 mutations are not a feature of sporadic ovarian cancer. Mutations in this gene appear to play a role in the development of approximately 50% of familial breast cancer cases and appear to account for the majority of hereditary ovarian cancers. Recent evidence suggests that BRCA1-related ovarian cancers may have a less aggressive clinical course than do sporadic ovarian cancers.
HNPCC or BRCA2 mutations Hereditary ovarian cancers not related to BRCA1 may be related to the HNPCC genes or to the BRCA2 gene.
Early-stage disease In the early stages, ovarian cancer is a totally insidious disease, producing essentially no symptoms. These cancers may grow to a size of about 10-12 cm before impinging on adjacent organs and producing symptoms of urinary frequency and rectal pressure.
Early ovarian cancers may be detected as a pelvic mass noted fortuitously at the time of a routine pelvic examination. Imaging with sonography, CT, or MRI will confirm the presence of a mass. The size, internal architecture, and blood flow of the mass can be used to make an educated guess as to whether it is benign or malignant, but imaging findings are not diagnostic in this regard. About half of patients with early ovarian cancers have an elevated serum CA-125 level.
Advanced-stage disease Even when advanced, ovarian cancers produce few symptoms. Patients may complain of abdominal bloating or swelling if ascites is present, and large pelvic masses may produce bladder or rectal symptoms. Occasional patients may have respiratory distress as a result of a large pleural effusion, which is more common on the right side. Infrequently, there may be a history of abnormal vaginal bleeding.
Most patients with advanced disease have ascites detectable by physical examination or imaging. Complex pelvic masses and omental tumor cakes may be present, and nodules can frequently be palpated in the pelvic cul-de-sac on rectovaginal examination. It should be noted that some patients with advanced ovarian cancer have essentially normal-sized ovaries.
Screening Unfortunately, no effective strategy exists for screening of the general population for ovarian cancer. Imaging techniques, including abdominal and transvaginal sonography, have been studied extensively, as has the serum marker CA-125. None of these techniques, alone or in combination, is specific enough to serve as an appropriate screening test, even in populations targeted by age.
Both the National Institutes of Health Consensus Conference (see NIH guidelines) and the American College of Obstetricians and Gynecologists have issued statements advising against routine screening for ovarian cancer, which, due to its high false-positive rate, leads to an unacceptable amount of invasive interventions in women without significant disease.
The NIH Prostate, Lung, Colon, and Ovarian (PLCO) Screening Trial has accrued its full complement of 152,000 patients. Half are female and half are male. For the ovarian cancer segment of the trial, half of the women will be screened via physical examination, CA-125, and vaginal ultrasound and the other half via standard medical care. Since patients will be followed for 13 years or more, it will be many years before results are available.
High-risk patients Management of women from families with hereditary ovarian cancer is controversial. As yet, there is no clear evidence that surveillance of such women with serum markers, sonography, laparoscopy, or frequent pelvic examinations is of any benefit, although periodic surveillance with sonography and CA-125 seems to be reasonable. Most experts would recommend prophylactic excision of the ovaries after age 35 years if the woman has completed childbearing. Recent evidence suggests that prophylactic oophorectomy may also lower the risk of breast cancer in women from high-risk families.
Exploratory laparotomy The diagnosis of ovarian cancer is generally made by histopathologic study following exploratory laparotomy. The stage of the disease can only be determined by surgery, as discussed below.
Preoperative evaluation Patients with suspected ovarian cancer should undergo a thorough evaluation prior to surgery. This should include a complete history and physical examination and serum CA-125 determination. In women below the age of 30 years, determinations of b-human chorionic gonadotropin (b-HCG) and a-fetoprotein (AFP) levels are useful, as germ-cell tumors are more common in this age group.
Abdominal CT and MRI In apparent early-stage cases, abdominal scanning by CT or MRI adds little to the diagnostic evaluation, and, thus, these studies are not routinely necessary. CT and MRI may be useful in providing a preoperative assessment of disease extent in probable advanced-stage cases.
Preoperative endometrial sampling Women with abnormal vaginal bleeding should have preoperative endometrial sampling.
Preoperative cytologic or histologic evaluation of effusions or tumor masses is neither necessary nor desirable. Often, patients with ascites and large pelvic masses, for whom exploration is necessary, are subjected to paracentesis or needle biopsy. These procedures only delay definitive management and may lead to seeding of tumor cells along needle tracts.
The ovary is notable for its ability to give rise to a large variety of neoplasms with distinct embryologic origins and differing histologic appearances.
Epithelial adenocarcinoma Approximately 90% of all ovarian malignancies are of epithelial origin, arising from the cells that invest the surface of the ovary. These cells give rise to a variety of adenocarcinomas, including serous, mucinous, endometrioid, and clear-cell types. These tumors have benign counterparts of similar histologic appearance and can also exist as "borderline" cancers, also known as "tumors of low malignant potential." There is little, if any, prognostic significance to the cell type of the tumor, with the exception of the clear cell variety, which tends to be especially virulent.
Histologic differentiation Pathologists also classify adenocarcinomas according to the degree of histologic differentiation. Those tumors retaining clear-cut glandular features are considered grade 1, or well-differentiated, while those that are largely composed of solid sheets of tumor are considered grade 3, or poorly differentiated. Tumors showing both glandular and solid areas are assigned to grade 2. The histologic grade seems to correlate roughly with biological aggressiveness.
Stromal and germ-cell tumors Malignancies can also arise from the ovarian stroma or the primordial germ cells contained within the ovary. Stromal tumors are often hormone-producing, and include such types as the granulosa tumor, Sertoli-Leydig tumor, and several variants. Germ-cell tumors, which tend to be highly aggressive, include the dysgerminoma, endodermal sinus tumor, malignant teratoma, embryonal carcinoma, and rare primary choriocarcinoma of the ovary.
Staging system
The staging system for ovarian cancer developed by the International Federation of Gynecology and Obstetrics (FIGO), is used uniformly in all developed countries. It is based on the results of a properly performed exploratory laparotomy?/font>a fact that bears emphasis, since inadequate surgical staging has been and continues to be a significant problem.
Surgical staging The surgical staging of ovarian cancer is based on an understanding of the patterns of disease spread and must be conducted in a systematic and thorough manner. It should include a complete evaluation of all visceral and parietal surfaces within the peritoneal cavity, omentectomy, and biopsy of aortic and pelvic lymph nodes. It generally includes removal of the internal reproductive organs as well.
The issue of adequate surgical staging becomes particularly acute in just the patient population likely to be operated upon by individuals with no specialized training in gynecologic oncology: patients with adnexal masses that are not obvious cancers on preoperative evaluation. At the time of exploration, if the mass is shown to be malignant on frozen section and there is no obvious metastatic disease, a complete staging operation is essential to search for occult metastatic spread, which may be present in 20%-30% of such cases. Also, if the tumor is documented to be stage IA by thorough staging and the patient wishes to preserve the potential for future fertility, it may be appropriate to conserve the uterus and uninvolved ovary and fallopian tube?/font>an option often overlooked by the inexperienced surgeon.
Prognostic factors
The prognosis of epithelial ovarian cancer depends on a number of factors.
Disease stage Of primary importance is disease stage, which, when properly determined, is of strong prognostic significance. The distribution of ovarian cancer cases by stage is as follows: stage I, 26%; stage II, 15%; stage III, 42%; stage IV, 17%. For patients with advanced ovarian cancer, the amount of residual tumor at the conclusion of the initial operation is of major importance. Patients with stage III disease who have minimal or no residual tumor may have a 30%-50% chance of 5-year survival, while those stage III patients left with a bulky tumor have a 5-year survival rate of only about 10%.
Histologic grade and type Most studies have found the histologic grade of the tumor to have prognostic significance; the histologic cell type of the tumor is of lesser importance.
Molecular markers In recent years, a great deal of effort has been devoted to the identification of molecular markers of prognosis in ovarian cancer. Studies of erb-B2, p53, ras, and other oncogenes and tumor-suppressor genes have had varying results relative to prognostic significance. Currently, the assessment of molecular markers of prognosis has no clinical utility, although much work continues in this promising area.
Predictors of chemosensitivity Similarly, after 20 years of investigations assessing in vitro and in vivo methods to predict the sensitivity or resistance of ovarian cancers to various chemotherapeutic drugs, the clinical usefulness of such an approach remains under investigation.
Surgery plays a crucial role in all phases of the management of ovarian cancer and, when applied as part of a multidisciplinary approach, affords the patient the highest likelihood of a favorable outcome. For most patients with ovarian carcinoma, surgery is not curative due to dissemination of tumor cells throughout the abdominal cavity. Therefore, successful management generally requires additional treatment.
The use of postoperative chemotherapy is standard for all advanced-stage patients and for many early-stage patients. Adjunctive chemotherapy significantly prolongs survival, particularly when platinum- and paclitaxel (Taxol)-based regimens are used.
Despite a long history of the use of radiation therapy in ovarian carcinoma, opinions on its utility differ widely. Presumably, this is due to the limited amount and adequacy of data comparing radiotherapy with modern chemotherapy regimens. Similarly, the role of radiotherapy as part of up-front combined-modality therapy, as salvage treatment following chemotherapy, and as palliative therapy remains unclear.
TREATMENT OF EARLY DISEASE
Clearly, comprehensive surgical staging is necessary to properly identify patients with stages I and II ovarian carcinoma. Beyond surgery, it is unclear whether further therapy is indicated for stage I or II disease and, if so, which therapy is most efficacious.
Surgery
Suspicious adnexal masses should be excised intact and submitted for frozen section. If a malignancy is confirmed and there is no obvious metastatic spread, complete surgical staging should be undertaken. As discussed earlier (see "Staging and prognosis"), it is of critical importance that surgical staging be done in a systematic and complete manner. Inadequate staging may result in inappropriate postoperative treatment that can severely compromise the patient𠏋 chances for cure.
Data from the American College of Surgeons community hospital㼀ased tumor registry show that almost 75% of the primary surgery for ovarian cancer performed in this country is done without the involvement of a gynecologic oncologist. This is particularly unfortunate given the fact that, with physical examination, measurement of CA-125, and appropriate imaging tests, the majority of cases of ovarian cancer can be identified preoperatively. Results from other studies suggest that when a gynecologic oncologist is not present at the initial operation, staging is more often inadequate, cytoreduction is more often suboptimal, and long-term survival is poorer.
Reproductive organ conservation In a woman of reproductive age with cancer limited to one ovary, it may be possible to conserve the uterus and opposite fallopian tube and ovary if the patient wishes to maintain the option of future fertility. To facilitate such intraoperative decision-making, it is essential that the surgeon𠏋 preoperative discussion with the patient and her family address the possibility of malignancy and review the surgical options for both benign and malignant disease.
Operative laparoscopy Recent advances in the instrumentation for operative laparoscopy have led to an increase in the proportion of adnexal masses being managed with this technique. Physicians should exercise caution in selecting patients with adnexal masses for operative laparoscopic approaches. Unless one𠏋 laparoscopic skills are extraordinary, suspicious masses are best managed by laparotomy. For masses that are approached laparoscopically, the same surgical principles of removal without spill and complete surgical staging apply.
Systemic chemotherapy
The current management of patients with early-stage disease focuses on comprehensive surgical staging and the identification of high-risk features. Patients with stage IA or IB tumors with well-differentiated histology have excellent 5-year survival rates, and adjuvant chemotherapy is generally not used in such patients. High-risk features include moderately to poorly differentiated tumors, stage IC or II disease, and clear-cell histology.
The reported survival rates of 60%-80% in patients who have early-stage tumors with high-risk features suggest a potential role for adjuvant therapy. The Italian Inter-Regional Cooperative Group conducted two randomized trials to evaluate the role of adjuvant therapy in patients with stage I disease. The first trial compared cisplatin (Platinol), 50 mg/m2 q28d ?/font> 6, to observation in 85 patients with stage IA or IB, grade 2-3 disease. The 5-year disease-free survival rate was higher in patients treated with cisplatin than in those who were observed (83% vs 63%), but the 5-year overall survival rate was similar in the two groups (88% vs 82%).
The second trial compared cisplatin (same dose) to phosphorus-32 (P-32) administration in 161 patients with stage IA-IB, grade 2, or stage IC disease. The 5-year disease-free survival rate again favored the platinum arm (85% vs 65%), but the 5-year overall survival rate was unchanged and similar to that reported in the previous trial.
The Gynecologic Oncology Group (GOG) recently reported a similar trial comparing IV cisplatin plus cyclophosphamide (Cytoxan) to intraperitoneal P-32. Results showed a 31% reduction in recurrence rate at 5 years favoring systemic therapy, but ultimately no difference in overall survival in patients with early stage disease was seen. Intraperitoneal P-32 was associated with more toxicity (Young RC, Brady MF, Nieberg RM, et al: Proc Am Soc Clin Oncol [abstract] 18:357a, 1999).
Improvements in the systemic chemotherapy of advanced ovarian cancer with associated improvements in survival are relevant to the design of regimens for early-stage disease. A recently completed Gynecologic Oncology Group trial (GOG 157) evaluated 3 vs 6 cycles of paclitaxel and carboplatin (Paraplatin) in patients with stage IA or IB, grade 2-3; stage IC; or stage II disease. The trial completed accrual in 1995, but it is too early to interpret the data. The GOG replacement trial is evaluating 3 cycles of paclitaxel plus carboplatin with or without additional weekly paclitaxel (40 mg/m2) in patients with early-stage disease.
In the absence of additional data, taxane- and platinum-based systemic chemotherapy should be considered the standard approach for patients who have early-stage disease with high-risk features. The optimum number of cycles is currently unclear.
Radiation therapy
Past GOG trials have established that patients with stages IA and IB, well-differentiated or moderately differentiated tumors have a 5-year survival rate of 90%-98%, which does not seem to be improved with adjuvant chemotherapy. However, patients with less favorable neoplasms by virtue of higher grade or stage have poorer outcomes (80% 5-year survival rate among treated patients).
Although reasonable therapy, the use of P-32 in intermediate-prognosis patients remains subject to question, as do all adjuvant therapies, particularly in stage I disease. Patients with stage II disease, particularly those with macroscopic residual disease following surgery, have relapse rates that require consideration of adjuvant therapy.
The current GOG trial in high-risk stage I and II patients does not involve either P-32 or external-beam radiation therapy; rather, the combination of carboplatin plus paclitaxel is being studied.
Whole-abdominal irradiation Externally administered whole-abdominal irradiation (WAI) has a number of theoretical and practical advantages over P-32 therapy. These include improved homogeneity of radiation dose, treatment of pelvic and para-aortic lymph nodes, better coverage of all peritoneal surfaces, and lack of treatment restrictions due to post-operative adhesions.
In addition, a retrospective study found that patients who received 6 cycles of cisplatin and cyclophosphamide with WAI administered between the third and fourth cycles had significantly better outcomes than those given single-agent cisplatin. The difference was particularly evident in patients with stage I or II, grade 3 tumors without gross residual disease.
The findings indicate that 5- and 10-year survival rates obtained with WAI are at least equivalent to results obtained using modern systemic agents. However, in view of the recognized limitations of these trials, more rigorously gathered data will be required to establish the role of WAI in these patients.
Collectively, existing data suggest that WAI should be studied further as a primary adjuvant treatment modality in patients felt to require treatment. Appropriate patients for trials including WAI are intermediate-risk patients, as defined by Dembo. The entire abdomen should be treated with an open-field technique using 100-150 cGy/d to a total dose of 2,500-3,000 cGy. The utility of routine pelvic boosts is questionable in patients with completely debulked tumors.
TREATMENT OF ADVANCED DISEASE
Surgery
Typically, surgeons operating on patients with ovarian cancer find obvious evidence of widespread metastatic disease. Ascites is often present, with diffuse peritoneal tumor studding and extensive omental involvement. In such cases, it is still important to document the surgical stage (usually a substage of stage III) and carefully evaluate and describe the extent and location of tumor identified at both the beginning and conclusion of surgery.
Optimal cytoreduction The primary function of surgery in patients with advanced ovarian cancer is cytoreduction or debulking. When operated on by experienced gynecologic cancer surgeons, approximately 50% of patients with stage III ovarian cancer can be left with "optimal" residual tumor (ie, < 1 cm). The morbidity associated with such surgery is low, and operative mortality is rare.
Several benefits accrue to patients who can be left with optimal residual disease. These patients have an increased likelihood of achieving a complete clinical response to chemotherapy, and among those who achieve a complete response and have a second-look operation, a greater proportion will have no tumor detectable. In addition, the risk of relapse after negative second-look surgery is reduced in patients left with small-volume residual disease at the conclusion of their primary operation. Progression-free interval, median survival, and long-term survival are all improved in patients who have optimal cytoreduction.
Even among patients with suboptimal residual disease (> 1 cm) after primary surgery, those left with smaller tumor volumes (1-2 cm) have a survival advantage over those with a larger residuum. It is thus clear that aggressive surgical cytoreduction, if successful in reducing tumor to small volumes, improves several measures of outcome.
Interval cytoreduction In a European Organization for Research and Treatment of Cancer (EORTC) trial, 299 patients with suboptimal advanced ovarian cancer were randomized to 6 cycles of cisplatin plus cyclophosphamide with or without interval surgical cytoreduction after the third cycle. Median survival for patients who underwent interval debulking surgery was 27 months vs 19 months for patients who did not have interval debulking (P = .01). The GOG is currently conducting a randomized trial of interval cytoreduction using a cisplatin-paclitaxel chemotherapy regimen.
Chemotherapy
Primary treatment The results of two randomized trials support a survival advantage for patients treated with combinations of IV platinum and paclitaxel, as compared with those given a platinum plus cyclophosphamide. McGuire et al found a 37- vs 24-month median survival advantage for the platinum-paclitaxel arm. Similarly, a preliminary analysis of the intergroup trial by Stuart et al showed an improvement in median survival from 25 to 35 months (P = .001) in favor of the paclitaxel-containing arm.
A randomized trial (GOG 158) comparing paclitaxel (175 mg/m2 via a 3-hour infusion) plus carboplatin (dosed to achieve an area under the curve [AUC] of 7.5) vs the standard regimen of paclitaxel (135 mg/m2 via a 24-hour infusion) plus cisplatin (75 mg/m2) in patients with optimally debulked disease was recently reported in abstract form. The shorter infusion schedule appeared to be as effective as the standard regimen. Due to its lesser toxicity and ease of administration, the shorter schedule with carboplatin is the preferred regimen.
Recurrent disease Patients who respond to primary chemotherapy with paclitaxel and platinum agents and who relapse ?/font> 6 months after the completion of treatment often have additional responses of limited duration when retreated with the same agents. In addition, a plethora of new agents have demonstrated phase II activity in patients with refractory disease.
Topotecan (Hycamtin) has FDA approval for the treatment of patients with refractory disease. An oral preparation is in phase III trials.
An open, randomized study compared topotecan (1.5 mg/m2/d for 5 days) to paclitaxel (175 mg/m2 q21d) in 226 women whose ovarian cancer had recurred after first-line platinum therapy. There were no statistically significant differences between the treatment groups with respect to response rate (20.5% vs 14%), response duration (25.9 vs 21.6 weeks), or median survival (63 vs 53 weeks).
Topotecan has efficacy comparable to paclitaxel in this setting, and is being evaluated in combination with platinum and other agents.
Liposomal doxorubicin (Doxil) also received FDA approval recently for the treatment of patients with metastatic platinum- and paclitaxel- refractory disease. A recent randomized trial (Gordon AN, Fleagle JT, Guthrie D, et al: Proc Am Soc Clin Oncol [abstract] 19:380a, 2000) compared liposomal doxorubicin with topotecan in this setting; similar response rates, time to progression, and overall survival (53.4 vs 53.1 weeks) were seen with these two agents.
Other agents Recent phase II trials have demonstrated the activity of other agents in patients with recurrent ovarian cancer. These include, gemcitabine (Gemzar), vinorelbine (Navelbine), oral altretamine (Hexalen) and oral etoposide. In general, these agents have similar response rates, ranging from 10% to 30%, with a median duration of response ranging from 4 to 8+ months. Despite achieving these responses, and often effective but limited palliation, these drugs have not altered overall median survival (10 to 12 months).
High-dose chemotherapy
Currently, there is no role for high-dose therapy in the standard management of patients with epithelial ovarian cancer.
In a trial conducted largely in patients having platinum-resistant (66%) and bulky disease (61%), the median progression-free survival and overall survival intervals were short (7 and 13 months, respectively) in patients treated with high-dose therapy and stem-cell support. Based on these and other similar data, patients with platinum-resistant, bulky disease should not receive high-dose therapy.
Intraperitoneal chemotherapy
Despite the significant responses obtained with platinum-based therapy, the number of patients achieving a pathologically negative second-look assessment remains in the range of 20%-30%.
A randomized, phase III study conducted by the Southwest Oncology Group (SWOG), Eastern Cooperative Oncology Group (ECOG), and GOG compared IV cisplatin (75 mg/m2) and paclitaxel (135 mg/m2 over 24 hours) to IV carboplatin (dosed to an AUC of 9) followed by IV paclitaxel (135 mg/m2 over 24 hours) and intraperitoneal cisplatin (100 mg/m2) in patients with optimally debulked disease. Preliminary results, reported in abstract form, indicated superior recurrence-free survival tine in the patients treated with intraperitoneal cisplatin (27.6 vs 22.5 months; P = .020), as well as an improvement in overall survival duration that was of borderline statistical significance (52.9 vs 47.6 months; P = .056).
Cisplatin is well suited to intraperitoneal administration. Phase II data on cisplatin-based intraperitoneal treatment as "consolidation" therapy in patients who have minimal persistent disease following primary chemotherapy or who achieve pathologic complete response to platinum-based front-line therapy have been encouraging.
A phase III study of intraperitoneal therapy is ongoing and hopefully will prove definitive. The current GOG trial in patients with optimally debulked disease compares IV paclitaxel plus IV cisplatin as the standard treatment arm with IV paclitaxel plus intraperitoneal cisplatin and intraperitoneal paclitaxel as the investigational arm.
Treatment recommendations and unresolved issues
For advanced ovarian cancer, current front-line management should incorporate paclitaxel with platinum-based therapy.
Issues that remain to be resolved include: (1) the role of intraperitoneal therapy in primary treatment and in patients with persistent disease following initial systemic chemotherapy; and (2) the role of the multiple new agents with documented phase II activity, both in combination and as single agents in primary treatment.
Radiation therapy as a single modality
In a 1975 study from M. D. Anderson Hospital, 5-year survival rates with WAI and chemotherapy were similar, although toxicity and cost seemed to be lower with oral melphalan (Alkeran). A subsequent trial from Toronto randomized patients with advanced disease between pelvic radiotherapy plus chlorambucil (Leukeran) and WAI. Although surgical staging and chemotherapy were less aggressive than current protocols, the survival advantage and altered failure patterns seen with the Canadian WAI regimen were quite provocative.
No prospective, randomized trial has compared WAI, performed with modern techniques and equipment, with a modern chemotherapy regimen. However, published series document treatment outcomes with WAI that are at least comparable, if not superior, to outcomes with platinum-based chemotherapy regimens. The comparability of WAI to newer chemotherapy regimens, such as those including paclitaxel, also is unknown. In view of the encouraging data reported, WAI should be studied further using current concepts and techniques.
Large-volume disease The ability of WAI to sterilize macroscopic deposits of ovarian carcinoma is limited. Patients with any site of residual disease > 1 cm have compromised outcomes, no matter what therapy they receive. However, given the limited radiation tolerance of the abdominal organs, patients with larger volumes of disease are not candidates for WAI as sole adjuvant treatment.
Chemotherapy plus radiation
It is possible to identify patients for whom chemotherapy or radiotherapy is very unlikely to be curative because of unfavorable histologic subtype, grade, and amount of residual disease following surgical cytoreduction. Combined-modality therapy incorporating various combinations and sequences of chemotherapy and radiation therapy has been studied in these patients.
Chemotherapy plus WAI Sequential combined-modality therapy (CMT) employing chemotherapy and irradiation has been shown to be feasible. There are a number of important differences between sequential CMT and salvage irradiation: (1) Planned sequential CMT permits the omission of second-look surgery in selected patients, possibly limiting late toxicity. (2) Clinical studies of CMT have often incorporated a reduction in chemotherapy duration, providing improved tolerance to radiation therapy; this permits appropriate radiation doses to be given and potentially limits the emergence of platinum-radiation therapy cross-resistance. (3) With CMT, many patients will have no demonstrable disease but are at high risk of recurrence, whereas with salvage WAI, all patients have clinical or pathologic evidence of disease.
In a recent European study, 64 of 94 patients with stage IC-IV disease who had undergone "radical" surgery and who had no evidence of gross residual disease after 6 courses of chemotherapy (carboplatin, epirubicin, and prednimustine [Sterecyt]) were randomized to receive either (1) consolidation WAI (30 Gy), followed by a boost to the para-aortic region and pelvis (12 and 21.6 Gy, respectively), or (2) no further therapy. Relapse-free survival rates were significantly higher in patients who received adjuvant chemoradiation than in those who received adjuvant chemotherapy only (2- and 5-year relapse-free survival rates, 68% vs 56% and 49% vs 26%, respectively); the same was true of overall survival rates (2- and 5-year overall survival rates, 87% vs 61% and 59% vs 33%, respectively). The differences between the two treatment groups were more pronounced in patients with stage III disease (2- and 5-year relapse-free survival rates, 77% vs 54% and 45% vs 19%, respectively; 2- and 5-year overall survival rates, 88% vs 58% and 59% vs 26%, respectively).
Einhorn et al, from the Karolinska Hospital in Stockholm, treated 75 patients with stages IIB-IV ovarian carcinoma with combined surgery, chemotherapy and whole abdominal RT to 40 Gy, utilizing a "six-field" approach. Outcomes were compared to those of 98 patients treated in subsequent years with only surgery and chemotherapy. After controlling statistically for different prognostic factors, it was found that patients who received WAI had a significantly better survival rate. The authors suggest that, given the results of this and other studies combined with the very limited success of modern combination chemotherapy regimens, the role of abdominal RT should be further investigated in a prospective fashion.
Salvage radiotherapy after chemotherapy
Patients in whom microscopic disease is detected at surgical reassessment have been reported to have median overall and progression-free survival times of 27 and 19 months, respectively. Unfortunately, residual or recurrent disease following first-line chemotherapy is frequent and salvage rates are dismal.
Patients with residual tumor detected at a planned surgical reassessment have a spectrum of disease, ranging from isolated positive cytology and/or microscopic serosal involvement to gross residual disease. In contrast, relapsing patients generally present with abdominal symptoms from advanced larger-volume recurrences. The latter clinical situation is not particularly amenable to salvage radiotherapy. However, in the setting of small-volume residual disease detected immediately following chemotherapy, two radiotherapy approaches, external-beam radiation and intraperitoneal radioisotopes, have been used with variable success. Most likely, this variability is related to significant differences in prognostic factors among treated patients. Unfortunately, there are only limited data that can be used to define subgroups who may or may not benefit from salvage WAI. Given the number of possible prognostic variables , a clear consensus on this issue is unlikely to be reached.
Chemotherapy-refractory disease Favorable experiences with salvage radiation therapy in chemotherapy-refractory ovarian carcinomas continue to be reported. Sedlaceck et al described 27 patients who had not responded to aggressive cytoreductive surgery followed by multiple-drug platinum-based chemotherapy and who received WAI (30-35 Gy at 100-150 cGy/fraction, with a pelvic boost to a total dose of 45 Gy). The 5-year survival rate was 15%. Residual disease at the initiation of radiation therapy strongly correlated with length of survival.
Baker et al analyzed the efficacy of salvage WAI in 47 patients with ovarian cancer who had not responded to one or more chemotherapy regimens. Actuarial 4-year survival and disease-free survival rates were 48% and 37%, respectively, in patients with microscopic residual disease, vs 11% and 5%, respectively, in patients with macroscopic residual disease. In addition, patients with disease limited to the pelvis after laparotomy (including gross disease) had a 4-year actuarial survival rate of 60% and disease-free survival rate of 54%, as compared with 16% and 4%, respectively, in patients with upper abdominal involvement. Bowel complications developed in 22% of patients, 12% of whom required surgical intervention.
Similarly, high response rates were reported by Suzuki et al in a series of patients with platinum-refractory disease, most of whom had already received taxane-based second-line chemotherapy.
Based on these and other studies, certain treatment guidelines can be suggested:
Patients with any site of residual disease > 0.5 cm will fare poorly with salvage WAI. However, salvage WAI can be considered in selected patients with microscopic residual disease following first-line chemotherapy.
Radiation-related morbidity can be minimized by limiting the abdominal dose to 25 Gy and by abandoning WAI in patients who require treatment breaks of more than 1-2 weeks. In fact, randomized clinical trial data from Fyles et al show no benefit from WAI doses > 22.5 Gy.
Patients with limited gross residual disease confined to the pelvis may constitute a prognostically favorable group in whom pelvic boosts may be warranted.
The relative merits of salvage WAI compared to other treatments, such as intraperitoneal chemotherapy, second-line chemotherapy, and high-dose chemotherapy/bone marrow transplantation, can only be determined in a prospective, randomized, controlled trial.
Radiotherapy as palliative treatment
Patients with grossly recurrent or metastatic ovarian carcinoma following first-line and sometimes second-line chemotherapy often have significant symptoms that do not respond to further systemic therapy. Symptoms are most commonly due to recurrent disease in the pelvis, which causes pain and/or bleeding, but recurrences in the brain, chest, groin, and other areas can also produce symptoms that are difficult to manage.
High rates of symptomatic response to palliative radiation therapy have been reported by Gelblum et al in platinum-refractory ovarian carcinoma. In this series of 33 evaluable patients, 70% had complete resolution of symptoms, and the median response duration was 11 months.
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