Ovarian Cancer

Overview

Despite the fact that it is highly curable if diagnosed early, ovarian cancer causes more mortality in American women each year than all other gynecologic malignancies combined. An estimated 22,280 new cases of ovarian cancer will be diagnosed in the United States in 2016, with about 14,240 deaths.

Notable advances in chemotherapy and surgery over the past several decades have begun to translate into improved survival. According to American Cancer Society data, the 5-year overall survival rate from ovarian cancer has increased significantly, from 37% in the mid-1970s to 46% in the mid-2000s (P < .05). Recent data from the National Cancer Institute show a similar increase in stage-specific survival. It is expected that data from the current decade, reflecting continued improvements in chemotherapy and surgery, will continue this trend.

This chapter will focus on epithelial cancers of the ovaries, which account for about 90% of ovarian malignancies.

Epidemiology

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 61.5 per 100,000 women aged 75 to 79 years.

Race

The incidence of ovarian cancer appears to vary by race, although the effects of race are difficult to separate from those of environmental associations related to culture, geography, and socioeconomic status. In the United States, the age-adjusted rate of ovarian cancer for Caucasians is estimated to be 17.9 per 100,000 population, which is significantly higher than 11.9 per 100,000 for the African-American population. Unfortunately, while data indicate survival improvement for Caucasians, this trend is not reflected in survival rates for African-American women in the United States, where access to standard care is likely a key factor.

Geography

There are distinct geographic variations in the incidence of ovarian cancer, with the highest rates found in industrialized countries and the lowest rates seen in underdeveloped nations. Japan, with an incidence of only about 3 per 100,000 population, 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 women of Eastern European Jewish ancestry, who have an estimated incidence of 17.2 per 100,000 population, a probable result of the relatively high frequency of BRCA1 and BRCA2 mutations in this population.

Etiology and Risk Factors

The cause of epithelial ovarian cancer remains unknown. However, mounting evidence supports that 30% to 60% of serous “pelvic” cancers may arise from the oviduct or distal fallopian tube. Although it now appears certain that at the cellular level ovarian cancer results from the accumulation of multiple discrete genetic defects, the mechanism(s) by which these defects develop have yet to be determined. Evidence from studies of high-risk populations (BRCA mutation carriers) has revealed that ovarian or pelvic serous tumors may begin as a serous tubal intraepithelial carcinoma (STIC). Within these cell populations, p53 mutations are commonly found.

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 in the United States, approximately 5% to 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, although the magnitude of the reported increase is relatively modest. A low-fat diet may reduce the incidence of ovarian cancer among postmenopausal women.

Populations with a high dietary intake of lactose who lack the enzyme galactose-1-phosphate uridyltransferase have been reported to be at increased risk.

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.

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.

No association between exposure to ionizing radiation and the risk of ovarian cancer has been documented.

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.

Physical activity may decrease the risk of ovarian cancer.

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 ovarian cancer. Overall, the risk of the disease is directly proportional to the number of lifetime ovulations. Thus, suppression via various routes (increasing number of pregnancies, increased duration of lactation, and increased duration of oral contraceptive use) is associated with decreased risk of ovarian cancer.

Several analyses have documented that women with a history of low parity or involuntary infertility are at increased risk for ovarian cancer.

Tubal ligation significantly decreases the risk of ovarian cancer, as demonstrated by several epidemiologic studies.

Evidence suggests that treatment with ovulation-inducing drugs, particularly for prolonged periods, may be a risk factor, although it is difficult to separate the increased risk related to the infertility itself from the risk carried by use of ovulation-inducing agents.

Breastfeeding for long durations may decrease ovarian cancer risk.

Although the data are not consistent, some studies have shown an association between the use of postmenopausal hormone replacement and the development of ovarian cancer. Data from the Women's Health Initiative randomized trial of estrogen plus progestin showed a slight increase in the risk of ovarian cancer in users of hormone replacement therapy, although it was not statistically significant.

Several large case-controlled studies have documented a marked protective effect of oral contraceptives against ovarian cancer. Women who have used oral contraceptives for at least several years 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. Evidence suggests that the protective effect of oral contraceptives also applies to women carrying BRCA mutations.

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 ovaries or breasts, are themselves at increased risk for ovarian cancer. In the 1980s, Lynch and colleagues 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 (HNPCC).

Epidemiologically, these syndromes appear to be inherited as an autosomal dominant trait with variable penetrance. During the past decade, the specific genes responsible for HNPCC (MSH1 and MLH2) and for most cases of hereditary ovarian cancer have been identified, allowing fundamental observations to be made regarding their molecular pathophysiology.

The BRCA1 gene is classified as a tumor suppressor, since mutations in this gene increase the risk of breast and ovarian cancers. Definitive identification of the function of the protein translated from this gene remains to be elucidated, although 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 who carry a germline mutation of BRCA1 have a significantly elevated risk of both breast and ovarian cancers compared with the general population. The average population risk of developing breast cancer is about 12.5% (one in eight) and of 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 40% for breast and ovarian cancers, 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 for ovarian cancer, perhaps in the range of 15% to 20%.

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 usually 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 may account for the majority of hereditary ovarian cancers. Evidence from multiple studies suggests that BRCA1-related ovarian cancers may have a less aggressive clinical course than do sporadic ovarian cancers.

Hereditary ovarian cancers not related to BRCA1 are most often related to mutations in the BRCA2 gene.

The mean age of onset of ovarian cancer is significantly earlier in women with BRCA1 mutations-45 years-compared with age 60 in BRCA2-mutation carriers. For patients who have a BRCA1 or BRCA2 mutation, laparoscopic prophylactic risk-reducing salpingo-oophorectomy after childbearing can reduce the risk of both breast and ovarian carcinomas.

Signs and Symptoms

Early-Stage Disease

In the early stages, ovarian cancer may be an insidious disease, but nonspecific symptoms that may be clues to the diagnosis are present more often than previously thought. A case-controlled series by Goff et al proposed that a symptom index could be devised that might suggest a diagnosis of ovarian cancer. It was based on the presence of any of the following symptoms more than 12 times in a given month, but with overall duration less than 1 year: pelvic/abdominal pain, urinary frequency, increased abdominal size, and difficulty in eating (feeling full). When these criteria were met, the specificity for a diagnosis of ovarian cancer was 90% for women older than 50 years. This illustrates the diffuse nature of ovarian cancer symptoms, and taken alone will not yield early diagnosis in most patients. Thus, more than 70% of patients with ovarian cancer will present with disease beyond the confines of the ovaries at initial diagnosis.

Early ovarian cancer also may be detected as a pelvic mass noted fortuitously at the time of a routine pelvic examination. Imaging with sonography, CT, or magnetic resonance imaging (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. Approximately 50% of patients with early ovarian cancers have an elevated serum CA-125 level.

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 an omental tumor cake 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. Approximately 80% of patients with advanced ovarian cancer will have an elevated serum CA-125 level.

Screening and Diagnosis

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 (NIH) Consensus Conference (see full page of NIH guidelines) and the American College of Obstetricians and Gynecologists have issued statements advising against routine screening for ovarian cancer, which, because of its high false-positive rate, leads to an unacceptable amount of invasive interventions in women without significant disease.

In September 2009, the Food and Drug Administration (FDA) approved a test called OVA1 as an adjunct to other clinical and radiographic tests to help predict the likelihood that an adnexal mass might represent ovarian cancer. OVA1 uses a blood sample to test for levels of five proteins that change in women with ovarian cancer. The test combines the five separate results into a single numerical score between 0 and 10 to indicate the likelihood that a pelvic mass known to require surgery is benign or malignant. Approval of OVA1 was based on the FDA's review of a study of 516 patients that compared OVA1 results with biopsy results. A total of 269 of these patients were evaluated by non-gynecologic oncologists. Results of the study also indicated that OVA1 may help identify patients who might benefit from referral to a gynecologic oncologist. The study was presented earlier in 2009 at a meeting of the Society of Gynecologic Oncologists (Ueland et al: Gynecol Oncol 2010).

Recent studies using serum proteomics to screen for early ovarian cancer have yielded disappointing results. Work in this area is ongoing and may result in a clinically useful assay.

Management of women from families with hereditary ovarian cancer is controversial. Evidence suggests that surveillance of such women with serum markers and sonography is of limited benefit in early detection of ovarian cancer and does not reduce mortality of the disease. Most experts recommend prophylactic laparoscopic excision of the ovaries and fallopian tubes after age 35 if the woman has completed childbearing, because several studies have shown that it will dramatically reduce the risk of ovarian cancer. Evidence also suggests that prophylactic oophorectomy, before the age of 40, substantially lowers the risk of breast cancer in women from high-risk families.

Patients with suspected ovarian cancer should undergo a thorough evaluation before surgery. This assessment should include a complete history and physical examination and serum CA-125 level determination. In women younger than 30, determinations of β-human chorionic gonadotropin and α-fetoprotein levels are useful, because germ cell tumors are more common in this age group.

Currently, four major studies are evaluating the role of screening in the general population, using some combination of ultrasound, CA-125, and in some cases predictive algorithm. The ovarian arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was a randomized controlled trial of 68,616 women aged 55 to 74, of whom 30,630 underwent screening between 1993 and 2007. The long follow-up resulted in 40.6% of women with ovarian cancer in the study arm being diagnosed after the end of screening. It was these findings that led the United States Preventive Services Task Force (USPST) to reconfirm that screening for ovarian cancer should not be undertaken in the low-risk population.

The Kentucky Screening Study was a single-arm annual ultrasound screening study of 25,327 women. At a mean follow-up of 5.8 years, the 5-year survival rates in women diagnosed with primary invasive epithelial ovarian cancer (screen positives and interval cancers) in the screening study were significantly higher (74.8% ± 6.6%) compared with women treated at the same institution during the same period who were not study participants (53.7% ± 2.3%). However, these rates are not comparable, owing to the ‘lead time effect’ of screening. In addition, since the Kentucky Study was not a randomized controlled trial, it is likely that there was a significant ‘healthy volunteer effect’ that contributed to higher survival among those who participated.

The Japanese Shizuoka Cohort Study of Ovarian Cancer Screening was a randomized controlled study of 82,487 low-risk postmenopausal women who were screened using an annual ultrasound and CA-125, using a cut-off value. The trial showed encouraging sensitivity (77.1%) and specificity (99.9%), with the screened women more likely to have ovarian cancer detected at an early stage (63%) compared with women in the control arm (38%). However, the mortality effect has not yet been reported.

The largest screening trial to date is the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), a randomized controlled trial of 202,638 women from the general population who were randomized in 2001 through 2005 to no intervention (control) or annual screening using either transvaginal ultrasound (USS) or serum CA-125 interpreted by a ‘Risk of Ovarian Cancer’ algorithm (ROCA), with transvaginal ultrasound as a second-line test (multimodal screening, MMS). The findings were reported in 2013 by Menon et al. Positive predictive value was significantly higher in the MMS group (35.1% vs 2.8% in USS), resulting in lower rates of repeat testing and surgery. The performance of the ultrasound strategy was similar between PLCO and UKCTOCS. The proportion of cases detected in stage I/II was 47.1% at prevalence and 40.3% at incidence in the MMS arm and 50% at prevalence and 51.5% at incidence in the USS arm. Screening in the trial was completed in December 2011. Results of the mortality impact were reported by Jacobs et al in The Lancet in March 2016 (and online before print in December 2015). The authors wrote that their prespecified analysis of mortality from ovarian cancer of MMS vs no screening, with prevalent cases excluded, yielded a significant difference in death rates (P = .021) in favor of MMS, with an overall average mortality reduction of 20% (range: −2 to 40), and an average mortality reduction of 8% in years 0–7 (range: −27 to 43) and of 28% in years 7–14 (range: −3 to 49). They emphasized that additional follow-up is needed before firm conclusions can be drawn regarding the efficacy and cost-effectiveness of ovarian cancer screening. Cancer Research UK put the findings into context in a newsbrief when the results were first published in late 2015.

Abdominal CT and MRI

CT or MRI may be useful in providing a preoperative assessment of disease extent in probable advanced-stage cases.

Exploratory Laparotomy

The diagnosis of ovarian cancer is generally made by histopathologic study following exploratory laparotomy or laparoscopy. The stage of the disease can only be determined by surgery, as discussed later.

Preoperative Endometrial Sampling

Women with abnormal vaginal bleeding should undergo preoperative endometrial sampling to ensure the correct differential diagnosis between potential advanced endometrial or ovarian cancers or, rarely, both.

Preoperative Cytologic or Histologic Evaluation

Preoperative cytologic or histologic evaluation may be utilized to determine definitive pathologic diagosis. The standard of care is to utilize laparoscopy or laparotomy as both a diagnostic and therapuetic option. However, patients with ascites, plueral effusions, and carcinomatosis can be undergo paracentesis, thoracentesis or needle biopsy for diagnostic purposes. These procedures may be useful when the differential diagnosis includes pancreatic or gastrointestinal cancers. They may also provide an accurate diagnosis when the patient is not deemed to be a surgical candidate, based on cormorbid conditions or extent of disease involvement.

Pathology

The ovaries are notable for their 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 on the surface of the ovaries. 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 exist as “borderline” cancers, also known as “tumors of low malignant potential.” There is some prognostic significance to the cell type of the tumor, with clear-cell and mucinous varieties tending to be especially virulent in the advanced-disease setting, as they are more chemotherapy-resistant.

Pathologists also classify adenocarcinomas according to the degree of histologic differentiation. Those tumors that retain clear-cut glandular features are considered grade 1, or well differentiated, whereas those that are largely composed of solid sheets of tumor are considered grade 3, or poorly differentiated. Tumors that show both glandular and solid areas are assigned to grade 2. The histologic grade seems to correlate roughly with biologic aggressiveness.

Stromal and Germ Cell Tumors

Malignancies can also arise from the ovarian stroma or the primordial germ cells contained within the ovaries. 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 ovaries. Malignant germ cell tumors occur primarily in younger patients, with an average age at diagnosis of about 19 years.

Staging and Prognosis

TABLE 1: FIGO staging system for ovarian cancer

Staging System

The staging system for ovarian cancer shown in Table 1, 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 or laparoscopy in the hands of an advanced laparoscopic surgeon, 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, although exceptions to this rule can be made for younger women with limited disease who may wish to retain fertility.

At the time of exploration for an adnexal mass, 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% to 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, uninvolved ovary, and fallopian tubes. It is important that an individual with specialized training in gynecologic oncology be available to assist in the event that the mass is malignant. Less optimal, but sometimes necessary, is for the operating surgeon to remove only the involved ovary and refer the patient to a surgeon with specialized training in gynecologic oncology to reoperate on the patient.

The elements of surgical staging for apparent early ovarian cancer are listed in Table 2.

TABLE 2: Procedures for surgical staging for apparent early ovarian cancer

Prognostic Factors

The prognosis of epithelial ovarian cancer depends on a number of factors.

Disease stage

Of primary importance is the 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% to 50% chance of 5-year survival, whereas those patients with stage III disease left with bulky tumor masses 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 less importance, although patients with clear-cell and mucinous tumors have a worse prognosis.

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 HER2, p53, ras, and other oncogenes and tumor-suppressor genes have had varying results relative to prognostic significance. Currently, the assessment of molecular markers is ongoing in numerous studies, in the hope of identifying clinically relevant targets that are susceptible to available agents. The continued progress in developing high-throughput techniques for determining gene and protein expression increases the likelihood that good candidates will be found. The Cancer Genome Atlas Project is currently evaluating gene expression patterns to see whether these corrlate with overall survival and would predict response to targeted therapies. To date, ovarian cancer appears to be more one of DNA instability (“BRCA-ness”) rather than having frequent and easily identifiable driver mutations that are targetable with currently available novel agents.

Predictors of chemosensitivity

Despite a continued effort to assess in vitro methods to predict the sensitivity or resistance of ovarian cancers to various chemotherapeutic drugs, the clinical usefulness of such an approach remains under investigation. The American Society of Clinical Oncology (ASCO) recently reviewed the relevant literature on the subject and reached the same conclusion for cancers in general.

Treatment

Surgery plays a crucial role in all phases of the management of ovarian cancer and, when applied as part of a multidisciplinary approach, affords patients the highest likelihood of a favorable outcome. For most patients with ovarian carcinoma, surgery is not curative because of dissemination of tumor cells throughout the abdominal cavity. Therefore, successful management generally requires additional treatment.

The use of postoperative chemotherapy is standard for all patients with advanced-stage disease and for many patients with early-stage disease. Adjunctive chemotherapy significantly prolongs survival, with most current data supporting the use of platinum- and taxane-based regimens.

Despite a long history of the use of radiation therapy in ovarian carcinoma, because of the low sensitivity of ovarian cancer to radiation in general, opinions on indications for its use differ widely. Presumably, this controversy is due to the limited amount and adequacy of data comparing radiotherapy with modern chemotherapy regimens, as well as concerns regarding potential toxicities. Studies using radiation in both radical and palliative settings have been published, but standardization of the use of radiation varies significantly worldwide.

Management of Early-Stage Disease

Clearly, comprehensive surgical staging is necessary to properly identify patients with stages I and II ovarian carcinoma. Beyond surgery, the need for adjuvant treatment with chemotherapy has been recently supported, with the exception of patients with stage I disease and well-differentiated histology.

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 previously (see section on “Staging and prognosis”), it is of critical importance that surgical staging be performed systematically and completely. Inadequate staging may result in inappropriate postoperative treatment, which can severely compromise the chances for cure.

Data from the American College of Surgeons community hospital–based tumor registry show that almost 75% of the primary surgeries for ovarian cancer performed in this country are done so without the involvement of a gynecologic oncologist. This finding is unfortunate given the fact that with physical examination, measurement of cancer antigen 125 (CA-125) levels, 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.

Conservation of reproductive organs. 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 she wishes to maintain the option of future fertility. To facilitate such intraoperative decision making, it is essential that the surgeon's preoperative discussion with the patient and her family address the possibility of malignancy and review the surgical options for both benign and malignant diseases.

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. Depending on tumor size, level of involvement with other structures and patient factors, gynecologic oncologists possessing advanced skills in minimally invasive surgery may choose this approach, utilizing the same surgical principles of removal without spill and complete surgical staging. Laparotomy should be the default procedure if the oncologist lacks these advanced skills .

Systemic chemotherapy for early-stage disease

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% to 80% in patients who have early-stage tumors with high-risk features suggested a potential role for adjuvant therapy. The Italian Interregional Cooperative Group (IICG) conducted two randomized trials to evaluate the role of adjuvant therapy in patients with stage I disease. The first trial compared cisplatin, 50 mg/ m² q28d × 6, with 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) with phosphorus-32 (P-32) administration in 161 patients with stages 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. P-32 administration was associated with more long-term toxicity.

More recent data have provided support for a survival benefit to the immediate use of adjuvant chemotherapy in patients with early-stage disease. The results of the European Organisation for Research and Treatment of Cancer (EORTC)–Adjuvant Treatment in Ovarian Neoplasms (ACTION) trial and the International Collaborative on Ovarian Neoplasms (ICON) 1 trial were combined and reported. An absolute 5-year survival rate improvement of 8% was reported for those who received immediate chemotherapy compared with reserving chemotherapy for those who relapsed (74% vs 82%; 95% CI, 2%–12%).

Improvements in systemic chemotherapy for advanced ovarian cancer with associated improvements in survival are relevant to the design of regimens for early-stage disease. The Gynecologic Oncology Group (GOG) 157 evaluated three vs six cycles of paclitaxel and carboplatin in patients with stage IA or IB, grade 2–3; stage IC; or stage II disease. The trial completed accrual in 1995, and final results showed no significant benefit to the longer regimen. The GOG replacement trial evaluated three cycles of paclitaxel plus carboplatin with or without additional weekly paclitaxel (40 mg/ m²) in patients with early-stage disease. These data are reported in abstract form, but no benefit to extended-schedule paclitaxel was seen.

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 the exception of well-staged IA or IB, grade 1 disease. The optimal number of cycles is currently unclear, but three cycles were considered the standard arm in the GOG 157 trial, although many clinicians offer six cycles of therapy in the absence of prohibitive toxicity.

Past GOG trials have established that patients with stages IA–IB, well-differentiated or moderately differentiated tumors have a 5-year survival rate of 90% to 98%, which does not seem to improve 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).

Radiation therapy

Whole-abdominal irradiation. The techniques used for whole abdominal irradiation (WAI) have changed dramatically over the past 40 years. Initially, treatments with a moving field of radiation caused an unacceptably high risk of bowel complications. Subsequent evolution to an AP-PA approach also produced potential liver, bowel, kidney and bone marrow toxicity. In the modern era, the use of intensity-modulated radiation therapy (IMRT) may be considered. IMRT reduces the bone marrow dose and liver dose, and tailors treatment in a more conformal manner. This technique is currently being tested in many institutions. The efficacy of WAI in ovarian cancer has been widely reported over many years but has always been hampered by the toxicities incurred. One study (Hepp et al: Int J Radiat Oncol Biol Phys 2002) found WAI to be an effective adjuvant therapy in patients with optimally debulked tumors. In a series of 60 patients, the 5-year survival rate was 55%, with a median follow-up of 96.5 months. Patients who received chemotherapy (n = 41) fared slightly worse than those who received radiation therapy only. The abdominal control rate was 83%, and the grade 3 and 4 late toxicity rates were 7% and 3%, respectively. A more recent prospective analysis from Canada showed a significant 20% disease-free survival benefit for patients treated with radiation after carboplatin/paclitaxel chemotherapy for stage IC and II clear cell carcinoma. The integration of post-chemotherapy radiation may be indicated in selected cases.

Management of Advanced Disease

Surgery

In the majority of cases (upwards of 75%), 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 surgery is performed by experienced gynecologic cancer surgeons, at least 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. Patients with optimally debulked disease have an increased likelihood of achieving a complete clinical response to chemotherapy. The disease progression–free interval, median survival, and long-term survival are all improved in patients who have optimal cytoreduction. Mounting evidence indicates that patients with no visible residual disease (R0) have the greatest improvement in outcome, and that this benchmark should represent the standard. To avoid bias that is related to single institutional and individual surgeon or group experience, data from several GOG clinical trials (GOG 111, 114, 132, 152, 158, 162, and 172) were analyzed by Winter et al (J Clin Oncol 2008) and revealed that R0 resection was achieved in 8.1% of women with advanced-stage resectable disease, and was associated with the longest median overall survival (64 months vs 29 months for patients with < 1 cm disease; HR = 2.09; 95% CI, 1.36–3.21; P = 0.008) compared with any visible residual disease remaining following surgery. Similarly, data from three European prospective randomized trials (AGO-OVAR 3, AGOOVAR 5, and AGO-OVAR 7), analyzed by du Bois et al (Cancer 2009), demonstrated that R0 resection was associated with significantly longer median overall survival (with R0 resection, survival of 99.1 months [95% CI, 8.35 to not reached] vs 36.2 months for patients with < 1 cm residual disease [95% CI, 34.6–39.4] vs 29.6 months for patients with >1 cm residual disease [95% CI, 27.4–32.2]; P < .0001) after stratifying for FIGO stage. This study further supports the concept that achieving a status of no visible residual disease should represent the standard for surgical debulking. Given the survival benefit observed with R0 resection, patients with advanced-stage ovarian cancer in whom R0 resection is unlikely to be achieved, especially without significant surgical morbidity, should potentially be considered for neoadjuvant chemotherapy followed by interval cytoreductive surgery. Many groups are working toward identifying “resectability” criteria and scoring systems that may better serve patients with advanced disease. Nomograms that may combine disease extent, CA-125 levels, age, and other variables are being assessed to better provide predictive scores for optimal cytoreduction.

Interval cytoreduction following suboptimal initial cytoreduction. In an EORTC trial, 299 patients with suboptimal advanced ovarian cancer were randomized to receive six 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 then completed a randomized trial of interval cytoreduction using a cisplatin-paclitaxel chemotherapy regimen. These results show no benefit for interval cytoreduction (median overall survival, 32 months vs 33 months). Taxane-based chemotherapy and more standardized aggressive initial debulking by experienced gynecologic oncologists in the GOG trial have been offered as possible explanations for the discordant outcomes. If an aggressive initial surgical attempt is provided by a gynecologic oncologist, interval surgical cytoreduction cannot be routinely recommended.

Chemotherapy

Primary treatment. The results of two randomized trials support a survival advantage for patients treated with combinations of IV platinum and paclitaxel, compared with those given a platinum plus cyclophosphamide. McGuire et al (N Engl J Med 1996) found a 37-month vs 24-month median survival advantage for the platinum-paclitaxel arm. Similarly, an analysis of the intergroup trial by Piccart et al (J Natl Cancer Inst 2000) showed an improvement in median survival from 25 months to 35 months (P = .001) in favor of the paclitaxel arm. In contrast, the initial analysis of the ICON 3 trial evaluating a control arm (carboplatin or cyclophosphamide, Adriamycin [doxorubicin], Platinol [carboplatin] chemotherapy) vs paclitaxel and carboplatin failed to show a survival advantage for the taxane-containing arm. Many factors in the study have been proposed to explain this difference, and for the present, taxane- and platinum-based therapy remains the standard.

A randomized trial (GOG 158) comparing paclitaxel (175 mg/m² via a 3-hour infusion) plus carboplatin (dosed to achieve an area under the concentration-time curve 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 showed the shorter schedule with carboplatin to be as effective as the older regimen. Because of its decreased toxicity and ease of administration, the shorter schedule with carboplatin is the preferred treatment.

In addition, the Scottish Randomized Trial in Ovarian Cancer (SCOTROC) trial suggested that as primary treatment, docetaxel and paclitaxel have similar efficacy when combined with carboplatin and that docetaxel produces less neuropathy.

A five-arm international randomized study of primary therapy for patients with stage III or IV disease evaluated carboplatin and paclitaxel as the control arm and studied two triplets (carboplatin + paclitaxel with either gemcitabine or liposomal doxorubicin [Doxil]) and two sequential doublets (topotecan/carboplatin + carboplatin/paclitaxel or carboplatin/gemcitabine + carboplatin/paclitaxel). No difference in progression-free survival or overall survival rates were seen among the arms, and therefore paclitaxel and carboplatin remains the standard. Based on the variety of phase III trials employing IV paclitaxel and carboplatin therapy following maximal surgical cytoreduction, the expected progression-free survival and overall survival rates for patients with stage III disease are as follows: stage III optimal (progression-free survival, 21 months to 28 months; overall survival, 52 months to 57 months) and stage III suboptimal (progression-free survival, 18 months; overall survival, 38 months).

A randomized trial by Katsumata et al also evaluated paclitaxel and carbolpatin given IV with one arm receiving paclitaxel at 80 mg/m² weekly vs conventional dosing at 175 mg/m² every 21 days. Of 631 eligible patients with stage II–IV disease, the progression-free survival outcome favored the dose-dense paclitaxel arm at 28.2 months vs 17.5 months (hazard ratio [HR] = 0.76; 95% CI, 0.62–0.91; P = .0037). Median overall survival was also higher for patients in the dose-dense arm (100.5 months vs 62.2 months; HR = 0.79, 95% CI, 0.63–0.99; P = .039).

GOG 262 also compared carboplatin plus dose-dense weekly paclitaxel at 80 mg/m² vs carboplatin plus conventional dosed paclitaxel at 175 mg/m² every 21 days, in patients with stage I–IV disease. The addition of bevacizumab (Avastin) was optional for patients in both arms of this study. The primary endpoint of the study was improved progression-free survival with dose-dense vs conventionally dosed paclitaxel. This study was presented at the 2013 meeting of the European Society of Gynecologic Oncology, with no difference in progression-free survival (14.8 months for dose-dense paclitaxel vs 14.3 months for conventional dosing; HR = 0.97; 95% CI, 0.79–1.18) by treatment group. However, in a stratified analysis, there was a progression-free–survival advantage for patients receiving dose-dense weekly paclitaxel (14.2 months vs 10.3 months for patients on conventional dosing; HR = 0.6; 95% CI, 0.34–0.96; P = .033) for those who opted not to receive bevacizumab that was lost in the group receiving the antibody (14.9 vs 14.9, HR = 1.06, 95% CI, 0.86–1.31; P = .6). Quality-of-life data presented at SGO in 2014 noted increased neurotoxicity and anemia but less neutropenia with the dose-dense regimen. Mature overall survival data are awaited. In addition, the results of the Medical Research Council UK ICON8 trial are awaited; this is a three-arm study assessing outcomes with carboplatin AUC 5 with paclitaxel at 175 mg/m² every 21 days vs carboplatin AUC 5 every 21 days with paclitaxel at 80 mg/m² weekly vs carboplatin AUC2 weekly with paclitaxel at 80 mg/m² weekly.

Sidebar: The Japanese Gynecologic Oncology Group (JGOG) presented the JGOG 3017 trial at the 2014 ASCO meeting. This was a randomized phase III study of conventionally dosed paclitaxel with carboplatin IV vs irinotecan with cisplatin as first-line therapy for patients with stage I–IV clear cell ovarian cancer, with a primary endpoint of progression-free survival. There was no difference in 2-year progression-free or overall survival between the two arms.

Neoadjuvant chemotherapy (NACT) with interval cytoreductive surgery. In patients with an inadequate performance status to undergo aggressive primary debulking or in whom the level of tumor involvement is not believed to support “optimal cytoreduction,” a “neoadjuvant” approach with paclitaxel and carboplatin is often considered for several cycles before a maximal cytoreductive effort. A large randomized trial reported by Vergote et al evaluated the use of neoadjuvant chemotherapy in 670 patients with stages IIIC–IV ovarian cancer. Patients were randomized to undergo primary debulking followed by six courses of paclitaxel and carboplatin chemotherapy (arm A) or to receive three courses of neoadjuvant chemotherapy, interval debulking, and then three additional courses (arm B). In the reported data, median overall survival was 29 months and 30 months for arms A and B, respectively (HR = 0.098; 90% CI, 0.84–1.13); the median progression-free survival was 12 months in both arms (HR = 1.01; 90% CI, 0.89–1.15). The overall survival in both arms was lower than expected, but there was no difference between them. The approach is still controversial, and most gynecologic oncologists still consider primary surgical debulking the standard of care, reserving neoadjuvant therapy only for those patients in whom primary optimal debulking will not be achieved. Further developments in this area will be forthcoming.

Sidebar: The JGOG presented a phase III study of upfront surgery vs neoadjuvant chemotherapy at the 2014 ASCO meeting. The primary endpoint of this study is overall survival. The investigators noted a decreased in operative time and in adverse postoperative events with neoadjuvant therapy, however the progression-free and overall survival data for this study are expected in 2017.

The role of bevacizumab in primary treatment. Bevacizumab has demonstrated activity in patients with recurrent ovarian cancer. Response rates of 16% and 21% have been reported when it is used as a single agent and a rate of 24% was shown when it is used in conjunction with oral cyclophosphamide. The progression-free intervals across trials range from 4.4 months to 7.2 months, and the median overall survival ranges from 10.7 months to 17 months. This prompted evaluation of bevacizumab as part of primary treatment. An important and large first-line chemotherapy trial (GOG 218) randomized patients with stages III and IV ovarian cancer following surgical debulking to receive paclitaxel and carboplatin + placebo followed by placebo maintenance (total therapy, 15 months); paclitaxel and carboplatin + bevacizumab (at 15 mg/kg) followed by placebo maintenance; or paclitaxel and carboplatin + bevacizumab (at 15 mg/kg) with bevacizumab maintenance. This trial evaluated toxicity, progression-free survival, and overall survival. A total of 1,873 patients were enrolled in the study. The baseline clinical characteristics were well balanced. Adverse events were typical of those seen in other bevacizumab-containing studies. Hypertension was seen in 16% to 22% of the bevacizumab-containing arms, and bowel perforations occurred in fewer than 3%. The median progression-free survival was 10.3 months for patients treated with chemotherapy alone vs 14.1 months for those who received extended-schedule bevacizumab (HR = 0.717; 95% CI, 0.625–0.824; P < .001). No difference in overall survival was seen. However, as 40% of patients in the chemotherapy-only arm subsequently received bevacizumab at progression, a potential overall survival would be difficult to demonstrate. The ICON 7 study evaluated paclitaxel and carboplatin with or without bevacizumab (at 7.5 mg/kg) for 12 additional cycles, with recent follow-up showing a progression-free survival advantage in favor of bevacizumab of 21.8 months vs 20.3 months (HR = 0.81; 95% CI, 0.70–0.94; P = .004). A trend toward a survival advantage is seen in patients who entered the study with bulk disease (“high risk”) but not in those without bulk disease (“low risk”). No differences in overall survival have emerged. Important differences in this study are the bevacizumab dose; length of administration; and the eligibility criteria, which included high-risk early-stage patients.

As a result of these data, there are many questions to consider regarding bevacizumab use in the first-line setting. Key questions are: Will there be an overall survival benefit in prolonged follow-up? If not, is a strategy that prolongs only progression-free survival sufficient? How long should bevacizumab be given? Should it be continued longer than 15 months, until disease progression, or for life? What happens when bevacizumab is discontinued? Is the phenotype of relapsed disease on bevacizumab more aggressive? Finally, is the proportion with “cure” improved by prolonged bevacizumab?

Intraperitoneal chemotherapy

The randomized study by Armstrong et al employed intraperitoneal (IP) therapy as part of primary treatment. They showed a median overall survival of 65.6 months for the IP arm vs 49 months for the IV group. This finding represents the largest difference to date between two treatment arms in any study evaluating primary therapy. The study is the third (to be discussed further below) in a series of studies supporting the IP administration of primary chemotherapy to optimally debulked stage III patients.

The first study (Alberts et al: N Engl J Med 1996) predated paclitaxel and carboplatin use and simply asked the question of whether the IV or IP administration of cisplatin was better, showing an advantage for the latter (median overall survival, 49 months vs 41 months; P = .02) This first IP study has been criticized because it does not contain paclitaxel and thus does not reflect contemporary treatment.

The second study, by Markman et al (J Clin Oncol 2003), included paclitaxel, but the experimental arm not only included IP delivery of cisplatin but also added high-dose IV carboplatin in an attempt to “chemically debulk” the tumor before IP administration. The Markman study, while also showing an advantage for the IP-containing experimental arm (overall survival, 52 months vs 63 months; P = .05), was criticized because more than one variable was changed and the benefit could not be directly attributed to IP therapy.

As previously discussed, the third and well-designed trial by Armstrong et al showed a median overall survival of 65.6 months for the IP arm vs 49 months for the IV group. This study used IV paclitaxel (135 mg/m²) over 24 hours on day 1, IP cisplatin (100 mg/m²) on day 2, and IP paclitaxel (60 mg/m²) on day 8 for six total cycles. Because of increased toxicity in the IP arm (metabolic, neuropathy), only 42% of patients completed all six cycles. However, a quality-of-life analysis at 12 months showed no difference between the IP and IV groups, suggesting the toxicity was reversible.

The consensus opinion is that patients with stage III optimally debulked disease should be offered IP primary therapy. Studies are under way to modulate the regimen in an attempt to preserve the benefit and lessen toxicity. Initial modifications have included changing the IV paclitaxel to 135 mg/m² over 3 hours on day 1 and lowering the IP cisplatin dose to 75 mg/m² on day 2. If toxicity becomes prohibitive for a given patient, therapy is completed using IV paclitaxel and carboplatin. For patients not suited for IP treatment or for patients with suboptimally debulked stage III disease or those with stage IV disease, IV paclitaxel with carboplatin also remains the standard.

Sidebar: GOG 252 is a three-arm randomized study comparing IV dose-dense weekly paclitaxel at 80 mg/m² with IV carboplatin vs IV dose-dense weekly paclitaxel at 80 mg/m² with IP carboplatin vs conventional dose IV paclitaxel at 135 mg/m² every 21 days with IP cisplatin and IP paclitaxel. This study has completed accrual and results are expected in 2016. All arms of this study received bevacizumab as both concurrent treatment and maintenance therapy.

Radiation therapy as a single modality

In ovarian cancer, no prospective randomized trial has compared WAI, performed with modern techniques and equipment, with a paclitaxel-containing chemotherapy regimen. It has been demonstrated that the ability of WAI to sterilize macroscopic deposits of ovarian carcinoma is limited. Patients with any site of residual disease of greater than 1 cm have compromised outcomes. The limited radiation tolerance of the abdominal organs also limits the radiation dose. Chemotherapy remains the standard of care for the adjuvant treatment of ovarian cancer.

Chemotherapy plus radiation therapy

Sequential combined-modality therapy employing chemotherapy and irradiation has been shown in randomized trials to significantly increase survival compared with use of chemotherapy alone. A phase III prospective randomized trial in patients with stage III ovarian cancer from the Swedish-Norwegian Group showed a significant 20% improvement in 5-year progression-free survival for patients treated with chemotherapy and WAI vs chemotherapy alone. Similarly, a study in stage I–II clear cell carcinoma patients showed a 20% survival advantage for the use of radiation after carboplatin and paclitaxel chemotherapy.

In another European study, 64 of 94 patients with stages IC–IV disease who had undergone “radical” surgery and had no evidence of gross residual disease after six courses of chemotherapy (carboplatin, epirubicin, and prednimustine) were randomized to receive either consolidation WAI (30 Gy), followed by a boost to the para-aortic region and pelvis (12 and 21.6 Gy, respectively), or no further therapy. Relapse-free survival rates were significantly higher in patients who received adjuvant chemoradiation therapy than in those who received adjuvant chemotherapy only (2-year and 5-year relapse-free survival rates, 68% vs 56% and 49% vs 26%, respectively); the same was true of overall survival rates (2-year 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-year and 5-year relapse-free survival rates, 77% vs 54% and 45% vs 19%, respectively; 2-year and 5-year overall survival rates, 88% vs 58% and 59% vs 26%, respectively).

Einhorn et al (Radiother Oncol 1999), from the Karolinska Hospital in Stockholm, treated 75 patients with stages IIB–IV ovarian carcinoma with combined surgery, chemotherapy, and WAI to 40 Gy, using a “six-field” approach. Outcomes were compared with those of 98 patients treated in subsequent years with only surgery and chemotherapy. After different prognostic factors were controlled statistically, it was found that patients who received WAI had a significantly better survival rate than those who did not. The authors suggest that given the results of this and other studies combined with the limited success of modern combination chemotherapy regimens, the role of abdominal radiation therapy should be further investigated in a prospective fashion.

Despite these successful European trials, the regimen of chemotherapy and radiation in the up-front management of stage III ovarian cancer has not been implemented in the United States because of many factors. Paclitaxel-based chemotherapy provides a significant benefit for patients, as does IP chemotherapy. The use of radiation may increase potential bowel toxicity, particularly IP chemotherapy, and in some patients may cause bone marrow suppression, which theoretically may hinder future administration of chemotherapy.

Recurrent disease

Patients who progress on primary platinum treatment are classified as refractory. Patients who respond (approximately 70%) and then have a recurrence are generally categorized into those who relapse 6 months or less from prior therapy (considered platinum-resistant) or those who relapse more than 6 months after treatment (considered platinum-sensitive).

Data presented by Rustin et al at the 2009 ASCO meeting indicate that in women whose ovarian cancer is in clinical complete remission, early treatment of relapse immediately after the patient tests positive for elevated CA-125 levels does not improve survival over delaying treatment until clinical symptoms of relapse occur, such as pelvic pain or bloating. In their study, these investigators compared overall survival in 265 women with ovarian cancer in remission after initial chemotherapy who began second-line chemotherapy after experiencing a rise in CA-125 level with overall survival in 264 women with rising CA-125 levels whose treatment was delayed until symptoms of relapse appeared. Second-line chemotherapy was started in the early-treatment group a median of 5 months before it was started in the delayed-treatment group. At the time the study was presented, overall survival was the same between both groups (HR = 1.01; 95% CI, 0.82–1.25; P = .91). Researchers concluded that there was no survival benefit from early treatment based on a raised serum marker level alone. They added that consequently, there was no value in routine measurement of CA-125 levels in the follow-up of ovarian cancer patients.

Platinum-resistant recurrence. For platinum-resistant patients, a series of agents have demonstrated modest activity, and they are chosen on the basis of schedule and expected toxicity. Doublets have not been shown to be more effective than sequential single agents for patients with platinum-refractory or platinum-resistant disease. Topotecan and liposomal doxorubicin have FDA approval as single agents for ovarian cancer patients with recurrence.

TABLE 3: Chemotherapy regimens for ovarian carcinoma

An open randomized study compared topotecan (1.5 mg/m²/d for 5 days) with 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 weeks vs 21.6 weeks), or median survival (63 weeks vs 53 weeks). Liposomal doxorubicin was then compared with topotecan in patients with metastatic platinum- and paclitaxel-refractory disease in a randomized trial by Gordon et al, which showed similar response rates, time to disease progression, and median survival (60 weeks vs 56.7 weeks) in the overall population.

Phase II trials have demonstrated the activity of other agents in patients with recurrent ovarian cancer. They include gemcitabine, vinorelbine, oral altretamine, oral etoposide, irinotecan, bevacizumab and, recently, pemetrexed. In general, these agents have similar response rates, ranging from 10% to 15% in patients with platinum-resistant disease and 30% in patients with platinum-sensitive disease, with a median duration of response ranging from 4 months to 8 or more months. With the judicious selection and dosing of available agents to keep symptoms from disease and treatment to a minimum, a good quality of life can be maintained throughout much of the disease course.

Platinum-sensitive recurrence. A randomized ICON 4/Arbeitsgemeinschaft Gynaekologische Onkologie Studiengrappe Ovarialkarzinom (AGO-OVAR) 2.2 study addressed the issue of using single-agent carboplatin vs paclitaxel with carboplatin for patients with platinum-sensitive recurrent disease (defined generally as patients relapsing more than 6 months from prior platinum therapy). Both progression-free survival (HR = 0.76; 95% CI, 0.66–0.8; P = .0004) and 1-year overall survival rates (50% vs 40%) favored combination therapy. An AGO study evaluating carboplatin vs carboplatin with gemcitabine in a similar population was reported. This study likewise showed an improved response rate (47.2% vs 30.9%; P = .0016) and disease progression-free survival (8.6 months vs 5.8 months; P = .0031) favoring the combination.

Results of the CALYPSO study have been reported in the platinum-sensitive population. This study compared paclitaxel and carboplatin with liposomal doxorubicin and carboplatin. It showed an extended progression-free survival favoring the liposomal doxorubicin and carboplatin combination, from 9.4 months to 11.3 months (HR = 0.82; 95% CI, 0.72–0.94; P = .005). Additional follow-up showed no difference in overall survival between the two arms. Taken together, these data at a minimum suggest a benefit for platinum-based combination therapy over single-agent carboplatin in patients with platinum-sensitive recurrence; there was no difference in overall survival (31.5 months for both groups; P = .987), suggesting equivalence of the paclitaxel and carboplatin regimens in terms of efficacy. The benefits of the nontaxane doublets for platinum-sensitive recurrence (ie, with gemcitabine or liposomal doxorubicin) include the lack of worsening neuropathy and no alopecia, making these attractive alternatives in this patient population.

The role of antivascular agents in recurrent disease

The single-agent and combination chemotherapy response rates for bevacizumab in patients with recurrent disease are reviewed in the section justifying the clinical trials and evaluating its potential use in the first-line setting. Several large important phase III studies are also ongoing in patients with platinum-sensitive recurrent disease (defined as > 6 months from prior platinum treatment). The GOG trial (ClinicalTrials.gov identifer: NCT0056551) is randomizing patients with recurrent disease to a secondary debulking or not and then to paclitaxel and carboplatin with or without bevacizumab. Primary objectives are to determine whether secondary surgical cytoreduction followed by adjuvant chemotherapy with or without bevacizumab prolongs overall survival. Bevacizumab is continued in responders to evaluate the potential benefit of maintenance. Secondary objectives are to evaluate progression-free survival and quality of life, with a planned enrollment of 660 patients.

The ICON 6 study (ClinicalTrials.gov identifer: NCT00544973) is evaluating patients treated with paclitaxel and carboplatin with or without AZ2171 (cediranib) and includes both a concurrent arm and a concurrent approach followed by maintenance therapy. Primary endpoints are safety, progression-free survival, and overall survival, with a planned enrollment estimate of 2,000 patients. The OCEANS study, with 484 patients enrolled, evaluated use of gemcitabine and carboplatin with or without bevacizumab in patients with platinum-sensitive disease, with continued administration of bevacizumab until progression or toxicity. The primary endpoint was progression-free survival; secondary endpoints included overall survival and safety, particularly characterizing the incidence of gastrointestinal perforation. Preliminary results were presented at ASCO 2011. The arms were well balanced. Efficacy outcomes favored the bevacizumab arm, with response rates of 79% vs 57% (P < .0001) and progression-free survival of 12.4 months vs 8.4 months (HR = 0.484; 95% CI, 0.388–0.605; P < .0001). All subgroups (platinum-free interval, age, performance status, and presence or absence of cytoreductive surgery) showed similar benefit. A difference in overall survival was not noted. Toxicity was as seen in previous studies, with hypertension and proteinuria being the most common (but manageable) toxicities; no bowel perforations were seen. The combination of gemcitabine and carboplatin with bevacizumab followed by bevacizumab maintenance showed a progression-free survival benefit over gemcitabine and carboplatin alone. However, no overall survival benefit was seen (58.2 months vs 56.4 months; P = .65). The AURELIA study, a phase III trial in patients with recurrent platinum-resistent disease receiving bevacizumab in combination with paclitaxel, topotecan, or liposomal doxorubicin (chemotherapy chosen at the discretion of the treating physician) showed a significant improvement in overall response rate (31% vs 13%) and progression-free survival (3.4 months vs 6.7 months) but there was no statistically significant improvement in overall survival (16.6 months vs 13.3 months; P < .174). This lack of overall survival benefit may be due, at least in part, to the cross-over allowed for patients in the chemotherapy-only arms. Given the clinical benefit observed in patients with platinum-resistant disease, in November 2014 the FDA approved the use of bevacizumab in this setting.

Salvage and palliative radiotherapy after chemotherapy

In the setting of small-volume residual disease detected after chemotherapy, external beam irradiation has been used with some success. Favorable experiences with salvage radiation therapy in patients with chemotherapy-refractory ovarian carcinomas continue to be reported. Table 4 lists possible prognostic variables in these patients.

TABLE 4: Possible prognostic factors for salvage radiation therapy following chemotherapy

In a report of 20 patients who received multiple chemotherapy regimens for recurrent disease located in the pelvis, surgical debulking of the recurrent mass was followed by postoperative radiation therapy to 50.4 Gy. Patients who were able to have complete debulking and radiation had a 3-year overall survival of 50%, a disease-free survival of 72%, and local relapse-free survival of 89%; those with residual disease had corresponding values of 19%, 22%, and 42%, respectively. Radiation therapy should be considered for patients with localized recurrence of ovarian cancer who have failed to respond to multiple chemotherapy regimens, given the general sensitivity of ovarian cancer to radiation therapy.

Sedlacek et al (ASCO 1997, abstract 1263) described 27 patients who had not responded to aggressive cytoreductive surgery followed by multiple-drug platinum-based chemotherapy and who received WAI (30 to 35 Gy at 100 to 150 cGy/fraction, with a pelvic boost to a total dose of 45 Gy). The 5-year survival rate was 15%. The extent of residual disease at the initiation of radiation therapy strongly correlated with the 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 a disease-free survival rate of 54%, compared with 16% and 4%, respectively, in patients with upper abdominal involvement.

This finding was confirmed by Firat and Erickson (Gynecol Oncol 2001), who described their experience with selective radiotherapy in 28 patients with recurrent or persistent disease involving the vagina and/or rectum. Pelvic radiotherapy was uniformly successful in palliating vaginal bleeding. Furthermore, there were eight long-term survivors (five with no evidence of disease), implying that pelvic radiotherapy alone can be effective salvage therapy, particularly when there is no extrapelvic disease.

Fujiwara and colleagues (Int J Gynecol Cancer 2002) reported high rates of objective and symptomatic responses using local radiotherapy in 20 patients (42 evaluable lesions) with recurrent ovarian cancer following chemotherapy. Lymph node metastases appeared to be particularly responsive.

Tinger et al (Int J Radiat Oncol Biol Phys 2001) reported an overall response rate of 73% in 80 patients with advanced and recurrent disease treated with palliative intent. Responses were maintained until death in all but 10 patients. Toxicity was limited, and there was no grade 4 toxicity. It was suggested that response rate, survival, and toxicity with palliative radiotherapy compared favorably with those of second- and third-line chemotherapies.

On the basis of these and other studies, certain treatment guidelines can be suggested:

• Palliation of vaginal bleeding, pelvic pain, or bowel or bladder blockage due to tumor compression may be feasible.

• Salvage radiation therapy may also be considered in select patients after a localized pelvic recurrence following maximal debulking.

Novel approaches

The randomized trials evaluating the role of antivascular strategies in patients with ovarian cancer are all nearing completion, and results will guide their use in both the primary and recurrent settings. Emerging data are confirming the activity of PARP inhibitors in patients with ovarian cancer. Approximately 10% to 15% of patients with ovarian cancer are known to be deficient in homologous recombination repair, because of germline BRCA1 or BRCA2 mutations. Up to 50% of all patients are, however, likely deficient because of somatically acquired mutations, epigenetic inactivation, or BRCA1- or BRCA2-independent defects in addition. Olaparib, as one example, has shown single-agent response rates ranging from 28% to 41%, depending on dose and BRCA status. A trial reported by Ledermann in 2012 assessed the activity of olaparib vs placebo in patients with platinum-sensitive recurrence returning to complete remission or partial remission after treatment. This maintenance trial enrolled 265 patients and administered oral olaparib at 400 mg bid or placebo. Treatment was well tolerated and the arms were reasonably balanced. The progression-free survival was 8.4 months vs 4.8 months, respectively (HR = 0.35; 95% CI, 0.25–0.49; P < .00001). A multicenter phase III study of olaparib monotherapy for patients with germline BRCA mutations (Kaufman et al: J Clin Oncol 2015) included 193 patients with ovarian cancer, the majority of whom had platinum-resistant disease. This study demonstrated a response rate of 31.1% in the ovarian cancer cohort. More than half of the ovarian cancer patients (54.6%) were progression-free at 6 months, and median overall survival was 16.6 months. These findings resulted in accelerated FDA approval of olaparib in December 2014, for women with a germline BRCA mutation who had received at least three prior lines of therapy. Further studies with olaparib and other PARP inhibitors are under way, both in the adjuvant and maintenance settings.

Other targeted approaches are under evaluation, and enrollment in clinical trials should be encouraged when possible.

High-dose chemotherapy. In a trial conducted largely in patients with platinum-resistant disease (66%) and bulky disease (61%), the median progression-free survival interval and overall survival time were short (7 months and 13 months, respectively) in those treated with high-dose chemotherapy and stem cell support, suggesting no benefit. There is no role for high-dose chemotherapy in the standard management of patients with epithelial ovarian cancer.

Treatment recommendations and unresolved issues

For advanced ovarian cancer, current front-line management should incorporate a taxane with platinum-based therapy, using an IV and/or IP route. Results also support the use of a taxane and platinum-based therapy in patients with high-risk early-stage disease.

Issues that are evolving include (1) considering a variety of IP doses, agents, and schedules in the primary treatment setting to reduce toxicity; (2) the role of maintenance or consolidation treatment with standard chemotherapy or with novel agents following primary therapy; (3) the optimal use of platinum vs nonplatinum agents for patients with recurrent disease; (4) the role of novel drugs, notably bevacizumab or other antivascular agents, as well as PARP inhibitors in the adjuvant, recurrent, and maintenance settings; and (5) the identification of driver mutations, which, if present, may enable a more targeted approach to therapy overall.

Suggested Reading

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