David E. Cohn and Ronald D. Alvarez
Epithelial ovarian, fallopian tube, and primary peritoneal cancers remain the most lethal of all the gynecologic malignancies. In 2010, approximately 21,880 women will be diagnosed with ovarian cancer in the United States; of these, 13,850 will be expected to die from this disease.1 Cancers arising from the fallopian tube and peritoneum are significantly less common that those arising from the ovarian epithelium, but share several similarities in their epidemiology, diagnosis, treatment, and associated outcomes. Because the vast majority of fallopian tube and primary peritoneal cancers exhibit a high-grade papillary serous histology, comparisons to similar disease in primary ovarian cancers suggest common molecular pathways that may promote carcinogenesis within the serous classification of these tumors. Several recent hypotheses also propose a fallopian tube origin for metastatic disease that would traditionally be considered as primary ovarian or peritoneal. Given the recent advances surrounding these diseases, this chapter considers this subset of high-grade serous reproductive cancers as a group, with specific differences highlighted.
EPIDEMIOLOGY
Key Points
1. Women with an inherited ovarian cancer syndrome, particularly those with mutations in the BRCA1 and BRCA2 genes, have the highest lifetime risk of developing high-grade, papillary serous epithelial ovarian, primary peritoneal, and fallopian tube cancer.
2. For ovarian cancer, epidemiologic factors that are associated with an increase in lifetime ovulatory cycles confer an increased risk.
3. Bilateral salpingo-oophorectomy, oral contraceptives, tubal ligation, and hysterectomy are all well established risk modifiers of epithelial ovarian, fallopian tube, and primary peritoneal cancer.
Epidemiologic data indicate that ovarian cancer is the ninth most common malignancy affecting women in the United States, with 21,880 cases predicted for 2010; unfortunately, it is the fifth most common cause of cancer-related deaths, with 13,850 women estimated to die of this disease in the same time period.1 The incidence of ovarian cancer increases with age and is most prevalent in the eighth decade of life, with a rate of 57 per 100,000 women. The median age at diagnosis is 63 years, and 70% of patients present with advanced disease.2
The true incidence of fallopian tube and primary peritoneal malignancies is more difficult to quantify. Despite criteria established by the Gynecologic Oncology Group to define primary peritoneal cancers, uniform application by pathologists remains unclear, which clouds identification of the true incidence of this disease. High-grade serous carcinomas of the fallopian tube are rare entities, with 3479 new cases expected to be diagnosed yearly.3 However, incomplete pathologic sectioning and evaluation of the tubes in women with presumed metastatic ovarian cancer may preclude identification of a true tubal origin. Recent evidence suggests that nearly 60% of all high-grade, non-uterine serous cancers initially classified as primary ovarian or peritoneal in origin demonstrate serous tubal intraepithelial carcinoma (STIC), suggesting that the fallopian tube may be the organ of origin.4,5
One of the strongest risk factors for the development of serous gynecologic cancers is the presence of a genetic predisposition to the disease. The majority of patients with a genetic predisposition to ovarian cancer have mutations in the BRCA1 or BRCA2 genes. As such, a personal or family history of premenopausal breast cancer or any ovarian cancer suggests that the presence of a BRCA gene mutation is more probable and thus increases the risk of these diseases (Table 12-1).
Table 12-1 Risk Factors for Ovarian Cancer
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Increased Risk |
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Advancing age |
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Residence in developed world |
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Nulliparity |
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No breast feeding |
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Early menarche |
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Late menopause |
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Obesity |
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Menopausal estrogen replacement (variable association) |
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Perineal talc exposure (variable association) |
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Infertility medications (variable association) |
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Personal or family history of premenopausal breast cancer or any ovarian cancer |
|
Decreased Risk |
|
Oral contraceptives |
|
Hysterectomy |
|
Tubal ligation |
|
Oophorectomy |
Epithelial ovarian cancer is, however, a disease that occurs most commonly as a result of sporadic (noninherited) acquisition. The median age of patients diagnosed with epithelial ovarian cancer is in the early seventh decade. Epidemiologic studies have established several specific risk modifiers that are associated with an increased risk for the development of ovarian cancer, including increased lifetime exposure to ovulation. These factors include a longer duration of menstruation (early menarche, late menopause), nulliparity, and lack of breast feeding.6 Although it would intuitively make sense that medications that induce ovulations (such as those used for the treatment of infertility) would increase the risk for ovarian cancer, this has only been suggested but not proven. Ovarian cancer occurs more frequently in industrialized countries, where obesity and a high-fat diet are more common. The hormonal basis of ovarian cancer is less certain, with some studies associating menopausal estrogen replacement with an increased risk and others with a decreased or no impact on the disease.7
Protection against ovarian cancer may be provided through several interventions. Factors that decrease ovulation, such as oral contraceptives, decrease the risk of the disease both in patients with and without a genetic predisposition to developing ovarian cancer. Removal of the ovaries will in large part guarantee the prevention of ovarian cancer, although rare cases of adenocarcinoma of the peritoneal cavity (primary peritoneal cancer) can occur in high-risk women. Likely due to the disruption of the ovarian blood supply, hysterectomy also decreases the risk for developing ovarian cancer. Given the relationship between peritoneal and iatrogenic irritants (possibly such as talc) and ovarian cancer, tubal ligation has been proven to decrease the risk of the disease as well.
High-grade papillary serous epithelial malignancies can arise from numerous anatomic locations in the gynecologic system, including the ovaries, peritoneum, uterus, and cervix. This chapter focuses on the most common sites of epithelial serous malignancies: the ovaries, fallopian tubes, and peritoneum. Epithelial ovarian and peritoneal cancers are predominantly of serous histology (85%) and histologically recapitulate the appearance of the fallopian tubal epithelium. The remaining histologies of epithelial ovarian cancers (endometrioid, mucinous, clear cell, and Brenner tumor) are discussed in Chapter 13.
Serous adenocarcinomas of the ovary, peritoneum, or fallopian tubes can be cytologically low grade or high grade, with high-grade adenocarcinomas comprising more than 80% of all serous cancers. The clinical importance of segregating invasive ovarian neoplasms by cytology relates to the strong influence of grade on the biologic behavior of these. Comparisons of low-grade with high-grade serous ovarian cancers show differences in genetics, response to chemotherapy, and survival. The “2-tier” system has been shown to be both reproducible and biologically relevant. High-grade serous cancers are generally diagnosed at advanced stages and are responsive to taxane and platinum chemotherapy. Low-grade serous cancers are considered to be chemotherapy resistant and may not respond as robustly to the adjuvant chemotherapy generally administered to patients with ovarian cancer.8 In fact, genetic profiling of low-grade serous cancers demonstrates distinct fingerprints from high-grade tumors, with segregation closer to the profile of borderline cancers.9 These studies have been invaluable in providing insight into potential molecular targets for the treatment of low-grade serous cancers.
Recently, increasing attention has been paid to the biology and pathogenesis of ovarian cancer. Whereas historically, high-grade serous ovarian cancer was thought to develop from precursor lesions of the ovarian surface epithelium (mesothelium), with metaplastic changes leading to transformation into malignancy, increasing scrutiny has challenged this long-held theory. It is now hypothesized that the majority of epithelial ovarian and primary peritoneal cancers arise from the fallopian tubes, either from high-grade intraepithelial neoplasia of the tubal epithelium or from the ciliated columnar epithelium residing in the para-tubal and para-ovarian tissues.10 Although this recent shift in the description of the origin of ovarian cancer is conceptually attractive, it is by no means definitive, and substantial research will need to be completed before its universal adoption.
Screening for Ovarian Cancer
Ovarian cancer is a rare disease, with a woman’s lifetime risk of being diagnosed approaching 1 in 75 (1.5%) in the general population. The prevalence of the disease is approximately 1 in 2500 in postmenopausal women. This rate, in contrast with a woman’s lifetime risk of being diagnosed with breast cancer (1 in 9, or 11%), is responsible for the challenges of ovarian cancer screening in the general population. In women with an increased risk of developing ovarian cancer as a result of a hereditary predisposition, screening becomes more feasible, as the tests required to detect the disease do not require as high a sensitivity and specificity as with detection of a more rare disease. Given that more than 90% of women diagnosed with ovarian cancer have sporadic disease, accurate screening remains a challenge. As such, fewer than 30% of patients with ovarian cancer are diagnosed with stage I disease (when the 5-year survival rates can exceed 90%).
Currently used modalities attempting to identify early-stage ovarian cancer (and thus improve survival) have mainly focused on transvaginal pelvic ultrasonography and serum CA-125 testing. Although novel serum markers and other imaging technologies are in evaluation, previous and current clinical protocols evaluating the role of ovarian cancer screening have tested pelvic ultrasound and CA-125. To date, there has been no evidence in the general population that routine screening for ovarian cancer reduces mortality related to this disease.11 However, 2 ongoing clinical trials are continuing to gather information to assess the value of screening in the general population. The PLCO (Prostate, Lung, Colorectal, Ovary) screening trial randomized more than 34,000 postmenopausal women without oophorectomy to both annual CA-125 and pelvic ultrasounds for 4 years versus routine care. The most recent results from the screening arm demonstrated that 60 of 89 invasive ovarian or peritoneal cancers were detected by screening, although 72% of the screen-detected cases were diagnosed at an advanced stage.12 The primary objective of the study, the impact of screening on mortality, has yet to be reported.
In the United Kingdom, the UKCTOCS (Collaborative Trial of Ovarian Cancer Screening) randomized more than 100,000 postmenopausal women to routine care, versus more than 50,000 postmenopausal women to screening with both pelvic ultrasound and CA-125, versus more than 50,000 to pelvic ultrasound alone. Although the data regarding ovarian cancer mortality are not yet mature, preliminary results suggest that the use of multimodality screening with CA-125 and ultrasound is superior to ultrasound alone or routine care in the detection of ovarian cancer.13 Recently, a single arm multi-institutional study describing the use of the Risk of Ovarian Cancer Algorithm (ROCA) interpretation of the trend of multiple CA-125 levels followed by ultrasound for a positive ROCA screen in a general population cohort of 3251 postmenopausal women over 9 years demonstrated that of the 5 women diagnosed with ovarian cancer, 3 (60%) had early-stage disease, and most had a normal (but increasing by ROCA) level of CA-125 that would have gone without detection by standard CA-125 screening. The ROCA triage strategy was associated with a positive predictive value of 37% and a specificity of 99.9%.14 Together, these trials suggest that screening of ovarian cancer may be feasible, but data regarding its impact on mortality are imperative for the widespread introduction of this technique into the general population.
DIAGNOSIS
Key Points
1. Women with ovarian cancer often experience symptoms that may include bloating, pelvic or abdominal pain, difficulty eating, early satiety, or urinary symptoms (urgency or frequency).
2. The evaluation of a patient with such symptoms or suspected ovarian cancer should include a thorough abdominal and pelvic examination, selective imaging studies, and selective tumor markers.
Until recently, many providers have described ovarian, fallopian tube, and peritoneal cancers as a “silent” disease, with the thought that there are no classic symptoms until metastases have developed. There is evidence now to suggest that most women with these cancers, including those with early-stage disease, often experience distinct clinical features and symptoms for several months before their initial diagnosis. A national survey of 1500 women, before their diagnosis of ovarian cancer, identified common signs that included abdominal, gastrointestinal, pain, constitutional, urinary, or pelvic symptoms in nature.15 In a landmark prospective case-control study, Goff et al16identified 4 symptoms more likely to occur in women with ovarian cancer than in the general population of women presenting to primary clinics. These symptoms included an increase in abdominal size, bloating, urinary urgency, and pain. Symptoms in women with malignant ovarian masses were likely to be more recent in onset, more frequent, and higher in severity than those experienced by women without an ovarian malignancy. The results of this study and others led to the development of an Ovarian Cancer Symptoms Consensus Statement (Table 12-2).17
Table 12-2 Symptoms Likely to Occur More Commonly in Women With Ovarian Cancer Than in the General Population
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Bloating |
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Pelvic or abdominal pain |
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Difficulty eating or feeling full quickly |
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Urinary symptoms (urgency or frequency) |
Fallopian tube cancer may present with similar symptoms. A specific clinical entity, hydrops tubae profluens, is also considered classic for this disease, but is typically not identified in women diagnosed with tubal cancer. This cluster of symptoms includes cramping lower abdominal pain, which resolves after passage of a profuse, watery, and/or yellow vaginal discharge.
The importance of both the patient and the clinician recognizing the symptoms suggestive of epithelial ovarian, fallopian tube, or primary peritoneal cancer cannot be understated. Studies have demonstrated that even 80% to 90% of patients with early-stage disease are symptomatic.15 Given the lack of effective screening strategies, early recognition of symptoms associated with ovarian cancer may facilitate diagnosis of ovarian cancer at an earlier stage where outcome is improved. Several efforts are underway to develop algorithms that direct the evaluation and management of women who present with symptoms of ovarian cancer that include physical examination by a gynecologist and appropriate imaging and laboratory assessment.
Patients with symptoms such as those previously described should undergo a thorough physical assessment, which should include an abdominal and pelvic examination. Physical examination findings are often based on the stage of disease. Patients with early-stage disease may be found to have an adnexal mass appreciated on abdominal or pelvic examination.18 Patients with a malignant ovarian neoplasm may have a mass of various dimensions but typically such masses are solid, irregular, or fixed. However, pelvic examination has limited sensitivity in the detection of adnexal masses; thus many patients with early- or late-stage ovarian cancer have a normal pelvic examination.19 The adnexal mass may be tender to the patient on palpation, but rarely do patients have significant guarding or rebound tenderness. Patients with more advanced-stage disease are often found to have, along with a pelvic mass, abdominal distension or a fluid wave indicating the presence of ascites. These patients are often noted to have an upper abdominal mass suggestive of omental metastasis.
Physical examination should also include evaluation of the supraclavicular and inguinal lymph nodes to assess for nodal metastasis and evaluation of the breasts and rectum to assess for cancers originating in these organs. Other aspects of the physical examination should focus on evaluation of the other major organ systems to appropriately assess for comorbidi-ties that may affect management decisions.
Various imaging studies can be selectively used to further evaluate a patient with a pelvic mass or with symptoms suggestive of ovarian cancer.20,21 Pelvic and/or transvaginal ultrasound remains the modality of choice to evaluate a patient with an adnexal mass due to its ease of use and relatively less expense. Pelvic ultrasound can most often distinguish uterine from ovarian pathology, and certain features noted on sonography can raise or lower suspicion for malignant disease. Findings most suggestive of malignancy in the postmenopausal woman with an ovarian mass include the presence of excrescences or papillary structures within a cyst, size greater than 10 cm, a solid or mixed solid and cystic mass, thickened septa, and color or Doppler demonstration of blood flow in the mass.20,21 Recent studies have confirmed the ability of such ultrasound findings alone and in combination with selective tumor markers (CA-125) to be predictive in discriminating between benign and malignant adnexal masses.22,23
Abdominal/pelvic computed tomography (CT) is also a very useful imaging modality, particularly in those patients with nonspecific symptoms suggestive of a malignant ovarian neoplasm or clinical evidence of potential metastatic disease.20,21 Although not as accurate as ultrasound in characterizing the components of an ovarian mass, abdominal/pelvic CT is able to accurately determine the presence of ascites or metastases to the omentum, peritoneal surfaces, retroperitoneal lymph nodes, or intraparenchymal organs such as the liver and spleen. In addition, valuable information can be ascertained regarding other intraperitoneal organ sites that may be contributing to clinical symptoms and findings or that may be secondarily involved with a malignant ovarian process.
Magnetic resonance imaging (MRI) or positron emission tomography (PET) imaging rarely adds to the assessment of a patient with a pelvic mass or evidence of metastases over that which can be achieved with pelvic ultrasound or abdominal/pelvic CT.20,21 MRI may be useful in the setting in which there is a sonographically indeterminate or complex pelvic mass and there is uncertainty about the ovary as an origin of the mass. Fluorodeoxyglucose (FDG) PET alone or combined with CT has improved sensitivity over CT in the evaluation of an adnexal mass; however, low specificity and false-positive physiologic signals are not infrequently noted, and rarely does FDG-PET imaging enhance the ability of a clinician to make a management decision over what can be decided with ultrasound or CT imaging.
Serum CA-125 may also be very useful in guiding clinical management decisions in patients with symptoms or physical examination findings suggestive of an ovarian neoplasm, particularly in the postmenopausal woman.24,25 An elevated CA-125 in the presence of an adnexal mass in a postmenopausal woman is highly predictive of a malignant ovarian neoplasm. Care must be exercised in interpreting a normal serum CA-125 level in a patient with an ovarian mass as an indication that the patient may not harbor a malignant ovarian mass. Serum CA-125 may not be elevated in patients with nonserous (eg, mucinous) ovarian neoplasms and is only elevated in approximately 50% of patients with early-stage ovarian cancer. OVA1 (Vermillion) is a laboratory test recently approved by the US Food and Drug Administration (FDA) that assesses 5 serum biomarkers including CA-125, prealbumin, transferrin, β2 microglobulin, and apolipoprotein A1.26,27 OVA1 is reported to improve the ability of physicians to predict whether an ovarian mass is malignant when used in combination with clinical and radiographic imaging as compared with when physicians use clinical and radiographic imaging alone. Continued investigation of this multiplex test, as well as others, is needed before its establishment as a routine investigation in women with ovarian cancer or as a screening tool.28
The American Congress of Obstetricians/Gynecologists and the Society of Gynecologic Oncologists have issued guidelines applicable to all primary care physicians that provide recommendations to obstetrician/gynecologists for the evaluation and management of patients with a pelvic or ovarian mass.29,30 The differential diagnosis in a patient with a pelvic mass should take into consideration problems that can arise from all organ systems located within the pelvis (Table 12-3).
Table 12-3 Differential Diagnosis of Pelvic Mass
|
Ovarian |
|
Functional cyst |
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Fallopian tube |
|
Hydrosalpinx |
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Uterine |
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Congenital anomaly |
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Other |
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Colon (diverticular abscess, colon cancer) |
The primary care physician must first have a high index of suspicion for a malignant ovarian neoplasm in patients who present with any of the previously described symptoms or signs commonly experienced in patients with a malignant ovarian mass. A thorough history and physical examination, including an abdominal and pelvic examination, are paramount. Primary care physicians should obtain selective imaging and laboratory studies to evaluate for a possible ovarian neoplasm in women with symptoms or physical examination findings suggestive of an ovarian neoplasm. A pelvic ultrasound can provide useful information about an adnexal mass that can guide clinical management decisions. An abdominal/pelvic CT may be helpful in evaluating whether symptoms may be attributable to other organ systems or, if an adnexal mass is present, whether metastases are present. A serum CA-125 is most useful in determining whether an adnexal mass may be malignant, particularly in the postmenopausal patient. An OVA1 study may also be useful in situations in which a serum CA-125 is normal, characteristics of an adnexal mass are not definitive, and concern persists for the possibility of an ovarian malignancy. It is important that primary care physicians take into consideration all clinical, radiographic, and laboratory findings to guide management decisions, in particular those findings that may determine the need for surgical evaluation or subspecialty referral.
PATHOLOGY
Key Points
1. Metastatic ovarian and primary peritoneal cancer may arise from an abnormal focus in the fallopian tube epithelium.
2. The majority of malignant epithelial ovarian, primary peritoneal, and fallopian tube neoplasms are serous cancers.
3. Staging of gynecologic cancers reflects the distribution of disease, but does not take into consideration other important prognostic factors, such as the volume of disease remaining after surgical resection.
High-grade papillary serous cancers of the ovarian, fallopian tube, and peritoneum share similar histologic characteristics that frequently do not permit determination of the organ of origin. These malignancies are characterized by clusters of atypical cells arranged in papillary patterns with irregular underlying stroma or may appear as sheets of malignant cells with marked atypia without underlying stroma (Figure 12-1). As with all grade 3 malignancies, the nuclear-to-cytoplasmic ratio is high, and observation of atypical mitoses is common. Psammoma bodies are more common in low-grade serous malignancies; they are rarely seen in grade 3 disease.
FIGURE 12-1. Photomicrograph of histologic specimen of grade 3 serous adenocarcinoma. (Reproduced, with permission, from Shorge JO, Schaffer JI, Halvorson LM, et al, eds. Williams’ Gynecology. New York, NY: McGraw-Hill; 2008.)
Spread of serous ovarian, tubal, and peritoneal cancer can be through a number of mechanisms, including direct tumor dissemination into the peritoneal cavity, lymphatic spread, and hematogenous spread (into solid organs and bone). The vast majority of patients with advanced serous cancers have peritoneal metastases. For epithelial ovarian cancer, disease most commonly spreads to the surface of the peritoneal cavity, the serosa of the large or small intestines, the omentum, and the surface of the liver or diaphragm (Figure 12-2). Although peritoneal spread of advanced ovarian cancer is quite common, it is estimated that at least 50% of these patients have concurrent or isolated retroperitoneal (pelvic, aortic, celiac) lymph node metastasis.31 The rate of solid organ involvement in newly diagnosed ovarian cancer is quite low,32 although involvement of solid organs in the context of recurrent disease has been increasing as patients are experiencing increased disease-free survival in the primary and recurrent settings, thus allowing for the manifestations of solid organ metastasis before death from peritoneal spread of ovarian cancer. The pattern of spread of peritoneal cancers is similar to that of ovarian cancers, with common dissemination throughout the peritoneal cavity and spread to the peritoneal surface of the pelvis, intestines, diaphragm, and omentum. Although generally the behavior of these malignancies is similar to those of the ovary and peritoneal cavity, fallopian tube cancers are different in that the rate of disease metastasis to the retroperitoneal lymph nodes exceeds that of the other high-grade serous gynecologic cancers; specifically, in tumors clinically confined to the fallopian tube, more than one-third have pathologic involvement of the retroperitoneal lymph nodes.33
FIGURE 12-2. Omental caking caused by tumor invasion. (Reproduced, with permission, from Shorge JO, Schaffer JI, Halvorson LM, et al, eds. Williams’ Gynecology. New York, NY: McGraw-Hill; 2008.)
The staging system for ovarian cancer was established to provide a common language for the communication of results regarding diagnosis and treatment of the disease. The International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system is shown in Table 12-4. Although stage clearly is an important prognostic factor in patients with ovarian cancer overall, what is not conveyed in the FIGO staging system is the description of the volume of residual disease after primary cytoreduction in women with advanced ovarian cancer, which has been shown to be the most important prognostic factor in women with metastatic disease. It is important to consider that although distant metastasis (to the upper abdomen or lymph nodes) is generally associated with stage IV disease in most other solid tumors, it is considered stage III in ovarian cancer, with stage IV cases reserved for those with parenchymal liver involvement, cytologically positive pleural effusions, or other extra-abdominal metastasis.
Table 12-4 FIGO Staging of Ovarian (and Peritoneal) Cancer
|
Stage I: Limited to 1 or both ovaries |
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IA: Involves 1 ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings |
|
Stage II: Pelvic extension or implants |
|
IIA: Extension or implants onto uterus or fallopian tube; negative washings |
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Stage III: Microscopic peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum |
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IIIA: Microscopic peritoneal metastases beyond pelvis |
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Stage IV: Distant metastases to the liver or outside the peritoneal cavity |
Although the treatment of fallopian tube cancer is identical to that of ovarian cancer, fallopian tube cancers are staged by a separate system (Table 12-5). In order for an adnexal malignancy to be designated a high-grade serous fallopian tube (and not ovarian) cancer, specific pathologic criteria must be met. Specifically, all or most of the adnexal malignancy must arise in the fallopian tube, and a transition from benign to invasive neoplasm must be identified in the fallopian tube.34,35 In the absence of these criteria, and adnexal malignancy is classified as an ovarian cancer. Primary peritoneal cancers are staged similarly to epithelial ovarian malignancies. The Gynecologic Oncology Group established pathologic definitions of primary peritoneal cancer in 1993: (1) The ovaries are normal in size or enlarged by a benign process; (2) the involvement in the extraovarian sites must be greater than the involvement on the surface of either ovary; (3) microscopically, the ovaries are not involved with the tumor or exhibited only serosal or cortical implants less than 5 × 5 mm; (4) the histopathologic and cytologic characteristics of the tumor are predominantly of the serous type.36
Table 12-5 FIGO Staging of Fallopian Tube Cancer
|
Stage I: Growth limited to the fallopian tubes |
|
IA: Growth is limited to 1 tube, with extension into the submucosa and/or muscularis, but not penetrating the serosal surface; no ascites |
|
Stage II: Growth involving 1 or both fallopian tubes with pelvic extension |
|
IIA: Extension and/or metastasis to the uterus and/or ovaries |
|
Stage III: Tumor involves 1 or both fallopian tubes, with peritoneal implants outside the pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastasis equals stage III; tumor appears limited to the true pelvis, but with histologically proven malignant extension to the small bowel or omentum |
|
IIIA: Tumor is grossly limited to the true pelvis, with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces |
|
Stage IV: Growth involving 1 or both fallopian tubes with distant metastases; if pleural effusion is present, there must be positive cytology to be stage IV; parenchymal liver metastases equals stage IV |
TREATMENT
Key Points
1. Patients with apparently confined or limited ovarian or fallopian tube cancer should undergo comprehensive surgical resection and staging.
2. In patients with metastatic disease, surgical cytoreduction to residual disease less than 1 cm correlates with improved outcome.
3. Combination taxane and platinum-based chemotherapy is the standard of care adjuvant treatment for most patients with newly diagnosed high-risk early-stage or advanced-stage ovarian, fallopian tube, and primary peritoneal cancer.
Treatment of Early-Stage Disease
Surgical Management and Staging
Fewer than 20% of patients with a pelvic mass who are found to harbor an invasive high-grade serous ovarian, tubal, or peritoneal cancer will be diagnosed with disease confined to the ovary, tube, or pelvis at the time of surgical evaluation. When this does occur, it is imperative to surgically resect the affected organ and involved pelvic structures. The decision to remove other involved or uninvolved gynecologic organs may be influenced by the patient’s age and her desire for future fertility. It is also important to assess for the presence of occult or microscopic metastasis when disease appears confined to pelvis to provide patients accurate prognostic information and to guide adjuvant therapy decisions. In the classic study of Young et al,37 30% of a cohort of 100 patients who were thought to have early-stage ovarian cancer were found to have evidence of metastasis at the time of restaging laparotomy. Despite recent studies that consistently confirm this observation, evaluation of Surveillance, Epidemiology, and End Results data has demonstrated that fewer than 10% of patients with clinically apparent early-stage malignant ovarian neoplasms are comprehensively staged.38,39
Procedures involved in the staging of ovarian, tubal, and peritoneal cancers include cytologic evaluation of ascites or abdominopelvic washings, excision or biopsy of suspicious peritoneal implants, omentectomy, and pelvic and para-aortic lymphadenectomy.40 The contralateral ovary and/or uterus should be removed if there is evidence of metastasis or if future fertility not desired. Although exploratory laparotomy is traditionally the operative modality of choice, recent studies suggest that staging of patients with an ovarian neoplasm can be adequately and safely done using laparoscopic and minimally invasive surgical techniques.41
Medical Management
Pathologic assessment of specimens obtained as part of staging in patients with an apparent early-stage high-grade serous cancer provides critical information necessary to assign risk for recurrence and to direct decisions regarding adjuvant therapy. Several prospective randomized clinical trials have provided guidance to clinicians regarding the management of patients with early-stage invasive serous ovarian cancer (Table 12-6). Patients with stage IA/B (grade 1 or 2) invasive serous ovarian cancer have classically been designated as having low risk for recurrence, and studies have demonstrated that the outcome for these patients, particularly when adequately staged, is not improved with the use of adjuvant therapy.42,43 Those patients with stage IA/B (grade 3), IC, or II invasive serous ovarian cancer are considered as having high risk for recurrence. Although some controversy exists regarding the need for adjuvant therapy in adequately staged patients, most prospective studies have demonstrated improved outcomes in such high-risk early-stage ovarian cancer patients when treated with adjuvant chemotherapy. Specifically, the ACTION (Adjuvant ChemoTherapy In Ovarian Neoplasm)/ICON (International Collaborative Ovarian Neoplasm) studies, which randomized patients with clinically apparent high-risk early-stage ovarian cancer to platinum-based chemotherapy versus observation, did demonstrate superior 5-year survival in chemotherapy-treated patients (82% vs. 74%).43-45
Table 12-6 Relevant Randomized Control Trials in Early-Stage Invasive Ovarian Cancer
In the modern era, a platinum-based regimen, specifically paclitaxel and carboplatin, is currently the most common adjuvant chemotherapy regimen administered to patients with high-risk early-stage invasive serous ovarian or tubal cancers.46,47 Although there are no randomized trials comparing a paclitaxel and carboplatin regimen with other non–taxane/non–platinum-based regimens, the superior antitumor activity noted with these agents in advanced-staged ovarian cancer justifies adoption of this regimen in patients with early-stage disease. Studies have attempted to identify the optimal number of cycles of chemotherapy for patients with early-stage disease. Specifically, Gynecologic Oncology Group (GOG) 157 randomized patient with high-risk early-stage ovarian cancer to 3 versus 6 cycles of paclitaxel and carboplatin.46 This study demonstrated that although the risk of recurrence was higher in patients treated with 3 cycles of this regimen compared with 6 cycles (25.4% vs. 20.1%), there was no significant difference in 5-year overall survival (81% vs. 83%). Toxicity, particularly hematologic (neutropenia) and neurologic (sensory neuropathy), was noted to be significantly higher in the patients who received the higher number of cycles. The conclusions rendered by the authors of this study advocated that 3 cycles of paclitaxel and carboplatin should be considered the standard of care in patients with high-risk early-stage ovarian cancer. Another recent GOG randomized clinical trial in this same patient population also demonstrated no improvement in outcome with the addition of 24 weeks of paclitaxel after completing 3 cycles of conventional paclitaxel and carboplatin.47
Of note, Chan et al,49 in a post-hoc subset analysis of patients enrolled in GOG-157, suggested that patients with serous cancers (23% of the study population) who underwent 6 cycles of chemotherapy had an improved outcome compared with those with serous cancers receiving 3 cycles. This finding was not noted in high-risk early-stage non-serous ovarian cancers. Specifically, the 5-year recurrence-free survival rate in those patients treated with 6 cycles was 83% in comparison with 60% in those treated with 3 cycles of chemotherapy. Although 3 cycles of paclitaxel and carboplatin should be considered the standard of care in adequately staged high-risk early-stage ovarian cancer patients, up to 6 cycles of chemotherapy should be considered in select patients in whom adequate staging has not been performed or in those patients with higher risk factors such as serous histology or stage II disease. Treatment of early-stage, low- and high-risk serous peritoneal cancer and fallopian tube cancer is identical to that described for ovarian cancer.
Treatment of Advanced-Stage Disease
Surgical Management
More than 70% of patients with ovarian, tubal, and peritoneal cancers present with advanced-stage disease. The primary approach to the management of such patients has included aggressive surgical cytoreduction followed by the administration of chemotherapy. Griffiths et al,50 in a landmark article published in 1975, was the first to demonstrate improved outcome in advanced-stage ovarian cancer patients who underwent surgical resection such that there was no residual disease implant greater than 2 cm in diameter (Griffith’s definition of an “optimal debulking”). Hoskins et al51 confirmed these findings in an analysis of patients enrolled on several GOG studies. In a meta-analysis evaluating the effect of cytoreduction on the outcome of 81 advanced ovarian cancer patient cohorts, Bristow et al52 demonstrated a 10% increase in survival with each 10% increase in the number of patients optimally debulked (Figure 12-3).
FIGURE 12-3. Simple linear regression analysis displaying de-logged median survival time plotted against the percentage of tumor removed at the time of debulking (“percent maximum cytoreductive surgery”).
The definition of what constitutes “optimal” cyto-reduction has evolved and is of continued debate. The modern day definition of optimal debulking is resection of all disease with residual metastatic implants less than 1 cm in diameter. Additional studies suggest that clinical outcome in advanced-stage ovarian, tubal, and peritoneal cancers is significantly improved when there is no macroscopic residual disease; several pundits have advocated that this should be the goal of all attempts at surgical cytoreduction of these patients.53 In an effort to optimally resect advanced-stage high-grade serous disease, surgeons have traditionally performed bilateral salpingo-oophorectomy, total abdominal hysterectomy, pelvic peritoneal stripping, omentectomy, and selective small and large bowel resection. It is estimated that more than a quarter of patients with advanced ovarian cancer undergo an intestinal resection as part of their cytoreductive operation.54 Increasingly, surgeons are using more advanced upper abdominal debulking surgical techniques such as subdiaphragm peritoneal stripping, splenectomy, and partial pancreatic and hepatic resection to achieve optimal debulking.55 Several studies have suggested that routine lymphadenectomy in patients with advanced ovarian cancer, particularly in those patients who have all other disease resected, may also be associated with improved outcome.56,57
In select patients who are poor surgical candidates or have disease that appears to be unresectable (eg, those with metastases in the liver parenchyma or in the chest), neoadjuvant chemotherapy may be used in lieu of a primary surgical cytoreductive effort. In some of these patients, an “interval” cytoreductive procedure to resect remaining disease may be considered after several cycles of chemotherapy. A randomized clinical trial in European Organization for Research and Treatment of Cancer (EORTC) suggested that an interval cytoreduction in patients with suboptimally resected disease after initial surgery may further render one-third of these patients optimally debulked and improve survival.58 A similar trial conducted within the GOG did not confirm these findings; the differing conclusions from these studies may be due to the fact that a higher proportion of patients in the GOG study underwent a maximum cytoreductive debulking procedure as compared with those in the EORTC study.59
A recent randomized clinical trial conducted within the Gynecologic Cancer Intergroup (GCI) demonstrated that advanced stage IIIC or IV ovarian, tubal, and peritoneal cancer patients managed with neoadjuvant chemotherapy followed by an interval cytoreductive procedure had a similar outcome to those patients managed with primary surgical resection followed by chemotherapy.60 The percentage of patients rendered optimally resected with disease ≤ 1 cm in the primary debulking group was 41.6% and in the neoadjuvant chemotherapy group was 80.6%. Postoperative morbidity and mortality tended to be higher after primary debulking. Other studies have concluded that survival in advanced invasive epithelial cancer with neoadjuvant chemotherapy and an interval debulking strategy is associated with an inferior outcome compared with a primary debulking strategy.61 Additional studies are required to clarify the role of neoadjuvant chemotherapy and interval debulking, but this approach is appropriate in select patients with significant comorbidities or advanced age when all risks versus benefits have been evaluated and discussed.
Medical Management
A combination taxane-platinum chemotherapy regimen is the standard of care for patients with advanced-stage invasive ovarian, tubal, and peritoneal cancers since the results of GOG 111 were published in 199662 (Table 12-7). In this study, McGuire et al62 reported that patients with suboptimally resected ovarian cancers treated with 6 cycles of paclitaxel and cisplatinum had a significantly improved progression-free (18 vs. 13 months) and median overall survival (38 vs. 24 months) compared with those treated with 6 cycles of cyclophosphamide and cisplatin, the standard of care before this study. This study was confirmed by a separate EORTC trial.63 Given the toxicity associated with the combination of cisplatin and paclitaxel, subsequent studies compared paclitaxel in combination with either cisplatinum or carboplatin (which is associated with decreased long-term toxicity related to neurotoxicity and nephrotoxicity). These results demonstrated that paclitaxel in combination with carboplatin was better tolerated and equally as effective as paclitaxel combined with cisplatin in the management of patients with advanced ovarian cancer.64,65 Another randomized trial confirmed that the combination of docetaxel and carboplatin was as effective as paclitaxel and carboplatin for patients with newly diagnosed ovarian cancer; although associated with more hematologic toxicity, there was a significant reduction in the rate of neurotoxicity.66
Table 12-7 Relevant Randomized Control Trials in Late-Stage Invasive Ovarian Cancer
Efforts to improve upon the outcome of patients with advanced high-grade, serous cancers have focused on modifying the paclitaxel/platinum combination regimen by adding other active cytotoxic or biologic agents, altering the route of drug delivery, intensifying the dose of paclitaxel, or evaluating various maintenance therapy regimens. Over the past 2 decades, there have been a number of cytotoxic agents that have been demonstrated to have antitumor activity in these diseases. These agents (gemcitabine, topotecan, liposomal doxorubicin) were added to paclitaxel and carboplatin as sequential doublet or triplet regimens in GCI/GOG-182, one of the largest randomized clinical trials in advanced ovarian cancer.67 This study demonstrated no improvement in outcome in advanced ovarian cancer patients treated with one of the sequential doublet or triplet regimens in comparison with those treated solely with paclitaxel and carboplatin. Recently, a phase 3 comparison of adjuvant intravenous carboplatin with either paclitaxel or gemcitabine demonstrated that the gemcitabine combination provided no additional survival benefit68 over the standard of carboplatin with paclitaxel.
Altering the route of delivery of chemotherapy has been demonstrated in 3 randomized GOG studies to improve outcome in patients with optimally resected ovarian, tubal, and peritoneal cancer.69 The results of the latest of these studies, GOG-172, was reported by Armstrong et al69 and led to the publication of a National Cancer Institute Clinical Alert in 2006.70 This study randomized patients with optimally resected ovarian cancer to 6 cycles of intravenous paclitaxel and cisplatin versus 6 cycles of intravenous paclitaxel in combination with intraperitoneal cisplatin and intraperitoneal paclitaxel. In this study, patients treated with the intraperitoneal regimen experienced additional complications associated with either the intraperitoneal catheter or the chemotherapy regimen, and only 42% were able to complete all 6 cycles. Nevertheless, the median survival in those treated with the intraperitoneal regimen was significantly improved over that achieved in patients who received traditional intravenous chemotherapy (65.6 vs. 49.7 months). Furthermore, quality of life was similar in both groups of patients 6 months after therapy. Retrospective studies have advocated modification of the intraperitoneal regimen by reducing the dose of cisplatin or using intraperitoneal carboplatin instead of cisplatin.71,72 Two prior randomized trials conducted within the GOG also demonstrated significant improvement in outcome in optimally debulked advanced-stage ovarian cancer with intraperitoneal chemotherapy regimens compared with those with intravenous chemotherapy alone.73,74 The decision to use intraperitoneal chemotherapy in this patient population should be individualized and based on a discussion of the risks versus benefits of this approach.
The concept of dose-dense chemotherapy in high-grade serous cancers of the ovary, tube, and peritoneum arises from data in metastatic breast cancer, where studies have demonstrated that intensifying the dose of paclitaxel improves overall survival. In ovarian cancer, a recent randomized Japanese GOG study evaluated the potential of using such an approach.75 Specifically, 631 eligible patients with stage II to IV ovarian cancer were randomized to receive every-3-weeks paclitaxel (conventional treatment) versus weekly paclitaxel (experimental treatment), both administered in combination with every-3-weeks carboplatin. This study demonstrated a significantly improved median progression-free survival (28.0 vs. 17.2 months) and 3-year overall survival rate (72.1% vs. 65.1%) in patients treated with the dose-dense paclitaxel strategy. Toxicity was similar in both arms with the exception of grade 3 or 4 anemia which was more commonly noted in the dose-dense chemotherapy regimen. The proportion of patients who completed 6 or more cycles of chemotherapy was higher in the conventional treatment arm (73% vs. 62%). Ongoing studies in the GOG are attempting to confirm the findings of this provocative study.
Solid tumors are often dependent on the development of new vessels to facilitate growth and metastasis. Ovarian cancer is no exception, and various studies have linked poor survival in this disease context to increased tumor angiogenesis and increased expression of vascular endothelial growth factor (VEGF), one of the major mediators of tumor angiogenesis.76 Bevacizumab, a humanized monoclonal antibody to VEGF, has been demonstrated to have significant antitumor activity in a number of solid tumors and has received FDA approval for use in lung and colon cancer. A GOG phase 2 trial demonstrated a 21% response rate and a 40.3% 6-month progression-free survival rate in a cohort of recurrent ovarian cancer patients, 42% of whom were considered to have platinum-resistant disease.77 Other early-phase and retrospective studies have demonstrated improved responses in patients with recurrent ovarian cancer when various chemotherapy agents were added to bevacizumab.78,79
Given the activity of this agent in the recurrent setting, bevacizumab was evaluated in a major GOG phase 3 trial in patients with newly diagnosed advanced-stage ovarian cancer.80 This study randomized 1873 eligible patients to receive standard paclitaxel and carboplatin alone (control group), chemotherapy in combination with bevacizumab (cycles 2-6), or chemotherapy with bevacizumab (cycles 2-6) followed by an additional 15 cycles of extended bevacizumab maintenance. Bevacizumab was administered at a dose of 15 mg/kg every 3 weeks. This study demonstrated a significant improvement in progression-free survival in the patients who received chemotherapy in combination with both concurrent and maintenance bevacizumab in comparison to the control group of patients (10.3 vs. 14.1 months). There was no difference in progression-free survival between the group of patients treated with chemotherapy and concurrent bevacizumab compared with the control group. Toxicity experienced in the bevacizumab-treated patients included hypertension and gastrointestinal perforation, but the frequency or severity of these toxicities was no more than that encountered in prior ovarian cancer or other solid tumor studies. Overall survival and quality of life analyses are ongoing. The preliminary results of a second trial, ICON 7, also affirm the potential of the anti-angiogenesis agent bevacizumab in this disease context. In this trial, 1528 patients with high-risk early-stage or advanced ovarian, primary peritoneal, or fallopian tube cancer were randomized to receive standard paclitaxel and carboplatin alone or in combination with both concurrent (cycles 2-6) and maintenance bevacizumab (additional 12 cycles). Bevacizumab was administered at a dose of 7.5 mg/kg every 3 weeks.81 The results of this study demonstrated that the risk of developing progression of disease at 12 months was 15% less in those patients treated with the combination of chemotherapy and bevacizumab when compared with that noted in patients treated with chemotherapy alone. Once mature, the results of GOG-218 and ICON 7 will provide further guidance regarding the role of bevacizumab in newly diagnosed ovarian cancer.
The concept of maintenance chemotherapy is another strategy that has been extensively evaluated as a means to improving outcome in patients with advanced-stage ovarian cancer. The rationale for this approach has been that although more than 70% of patients with advanced-stage ovarian, tubal, and peritoneal cancers will achieve a complete clinical remission with primary surgery and chemotherapy, the majority of these patients will ultimately develop recurrent disease. Investigators have evaluated various maintenance strategies after primary chemotherapy, including the whole abdominal radiation, intraperitoneal radioactive phosphorus (P32), and various intravenous and intraperitoneal chemotherapy or biologic agents.82 The only trial to demonstrate an improvement in outcome (before the results of GOG-218 demonstrating improved outcome in patients with maintenance bevacizumab after carboplatin, paclitaxel, and bevacizumab) was one in which 277 advanced-stage ovarian cancer patients who had achieved a complete clinical response to primary therapy were randomized to monthly paclitaxel for either an additional 3 or 12 months.83,84 A significant improvement in progression-free survival was noted in the patients who received 12 cycles of monthly paclitaxel (22 vs. 14 months). However, overall survival was noted to be similar in the patients who received 12 cycles of maintenance paclitaxel when compared with those who were treated with 3 cycles (53 vs. 48 months).84 An ongoing phase 3 trial in the GOG is currently further evaluating the potential of maintenance taxane-based therapies compared with observation in patients with advanced-stage ovarian, peritoneal, and tubal cancers.
In summary, the adjuvant treatment of patients with high-grade serous epithelial ovarian, primary peritoneal, and fallopian tube cancers is directed in large part by the assignment of FIGO stage and by the randomized clinical trials described in this chapter. Table 12-8 provides general recommendations for clinicians managing these patients.
Table 12-8 Treatment for Invasive Serous Epithelial Ovarian Cancer by Stage
SURVIVAL AND PROGNOSIS
Key Points
1. Early-stage epithelial ovarian, primary peritoneal, and fallopian tube cancers have a favorable prognosis, with relatively high progression-free and overall survival.
2. Advanced-stage disease is associated with a high likelihood of multiple recurrences, each with increasing chemoresistance.
3. Established prognostic factors for high-grade serous ovarian, peritoneal, and tubal cancers include age at diagnosis, stage of disease, and extent of cytoreduction at primary surgery.
Clinical outcome and survival in women with high-grade serous epithelial ovarian, fallopian tube, and primary peritoneal cancers are influenced by several clinical and pathologic factors. Although large, randomized clinical trials examining women with this disease have included all histologic variants of epithelial ovarian cancer (with many studies including primary peritoneal and fallopian tube malignancies), it is reasonable to extrapolate age at diagnosis, stage of disease, and cytoreductive effort at primary surgery as relevant prognosticators in high-grade, serous disease.
Studies typically report survival as a function of stage (Table 12-9). Again, the majority of data includes all histologic subtypes of epithelial ovarian cancer, and several observational studies confirm similar clinical outcomes for those with fallopian tube and primary peritoneal disease. For stage I and II disease, high-grade serous histology should be considered as high risk for recurrence, and 5-year overall survival rates range from 65% to 89% with adjuvant platinum-based chemotherapy.43,46 For stage III and IV disease, 5-year survival rates may range from 5% to 75%, depending on therapeutic modality. After an optimal cytoreductive effort, treatment with intravenous platinum and taxane chemotherapy results in a median survival of 50 months, whereas adjuvant therapy with a combined intravenous and intraperitoneal regimen is associated with a 66-month median survival.70
Table 12-9 Survival (Overall 5-Year) of Patients With Ovarian Cancer109
Prognostic Factors
Overall, the prognosis of these high-grade serous cancers is predominantly dependent on stage of disease, and the volume of residual cancer after cytoreduction (Table 12-9). Older age is also an established prognosticator, but its clinical impact is relatively limited in comparison with stage and cytoreductive effort. Many women with high-grade serous ovarian, tubal, and peritoneal cancers harbor deleterious mutations in the BRCA1 and BRCA2 genes; evidence suggests that tumors associated with BRCA mutations are more chemosensitive, with resulting improved overall survival when compared with women with sporadic disease.85
MANAGEMENT OF RECURRENT DISEASE
Key Points
1. Patients with recurrent high-grade serous ovarian, tubal, and peritoneal cancers should be classified as having either platinum-sensitive or -refractory disease based on the time interval between end of prior chemotherapy and date of recurrence (treatment-free interval).
2. Secondary cytoreduction should be considered for select patients with recurrent disease; namely, those with long treatment-free intervals and limited sites of recurrent implants.
3. In general, combination platinum-based chemotherapy is the treatment of choice for patients with platinum-sensitive recurrent disease.
Although the majority women with high-grade serous ovarian, tubal, and peritoneal cancers enter remission after surgical resection and advjuant chemotherapy, many will develop recurrence of disease and undergo additional treatment. In general, after completion of primary therapy, women with these diseases are followed at 3-month intervals for the first 2 years, at 4-month intervals for the third year, and then at 6-month intervals thereafter, with discharge at 10 years in the absence of recurrence. During these visits, a focused history and physical examination are performed, including pelvic and rectal evaluation. Traditionally, women have serial serum CA-125 tumor markers drawn, with elevations from their baseline (typically 2 times the nadir value) prompting CT imaging. There is no evidence to support the routine application of CT imaging for surveillance in otherwise asymptomatic patients with normal tumor markers and physical findings.
Several advances have modified this traditional approach to surveillance. Human epididymal secretory protein E4, or HE4, is a novel serum marker that is elevated in women with high-grade serous ovarian cancers, especially compared with those with mucinous or clear cell etiology.86 HE4 may also provide higher accurancy in differentiating cancer over benign adnexal masses.87 The FDA has approved HE4 for surveillance and monitoring for recurrent or progressive disease; HE4 has particular utility in following women without prior CA-125 elevations.
In addition, Rustin and colleagues88 reported on a large randomized trial of women with advanced-stage ovarian cancer and identified no improvement in survival with serial CA-125 monitoring after completion of standard therapy. In this study, women in complete remission underwent CA-125 measurement and clinical examination every 3 months; patients and clinicians were blinded to the CA-125 results. When the CA-125 exceeded twice the upper limit of normal, patients were randomized to either immediate chemotherapy or delay of treatment until relapse became clinical or symptomatic. Investigators could not observe any difference in overall survival and reported decreased quality of life scores in those women randomized to immediate therapy. Although several factors may have influenced these findings (including the very low application of secondary cytoreductive surgery), these findings suggest that serial tumor markers may not influence clinical outcome. CA-125 testing may be omitted except in the event of clinical suspicion of relapse or at the patient’s request.
Recommended Treatment Options
Recurrent ovarian, tubal, and peritoneal cancer are diseases unlikely to be cured with the current tools of surgery, chemotherapy, and radiation. As such, the goal of treatment of this disease is palliation of symptoms and extension of disease-free and overall survival. One of the most important factors in predicting outcome related to recurrent ovarian caner is the “platinum-free interval,” defined as the time between completion of primary therapy and disease recurrence. The longer this interval, the higher the probability of responding again to platinum-based chemotherapy. For this reason, cancer recurrences that occur greater than 6 months after completion of platinum-based chemotherapy are considered platinum-sensitive, and those occurring less than 6 months from completion of primary treatment are classified as platinum-resistant.
The decision regarding the modality of treatment of recurrent ovarian, tubal, and peritoneal cancer (chemotherapy vs. surgery followed by chemotherapy) is dependent on a variety of factors, not least of which is the judgment of the surgeon. The concept behind performing surgery for recurrent ovarian cancer (“secondary cytoreduction”) is based on the principle followed for the primary management of the disease. In primary disease, when there is little or no disease before initiation of chemotherapy, it has been demonstrated that prognosis is better, as delivery of chemotherapy is in theory more effective in the absence of large hypoxic tumors, the probability of sporadic cancer mutation favoring chemotherapy resistance should lessen in the absence of more frequent cellular division in larger tumors, and the total number of cancer cells needed to treat is less. Although these factors should also apply to recurrent ovarian cancer, there are no definitive data suggesting that this intervention improves prognosis in women with recurrent disease. The majority of studies regarding secondary cytoreduction are limited by their varied inclusion criteria, nonrandomized design, long reporting interval, and small sample size. Nonetheless, some general conclusions can be drawn from the literature regarding this intervention. In general, secondary cytoreduction is reserved for patients with platinum-sensitive disease, in that this group of patients has the best prognosis before surgery and the highest likelihood of demonstrating chemosensitive disease after surgery. Furthermore, this procedure is more commonly performed in patients with limited sites of recurrent disease; in those patients with diffuse peritoneal carcinomatosis, it is less likely that optimal resection may be performed.89 A recent meta-analysis suggested that the survival associated with secondary cytoreduction was significantly associated with complete cytoreduction.90
Regardless of whether patients with recurrent disease undergo secondary cytoreduction, patients are generally treated with systemic chemotherapy (unless palliative supportive care is pursued). Patients with platinum-sensitive cancers are treated with either single- or multiagent platinum-containing regimens. To date, 2 randomized clinical trials have reported that treatment of patients with platinum-sensitive recurrent ovarian cancer with combination platinum-paclitaxel or platinum-gemcitabine is associated with improved progression-free survival compared with treatment with platinum alone.91 Furthermore, the recently reported phase III CALYPSO (CAeLYx in Platinum Sensitive Ovarian) study reported that treatment with liposomal doxorubicin and carboplatin was associated with improved progression-free survival compared with paclitaxel and carboplatin.92 From these data, most clinicians choose to treat patients with platinum-sensitive recurrent ovarian cancer with platinum-containing doublets. The decision to use one cytotoxic over another (in combination with platinum) often is dictated by the expected toxicity of the combination. As an example, a patient with moderate preexisting peripheral neuropathy would likely be treated with platinum-gemcitabine rather than platinum-paclitaxel for her recurrence. Overall, the expected response rate for platinum-based combinations in the setting of platinum-sensitive recurrent ovarian cancer is approximately 70%.
For patients with persistent disease after primary therapy (platinum-refractory) or platinum-resistant disease, single-agent chemotherapy is often used. Given the poor prognosis associated with recurrent platinum-refractory or -resistant disease, the decision to treat with a specific regimen must be made in the context of maintaining quality of life. Current FDA-approved medications for the treatment of recurrent ovarian cancer include the doublet of carboplatinum and gemcitabine, paclitaxel, liposomal doxorubicin, and topotecan.93,94 In the setting of platinum-recurrent (or -refractory) disease, these agents are associated with response rates of approximately 15%. During the life of a patient with recurrent ovarian cancer, she will likely be treated with all of these medications; the sequence in which they are given is often based on toxicity and convenience of administration.
Although there is a great deal of enthusiasm regarding the expansion of knowledge related to the human genome and its alterations in cancer, until recently, these scientific discoveries have not translated into substantial improvements in the outcome of patients, recurrent ovarian cancer. Historically, investigation of oncogenic pathways and their inhibitors, such as the epidermal growth factor receptor (EGFR) family of inhibitors (eg, trastuzumab and pertuzumab) have not shown responses much different from those associated with single-agent cytotoxic therapy.95,96 More recently, investigation of inhibitors of angio-genesis (eg, bevacizumab) in the setting of primary and recurrent ovarian cancer has shown promise. The GOG investigated single-agent bevacizumab and found it to be well tolerated and associated with a greater than 20% response rate (median duration of response, 10 months).97 This agent has been combined with many other cytotoxic agents and is currently under investigation in patients with platinum-sensitive recurrent ovarian cancer in GOG-213.
More recently, identification of the role of inhibition of the poly (ADP-ribose) polymerase (PARP) pathway in the treatment of ovarian, tubal, and peritoneal cancers has led to enthusiasm in improving outcome in this disease.98-100The use of PARP inhibitors in the treatment of cancer represents the first successful clinical exploitation of tumor synthetic lethality (promotion of genomic instability). PARP activity is required for base-excision repair, a DNA-damage repair pathway that recognizes and eliminates the DNA that is commonly damaged during replication. In the absence of PARP activity, these damaged bases accumulate, and replication forks (the location of DNA replication during DNA synthesis) are arrested at sites of the damaged DNA, eventually causing double-strand DNA breaks. Normally, the process of homologous recombination repairs these breaks; in the situation in which this mechanism is unavailable (in the case when BRCA1 or BRCA2 is absent), the cell dies. The use of PARP inhibitors exploits this mechanism and causes the accumulation of damaged DNA, limits the repair of double-strand DNA breaks, and inhibits cancer growth. In the absence of 1 copy of the BRCA gene (in the case of an inherited BRCA defect), the use of PARP inhibitors has been shown to be effective. Patients with hereditary ovarian carcinoma are excellent candidates for treatment with PARP inhibitors, because these patients are heterozygous for mutations in BRCA1 or BRCA2 and thus have preserved homologous recombination in their somatic cells, whereas their tumors have lost the remaining wild-type copy of BRCA1 or BRCA2 and are therefore deficient in homologous recombination. Because many sporadic ovarian cancers develop somatic acquisition of a BRCA mutation, the applicability of PARP inhibitors in the treatment of ovarian cancer extends beyond just treatment of patients with hereditary ovarian cancer syndromes.101 In a recent phase 2 study of patients with recurrent epithelial ovarian cancer, the overall response rate to the PARP inhibitor olaparib was 33%, much higher than generally reported for this disease when treated with standard chemotherapy.98 Although encouraging, there is insufficient evidence to date to recommend the routine use of PARP inhibitors in the treatment of recurrent ovarian cancer. Results from ongoing phase 3 trials of PARP inhibitors in ovarian cancer are eagerly awaited.
Palliative Care
Given the usual course of recurrent ovarian cancer (in which patients become refractory to therapy), patients often experience conditions that require specific expertise in palliative care. It is estimated that the majority of patients with recurrent disease will undergo treatment for bowel dysfunction (constipation or obstruction), pain, ascites, pleural effusions, and nausea or emesis. These issues are addressed in general in the following section on Special Management Problems.
SPECIAL MANAGEMENT PROBLEMS
Thoracic Disease
Pleural effusions and intrathoracic metastases are not infrequently noted in patients who present with clinical findings suggestive of an advanced-stage ovarian, tubal, or peritoneal cancer. Eitan et al102 noted that the outcome in patients with malignant pleural effusions in optimally debulked advanced-stage ovarian cancer was worse than in those patients without an effusion. The optimal management of patients who are noted to have a pleural effusion is not well established, although video-assisted thoracic surgery (VATS) may be used to document intrathoracic disease, to potentially resect macroscopic disease, and to direct therapy in those ovarian cancer patients with moderate to large pleural effusions.103 For those patients with symptomatic pleural effusions, thoracentesis or VATS-assisted pleurodesis may be considered.
Ascites
Patients with newly diagnosed advanced-stage or recurrent ovarian cancer often experience symptoms related to the accumulation of malignant ascites. A paracentesis may be indicated in instances when patients with ascites experience shortness of breath, significant abdominal bloating, and difficulty with eating. In general, this procedure is accomplished at the bedside with a blind approach or under ultrasound guidance. An indwelling catheter has been demonstrated to be useful in patients with recurrent symptomatic ascites.104
Bowel Obstruction
Although uncommonly noted in patients with newly diagnosed ovarian cancer, patients with recurrent disease may often experience bowel dysfunction or obstruction. Clinicians must take into consideration the patient’s overall medical and performance status, the burden of disease, and her prior therapy in choosing the appropriate measures to correct or palliate obstructive symptoms. Nonsurgical options include temporary nasogastric suctioning with intravenous fluid supplementation and appropriate electrolyte supplementation. Intravenous octreotide has been reported to be potentially effective in ameliorating obstructive symptoms related to malignancies.105 A gastrostomy tube placed via endoscopy or by interventional radiology should be considered in those patients who do not respond to conservative measures, who are not good surgical candidates, and who do not have a life expectancy of greater than 3 to 6 months. A colonic stent may be considered in select patients with distal large bowel obstruction, but the reported success rates appear not to exceed 25%.106
For select ovarian cancer patients with a bowel obstruction who do not respond to conservative measures, have limited disease, and have a life expectancy of greater than 3 to 6 months, a surgical approach to correct anatomy or palliate their symptoms should be carefully considered. Depending on the nature of the obstruction and intraoperative findings, a surgeon may wish to consider a bowel resection with anastomosis, a bowel bypass, and/or an ileostomy or colostomy. Chi et al107 reported excellent improvement in symptoms with a surgical approach in a prospectively evaluated cohort of recurrent ovarian cancer patients with a bowel obstruction. However, median survival did not exceed 7 months. Despite only limited data to perform a systematic review, there is a suggestion that surgical management of recurrent ovarian cancer-associated bowel obstruction can improve survival compared with medical management.108
FUTURE DIRECTIONS
Substantial progress has been made toward improving the diagnosis and treatment of ovarian cancer, resulting in improved survival. With recent expansion of our understanding of the cancer genome, numerous advances have been made in the diagnosis, prognostication, and treatment of high-grade serous ovarian, peritoneal, and tubal cancers. Although the most encouraging data recently regarding targeted therapies focus on inhibition of angiogenesis with the monoclonal antibody bevacizumab and the exploitation of the PARP pathway, alternative means to inhibit the angiogenesis pathway or investigation of other pathways (eg, those in the EGFR family) have also been described in the treatment of these diseases. Preliminary results using a soluble decoy receptor of VEGF (VEGF trap) and small molecule inhibitors of the VEGF or platelet-derived growth factor pathway (sunitinib, sorafenib) have shown promise in the treatment of recurrent ovarian cancer. Furthermore, inhibition of the EGFR pathway (trastuzumab, cetuximab, pertuzumab, erlotinib) has demonstrated variable response, although at different rates. At this time, these agents remain experimental and are being evaluated in clinical trials in recurrent ovarian cancer. Blockade of other pathways, such as the src kinase inhbitors, antifolates, and insulin-like growth factor 1 receptor inhibitors, also are being studied in clinical trials. Other novel treatment strategies, such as immuno- and gene therapy, are also under development.
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