There are at least three distinct tumorigenic pathways to account for the heterogeneity of epithelial ovarian cancer. First, relatively few cases seem to arise from an accumulation of genetic alterations that leads to malignant transformation of benign cysts to LMP tumors and ultimate progression to invasive ovarian carcinoma (Makarla, 2005). Typically, these invasive tumors are low-grade and clinically indolent, and K-ras oncogenic mutations occur early. The ras family of oncogenes includes K-ras, H-ras, and N-ras. Their protein products participate in cell cycle regulation and cell proliferation control. As such, ras mutations are implicated in carcinogenesis by their inhibition of cellular apoptosis and promotion of cellular proliferation (Mammas, 2005).
Second, at least 10 percent of epithelial ovarian carcinomas, invariably high-grade serous tumors, result from an inherited predisposition. Women born with a BRCA gene mutation require only one “hit” to the other normal copy (allele) to “knock out” the BRCA tumor-suppressor gene product. As a result, BRCA-related cancers develop approximately 15 years before sporadic cases. Current data suggests that serous tubal intraepithelial carcinoma (STIC) is a precursor condition for a significant percentage of serous carcinomas, which were formerly thought to arise spontaneously on the ovarian or peritoneal surface (Fig. 35-4) (Levanon, 2008; Medeiros, 2006; Perets, 2013). Thereafter, BRCA-related serous cancers appear to have a unique molecular pathogenesis, requiring p53 inactivation to progress (Buller, 2001; Landen, 2008; Schorge, 2000). p53 is a tumor suppressor gene. Its protein product prohibits cells from entering subsequent stages of cell division and thereby halts uncontrolled tumor cell replication. Mutations in p53 are linked with various cancers. In fact, loss of BRCA and p53 protein function has been detected prior to invasion, further supporting its importance as an early triggering event (Werness, 2000).
A. Normal fallopian tube epithelium is composed of three cell types—ciliated cells, secretory cells, and intercalary cells. B. Serous carcinoma in situ of the fallopian tube. The cells of serous carcinoma lining this tube are markedly atypical, with nuclear pleomorphism, chromatin coarseness, loss of nuclear polarity, mitotic activity (arrow), and epithelial proliferation/tufting. (Used with permission from Dr. Kelley Carrick.)
Third, most carcinomas appear to originate de novo from ovarian surface epithelial cells that are sequestered in cortical inclusion cysts (CICs) within the ovarian stroma. Numerous inciting events and subsequent pathways have been proposed. For example, cyclic repair of the ovarian surface during long periods of repetitive ovulation requires abundant cellular proliferation. In these women, spontaneous p53 mutations arising during the DNA synthesis that accompanies this proliferation appear to play a primary carcinogenetic role (Schildkraut, 1997). Ultimately, the replicative stress and DNA damage transforms the entrapped surface epithelial cells within CICs into any of the histologic ovarian cancer variants (Levanon, 2008).
Symptoms and Physical Findings
Ovarian cancer is typically portrayed as a “silent” killer that lacks appreciable early signs or symptoms. This is a misconception. Actually, patients are often symptomatic for several months before the diagnosis, even with early-stage disease (Goff, 2000). The difficulty is distinguishing these symptoms from those that normally occur in women.
In general, persistent symptoms that are more severe or frequent than expected and have a recent onset warrant further diagnostic investigation. Commonly, increased abdominal size, bloating, urinary urgency, and pelvic pain are reported. Additionally, fatigue, indigestion, inability to eat normally, constipation, and back pain may be noted (Goff, 2004). Abnormal vaginal bleeding occurs rarely. Occasionally, patients may present with nausea, vomiting, and a partial bowel obstruction if carcinomatosis is particularly widespread. Unfortunately, many women and clinicians are quick to attribute most symptoms to menopause, aging, dietary changes, stress, depression, or functional bowel problems, and diagnosis is often delayed.
A pelvic or pelvic-abdominal mass is palpable in most patients with ovarian cancer during bimanual evaluation. Malignant tumors tend to be solid, nodular, and fixed, but there are no classic findings that distinguish these growths from benign tumors. Paradoxically, a huge mass filling the pelvis and abdomen more often represents a benign or borderline tumor. To aid surgical planning, a rectovaginal examination is also performed. For example, a woman with cancer involving the rectovaginal septum may need to be positioned in dorsal lithotomy to perform a low anterior colon resection as a part of tumor excision.
The presence of a fluid wave, or less commonly, flank bulging, suggests the presence of significant ascites. In a woman with a pelvic mass and ascites, the diagnosis is ovarian cancer until proven otherwise. However, ascites without an identifiable pelvic mass suggests the possibility of cirrhosis or other primary malignancies such as gastric or pancreatic cancers. In advanced disease, examination of the upper abdomen usually reveals a central mass signifying omental caking.
Auscultation of the chest is also important, since patients with malignant pleural effusions may not be overtly symptomatic. The remainder of the examination includes palpation of the peripheral nodes in addition to a general physical assessment.
A routine complete blood count and metabolic panel often demonstrates a few characteristic features. Of affected women, 20 to 25 percent will present with thrombocytosis (platelet count >400 × 109/L) (Li, 2004). Malignant ovarian cells releasing cytokines are believed to increase platelet production rates. Hyponatremia, typically ranging between 125 and 130 mEq/L, is another common finding. In these patients, tumor secretion of a vasopressin-like substance can cause a clinical picture suggesting a syndrome of inappropriate antidiuretic hormone (SIADH).
The serum CA125 level is integral to epithelial ovarian cancer management. In 90 percent of women presenting with malignant nonmucinous tumors, CA125 levels are elevated. However, there are caveats during adnexal mass evaluation. Half of stage I ovarian cancers will have a normal CA125 measurement (false-negative). Also, an elevated value (false-positive) may be associated with various common benign indications such as pelvic inflammatory disease, endometriosis, leiomyomas, pregnancy, and even menstruation. Thus, in postmenopausal women with a pelvic mass, a CA125 measurement may better predict a higher likelihood of malignancy (Im, 2005).
Another marker, the human epididymal protein 4 (HE4) tumor marker, is approved by the U.S. Food and Drug Administration (FDA), along with CA125, when used in the Risk of Ovarian Malignancy Algorithm (ROMA) to determine the likelihood of finding malignancy at surgery in women with an adnexal mass. The ROMA score is derived from the results of both blood tests, plus menopausal status (Moore, 2009, 2010).
OVA1 is another biomarker blood test panel that may be used for the preoperative triage of women with an identified ovarian mass when surgery is planned (Ueland, 2011; Ware Miller, 2011). Scores ≥5.0 in premenopausal and scores ≥4.4 in postmenopausal women suggest a need for gynecologic oncologist consultation. Importantly, this test is not a screening tool and is reserved for those with a known surgical mass to aid preoperative triage (Vermillion Inc, 2012; Zhang, 2010). Validation studies evaluating ROMA and OVA1 are limited, and their role in preoperative triage is yet to be clearly defined. As a result, they are not necessarily recommended for determining the status of an undiagnosed pelvic mass (Morgan, 2014). Last, when a mucinous ovarian tumor is identified, serum tumor markers that may be better indicators of disease are cancer antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA).
Transvaginal sonography is typically the most useful imaging test to differentiate benign tumors and early-stage ovarian cancers (Chap. 2). In general, malignant tumors are multiloculated, solid or echogenic, and large (>5 cm), and they have thick septa with areas of nodularity (Fig. 35-5A). Other features may include papillary projections or neovascularization—demonstrated by adding color Doppler (Figs. 35-5B and 35-5C). Although several presumptive models have been described in an attempt to distinguish benign masses from ovarian cancers preoperatively, none have been universally implemented (Timmerman, 2005; Twickler, 1999).
Sonograms of an ovarian cyst. A. Transvaginal sonogram depicts a complex ovarian mass (calipers). Cystic and solid components and a thick intracystic septum are seen. These findings increase clinical concern for malignancy. B. Color Doppler transvaginal sonogram shows neovascularization within this ovarian tumor. C. Transvaginal Doppler study of ovarian mass vessels reveals decreased impedance. (Used with permission from Dr. Diane Twickler.)
In patients with advanced disease, sonography is less helpful. The pelvic sonogram may be particularly difficult to interpret if a large mass encompasses the uterus, adnexa, and surrounding structures. Ascites, if present, is easily detected, but in general, abdominal sonography has limited use.
Of radiographic tests, patients with suspected ovarian cancer should have a chest radiograph to detect pulmonary effusions or infrequently, pulmonary metastases. Rarely, a barium enema is clinically helpful in excluding diverticular disease or colon cancer or in identifying ovarian cancer involvement of the rectosigmoid.
Computed tomography (CT) scanning has a primary role in treatment planning for women with advanced ovarian cancer. Preoperatively, implants in the liver, retroperitoneum, omentum, or other intraabdominal site are detected to thereby guide surgical cytoreduction or demonstrate obviously unresectable disease (Fig. 35-6) (Suidan, 2014). However, CT is not particularly reliable in detecting intraperitoneal disease smaller than 1 to 2 cm in diameter. Moreover, CT scanning accuracy is poor for differentiating a benign ovarian mass from a malignant tumor when disease is limited to the pelvis. In these cases, transvaginal sonography is superior. Other radiologic studies such as magnetic resonance (MR) imaging, bone scans, and positron emission tomography (PET) in general provide limited additional information preoperatively.
Computed tomographic scans in a woman with ovarian cancer. A. Axial CT scan at the level of the liver and spleen reveals metastatic lesions in the spleen and liver (curved arrows) and a bulky lesion at the splenorenal ligament (arrow). B. More caudal axial CT reveals ascites (curved arrows) and marked omental caking (arrows). (Used with permission from Dr. Diane Twickler.)
A woman with a pelvic mass and ascites can usually be assumed to have ovarian cancer until surgically proven otherwise. Thus, few patients require diagnostic paracentesis. Moreover, this procedure is typically avoided diagnostically as cytologic results are usually nonspecific and abdominal wall metastases may form at the needle entry site (Kruitwagen, 1996). However, paracentesis may be indicated for those with ascites in the absence of a pelvic mass.
Aside from diagnosis, paracentesis may also relieve volume-related symptoms in those with large accumulations. This may be done at the bedside, using connector tubing and vacuum bottles, or completed by an interventional radiologist. Relative dehydration is common afterward and manifest by thirst, oliguria, and short-term creatinine level rise, which all correct with normal oral intake.
Using the currently available diagnostic modalities, clinicians often face tremendous difficulty in distinguishing benign from malignant. However, ascites or evidence of metastases should prompt consultation with an oncologist (American College of Obstetricians and Gynecologists, 2011). Additionally, premenopausal women with elevated CA125 levels (i.e., >200 U/mL) or an OVA1 score ≥5.0 and postmenopausal women with any CA125 level elevation or an OVA1 score ≥4.4 are at higher risk.
Ideally, for patients with suspicious adnexal masses, surgery is performed in a hospital with a pathologist able to reliably interpret an intraoperative frozen section. At minimum, samples for peritoneal cytology are obtained when the abdomen is entered. The mass is then removed intact through an incision that permits thorough staging and resection of possible metastatic sites (American College of Obstetricians and Gynecologists, 2011).
If malignancy is diagnosed, then surgical staging is completed. However, in a study of more than 10,000 women with ovarian cancer, almost half of those with early-stage disease did not undergo the recommended surgical procedures (Goff, 2006). Surgeons should be prepared to appropriately stage and potentially debulk ovarian cancer or have a gynecologic oncologist immediately available. This type of careful planning has been shown to achieve the best possible surgical result and improve survival rates (Earle, 2006; Engelen, 2006; Mercado, 2010). Moreover, since broader resources are usually available, patients cared for at high-volume hospitals also tend to have better outcomes (Bristow, 2010).
For women with malignancy identified only postoperatively or intraoperatively and without adequate staging, management will vary. Women with suspected early-stage disease may be restaged laparoscopically. Those with advanced disease may undergo a second laparotomy to obtain optimal tumor debulking (Grabowski, 2012). However, if extensive disease is found at the initial surgery, then chemotherapy may be selected first and followed later by laparotomy to obtain optimal interval cytoreduction.
At some point during postoperative surveillance, many women with early-stage disease, depending on the diagnosis, will return to their referring physician. Monitoring for relapse is often coordinated between the gynecologic oncologist and generalist in obstetrics and gynecology, especially if no chemotherapy is required following surgery.
Although epithelial ovarian cancer is often considered a single entity, the different histologic types vary in their behavior (Table 35-3). Sometimes, two or more cell types are mixed. Within each histologic type, tumors are further categorized as benign, borderline (low malignant potential), or malignant.
TABLE 35-3World Health Organization Histological Classification of Ovarian Carcinoma ||Download (.pdf) TABLE 35-3 World Health Organization Histological Classification of Ovarian Carcinoma
Clear cell adenocarcinoma
Malignant Brenner tumor
Mixed epithelial and mesenchymal
Squamous cell carcinoma
Small cell carcinoma
Mainly in early-stage disease, grade is an important prognostic factor that affects treatment planning (Morgan, 2014). Unfortunately, no grading system for epithelial ovarian carcinoma is universally accepted. Instead, numerous different schemata, most based on architecture and/or nuclear pleomorphism, are currently used. In general, tumors are classified as grade 1 (well-differentiated), grade 2 (moderately differentiated), and grade 3 (poorly differentiated) lesions (Pecorelli, 1999).
Grossly, there are no distinguishing features among the types of epithelial ovarian cancer. In general, each has solid and cystic areas of varying sizes (Fig. 35-7).
A. Excised cystic ovarian mass. Note the fallopian tube stretched over the top of the ovarian capsule. B. Opened tumor reveals the inner cyst wall and scattered papillary tumor growth (arrow). (Photographs contributed by Dr. David Miller.)
More than 50 percent of all epithelial ovarian cancers have serous histology. Microscopically, in well-differentiated tumors, cells may resemble fallopian tube epithelium, whereas in poorly differentiated tumors, anaplastic cells with severe nuclear atypia predominate (Fig. 35-8). During frozen section analysis, psammoma bodies are essentially pathognomonic of an ovarian-type serous carcinoma. Often, these tumors contain various other cell types as a minor component (<10 percent) that may cause diagnostic problems but do not influence outcome (Lee, 2003).
Serous carcinomas vary in regard to their degree of differentiation, as manifested by their architecture, degree of cytologic atypia and pleomorphism, and mitotic rate. A. In this relatively well-differentiated example of serous carcinoma, serous-type cells with moderate nuclear atypia form papillae and project into a cystic space. Numerous psammoma bodies, which are extracellular round laminar eosinophilic collections of calcium, are seen here. B. In this less well-differentiated example of serous carcinoma, moderately to markedly atypical cells form sheets, as opposed to the glands and papillae formed by better-differentiated tumors. (Used with permission from Dr. Kelley Carrick.)
Endometrioid adenocarcinomas compose 15 to 20 percent of epithelial ovarian cancers and are the second most common histologic type (Fig. 35-9). The lower frequency results largely because poorly differentiated endometrioid and serous tumors cannot be easily distinguished and such cases are usually classified as serous. As a result, well-differentiated endometrioid tumors are proportionally more common, which may also explain their overall relatively good prognosis.
Ovarian endometrioid adenocarcinomas are morphologically similar to their more common counterparts arising in the endometrium. Better-differentiated tumors like this one have glands resembling proliferative endometrial glands, which grow in a confluent pattern. More poorly differentiated tumors have a variable percentage of solid growth and/or increased nuclear atypia. Like their endometrial counterparts, these tumors may show squamous differentiation. (Used with permission from Dr. Raheela Ashfaq.)
In 15 to 20 percent of cases, uterine endometrial adenocarcinoma coexists. This is usually regarded as a synchronous tumor, but metastasis from one site to the other is difficult to exclude (Soliman, 2004). A müllerian “field effect” is theorized to account for these independently developing, histologically similar tumors. In addition, many such patients are noted to have pelvic endometriosis.
Malignant mixed müllerian tumor, now preferably termed carcinosarcoma, by definition contains malignant epithelial and mesenchymal elements. It represents <1 percent of ovarian cancers, carries a poor prognosis, and is histologically similar to uterine primary tumors (Rauh-Hain, 2011).
Mucinous adenocarcinomas compose 5 to 10 percent of true epithelial ovarian cancers. The frequency is usually overestimated because many are undetected primary intestinal cancers from the appendix or colon. Well-differentiated ovarian mucinous tumors closely resemble mucin-secreting adenocarcinomas of intestinal or endocervical origin (Fig. 35-10). Histologically, the distinction may be impossible without clinical correlation (Lee, 2003). Advanced-stage mucinous ovarian carcinomas are rare, tend to be resistant to platinum chemotherapy, and have a prognosis significantly worse than that for serous tumors (Zaino, 2011).
This mucinous carcinoma arose within a 15-cm mucinous cystadenoma. Benign mucinous-type epithelium lining cystic spaces of the background cystadenoma is seen (arrows). A carcinomatous component (arrowhead) invades the stroma in a haphazard fashion at the center of the photomicrograph. The malignant cells are arranged in clusters and poorly formed glands, which have intracytoplasmic and intraluminal mucin (asterisks). (Used with permission from Dr. Kelley Carrick.)
This clinical term describes the rare finding of abundant mucoid or gelatinous material in the pelvis and abdominal cavity, surrounded by thin fibrous capsules. An ovarian mucinous carcinoma with ascites rarely results in this condition, and evidence suggests that ovarian mucinous tumors associated with pseudomyxoma peritonei are almost all metastatic rather than primary. As a result, appendiceal or other intestinal sites of origin should be excluded (Ronnett, 1997). The primary appendiceal tumor may be small relative to the ovarian tumor(s) and may not be appreciated macroscopically. Thus, removal and thorough histologic examination of the appendix is indicated in all cases of pseudomyxoma peritonei.
If the peritoneal epithelial cells are benign or borderline-appearing, the condition is referred to as disseminated peritoneal adenomucinosis. Affected patients have a benign or protracted, indolent clinical course (Ronnett, 2001). If the peritoneal epithelial cells appear malignant, the clinical course is invariably fatal.
Clear Cell Adenocarcinoma
Comprising 5 to 10 percent of epithelial ovarian cancers, clear cell adenocarcinomas are most frequently associated with pelvic endometriosis. These tumors appear similar to clear cell carcinomas that develop sporadically in the uterus, vagina, and cervix. Typically, tumors are confined to the ovary and generally are cured by surgery alone. However, the 20 percent presenting with advanced disease tend to be platinum resistant and carry a worse prognosis than serous carcinoma (Al-Barrak, 2011).
Microscopically, both clear and “hobnail” cells are characteristic (Fig. 35-11). In clear cells, the visibly clear cytoplasm results from the dissolution of glycogen as the tissue specimen is histologically prepared. Hobnail cells have bulbous nuclei that protrude far into the cystic lumen beyond the apparent cytoplasmic limits of the cell (Lee, 2003).
Clear cell adenocarcinoma is typically composed of cells with clear to eosinophilic cytoplasm that are arranged in cysts, tubules, papillae, and/or sheets. In the ovary, it looks similar to its counterparts in the endometrium and cervix/vagina. In this example, hobnail cells are marked by the arrows. (Used with permission from Dr. Kelley Carrick.)
Of these, the rare malignant Brenner tumor characteristically has poorly differentiated transitional cell carcinoma coupled with foci of benign or borderline Brenner tumor. Microscopically, the transitional cell component resembles carcinomas arising from the urinary tract, often with squamous differentiation. Brenner tumors classically have a dense, abundant fibrous stroma with embedded nests of transitional epithelium.
Transitional cell carcinoma accounts for fewer than 5 percent of ovarian cancers. These tumors lack a demonstrable Brenner component. Patients with transitional cell carcinoma have a worse prognosis than those with malignant Brenner tumors, but a better prognosis than those with other histologic types of epithelial ovarian cancer (Guseh, 2014). Microscopically, transitional cell carcinoma resembles a primary bladder carcinoma but has an immunoreactive pattern consistent with ovarian origin (Lee, 2003). Thus, transitional cell carcinoma is now considered a high-grade form of serous carcinoma.
Of these, primary squamous cell carcinoma of the ovary is rare. This is the newest category to be recognized and typically carries a poor prognosis for most with advanced disease (Park, 2010). More commonly, squamous cell carcinomas arise from mature cystic teratomas (dermoid cysts) and are classified as malignant ovarian germ cell tumors (Pins, 1996). In other cases, ovarian endometrioid variants may have extensive squamous differentiation, or alternatively, metastases from a cervical primary are present.
Mixed carcinoma describes an ovarian cancer that contains more than 10 percent of a second cell type. Common combinations include mixed clear cell/endometrioid or serous/endometrioid adenocarcinomas.
Undifferentiated carcinomas are rare epithelial ovarian tumors that are too poorly differentiated to be classified into any of the müllerian types previously described. Microscopically, the cells are arranged in solid groups or sheets with numerous mitotic figures and marked cytologic atypia. Typically, foci of müllerian carcinoma, usually serous, are found within the tumor. Overall, undifferentiated carcinomas of the ovary have a poor prognosis compared with the other histologic types (Silva, 1991).
Small cell carcinomas are rare, extremely malignant, and consist of two subgroups. Most patients have a hypercalcemic type, which typically develops in young women. Nearly all tumors are unilateral, and two thirds are associated with elevated serum calcium levels that resolve postoperatively (Young, 1994). Recent data suggest these highly lethal tumors arise via a specific mutation in the SMARCA4 gene (Jelinic, 2014). The pulmonary type resembles oat-cell carcinoma of the lung and develops in older women. Half of these women have bilateral ovarian disease (Eichhorn, 1992). In general, patients with small cell carcinoma die within 2 years from rapid disease progression.
Primary Peritoneal Carcinoma
Up to 15 percent of “typical” epithelial ovarian cancers are actually primary peritoneal carcinomas that develop de novo from the lining of the pelvis and abdomen. In some cases, especially among BRCA1 mutation carriers, independent malignant transformation occurs at multiple peritoneal sites simultaneously (Schorge, 1998). However, more recent data suggest that nearly half of presumed cases actually arise in the tubal fimbria (Carlson, 2008).
Clinically and histologically, these tumors are virtually indistinguishable from epithelial ovarian cancer. However, primary peritoneal carcinoma may develop in a woman years after undergoing BSO. If ovaries are still present, several criteria are required to make the diagnosis (Table 35-4). By far the most common variant is papillary serous, but any of the other histologic types are possible. In general, the staging, treatment, and prognosis of primary peritoneal carcinoma are the same as for epithelial ovarian cancer (Mok, 2003). The differential diagnosis mainly includes malignant mesothelioma.
TABLE 35-4Criteria for Diagnosing Primary Peritoneal Carcinoma When Ovaries Are Present ||Download (.pdf) TABLE 35-4 Criteria for Diagnosing Primary Peritoneal Carcinoma When Ovaries Are Present
Both ovaries must be normal in size or enlarged by a benign process
The involvement in the extraovarian sites must be greater than the involvement on the surface of either ovary
The ovarian tumor involvement must be either nonexistent, confined to the ovarian surface epithelium without stromal invasion, or involving the cortical stroma with tumor size less than 5 × 5 mm
Historically, this carcinoma was assumed to be rarer than epithelial ovarian cancer. However, the fallopian tube fimbria have recently been identified as an origin for many high-grade pelvic serous carcinomas that were previously assumed to arise from the ovary or peritoneum (Fig. 35-12) (Levanon, 2008).
A. Epithelial cells from the fimbria are released and implant on the denuded surface of the ovary at the site of ovulation. B & C. Subsequently, an inclusion cyst is formed.
Clinically, this fallopian tube carcinoma is similar to epithelial ovarian cancer. For the most part, risk factors, histologic types, surgical staging, pattern of spread, treatment, and prognosis are comparable. To be considered a primary fallopian tube carcinoma, the tumor must be located macroscopically within the tube or its fimbriated end. Additionally, the uterus and ovary must not contain carcinoma, or if they do, it must be clearly different from the fallopian tube lesion (Alvarado-Cabrero, 2003).
Malignant tumors that metastasize to the ovary are almost invariably bilateral. The term Krukenberg tumor refers to a metastatic mucinous/signet ring cell adenocarcinoma of the ovaries that typically originates from primary tumors of the intestinal tract, characteristically the stomach (Fig. 35-13). Ovarian metastases often represent a late disseminated stage of the disease in which other hematogenous metastases are also found (Prat, 2003).
Krukenberg tumor. This metastatic, poorly differentiated adenocarcinoma is characterized by singly disposed cells with an intracytoplasmic mucin globule that displaces the nucleus to the cell periphery, producing a signet-ring-like cytomorphology. (Used with permission from Dr. Raheela Ashfaq.)
In general, epithelial ovarian cancers predominantly metastasize by exfoliation. Malignant cells are first released into the peritoneal cavity when the tumor penetrates through the ovarian capsule surface. By following the normal circulation of peritoneal fluid, cells may then develop into implants anywhere in the abdomen. A unique characteristic of ovarian cancer is that metastatic tumors do not usually infiltrate visceral organs, but exist as surface implants. As a result, aggressive debulking is possible with reasonable morbidity.
Due to its marked vascularity, the omentum is the most frequent location to support metastatic disease and is often extensively involved with tumor (Fig. 35-14). Nodules are also commonly present on the undersurface of the right hemidiaphragm and small bowel serosa, but all intraperitoneal surfaces are at risk.
Photograph showing omental caking caused by tumor invasion.
Lymphatic dissemination is the other primary mode of spread. Malignant cells move through channels that follow the ovarian blood supply along the infundibulopelvic ligament and that terminate in paraaortic lymph nodes up to or above the level of the renal vessels. Other lymphatics pass laterally through the broad ligament and parametrium to the external iliac, obturator, and internal iliac nodal chains. Infrequently, metastases can also follow the round ligament to the inguinal nodes (Lee, 2003).
Direct extension of a progressively enlarging ovarian cancer may create confluent tumor involvement of the pelvic peritoneum and adjacent structures, including the uterus, rectosigmoid colon, and fallopian tubes. Usually, this is associated with significant induration of the surrounding tissues.
In advanced disease, several liters of ascites may collect. Either increased production of carcinomatous fluid or decreased clearance by obstructed lymphatic channels are purported causes. Similarly, by traversing the diaphragm, a malignant pleural effusion may develop, almost invariably on the right.
Hematogenous spread is atypical. In most cases, metastases to the liver or lung parenchyma, brain, or kidneys are observed in patients with recurrent, end-stage disease, and not at initial diagnosis.
Ovarian cancer is surgically staged, and stage is assigned according to findings before tumor removal and debulking (Fig. 35-15). The International Federation of Gynecology and Obstetrics (FIGO) stages reflect the typical patterns of ovarian cancer spread (Table 35-5) (Prat, 2014). Even if a tumor appears clinically confined to the ovary, in many cases it will have detectable metastases. Therefore, accurate surgical staging is crucial to guide treatment. Approximately one third of patients have surgical stage I or II disease (Table 35-6).
TABLE 35-5FIGO Staging of Carcinoma of the Ovary, Fallopian Tube, and Primary Peritoneal Carcinoma ||Download (.pdf) TABLE 35-5 FIGO Staging of Carcinoma of the Ovary, Fallopian Tube, and Primary Peritoneal Carcinoma
|Stage ||Characteristics |
|Tumor confined to ovaries (or to fallopian tubes) a |
Tumor limited to 1 ovary (or 1 tube); capsule intact, no tumor on surface, negative washings
Tumor involves both ovaries (or both tubes), otherwise like IA
Tumor limited to 1 or both ovaries (or tubes), with surgical spill
Tumor limited to 1 or both ovaries (or tubes), with capsule rupture before surgery or tumor on ovarian surface
Tumor limited to 1 or both ovaries (or tubes), with malignant cells in ascites or peritoneal washings
| II |
|Tumor involves 1 or both ovaries (or 1 or both tubes)a with pelvic extension (below the pelvic brim) or primary peritoneal cancer |
Extension and/or implants on uterus and/or fallopian tubes (and/or ovaries)
Extension to other pelvic intraperitoneal tissues
|Tumor involves 1 or both ovaries (or 1 or both tubes)a with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to retroperitoneal lymph nodes |
Positive retroperitoneal lymph nodes only
Metastasis ≤10 mm
Metastasis >10 mm
Microscopic, extrapelvic (above the brim) peritoneal involvement ± positive retroperitoneal nodes
Macroscopic, extrapelvic, peritoneal metastasis ≤2 cm ± positive retroperitoneal nodes. Includes extension to capsule of liver/spleen
Macroscopic, extrapelvic, peritoneal metastasis >2 cm ± positive retroperitoneal nodes. Includes extension to capsule of liver/spleen
| IV |
|Distant metastasis excluding peritoneal metastasis |
Pleural effusion with positive cytology
Hepatic and/or splenic parenchymal metastasis, metastasis to extraabdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)
TABLE 35-6Distribution of Epithelial Ovarian Cancer by FIGO Stage (n = 4825 patients) ||Download (.pdf) TABLE 35-6 Distribution of Epithelial Ovarian Cancer by FIGO Stage (n = 4825 patients)
|FIGO Stage ||Percent |
International Federation of Gynecology and Obstetrics (FIGO) staging for ovarian cancer.
Management of Early-stage Ovarian Cancer
If a malignancy appears clinically confined to the ovary, surgical removal and comprehensive staging is performed. Typically, the abdominal incision must be adequate to identify and resect any disease that may have been missed during physical examination or imaging. The operation begins by aspirating free ascitic fluid or collecting peritoneal washings. This is followed by inspection and palpation of all peritoneal surfaces. Next, an extrafascial hysterectomy and BSO are performed. In the absence of gross extraovarian disease, the infracolic omentum should be removed or at least biopsied (Section 46-14). Additionally, random peritoneal biopsies or scrapings are obtained, ideally near the diaphragms (Lee, 2014; Timmers, 2010). The most prognostically important step, a pelvic and infrarenal paraaortic lymphadenectomy, is also completed (Sections 46-11) (Chan, 2007; Cress, 2011; Whitney, 2011).
Laparoscopic staging is particularly valuable as a primary treatment in women who have an apparent stage I ovarian cancer. Alternatively, unstaged patients may have their staging completed laparoscopically. In general, for minimally invasive staging, all of the required procedures can be safely performed (Chi, 2005). The main putative benefits are a shorter hospital stay and quicker recovery (Tozzi, 2004). However, nodal counts may be inferior, and required exploration of the abdomen during staging is unavoidably limited.
Approximately 10 percent of epithelial ovarian cancers develop in women younger than 40 years. In selected cases, fertility-sparing surgery may be an option if disease appears confined to one ovary. Although many patients will be up-staged as a result of the operative findings, those with surgical stage I disease have an excellent long-term survival following unilateral adnexectomy. In some cases, postoperative chemotherapy may be required, but patients will usually retain their ability to conceive and ultimately carry a pregnancy to term (Schilder, 2002).
In women with stage IA or IB, grade 1 or 2 epithelial ovarian carcinoma, observation without further treatment following surgery is appropriate (Young, 1990). However, one third of patients who appear to have disease confined to the ovary will be “up-staged” by surgical staging and require postoperative chemotherapy.
Women with stage IA or IB, grade 3 epithelial ovarian cancer and all stage IC and II tumors are treated with carboplatin (Paraplatin) and paclitaxel (Taxol) chemotherapy (Morgan, 2014; Trimbos, 2003). In a Phase III Gynecologic Oncology Group (GOG) trial (protocol #157), women with early-stage disease were randomly assigned to either three or six cycles of this combination. Overall, three cycles resulted in a relapse rate comparable to that for six cycles but caused less toxicity (Bell, 2006). However, in a subanalysis of patients in this study who had serous tumors, treatment with six cycles decreased the relapse risk (Chan, 2010a).
Despite chemotherapy, more than 20 percent of women with early-stage disease develop recurrences within 5 years. In response, the GOG conducted a randomized Phase III trial of postoperative carboplatin and paclitaxel chemotherapy followed by observation or weekly paclitaxel for 24 weeks (protocol #175). Unfortunately, no benefit to maintenance paclitaxel was observed for early-stage patients (Mannel, 2011).
After treatment completion, women with early-stage ovarian cancer may be followed every 2 to 4 months for the first 2 years, then twice yearly for an additional 3 years, and then annually. At each visit, complete physical and pelvic examinations are performed. In addition, a serum CA125 level may be indicated if it was initially elevated (Morgan, 2014). However, a multi-institutional European trial evaluated the utility of CA125 levels for ovarian cancer monitoring after primary therapy completion. Women with relapsed ovarian cancer did not live longer by starting chemotherapy earlier based on a rising CA125 level compared with delaying treatment until symptoms developed. The group monitored with CA125 tests received 5 more months of chemotherapy overall, whereas women who were diagnosed and treated later for clinically evident recurrence had higher quality-of-life measures (Rustin, 2010).
Whether suspected by examination, CA125 level elevation, or new symptoms, recurrent disease must be confirmed with the aid of imaging. Of modalities, CT is initially most helpful to identify intraperitoneal disease.
Management of Advanced Ovarian Cancer
Approximately two thirds of patients will have stage III-IV disease, and sequenced multimodality therapy offers the most successful outcomes (Earle, 2006). Ideally, surgical cytoreduction is initially performed to remove all gross disease and is followed by six courses of platinum-based chemotherapy. However, some women are not appropriate candidates for primary surgery due to their medical condition, and others will have unresectable tumor. Additionally, one randomized trial concluded that initial treatment with chemotherapy followed by interval debulking surgery might achieve equivalent results (Vergote, 2010). To effectively balance all clinical factors, each patient is individually assessed before initiating treatment.
Primary Cytoreductive Surgery
Since the initial report by Griffiths (1975) suggested the clinical benefits of debulking, its value has been largely assumed. Numerous retrospective studies have subsequently supported the apparent survival advantage in women with advanced ovarian cancer. For subsequent decades, a cytoreductive effort was considered “optimal” if less than or equal to 1 cm residual disease could be achieved. Specifically, 1 cm residual disease describes a surgical result in which none of any remaining areas of tumor individually measures greater than 1 cm. However, the assessment of gross remaining disease is entirely subjective, and often inaccurate due to tissue induration or other factors (Chi, 2007). Perhaps due to the inability to reliably quantify remaining disease, a subanalysis of accumulated data from several prospective GOG trials was completed. It demonstrated for those with stage III ovarian cancer that patients with 0.1 to 1.0 cm residual had only marginally improved overall survival compared with patients with greater than 1 cm. In fact, dramatic survival benefit was only achieved with complete resection (Winter, 2007). Based on these findings and other similar reports, a growing consensus supports that optimal debulking should be defined as no gross residual disease (Chang, 2012; Schorge, 2014).
Several reasons substantiate beliefs that ovarian cancer implant resection prolongs survival. First, surgery removes large volumes of chemoresistant tumor cell clones. Second, excision of necrotic tissue improves drug delivery to remaining well-vascularized cells. Third, small residual tumor implants should be faster growing and therefore more susceptible to chemotherapy. Fourth, smaller cancer cell populations should require fewer chemotherapy cycles, which lowers chances of chemoresistance. Finally, removal of bulky disease potentially enhances the immune system.
Whether any of these supposed advantages to debulking are actually clinically relevant is debatable (Covens, 2000). However, because of the presumed benefits, primary surgical cytoreduction is generally performed whenever an optimal result is clinically feasible. Yet, physical examination and imaging findings alone inherently limit the ability to accurately predict surgical success. As a result, preoperative laparoscopic evaluation is being studied as a method for patient triage (Fagotti, 2005, 2013; Morgan, 2014). However, since the goal is the maximal resection of the primary ovarian cancer and all metastatic disease, laparoscopic or robotic surgery has a limited role in debulking (Magrina, 2011; Nezhat, 2010). Typically, various procedures are required to achieve minimal residual disease, as described subsequently.
Surgical Approach to Cytoreductive Surgery
In general, a vertical incision is recommended to provide access to the entire abdomen. Women with advanced disease do not require peritoneal washings or cytologic assessment of fluid, but often several liters of ascites will need to be evacuated to improve visualization. Next, the abdomen is carefully explored to quickly determine if optimal debulking is feasible. It is preferable to perform a limited surgical procedure rather than extensive debulking if it is obvious that bulky tumors will be left behind. If hysterectomy and BSO is not possible, a biopsy of the ovary and sampling of the endometrium by dilatation and curettage is performed to confirm an ovarian primary and exclude the possibility of widely metastatic uterine papillary serous carcinoma. However, if disease is resectable, then surgery should begin with the least complicated procedure.
Often, an infracolic omentectomy can be easily performed and extended (i.e., gastrocolic), as needed, to encompass the disease. A frozen section analysis can then be requested to confirm the presumed diagnosis of epithelial ovarian cancer. The pelvis is assessed next. Usually, an extrafascial type I abdominal hysterectomy and BSO is sufficient. However, when the tumor is confluent or invading the rectosigmoid, an en bloc resection, low anterior resection, or modified posterior pelvic exenteration may be required. These and other surgeries mentioned in this section are described and illustrated in Chapter 46.
Patients with abdominal tumor nodules measuring <2 cm (apparent stage IIIB) should have bilateral pelvic and paraaortic node lymphadenectomy to provide the most accurate surgical staging. In patients with stage IV disease and those with abdominal tumor nodules at least 2 cm (already stage IIIC disease), nodal dissection is not necessarily required for staging purposes (Whitney, 2011). However, if it is not performed, a significant percentage of otherwise completely resected patients may not benefit from removal of unrecognized macroscopic nodal disease (Eisenkop, 2001). Systematic lymphadenectomy in advanced ovarian cancer appears to benefit mainly those patients with complete intraperitoneal debulking (du Bois, 2010; Panici, 2005).
Optimal surgical cytoreduction may also require various other radical procedures, including splenectomy, diaphragm stripping/resection, and small or large bowel resection (Aletti, 2006; McCann, 2011). Surgically aggressive centers experienced in such techniques report higher rates of achieving minimal residual disease that correspond to better outcomes (Aletti, 2009; Chi, 2009a; Wimberger, 2007). For diagnostic purposes and since it is a frequent site of disease, an appendectomy is also commonly included (Timofeev, 2010).
Neoadjuvant Chemotherapy and Interval Cytoreductive Surgery
Many women do not undergo initial optimal surgical debulking. In some of these cases, imaging studies may suggest unresectable disease. Other patients may be too medically compromised, may not have received initial care by a gynecologic oncologist, or may have large-volume “suboptimal” residual disease despite attempted debulking. In such circumstances, three to four courses of chemotherapy are used to shrink disease before attempting an “interval” cytoreductive surgery.
Such neoadjuvant chemotherapy with an interval procedure is associated with less perioperative morbidity, increased rates of optimal cytoreduction, and similar survival rates, but had never been directly compared with primary debulking until more recently (Hou, 2007; Kang, 2009). Vergote and colleagues (2010) reported results of a randomized phase III trial of 634 patients with stage IIIC or IV epithelial ovarian cancer, many of whom had extensive upper abdominal disease. In that study, neoadjuvant chemotherapy followed by interval debulking was not inferior to primary cytoreductive surgery. Since fewer than half of the primary surgery patients had debulking to 1 cm residual disease, the survival rates of both groups were comparable to those in other chemotherapy trials of patients with large-volume residual disease (Ozols, 2003). As many expert centers in the United States routinely incorporate ultraradical procedures to achieve complete resection, it is reasonable to think that a more aggressive cytoreductive attempt might have led to a better outcome for the group randomized to surgery (Chi, 2012). Although this remains unproven, the strongest variable predicting overall survival was debulking to microscopic residual disease, whether performed as primary treatment or after three cycles of chemotherapy (Vergote, 2010). Thus, the benefits of interval debulking mainly occur in patients who have very advanced, unresectable disease or who did not initially have a maximal surgical effort by a gynecologic oncologist (Rose, 2004; Tangjitgamol, 2009; van der Burg, 1995).
Advanced ovarian cancer is considered to be relatively sensitive to cytotoxic agents. Largely due to recent advances in identifying active drugs, survival duration among patients has increased over the past two decades. Despite such improvements, fewer than 20 percent of those requiring chemotherapy will be cured. This is largely due to clinically occult residual chemoresistant tumor cells.
Platinum-based chemotherapy is the foundation for systemic treatment of most epithelial ovarian cancer types, although alternative regimens are currently being studied for advanced mucinous and clear cell carcinomas because of their known resistance. In two large collaborative group trials (GOG protocol #158 and Arbeitsgemeinschaft Gynäkologische Onkologie [AGO] protocol OVAR-3), the combination of carboplatin and paclitaxel was easier to administer, similarly efficacious, and less toxic than a cisplatin/paclitaxel regimen (du Bois, 2003; Ozols, 2003). As a result, the most widely used intravenous (IV) regimen in the United States is six courses of carboplatin and paclitaxel. If additional cycles are required to achieve clinical remission, this suggests relative tumor chemoresistance and usually leads to an earlier relapse. In Europe, single-agent carboplatin is often used. This preference is based on two large Phase III trials of the International Collaborative Ovarian Neoplasm (ICON) Group, which did not detect a survival advantage for combination chemotherapy (The ICON Collaborators, 1998; The ICON Group, 2002).
Although the carboplatin and paclitaxel regimen is undoubtedly effective, other modifications have been studied. For instance, the addition of a third cytotoxic agent was postulated to further improve outcome. Unfortunately, none of the experimental regimens demonstrated superiority compared with the control group (Bookman, 2009). Addition of the biologic agent bevacizumab (Avastin) during primary chemotherapy, followed by use as maintenance therapy, has been shown to provide only a modest improvement in progression-free survival (GOG protocol #218 and ICON-7) (Burger, 2011; Perren, 2011). Finally, administering paclitaxel in a dose-dense weekly schedule may have some advantages but at the cost of additional toxicity (Katsumata, 2009). The GOG conducted a definitive phase III trial comparing dose-dense paclitaxel with carboplatin versus every-3-week paclitaxel and carboplatin. In addition, suboptimally debulked patients in both groups received optional bevacizumab (protocol #262). The results are not yet available.
In 2006, the National Cancer Institute issued a rare Clinical Announcement encouraging the use of intraperitoneal (IP) chemotherapy. This coincided with the publication of results from a Phase III GOG trial (protocol #172) of optimally debulked stage III ovarian cancer patients who were randomly assigned to receive either IV or combination IV/IP paclitaxel and cisplatin chemotherapy (Table 35-7). The median duration of overall survival was 66 months in the IV/IP group compared with 50 months in the IV group (Armstrong, 2006). By comparison, survival in both groups far exceeded patients treated in the Vergote trial (29 to 30 months median survival), described on page 751 (Vergote, 2010). Despite this dramatic improvement in survival, many clinicians still remain unconvinced of its efficacy and do not routinely recommend IP chemotherapy (Gore, 2006).
TABLE 35-7Intraperitoneal Chemotherapy Regimen for Ovarian Cancer ||Download (.pdf) TABLE 35-7 Intraperitoneal Chemotherapy Regimen for Ovarian Cancer
The theoretical advantages of IP chemotherapy are dramatic. In general, epithelial ovarian cancer mainly spreads along peritoneal surfaces. In postoperative patients with minimal residual disease, a much higher dose of chemotherapy can be achieved at the tumor site by administration directly into the abdomen (Alberts, 1996; Markman, 2001).
Obviously, not every woman with advanced ovarian cancer is an appropriate candidate for IP chemotherapy. Stage IV patients and those with large-volume residual disease are theoretically least likely to benefit. In addition, toxicity is generally higher with IP therapy, catheter-related problems are common, and the true long-term survival advantage remains controversial (Walker, 2006). Regardless, IP therapy should certainly be considered for low-volume, optimally debulked disease (Morgan, 2014). However, the choice to receive or not receive IP chemotherapy should ultimately be a decision made by an informed patient (Alberts, 2006).
In light of the National Cancer Institute clinical announcement and ensuing debate, newer IP regimens are currently being tested. One current randomized phase III GOG trial (protocol #252) compared: (1) dose-dense paclitaxel and IV carboplatin, (2) dose-dense paclitaxel and IP carboplatin, and (3) a modified GOG protocol #172 IP cisplatin regimen. All groups received concurrent bevacizumab followed by maintenance bevacizumab. It is anticipated that when these data are published, they will shape future applications of ovarian cancer IP therapy.
Management of Patients in Remission
In most women with advanced ovarian cancer, the combination of surgery and platinum-based chemotherapy will result in clinical remission (normal examination, CA125 levels, and CT scan findings). However, up to 80 percent will eventually relapse and die from disease progression. Lower CA125 levels, that is, single-digit values, are generally associated with longer time until relapse and better survival rates (Juretzka, 2007). Since most patients achieving remission will have residual, clinically occult drug-resistant cells, several options are appropriate to consider and include surveillance, second-look surgery, maintenance chemotherapy, and abdominal radiotherapy. Unfortunately, there is no solid proof that any intervention is beneficial.
First, surveillance after treatment completion may include regular examinations and CA125 levels, as in early-stage disease. In those with new symptoms, physical findings, or rising CA125 titers, imaging may be indicated. In general, clinicians should maintain a heightened suspicion for relapse.
Another option, second-look surgery, is the “gold standard” to identify residual disease at treatment completion. For numerous reasons, mainly a lack of proven clinical benefit, this is not routinely performed. Instead, a second-look laparotomy or laparoscopy primarily serves as a useful early end point in assessing the treatment effectiveness within an experimental protocol. Otherwise, no prospective clinical trials have demonstrated a survival advantage. Second-look surgery does have prognostic value, since a procedure that reveals no recurrent disease is associated with an improved survival rate.
A third option is maintenance chemotherapy, also termed consolidation therapy. There is limited evidence to suggest any advantage for additional treatment in women who achieve clinical remission after six courses of platinum-based chemotherapy. However, due to the known high rate of recurrence, several agents have been tested as maintenance therapy, in randomized studies. Of these, monthly paclitaxel for 12 cycles was observed to extend progression-free survival by 7 months compared with only three courses of treatment. However, cumulative toxicity, most notably neuropathy, was substantial and resulted in frequent dose reductions. Unfortunately, the trial did not demonstrate improved overall survival rates among patients receiving prolonged maintenance therapy (Markman, 2003, 2009). To determine whether lower-dose paclitaxel or CT-2103 (Xyotax) could reduce the death rate compared with no maintenance therapy, the GOG is currently conducting a Phase III trial of women with advanced ovarian cancer who achieved clinical remission after standard platinum-based chemotherapy (protocol #212).
Bevacizumab, an antiangiogenic agent, has also been studied as maintenance therapy in several phase III trials. In GOG protocol #218 and the Gynecologic InterGroup Trial (ICON-7) studies noted earlier, when bevacizumab was combined with paclitaxel and carboplatin, then continued alone for a year of maintenance therapy, it demonstrated only a 2- to 4-month prolongation of progression-free survival, but no overall survival benefit. Of added interest, when maintenance bevacizumab was stopped, several patients experienced relapse soon after (Burger, 2011; Perren, 2011). Therefore, current trials allow maintenance bevacizumab to be continued indefinitely or until there is evidence for disease progression.
Pazopanib, an oral multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR), has also shown some promise as maintenance therapy. In a Phase III trial, patients receiving pazopanib had a 5.6-month improvement in progression-free survival compared with placebo, but with significant toxicity and lack of overall survival benefit (du Bois, 2014).
A fourth option, radiation therapy, is rarely used in the United States for patients in remission after primary therapy. Whole abdominal radiotherapy has unproven benefit, and fears of excessive toxicity such as radiation enteritis are a concern (Sorbe, 2003). However, the long-term effectiveness of this consolidation strategy is comparable to that achieved in women treated with other modalities.
The overall 5-year survival rate of all stages of epithelial ovarian cancer approximates 45 percent, far lower than uterine (84 percent) or cervical cancer (73 percent) (National Cancer Institute, 2014b). Survival rates mirror the assigned FIGO stage and largely depend on whether the disease has metastasized or not (Table 35-8). Additional prognostic factors are shown in Table 35-9). Interestingly, BRCA mutation carriers have a better prognosis, chiefly due to increased platinum sensitivity (Alsop, 2012; Lacour, 2011). However, even with favorable prognostic factors and despite recent innovations, most patients will ultimately relapse.
TABLE 35-8Epithelial Ovarian Cancer 5-Year Survival Rates ||Download (.pdf) TABLE 35-8 Epithelial Ovarian Cancer 5-Year Survival Rates
|Stage ||5-Year Survival (%) |
|Localized (confined to primary site) |
Regional (spread to regional nodes)
Distant (cancer has metastasized)
TABLE 35-9Most Important Favorable Prognostic Factors for Ovarian Cancer ||Download (.pdf) TABLE 35-9 Most Important Favorable Prognostic Factors for Ovarian Cancer
Good performance status
Cell type other than mucinous and clear cell
Smaller disease volume prior to surgical debulking
Smaller residual tumor after primary cytoreductive surgery
Management of Recurrent Ovarian Cancer
Gradual elevation of the CA125 level is usually the first sign of relapse. Tamoxifen may be administered when there is only “biochemical” evidence for disease progression, because it has some activity in treating recurrent disease and toxicity is minimal (Hurteau, 2010). Alternatively, patients may be offered participation in a clinical trial, started on conventional cytotoxic chemotherapy, or observed until clinical symptoms arise. Without treatment, the recurrence will usually become clinically obvious within 2 to 6 months. Almost invariably, the tumor will be located somewhere within the abdomen. Women who progress during primary chemotherapy are classified as having “platinum-refractory” disease and have a dismal prognosis. Those who relapse within 6 months of therapy have “platinum-resistant” ovarian cancer and a somewhat prolonged survival. In general, patients in either category are treated with palliative single-agent nonplatinum chemotherapy. For this, participation in an experimental clinical trial is offered whenever possible. Otherwise, response rates typically range from 5 to 15 percent using FDA-approved conventional cytotoxic drugs such as paclitaxel, pegylated liposomal doxorubicin (Doxil), docetaxel (Taxotere), topotecan (Hycamtin), or gemcitabine (Gemzar). Recently, bevacizumab in combination with weekly paclitaxel, doxorubicin, or topotecan was shown to provide a 27-percent response rate, which more than doubled the rate with single-agent chemotherapy alone in patients with platinum-resistant disease (Pujade-Lauraine, 2014). As a result, bevacizumab is now FDA-approved for this indication.
Women who relapse more than 6 to 12 months after primary therapy completion are considered “platinum-sensitive.” These patients, especially those in prolonged remission beyond 18, 24, or 36 months, are usually treated with a platinum-based combination. Carboplatin combined with either paclitaxel or gemcitabine has demonstrated modest superiority compared with carboplatin alone (Parmar, 2003; Pfisterer, 2006). Moreover, in one randomized phase III trial, the novel combination of carboplatin and pegylated liposomal doxorubicin was superior to carboplatin and paclitaxel (Pujade-Lauraine, 2010). Of interest, although patients with primary early-stage ovarian cancer have a more favorable overall prognosis, survival after relapse is comparable to those who recurred after treatment of advanced-stage disease (Chan, 2010b).
Secondary Cytoreductive Surgery
Although patient selection is somewhat arbitrary, the best candidates for secondary cytoreductive surgery have: (1) platinum-sensitive disease, (2) a prior prolonged disease-free interval, (3) a solitary-site recurrence, and (4) no ascites (Chi, 2006). To achieve a maximal survival benefit, debulking must result in minimal residual disease (Harter, 2006; Schorge, 2010b). However, approximately half of patients will be explored without achieving this goal.
The overall survival benefit of this approach is currently being studied in a Phase III GOG trial (protocol #213). This randomizes surgical candidates with platinum-sensitive relapsed disease to secondary debulking or not, followed by carboplatin and paclitaxel with or without additional bevacizumab. Of patients enrolled in this study, only 15 to 20 percent have thus far been considered surgical candidates.
In general, most relapsed ovarian cancer patients will end up receiving multiple sequential courses of chemotherapy (Morgan, 2014). Regardless of which regimen is selected initially, reevaluation usually follows two to four cycles of chemotherapy (depending on the agent) to determine the clinical benefit (Morgan, 2014). Typically, a CA125 level decline with or without confirmation of tumor shrinkage by CT provides sufficient reassurance to continue therapy. Nonresponders are changed to a different regimen. Patients with a germline BRCA1 or BRCA2 gene mutation who develop resistance to platinum may benefit from targeted therapy with olaparib (Lynparza), now FDA-approved for this indication (Chap. 27) (Kaufman, 2015). However, at some point, usually after multiple agents have been tried, treatment will no longer be efficacious, which should prompt a discussion about further goals of care.
It would seem plausible that targeting therapy for an individual patient's disease might be more effective than empiric drug selection. In vitro chemosensitivity testing is occasionally used for this purpose. In principle, different agents are tested against the patient's tumor, and the chemotherapeutic drug demonstrating the best response should result in a better outcome. Unfortunately, this approach lacks demonstrable efficacy and is not recommended outside of a clinical trial (Burstein, 2011; Morgan, 2014).
Palliation of End-stage Ovarian Cancer
At some point, patients with recurrent disease will develop worsening symptoms that warrant reevaluation of their overall treatment strategy. Of these, intermittent episodes of partial small and large bowel obstruction are common during treatment.
Bowel obstruction that does not resolve with nasogastric suction can be managed in two very different ways. Patients at first relapse or early in their course may warrant an aggressive approach that includes chemotherapy with or without surgical intervention and incorporates total parenteral nutrition. A colostomy, ileostomy, or intestinal bypass will often relieve symptoms (Chi, 2009b). Unfortunately, a satisfactory surgical result is sometimes impossible due to disease burden, and multiple sites of partial or complete obstruction. In addition, successful palliation is rarely achieved when the transit time is prolonged due to diffuse peritoneal carcinomatosis or when anatomy requires a bypass that results in the short bowel syndrome. Further, recovery may be complicated by an enterocutaneous fistula, reobstruction, or other morbid event (Pothuri, 2004). For patients with a refractory bowel obstruction due to progressive disease despite multiple lines of chemotherapy, the best approach is usually placement of a palliative gastrostomy tube, IV hydration, and hospice care. The final decision regarding how to proceed should be based on a frank discussion. Topics include treatment options, the natural history of progressive ovarian cancer, and the realistic improbability of further disease response by switching to a different therapy.
Another common scenario is a woman with symptomatic, rapidly reaccumulating ascitic fluid. This may be alleviated by repeated paracenteses or by placement of an indwelling peritoneal catheter (Pleurx), which can be self-drained as needed. Similarly, a refractory malignant pleural effusion can usually be managed by thoracentesis, indwelling pleural catheter placement, or pleurodesis. With the last, irritants are instilled into the pleural space to incite adhesions that obliterate the space.
Although these procedures and others may be appropriate in selected patients, the inability to halt disease progression should be acknowledged. In addition, any intervention has the potential to result in an unanticipated, catastrophic complication. Overall, palliative procedures are most compassionately used when incorporated into the overall treatment plan. For example, in a woman with stable disease and normal renal function, tumor-induced ureteral compression and hydronephrosis does not necessarily require stent placement or a nephrostomy tube.
All patients deserve a positive, hopeful, but honest approach to the management of progressive, incurable disease. Often, there are unrealistic expectations regarding the benefit of palliative chemotherapy, but emotionally it may be preferable to the idea of “giving up” (Doyle, 2001). There is no substitute for mutual trust in the doctor–patient relationship when making sound decisions aimed at improving the quality of life of women with end-stage ovarian cancer.