Gynecology_Novak

Gynecology_Novak. These cystic ovarian tumors have loculi lined with mucin-secreting epithelium. The lining epithelial cells contain intracytoplasmic mucin and resemble those of endocervix, gastric pylorus, or intestine. They represent about 8% to 10% of epithelial ovarian tumors. They may reach enormous size, filling the entire abdominal cavity (2). Borderline Mucinous Tumors The mucinous tumor of low malignant potential is often difficult to diagnose. Although it is common to find a rather uniform pattern from section to section in the serous borderline tumor, this is not true in the mucinous tumors. Well-differentiated mucinous epithelium may be seen immediately adjacent to a poorly differentiated focus. It is important to take multiple sections from many areas in the mucinous tumor to identify the most malignant alteration (2).


Gynecology_Novak

Gynecology_Novak. Mucinous Carcinomas Bilateral tumors occur in 8% to 10% of cases. The mucinous lesions are confined to the ovary in 95% to 98% of cases (Fig. 37.5). Because most ovarian mucinous carcinomas contain intestinal-type cells, they cannot be distinguished from Figure 37.4 High-grade serous adenocarcinoma. Papillae lined by sheets of cytologically malignant cells invade stroma, often with associated necrosis. Figure 37.5 Mucinous adenocarcinoma of the ovary. Irregular glandular spaces are lined with a layer of tall columnar cells with abundant mucinous cytoplasm, resembling intestinal epithelium at the left. At the right, there is destructive invasion into the ovarian stroma. metastatic carcinoma of the gastrointestinal tract on the basis of histology alone (2,6). Primary ovarian neoplasms rarely metastasize to the mucosa of the bowel, although they commonly involve the serosa, whereas gastrointestinal lesions frequently involve the ovary by direct extension or lymphatic spread (2).


Gynecology_Novak

Gynecology_Novak. Pseudomyxoma Peritonei Pseudomyxoma peritonei is a clinical term used to describe the finding of abundant mucoid or gelatinous material in the pelvis and abdominal cavity surrounded by fibrous tissue. It is most commonly secondary to a well-differentiated appendiceal mucinous neoplasm or other gastrointestinal primary; rarely, mucinous tumors arising in an ovarian mature teratoma are associated with pseudomyxoma peritonei. Endometrioid lesions constitute 6% to 8% of epithelial tumors. Endometrioid neoplasia includes all the benign demonstrations of endometriosis. In 1925, Sampson suggested that certain cases of adenocarcinoma of the ovary probably arose in areas of endometriosis (19). The adenocarcinomas are similar to those seen in the uterine corpus. The malignant potential of endometriosis is very low, although a transition from benign to malignant epithelium may be demonstrated.


Gynecology_Novak

Gynecology_Novak. Borderline Endometrioid Tumors The endometrioid tumor of low malignant potential has a wide morphologic spectrum. Tumors may resemble an endometrial polyp or complex endometrial hyperplasia with glandular crowding. When there are back-to-back, architecturally complex glands with no intervening stroma, the tumor is classified as a well-differentiated endometrioid carcinoma. Some borderline endometrioid tumors have a prominent fibromatous component. In such cases, the term adenofibroma is used to describe them (2). Endometrioid Carcinomas Endometrioid tumors are characterized by a markedly complex glandular pattern with all the potential variations of epithelia found in the uterus (Fig. 37.6). Multifocal Disease The endometrioid tumors afford the greatest opportunity to evaluate multifocal disease. Endometrioid carcinoma of the ovary is associated in 15% to 20% of the


Gynecology_Novak

Gynecology_Novak. Multifocal Disease The endometrioid tumors afford the greatest opportunity to evaluate multifocal disease. Endometrioid carcinoma of the ovary is associated in 15% to 20% of the Figure 37.6 Endometrioid cancer. Round to tubular glands lined by stratified columnar cells with conﬂuent growth pattern. cases with carcinoma of the endometrium. Identification of multifocal disease is important because patients with disease metastatic from the uterus to the ovaries have a 30% to 40% 5-year survival, whereas those with synchronous multifocal disease have a 75% to 80% 5-year survival (20). When the histologic appearance of endometrial and ovarian tumors is different, the two tumors most likely represent two separate primary lesions. When they appear similar, the endometrial tumor can be considered a separate primary tumor if it is well differentiated and only superficially invasive.


Gynecology_Novak

Gynecology_Novak. Several basic histologic patterns are present in the clear cell adenocarcinoma (i.e., tubulocystic, papillary, reticular, and solid). The tumors are made up of clear and hobnail cells that project their nuclei into the apical cytoplasm. The clear cells have abundant clear or vacuolated cytoplasm, hyperchromatic irregular nuclei, and nucleoli of various sizes (Fig. 37.7). Focal areas of endometriosis are common and mixed clear cell and endometrioid carcinoma may occur (20). The clear cell carcinoma seen in the ovary is histologically identical to that seen in the uterus or vagina of the young patient who has been exposed to diethylstilbestrol (DES) in utero. Nuclei of clear cell carcinoma range from grade 1 to grade 3, but pure grade 1 tumors are extremely rare. Almost invariably high-grade (grade 3) nuclei are identified. Hence, clear cell carcinoma is not graded.


Gynecology_Novak

Gynecology_Novak. Borderline Brenner Tumors In the past, proliferative Brenner tumors were subclassified as proliferating tumors (those tumors that resemble low-grade papillary urothelial carcinoma of the urinary bladder) and borderline tumors (those tumors that resemble high-grade papillary urothelial carcinoma), but both groups of tumors are now classified as borderline Brenner tumors (21). Complete surgical removal usually results in cure. Malignant Brenner Tumors These rare tumors are defined as benign or borderline Brenner tumors coexisting with invasive transitional cell carcinoma. Figure 37.7 Clear cell carcinoma of the ovary. Note the solid variant of clear cell carcinoma with sheets of cells that have clear cytoplasm (“hobnail” cells).


Gynecology_Novak

Gynecology_Novak. Figure 37.7 Clear cell carcinoma of the ovary. Note the solid variant of clear cell carcinoma with sheets of cells that have clear cytoplasm (“hobnail” cells). The designation transitional cell carcinoma refers to a primary ovarian carcinoma resembling transitional cell carcinoma of the urinary bladder without a recognizable Brenner tumor. It is reported that those ovarian carcinomas that contain more than 50% of transitional cell carcinoma are more sensitive to chemotherapy and have a more favorable prognosis than other poorly differentiated ovarian carcinomas of comparable stage (22,23). Transitional cell tumors differ from malignant Brenner tumors in that they are more frequently diagnosed in an advanced stage and are associated with a poorer survival rate (24).


Gynecology_Novak

Gynecology_Novak. Peritoneal Carcinomas Peritoneal tumors are histologically indistinguishable from ovarian serous tumors. In the case of borderline serous peritoneal tumors and serous peritoneal carcinomas, the ovaries are normal or minimally involved, and the tumors affect predominantly the uterosacral ligaments, pelvic peritoneum, or omentum. The overall prognosis for borderline serous peritoneal tumors is excellent and comparable to that of ovarian borderline serous tumors (25–27). In the review of 38 cases of peritoneal borderline serous tumors from the literature, 32 women had no persistent disease, 4 were well after resection of recurrence, 1 developed an invasive serous carcinoma, and 1 died from the effects of the tumor (25).


Gynecology_Novak

Gynecology_Novak. Carcinoma that appears predominantly as peritoneal carcinomatosis without appreciable ovarian or fallopian tube enlargement is called peritoneal carcinoma or m¨ullerian carcinoma when tumors spread from the breast, gastrointestinal tract, and other organs of nonm¨ullerian origin are excluded. Most are peritoneal serous carcinomas, which have the appearance of a moderately to poorly differentiated serous ovarian carcinoma. Peritoneal endometrioid carcinoma is less common. Peritoneal carcinoma should be considered clinically the same as ovarian and fallopian tube cancers. In patients for whom exploratory surgery is performed, there may be microscopic or small macroscopic cancer on the surface of the ovary and extensive disease in the upper abdomen, particularly in the omentum (28).


Gynecology_Novak

Gynecology_Novak. Mesotheliomas Peritoneal malignant mesotheliomas may be epithelial, sarcomatous, or biphasic (2,29). Deciduoid peritoneal mesothelioma is an unusual variant that resembles exuberant, ectopic decidual reaction of the peritoneum. Asbestos exposure is not correlated with peritoneal mesotheliomas in women. These lesions typically appear as multiple intraperitoneal masses, often coating the entire peritoneum and can develop after hysterectomy and bilateral salpingo-oophorectomy for benign disease. Malignant mesotheliomas should be distinguished from benign multicystic peritoneal mesothelioma (multilocular peritoneal inclusion cyst), and ovarian tumor implants and primary peritoneal m¨ullerian neoplasms.


Gynecology_Novak

Gynecology_Novak. Clinical Features More than 80% of epithelial ovarian cancers are found in postmenopausal women (Fig. 37.8). The peak incidence of invasive epithelial ovarian cancer is at 56 to 60 years of age (2,3,30). The age-specific incidence of ovarian epithelial cancer rises precipitously from 20 to 80 years of age and subsequently declines (30). These cancers are relatively uncommon in women younger than age 45. Fewer than 1% of epithelial ovarian cancers occur before the age of 21 years, two-thirds of ovarian malignancies in such patients being germ cell tumors (2,30,31). About 30% of ovarian neoplasms in postmenopausal women are malignant, whereas only about 7% of ovarian epithelial tumors in premenopausal patients are frankly malignant (2,3).


Gynecology_Novak

Gynecology_Novak. The average age of patients with borderline tumors is approximately 46 years (2,3,9). Eighty percent to 90% of ovarian cancers, including borderline forms, occur after the age of 40 years, whereas 30% to 40% of malignancies occur after the age of 65 years. The chance that a primary epithelial tumor will be of borderline or invasive malignancy in a patient younger than 40 years is approximately 1 in 10, but after that age it rises to 1 in 3 (2,3). Less than 1% of epithelial ovarian cancers occur before the age of 20 years, with two-thirds of ovarian malignancies in such patients being germ cell tumors (31). Etiology Ovarian cancer is associated with low parity and infertility (32). Although there are a variety of epidemiologic variables correlated with ovarian cancer, such as talc use, galactose consumption, and tubal ligation (see Chapter 4), none is so strongly correlated as prior reproductive history


Gynecology_Novak

Gynecology_Novak. Figure 37.8 Ovarian cancer incidence: distribution by age. (From Nagy K. The side effects of managed care on the drug industry. J Natl Cancer Inst 1995;87:1280, with permission.) and duration of the reproductive career (32,33). Early menarche and late menopause increase the risk of ovarian cancer (33). These factors and the relationship of parity and infertility to the risk of ovarian cancer led to the hypothesis that suppression of ovulation may be an important factor. Theoretically, the surface epithelium undergoes repetitive disruption and repair. It is thought that this process might lead to a higher probability of spontaneous mutations that can unmask germline mutations or otherwise lead to the oncogenic phenotype (see Chapter 6).


Gynecology_Novak

Gynecology_Novak. Prevention Because parity is inversely related to the risk of ovarian cancer, having at least one child is protective for the disease, with a risk reduction of 0.3 to 0.4. Oral contraceptive use reduces the risk of epithelial ovarian cancer (32). Women who use oral contraceptives for 5 or more years reduce their relative risk to 0.5 (i.e., there is a 50% reduction in the likelihood of development of ovarian cancer). Women who had two children and used oral contraceptives for 5 or more years have a relative risk of ovarian cancer as low as 0.3, or a 70% reduction (34). The oral contraceptive pill is the only documented method of chemoprevention for ovarian cancer, and it should be recommended to women for this purpose. When counseling patients regarding birth control options, this important benefit of oral contraceptive use should be emphasized. This is important for women with a strong family history of ovarian cancer.


Gynecology_Novak

Gynecology_Novak. The performance of a prophylactic salpingo-oophorectomy significantly reduces, but does not totally eliminate, the risk of nonuterine pelvic cancers; because the entire peritoneum is at risk, peritoneal carcinomas can occur in 2% to 3% of women even after prophylactic bilateral salpingo-oophorectomy (25,28). A thorough discussion of the risks and benefits of oophorectomy should be undertaken in premenopausal women who are undergoing a hysterectomy for benign disease, who do not carry germline mutations, and do not have a family history that suggests that they are at higher than average risk for ovarian cancer (35). The ovaries may provide protection from cardiovascular disease and osteoporosis, and long-term mortality may not be decreased by the performance of prophylactic oophorectomy in women at population risk of ovarian cancer (36).


Gynecology_Novak

Gynecology_Novak. Screening The value of tumor markers and ultrasonography to screen for epithelial ovarian cancer is not established by prospective studies. Screening results with transabdominal ultrasonography are encouraging in postmenopausal women, but specificity is limited (37–39). Advances in transvaginal ultrasonography showed a very high (>95%) sensitivity for the detection of early-stage ovarian cancer, although this test alone might require performance of as many as 10 to 15 laparotomy procedures for each case of ovarian cancer detected (37,38). Routine annual pelvic examinations have disappointing results in the early detection of ovarian cancer (40). Transvaginal color ﬂow Doppler to assess the vascularity of the ovarian vessels is a useful adjunct to ultrasonography, but it is not useful in screening (41,42).


Gynecology_Novak

Gynecology_Novak. CA125 is useful for monitoring epithelial ovarian cancer patients during their chemotherapy, but the role of CA125 is still being defined in a screening setting (43–49). Regarding the sensitivity of the test, elevated CA125 levels are seen in 50% of patients with stage I disease (43,48). Data suggest that the specificity of CA125 is improved when the test is combined with transvaginal ultrasonography or when the CA125 levels are followed over time (49,50). These data encouraged the development of prospective screening studies in Sweden and the United Kingdom (45,47). In these studies, patients with elevated CA125 levels (>30 U/mL) underwent abdominal ultrasonography, and 14 ovarian cancers were discovered among 27,000 women screened. About four laparotomies were performed for each case of cancer detected (47).


Gynecology_Novak

Gynecology_Novak. A randomized trial of nearly 22,000 women aged 45 years or older was performed in the United Kingdom (50). The patients were assigned to either a control group of routine pelvic examination (n = 0,977) or to a screening group (n = 10,958). The screening consisted of three annual screens that involved measurement of serum CA125 levels, pelvic ultrasonography if the CA125 was 30 U/mL or higher, and referral for gynecologic examination if the ovarian volume was 8.8 mL or greater on the ultrasonography. Of the 468 women in the screened group with an elevated CA125, 29 were referred for surgery, 6 cancers were discovered, and 23 had false-positive screening results, yielding a positive predictive value of 20.7%. During a 7-year follow-up period, cancer developed in 10 additional women in the screened group, as it did in 20 women in the control group. Although the median survival of women in whom cancer developed in the screened group was 72.9 months, compared with 41.8 months in the


Gynecology_Novak

Gynecology_Novak. the screened group, as it did in 20 women in the control group. Although the median survival of women in whom cancer developed in the screened group was 72.9 months, compared with 41.8 months in the control group (p = .0112), the number of deaths did not differ significantly between the control and screened groups (18/10,977 vs. 9/10,958; relative risk 2.0 [0.78 to 5.13]). These data show that a multimodal approach to ovarian cancer screening is feasible, but a larger trial is necessary to determine whether this approach affects mortality. Such a three-arm randomized trial is ongoing in the United Kingdom, and the anticipated accrual is approximately 50,000 women per study arm and 100,000 women in the control arm. Based on the risk of ovarian cancer (ROC) algorithm for CA125 levels, patients in the third group will be referred for transvaginal ultrasonography and/or surgery (51). Women will be screened for 3 years and studied for 7 years. The aims of this trial are to determine the


Gynecology_Novak

Gynecology_Novak. in the third group will be referred for transvaginal ultrasonography and/or surgery (51). Women will be screened for 3 years and studied for 7 years. The aims of this trial are to determine the feasibility of screening for ovarian cancer and whether ovarian cancers can be diagnosed at an earlier stage and the impact of early detection on survival.


Gynecology_Novak

Gynecology_Novak. Another approach is the use of proteomic patterns to identify ovarian cancer using surface-enhanced laser desorption ionization time-of-ﬂight (SELDI-TOF) technology (52). In a study using this technology, the sensitivity for predicting ovarian cancer was 100%, with a specificity of 95% and a positive predictive value of 94%. The assay correctly identified all 18 women with stage I tumors. This technology is in the early phases of development and validation, and its efficacy has yet to be demonstrated in large population-based studies (53).


Gynecology_Novak

Gynecology_Novak. Given the false-positive and false-negative results for both CA125 and transvaginal ultrasonography and the absence of good data to show that screening detects ovarian cancers at an earlier stage, these tests are not recommended and should not be used routinely to screen women with a population risk or high risk for ovarian cancer (54–56). In the future, new markers or technologies may improve the specificity of ovarian cancer screening, but proof of this will require a large, prospective study (47,48). Screening in women who have a familial risk may have a better yield, but to date there is no evidence to demonstrate a benefit of screening even in high-risk women, and this is being actively investigated (55,57). The findings of two prospective studies of annual transvaginal ultrasound and CA125 screening in 888 BRCA1and BRCA2 mutation carriers in the Netherlands and 279 mutation carriers in the United Kingdom are not encouraging and suggest a very limited benefit of screening in


Gynecology_Novak

Gynecology_Novak. and CA125 screening in 888 BRCA1and BRCA2 mutation carriers in the Netherlands and 279 mutation carriers in the United Kingdom are not encouraging and suggest a very limited benefit of screening in high-risk women (55,56). Despite annual gynecologic screening Hermsen et al. reported that a high proportion of ovarian cancers in BRCA1-2 carriers were interval cancers and the large majority of all cancers diagnosed were at advanced stages; similar results were reported by Woodward et al. (55,56).


Gynecology_Novak

Gynecology_Novak. Genetic Risk for The lifetime risk of ovarian carcinoma for women in the United States is about 1.4% (1–3). The Epithelial Ovarian risk of ovarian cancer is higher than that in the general population in women with certain family Cancer histories (51–60). Most epithelial ovarian cancer is sporadic, with familial or hereditary causes accounting for 5% to 10% of invasive epithelial ovarian cancer (59). Most hereditary ovarian cancer is associated with mutations in the BRCA1 gene, located on chromosome 17 (58–69). A small proportion of inherited disease is associated with germline mutations in another gene, BRCA2, located on chromosome 13 (60). Discovered through linkage analyses, these two high-penetrance genes are associated with the genetic predisposition to both ovarian and breast cancers. There are almost certainly other low-to moderate-penetrance genes that predispose to ovarian and breast cancer, and this is an area of intense research interest (1).


Gynecology_Novak

Gynecology_Novak. It was thought that there were two distinct syndromes associated with a genetic risk, site-specific hereditary ovarian cancer and hereditary breast-ovarian cancer syndrome. It is now believed that these groups represent a continuum of mutations with different degrees of penetrance within a given family (62,70). There is a higher-than-expected risk of ovarian and endometrial cancer in Lynch syndrome, known as the hereditary nonpolyposis colorectal cancer syndrome (HNPCC syndrome) (71).


Gynecology_Novak

Gynecology_Novak. The mutations are inherited in an autosomal dominant fashion, and therefore a full pedigree analysis (i.e., both maternal and paternal sides of the family) must be carefully evaluated (62). There are numerous distinct mutations that were identified on each of these genes, and the mutations have different degrees of penetrance that may account for the preponderance of either breast cancer, ovarian cancer, or both, in any given family. Based on analysis of women who have a mutation in the BRCA1 gene and are from high-risk families, the lifetime risk of ovarian cancer may be as high as 28% to 44%, and the risk was calculated to be as high as 27% for those women with a BRCA2 mutation (59,60,66–69). The risk of breast cancer in women with a BRCA1 or BRCA2 mutation may be as high as 56% to 87%.


Gynecology_Novak

Gynecology_Novak. Hereditary ovarian cancers occur in women approximately 10 years younger than those with nonhereditary tumors (i.e., closer to age 50 compared to age 60 for those with sporadic cancer) (59). A woman with a first-or second-degree relative who had premenopausal ovarian cancer may have a higher probability of carrying an affected gene. Breast and ovarian cancer may exist in a family in which there is a combination of epithelial ovarian and breast cancers, affecting a mixture of first-and second-degree relatives. Women with this syndrome tend to have these tumors at a young age, and the breast cancers may be bilateral. If two first-degree relatives are affected, this pedigree is consistent with an autosomal dominant mode of inheritance (50,58). Most BRCA1 ovarian cancers are high-grade serous carcinomas (Fig. 37.9).


Gynecology_Novak

Gynecology_Novak. There is a higher carrier rate of BRCA1 and BRCA2 mutations in women of Ashkenazi Jewish descent, in Icelandic women, and in many other ethnic groups (64,65,67–69). There are three specific founder mutations carried by the Ashkenazi population, 185delAG and 5382insC on BRCA1, and 6174delT on BRCA2. Individuals of Ashkenazi Jewish descent have a 1 in 40, or 2.5%, chance of having a mutation in BRCA1 or BRCA2, and thus there is a greater risk in this population. The increased risk is a result of the founder effect, in which a higher rate of specific mutations occurs in an ethnic group from a defined geographic area. These founder mutations generated considerable interest, because they facilitate studies of prevalence and penetrance and can be used to quantify the degree of homogeneity within a population. CHAPTER 37 Ovarian, Fallopian Tube, and Peritoneal Cancer


Gynecology_Novak

Gynecology_Novak. CHAPTER 37 Ovarian, Fallopian Tube, and Peritoneal Cancer Figure 37.9 BRCA1-associated ovarian carcinoma is typically a high-grade serous adenocarcinoma with numerous mitotic figures and marked nuclear pleomorphism. A brisk lymphocytic infiltrate with tumor infiltrating lymphocytes is not uncommon in these tumors. The risk of carrying a germline mutation that predisposes to ovarian cancer depends on the number of first-or second-degree relatives (or both) with a history of epithelial ovarian carcinoma or breast cancer (or both) and on the number of malignancies that occurs at an earlier age. The degree of risk is difficult to determine precisely unless a full pedigree analysis is performed. 1. In families with two first-degree relatives (i.e., mother, sister, or daughter) with documented premenopausal epithelial ovarian cancer, the risk that a female first-degree relative has an affected gene could be as high as 35% to 40% (60). 2.


Gynecology_Novak

Gynecology_Novak. 2. In families with a single first-degree relative and a single second-degree relative (i.e., grandmother, aunt, first cousin, or granddaughter) with epithelial ovarian cancer, the risk that a woman has an affected gene may be increased. The risk may be two-to 10-fold higher than in those without a familial history of the disease (60). 3. In families with a single postmenopausal first-degree relative with epithelial ovarian carcinoma, a woman may not have an increased risk of having an affected gene because the case is most likely to be sporadic. If the ovarian cancer occurs in a premenopausal relative, this could be significant, and a full pedigree analysis should be undertaken. 4. Women with a primary history of breast cancer have twice the expected incidence of subsequent ovarian cancer (59).


Gynecology_Novak

Gynecology_Novak. 4. Women with a primary history of breast cancer have twice the expected incidence of subsequent ovarian cancer (59). Lynch syndrome (HNPCC), which includes multiple adenocarcinomas, involves a combination of colon cancer and endometrial or ovarian cancer and other malignancies of the gastrointestinal and genitourinary systems (71). The mutations that are associated with this syndrome are MSH2, MLH1, PMS1, and PMS2. The risk that a woman who is a member of one of these families will develop epithelial ovarian cancer depends on the frequency of this disease in first-and second-degree relatives, although these women appear to have at least three times the relative risk of the general population. A full pedigree analysis of such families should be performed by a geneticist to more accurately determine the risk. Management of Women at High Risk for Ovarian Cancer


Gynecology_Novak

Gynecology_Novak. Management of Women at High Risk for Ovarian Cancer The management of a woman with a strong family history of epithelial ovarian cancer must be individualized and depends on her age, her reproductive plans, and the extent of risk. In all of these syndromes, women at risk benefit from a thorough pedigree analysis. A geneticist should evaluate the family pedigree for at least three generations. Decisions about management are best made after careful study and, whenever possible, verification of the histologic diagnosis of the family members’ ovarian cancer.


Gynecology_Novak

Gynecology_Novak. The value of testing for BRCA1 and BRCA2 is established, and there are guidelines for testing (62,70,72). The importance of genetic counseling cannot be overemphasized because the decision is complex. The American Society of Clinical Oncology offered guidelines that emphasize careful evaluation by geneticists, careful maintenance of medical records, and an understanding in a genetic screening clinic of how to effectively counsel and manage these patients. Concerns remain over the use of the information, the impact on insurability, the interpretation of the results, and how the information will be used within a specific family (e.g., to counsel children).


Gynecology_Novak

Gynecology_Novak. Although there are some conﬂicting data, the behavior of breast cancers arising in women with germline mutations in BRCA1 or BRCA2 is comparable to the behavior of sporadic tumors (61,73). Women with breast cancer who carry these mutations are at a greatly increased risk of ovarian cancer and a second breast cancer: the lifetime risk of ovarian cancer is 54% for women who have a BRCA1 mutation and 23% for those with a BRCA2 mutation, and for the two groups together, there is an 82% lifetime risk of breast cancer (73).


Gynecology_Novak

Gynecology_Novak. Despite recommendation by the National Institutes of Health Consensus Conference on Ovarian Cancer, the value of screening with transvaginal ultrasonography, CA125 levels, or other procedures is not established in women at high risk (74). Bourne and coworkers showed that, using this approach, tumors can be detected approximately 10 times more often than in the general population, and they recommend screening in high-risk women, but other groups have not confirmed these findings, and bilateral salpingo-oophorectomy remains the most effective way to reduce risk (57,75).


Gynecology_Novak

Gynecology_Novak. Data derived from a multicenter consortium of genetic screening centers indicate that the use of the oral contraceptive pill is associated with a lower risk for development of ovarian cancer in women who have a mutation in either BRCA1 or BRCA2 (76). The risk reduction is significant: in women who take oral contraceptives for 5 or more years, the relative risk of ovarian cancer is 0.4, or a 60% reduction in the incidence of the disease.


Gynecology_Novak

Gynecology_Novak. The value of prophylactic salpingo-oophorectomy in these patients is documented (77–83). Women at high risk for ovarian cancer who undergo prophylactic salpingo-oophorectomy have a risk of harboring occult neoplasia: in one series of 98 such operations, 3 (3.1%) patients had a low-stage ovarian malignancy (80). The protection against ovarian cancer is excellent: the performance of a prophylactic salpingo-oophorectomy reduced the risk of BRCA-related gynecologic cancer by 96% (80). In a series of 42 such operations, 4 patients (9.5%) had a malignancy, 1 of which was noted at surgery and 3 that were microscopic; all were smaller than 5 mm (78). Although the risk of ovarian cancer is significantly diminished, there remains the small risk of peritoneal carcinoma, a tumor for which women who have mutations in BRCA1 and BRCA2 may have a higher predisposition. In these series, the subsequent development of peritoneal carcinoma was 0.8% and 1%, respectively (78,79). The risk of developing


Gynecology_Novak

Gynecology_Novak. have mutations in BRCA1 and BRCA2 may have a higher predisposition. In these series, the subsequent development of peritoneal carcinoma was 0.8% and 1%, respectively (78,79). The risk of developing subsequent breast cancer was reduced by 50% to 80%.


Gynecology_Novak

Gynecology_Novak. The role of hysterectomy is more controversial. Most studies show no increase in the rate of uterine and cervical tumors, but there are rare reports of an increase of papillary serous tumors of the endometrium (83). Women on tamoxifen are at higher risk for benign endometrial lesions (e.g., polyps) and endometrial cancer. It is reasonable to consider the performance of a prophylactic hysterectomy in conjunction with salpingo-oophorectomy, but this decision should be individualized. The survival of women who have a BRCA1 or BRCA2 mutation and develop ovarian cancer is longer than that for those who do not have a mutation. In one study, the median survival for mutation carriers was 53.4 months compared with 37.8 months for those with sporadic ovarian cancer from the same institution (84). Current recommendations for management of women at high risk for ovarian cancer are summarized as follows (72,82): 1.


Gynecology_Novak

Gynecology_Novak. Current recommendations for management of women at high risk for ovarian cancer are summarized as follows (72,82): 1. Women who appear to be at high risk for ovarian or breast cancer should undergo genetic counseling and, if the risk appears to be substantial (i.e., a calculated risk of at least 10% in having a mutation in BRCA1 or BRCA2), may be offered genetic testing for BRCA1 and BRCA2. 2. Women who wish to preserve their reproductive capacity can undergo screening by transvaginal ultrasonography every 6 months, although the efficacy of this approach is not established. 3. Oral contraceptives should be recommended to young women before they embark on an attempt to have a family. 4.


Gynecology_Novak

Gynecology_Novak. 3. Oral contraceptives should be recommended to young women before they embark on an attempt to have a family. 4. Women who do not wish to maintain their fertility or who have completed their families should be recommended to undergo prophylactic bilateral salpingooophorectomy after the age of 35, but by age 40 years. The risk of ovarian cancers under the age of 40 is very low but the decision regarding the age of surgery should be based on the age of onset of ovarian cancers in the family. Most BRCA2-related ovarian cancers tend to occur after the age of 50, whereas BRCA1-related cancers occur at an earlier age. The risk should be clearly documented, preferably established by BRCA1 and BRCA2 testing, before salpingo-oophorectomy is performed. These women should be counseled that this operation does not offer absolute protection, because peritoneal carcinomas can occur after bilateral salpingo-oophorectomy (25,28,83). 5.


Gynecology_Novak

Gynecology_Novak. 5. In women who have a strong family history of breast or ovarian cancer, annual breast screening should be performed beginning at age 30 years using a combination of magnetic resonance imaging (MRI), mammograms, and ultrasound. Ideally, these women should be followed in clinics that manage women at high risk for cancer. 6. Women with a documented HNPCC syndrome should be treated as mentioned above, and they should undergo periodic colonoscopy, endometrial biopsy, or prophylactic hysterectomy after the completion of childbearing (71).


Gynecology_Novak

Gynecology_Novak. Symptoms The majority of women with epithelial ovarian cancer have vague and nonspecific symptoms (3,85–87). In early-stage disease, if the patient is premenopausal, she may experience irregular menses. If a pelvic mass is compressing the bladder or rectum, she may report urinary frequency or constipation (85–87). Occasionally, she may perceive lower abdominal distention, pressure, or pain, such as dyspareunia. Acute symptoms, such as pain secondary to rupture or torsion, are unusual. In advanced-stage disease, patients have symptoms related to the presence of ascites, omental metastases, or bowel metastases. The symptoms include abdominal distention, bloating, constipation, nausea, anorexia, or early satiety. Premenopausal women may report irregular or heavy menses, whereas vaginal bleeding may occur in postmenopausal women (86).


Gynecology_Novak

Gynecology_Novak. Traditionally, ovarian cancer was considered a “silent killer” that did not produce symptoms until far advanced. Some patients with ovarian cancers confined to the ovary are asymptomatic, but the majority will have nonspecific symptoms that do not necessarily suggest an origin in the ovary (86,88–90). In one survey of 1,725 with ovarian cancer, 95% recalled symptoms before diagnosis, including 89% with stage I and II disease and 97% with stages III and IV disease (86). Some 70% had abdominal or gastrointestinal symptoms, 58% pain, 34% urinary symptoms, and 26% pelvic discomfort. At least some of these symptoms could have reﬂected pressure on the pelvic viscera from the enlarging ovary. Goff et al. developed an ovarian cancer symptom index and reported that symptoms associated with ovarian cancer, when present for less than 1 year and occurring longer than 12 days a month, were pelvic/abdominal pain, urinary frequency/urgency, increased abdominal size or bloating, and difficulty eating


Gynecology_Novak

Gynecology_Novak. cancer, when present for less than 1 year and occurring longer than 12 days a month, were pelvic/abdominal pain, urinary frequency/urgency, increased abdominal size or bloating, and difficulty eating or feeing full (88). The index had a sensitivity of 56.7% for early ovarian cancer and 79.5% for advanced stage disease. A population-based study from Australia found that there did not appear to be a significant difference in the duration of symptoms or the nature of symptoms in patients with early as opposed to advanced stage ovarian cancer, reinforcing the concept that they are biologically different entities and arguing against the widely held misconception that early stage ovarian cancers are at an early stage because they were diagnosed earlier than patients with more advanced stage cancers (89).


Gynecology_Novak

Gynecology_Novak. Signs The most important sign of epithelial ovarian cancer is the presence of a pelvic mass on physical examination. A solid, irregular, fixed pelvic mass is highly suggestive of an ovarian malignancy. If an upper abdominal mass or ascites is present, the diagnosis of ovarian cancer is almost certain. Because the patient usually reports abdominal symptoms, she may not have a pelvic examination, and a tumor may be missed. In patients who are at least 1 year past menopause, the ovaries should be atrophic and not palpable. It was proposed that any palpable pelvic mass in these patients should be considered potentially malignant, a situation that was referred to as the postmenopausal palpable ovary syndrome (91). This concept was challenged, because subsequent authors reported that only about 3% of palpable masses measuring less than 5 cm in postmenopausal women are malignant (57).


Gynecology_Novak

Gynecology_Novak. Diagnosis Ovarian epithelial cancers must be differentiated from benign neoplasms and functional cysts of the ovaries. A variety of benign conditions of the reproductive tract, such as pelvic inﬂammatory disease, endometriosis, and pedunculated uterine leiomyomas, can simulate ovarian cancer. Nongynecologic causes of a pelvic tumor, such as an inﬂammatory (e.g., diverticular) disease or neoplastic colonic mass, must be excluded (3). A pelvic kidney can simulate ovarian cancer. Serum CA125 levels are useful in distinguishing malignant from benign pelvic masses (92). For a postmenopausal patient with an adnexal mass and a very high serum CA125 level (>200 U/mL), there is a 96% positive predictive value for malignancy. For premenopausal patients, the specificity of the test is low because the CA125 level tends to be elevated in common benign conditions.


Gynecology_Novak

Gynecology_Novak. For the premenopausal patient, a period of observation is reasonable provided the adnexal mass does not have characteristics that suggest malignancy (i.e., it is mobile, mostly cystic, unilateral, and of regular contour). An interval of no more than 2 months is allowed, during which hormonal suppression with an oral contraceptive may be used. If the lesion is not neoplastic, it should regress, as measured by pelvic examination and pelvic ultrasonography. If the mass does not regress or if it increases in size, it must be presumed to be neoplastic and must be removed surgically.


Gynecology_Novak

Gynecology_Novak. The size of the lesion is important. If a cystic mass is greater than 8 cm in diameter, the probability is high that the lesion is neoplastic, unless the patient is taking clomiphene citrate or other agents to induce ovulation (37–40). Premenopausal patients whose lesions are clinically suspicious (i.e., large, predominantly solid, relatively fixed, or irregularly shaped) should undergo laparotomy, as should postmenopausal patients with complex adnexal masses of any size.


Gynecology_Novak

Gynecology_Novak. Ultrasonographic signs of malignancy include an adnexal pelvic mass with areas of complexity, such as irregular borders, multiple echogenic patterns within the mass, and dense multiple irregular septae. Bilateral tumors are more likely to be malignant, although the individual characteristics of the lesions are of greater significance. Transvaginal ultrasonography may have a somewhat better resolution than transabdominal ultrasonography for adnexal neoplasms (93–96). Doppler color ﬂow imaging may enhance the specificity of ultrasonography for demonstrating findings consistent with malignancy (97–99). In postmenopausal women with unilocular cysts measuring 8 to 10 cm or less and normal serial CA125 levels, expectant management is acceptable, and this approach may decrease the number of surgical interventions (100–102).


Gynecology_Novak

Gynecology_Novak. The diagnosis of an ovarian cancer requires an exploratory laparotomy. The preoperative evaluation of the patient with an adnexal mass is outlined in Figure 14.19 (see Chapter 14). Before the planned exploration, the patient should undergo routine hematologic and biochemical assessments. A preoperative evaluation in a patient undergoing laparotomy should include a radiograph of the chest. Abdominal and pelvic computed tomography (CT) or MRI are of limited value for a patient with a definite pelvic mass (103–105). A CT or MRI should be performed for patients with ascites and no pelvic mass to look for liver or pancreatic tumors. The findings only rarely preclude laparotomy (103). The value of PET scanning is still being evaluated (105–107). If the hepatic enzyme values are normal, the likelihood of liver disease is low. Liver-spleen scans, bone scans, and brain scans are unnecessary unless symptoms or signs suggest metastases to these sites.


Gynecology_Novak

Gynecology_Novak. The preoperative evaluation should exclude other primary cancers metastatic to the ovary. A barium enema or colonoscopy is indicated in selected patients with symptoms and signs suspicious for colon cancer. This study should be performed for any patient who has evidence of occult blood in the stool or of intestinal obstruction. An upper gastrointestinal radiographic series or gastroscopy is indicated if there are upper gastrointestinal symptoms such as nausea, vomiting, or hematemesis (3,108). Bilateral mammography is indicated if there is any breast mass, because breast cancer metastatic to the ovaries can simulate primary ovarian cancer. A Papanicolaou (Pap) test should be performed, although its value for the detection of ovarian cancer is very limited. Patients who have irregular menses or postmenopausal vaginal bleeding should have endometrial biopsy and endocervical curettage to exclude the presence of uterine or endocervical cancer metastatic to the ovary.


Gynecology_Novak

Gynecology_Novak. Differential Diagnosis Ovarian epithelial cancers must be differentiated from benign neoplasms and functional cysts of the ovaries (100–102). A variety of benign conditions of the reproductive tract, such as pelvic inﬂammatory disease, endometriosis, and pedunculated uterine leiomyomata, can simulate ovarian cancer. Nongynecologic causes of a pelvic tumor, such as an inﬂammatory or neoplastic colonic mass, must be excluded. A pelvic kidney can simulate ovarian cancer. Patterns of Spread Ovarian epithelial cancers spread primarily by exfoliation of cells into the peritoneal cavity, by lymphatic dissemination, and by hematogenous spread. Transcoelomic The most common and earliest mode of dissemination of ovarian epithelial cancer is by exfoliation of cells that implant along the surfaces of the peritoneal cavity.


Gynecology_Novak

Gynecology_Novak. Transcoelomic The most common and earliest mode of dissemination of ovarian epithelial cancer is by exfoliation of cells that implant along the surfaces of the peritoneal cavity. The cells tend to follow the circulatory path of the peritoneal ﬂuid. The ﬂuid moves with the forces of respiration from the pelvis, up the paracolic gutters, especially on the right, along the intestinal mesenteries, to the right hemidiaphragm. Metastases are typically seen on the posterior cul-de-sac, paracolic gutters, right hemidiaphragm, liver capsule, the peritoneal surfaces of the intestines and their mesenteries, and the omentum. The disease seldom invades the intestinal lumen but progressively agglutinates loops of bowel, leading to a functional intestinal obstruction. This condition is known as carcinomatous ileus (3).


Gynecology_Novak

Gynecology_Novak. Lymphatic Lymphatic dissemination to the pelvic and para-aortic lymph nodes is common, particularly in advanced-stage disease (109–111). Spread through the lymphatic channels of the diaphragm and through the retroperitoneal lymph nodes can lead to dissemination above the diaphragm, especially to the supraclavicular lymph nodes (109). Burghardt et al. reported that 78% of patients with stage III disease have metastases to the pelvic lymph nodes (111). In another series, the rate of para-aortic lymph nodes positive for metastasis was 18% in stage I, 20% in stage II, 42% in stage III, and 67% in stage IV (109). Hematogenous Hematogenous dissemination at the time of diagnosis is uncommon.


Gynecology_Novak

Gynecology_Novak. Hematogenous Hematogenous dissemination at the time of diagnosis is uncommon. Spread to vital organ parenchyma, such as the lungs and liver, occurs in only about 2% to 3% of patients. Most patients with disease above the diaphragm when diagnosed have a right pleural effusion (3). Systemic metastases appear more frequently in patients who survived for some years. Dauplat et al. reported that distant metastasis consistent with stage IV disease ultimately occurred in 38% of the patients whose disease was originally intraperitoneal (112). Prognostic Factors The outcome of treatment can be evaluated in the context of prognostic factors, which can be grouped into pathologic, biologic, and clinical factors (113).


Gynecology_Novak

Gynecology_Novak. Prognostic Factors The outcome of treatment can be evaluated in the context of prognostic factors, which can be grouped into pathologic, biologic, and clinical factors (113). Pathologic Factors The morphology and histologic pattern, including the architecture and grade of the lesion, are important prognostic variables (3). Histologic type was not believed to have prognostic significance, but several papers contained suggestions that clear cell carcinomas are associated with a prognosis worse than that of other histologic types (113,114).


Gynecology_Novak

Gynecology_Novak. Histologic grade, as determined either by the pattern of differentiation or by the extent of cellular anaplasia and the proportion of undifferentiated cells, seems to be of prognostic significance (115–118). Studies of the reproducibility of grading ovarian cancers show a high degree of intraobserver and interobserver variation (119,120). Because there is significant heterogeneity of tumors and observational bias, the value of histologic grade as an independent prognostic factor is not established. Baak et al. have presented a standard grading system based on morphometric analysis, and the system seems to correlate with prognosis, especially in its ability to distinguish low-grade or borderline patterns from other tumors (121).


Gynecology_Novak

Gynecology_Novak. Clinical Factors In addition to stage, the extent of residual disease after primary surgery, the volume of ascites, patient age, and performance status are all independent prognostic variables (122– 131). Among patients with stage I disease, Dembo et al. showed, in a multivariate analysis, that tumor grade and dense adherence to the pelvic peritoneum had a significant adverse impact on prognosis, whereas intraoperative tumor spillage or rupture did not (128). Sj¨ovall et al. confirmed that ovarian cancers that undergo intraoperative rupture or spillage do not worsen prognosis, whereas tumors that are ruptured preoperatively do have a poorer prognosis (129). A multivariate analysis of these and several other studies was performed by Vergote et al., who found that for early-stage disease, poor prognostic variables were tumor grade, capsular penetration, surface excrescences, and malignant ascites, but not iatrogenic rupture (131).


Gynecology_Novak

Gynecology_Novak. Staging Ovarian epithelial malignancies are staged according to the FIGO system listed in Table 37.2 (30). The FIGO staging is based on findings at surgical exploration. A preoperative evaluation should exclude the presence of extraperitoneal metastases. The importance of thorough surgical staging cannot be overemphasized, because subsequent treatment will be determined by the stage of disease. For patients in whom exploratory laparotomy does not reveal any macroscopic evidence of disease on inspection and palpation of the entire intra-abdominal space, a careful search for microscopic spread must be undertaken. In earlier series in which patients did not undergo careful surgical staging, the overall 5-year survival for patients with apparent stage I epithelial ovarian cancer was only about 60% (132). Since then, survival rates of 90% to 100% are reported for patients who were properly staged and were found to have stage IA or IB disease (133,134).


Gynecology_Novak

Gynecology_Novak. In patients whose preoperative evaluation suggests a probable malignancy, a midline or paramedian abdominal incision is recommended to allow adequate access to the upper abdomen (3,132). When a malignancy is unexpectedly discovered in a patient who has a lower transverse incision, the rectus muscles can be either divided or detached from the symphysis pubis to allow better access to the upper abdomen. If this is not sufficient, the incision can be extended on one side to create a “J” incision (3). The ovarian tumor should be removed intact, if possible, and a frozen histologic section should be obtained. If ovarian malignancy is present and the tumor is apparently confined to the ovaries or the pelvis, thorough surgical staging should be performed. Staging involves the following steps (3,132): 1. Any free ﬂuid, especially in the pelvic cul-de-sac, should be submitted for cytologic evaluation. Table 37.2 FIGO Staging for Primary Carcinoma of the Ovary


Gynecology_Novak

Gynecology_Novak. Table 37.2 FIGO Staging for Primary Carcinoma of the Ovary These categories are based on findings at clinical examination or surgical exploration or both. The histologic characteristics are to be considered in the staging, as are results of cytologic testing as far as effusions are concerned. It is desirable that a biopsy be performed on suspicious areas outside the pelvis. FIGO, International Federation of Obstetrics and Gynecology. aTo evaluate the impact on prognosis of the different criteria for allotting cases to stage IC or IIC, it would be of value to know if rupture of the capsule was (i) spontaneous or (ii) caused by the surgeon and if the source of malignant cells detected was (i) peritoneal washings or (ii) ascites. Reproduced from Berek JS, Hacker NF, Berek & Hacker’s Gynecologic Oncology. 5th ed. Lippincott Williams & Wilkins. 2010:455, adapted from FIGO Annual Report, Vol 26, Int J Gynecol Obstet 2006;105:3–4. 2.


Gynecology_Novak

Gynecology_Novak. 2. If no free ﬂuid is present, peritoneal washings should be performed by instilling and recovering 50 to 100 mL of saline from the pelvic cul-de-sac, each paracolic gutter, and beneath each hemidiaphragm. Obtaining the specimens from under the diaphragms can be facilitated with the use of a rubber catheter attached to the end of a bulb syringe. 3. A systematic exploration of all the intra-abdominal surfaces and viscera is performed, proceeding in a clockwise fashion from the cecum cephalad along the paracolic gutter and the ascending colon to the right kidney, the liver and gallbladder, the right hemidiaphragm, the entrance to the lesser sac at the para-aortic area, across the transverse colon to the left hemidiaphragm, down the left gutter and the descending colon to the rectosigmoid colon. The small intestine and its mesentery from the Treitz ligament to the cecum should be inspected. 4.


Gynecology_Novak

Gynecology_Novak. 4. Any suspicious areas or adhesions on the peritoneal surfaces should be biopsied. If there is no evidence of disease, multiple intraperitoneal biopsies should be performed. Tissue from the peritoneum of the pelvic cul-de-sac, both paracolic gutters, the peritoneum over the bladder, and the intestinal mesenteries should be taken for biopsy. 5. The diaphragm should be sampled, either by biopsy or by scraping with a tongue depressor, and a sample obtained for cytologic assessment. Biopsies of any irregularities on the surface of the diaphragm can be facilitated by use of the laparoscope and the associated biopsy instrument.


Gynecology_Novak

Gynecology_Novak. 6. The omentum should be resected from the transverse colon, a procedure called an infracolic omentectomy. The procedure is initiated on the underside of the greater omen-tum, where the peritoneum is incised just a few millimeters away from the transverse colon. The branches of the gastroepiploic vessels are clamped, ligated, and divided, along with all the small branching vessels that feed the infracolic omentum. If the gastrocolic ligament is palpably normal, it does not need to be resected. 7. The retroperitoneal spaces should be explored to evaluate the pelvic and paraaortic lymph nodes. The retroperitoneal dissection is performed by incision of the peritoneum over the psoas muscles. This may be performed on the ipsilateral side only for unilateral tumors. Any enlarged lymph nodes should be resected and submitted for frozen section. If no metastases are present, a formal pelvic lymphadenectomy should be performed. The para-aortic area should be explored.


Gynecology_Novak

Gynecology_Novak. Metastases in apparent stage I and II epithelial ovarian cancer occur in as many as 3 in 10 patients whose tumors appear to be confined to the pelvis but who have occult metastatic disease in the upper abdomen or the retroperitoneal lymph nodes (110,133–140). In a literature review, occult metastases in such patients were found in biopsies of the diaphragm in 7.3%, biopsies of the omentum in 8.6%, the pelvic lymph nodes in 5.9%, the aortic lymph nodes in 18.1%, and in 26.4% of peritoneal washings (132).


Gynecology_Novak

Gynecology_Novak. The importance of careful initial surgical staging is emphasized by the findings of a cooperative national study in which 100 patients with apparent stage I and II disease were referred for subsequent therapy and underwent additional surgical staging (133). In this series, 28% of the patients initially believed to have stage I disease were upstaged and 43% of those believed to have stage II disease had more advanced lesions. A total of 31% of the patients were upstaged as a result of additional surgery, and 77% were reclassified as having actual stage III disease. Histologic grade was a significant predictor of occult metastasis. Sixteen percent of the patients with grade 1 lesions were upstaged, compared with 34% with grade 2 disease and 46% with grade 3 disease.


Gynecology_Novak

Gynecology_Novak. Borderline Tumors The principal treatment of borderline (low malignant potential) ovarian tumors is surgical resection of the primary tumor. There is no evidence that either subsequent chemotherapy or radiation therapy improves survival. When a frozen section determines that the histology is borderline, premenopausal patients who desire preservation of ovarian function may undergo a conservative operation, a unilateral oophorectomy (3,141). In a study of patients who underwent unilateral ovarian cystectomy only for apparent stage I borderline serous tumors, Lim-Tan et al. found that this conservative operation was safe, with only 8% of the patients developing recurrences 2 to 18 years later, all with curable disease confined to the ovaries (141). Recurrence was associated with positive margins of the removed ovarian cyst. Thus, hormonal function and fertility can be maintained (3,141). For patients who had an oophorectomy or cystectomy and a borderline tumor is documented later in the


Gynecology_Novak

Gynecology_Novak. of the removed ovarian cyst. Thus, hormonal function and fertility can be maintained (3,141). For patients who had an oophorectomy or cystectomy and a borderline tumor is documented later in the permanent pathology, no additional immediate surgery is necessary.


Gynecology_Novak

Gynecology_Novak. Stage I After a comprehensive staging laparotomy, only a minority of women will have local disease (FIGO stage I). There are over 20,000 women diagnosed yearly with epithelial ovarian cancer in the United States, and nearly 4,000 of these have disease confined to the ovaries (1,142). The prognosis for these patients depends on the clinical–pathologic features, as outlined below. Because of this emphasis on the importance of surgical staging, the rate of lymph node sampling increased in the United States, with a study showing that for women with stages I and II disease, the percentage having lymph nodes sampled increased from 38% to 59% from 1991 to 1996 (143).


Gynecology_Novak

Gynecology_Novak. The primary surgical treatment for stage I epithelial ovarian cancer is surgical, and patients should undergo total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging (132,133). In certain circumstances, a unilateral salpingo-oophorectomy may be performed. Based on the findings at surgery and the pathologic evaluation, patients with stage I ovarian cancer can be grouped into low-risk and high-risk categories (Table 37.3). Table 37.3 Prognostic Variables in Early-Stage Epithelial Ovarian Cancer Modified from Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:458,with permission.


Gynecology_Novak

Gynecology_Novak. Modified from Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:458,with permission. Fertility Preservation in Early-Stage Ovarian Cancer For patients who underwent a thorough staging laparotomy and who have no evidence of spread beyond the ovary, abdominal hysterectomy and bilateral salpingo-oophorectomy are appropriate therapy. The uterus and the contralateral ovary can be preserved in women with stage IA, grade 1 to 2 disease who desire to preserve fertility. The conditions of the women should be monitored carefully with routine periodic pelvic examinations and determinations of serum CA125 levels. Generally, the other ovary and the uterus are removed at the completion of childbearing.


Gynecology_Novak

Gynecology_Novak. Guthrie et al. studied the outcome of 656 patients with early-stage epithelial ovarian cancer (140). No untreated patients who had stage IA, grade 1 cancer died of their disease; thus, adjuvant radiation and chemotherapy are unnecessary. Furthermore, the Gynecologic Oncology Group (GOG) carried out a prospective, randomized trial of observation versus melphalan for patients with stage IA and IB, grade 1 or 2 disease (114). Five-year survival for each group was 94% and 96%, respectively, confirming that no further treatment is needed for such patients.


Gynecology_Novak

Gynecology_Novak. Patients who have more poorly differentiated disease or who have malignant cells, either in ascites ﬂuid or in peritoneal washings, must undergo complete surgical staging (3). The surgery should include the performance of a hysterectomy and bilateral salpingo-oophorectomy in addition to the staging laparotomy. Although the optimal supportive therapy for these patients is not known, most patients are treated with chemotherapy, as outlined below. The surgical management of all patients with advanced-stage disease is approached in a similar manner, with modifications made in response to the overall status and general health of the patient and the extent of residual disease present at the time treatment is initiated. A treatment scheme is outlined in Figure 37.10. Most patients subsequently receive combination chemotherapy for an empiric number of cycles.


Gynecology_Novak

Gynecology_Novak. If the patient is medically stable, she should undergo cytoreductive surgery to remove as much of the tumor and its metastases as possible (144–171). The operation to remove the primary tumor and the associated metastatic disease is referred to as debulking or cytoreductive surgery. The operation typically includes the performance of a total abdominal hysterectomy and bilateral salpingo-oophorectomy, along with a complete omentectomy and resection of any metastatic lesions from the peritoneal surfaces or from the intestines. The pelvic tumor often directly involves the rectosigmoid colon, the terminal ileum, and the cecum


Gynecology_Novak

Gynecology_Novak. Primary cytoreductive surgery* Optimal debulking  microscopic or <1 cm residual Nonoptimal debulking or s/p neoadjuvant chemotherapy Chemotherapy 3 cycles Chemotherapy 3–5 cycles Chemotherapy 6–8 cycles Consider interval surgical cytoreduction No clinical evidence of disease More chemotherapy, experimental protocols, or palliative care Progressive disease Progressive disease Second-line chemotherapy+ Observation vs. maintenance treatment Figure 37.10 Treatment scheme for patients with advanced-stage ovarian cancer. *In selected cases of Stage IIIc/IV disease, neoadjuvant chemotherapy may be given, and then an interval cytoreductive surgery is performed after 3 cycles. +Chemotherapy depends on whether platinum-sensitive or platinum-resistant. (Modified from Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:460, with permission.) CHAPTER 37 Ovarian, Fallopian Tube, and Peritoneal Cancer


Gynecology_Novak

Gynecology_Novak. CHAPTER 37 Ovarian, Fallopian Tube, and Peritoneal Cancer Figure 37.11 Extensive ovarian carcinoma involving the bladder, rectosigmoid, and ileocecal area. (Redrawn from Heintz APM, Berek JS. Cytoreductive surgery for ovarian carcinoma. In: Piver MS, ed. Ovarian malignancies. Edinburgh, UK: Churchill Livingstone, 1987:134, with permission.) (Fig. 37.11). In a minority of patients, most or all of the disease is confined to the pelvic viscera and the omentum, so that removal of these organs will result in extirpation of all gross tumor, a situation that is associated with a reasonable chance of prolonged progression-free survival.


Gynecology_Novak

Gynecology_Novak. The removal of bulky tumor masses may reduce the volume of ascites present. Often, ascites will disappear after removal of the primary tumor and a large omental “cake.” Removal of the omental cake may alleviate the nausea and early satiety that many patients experience. Removal of intestinal metastases may restore adequate intestinal function and improve the overall nutritional status of the patient, thereby facilitating the patient’s ability to tolerate subsequent chemotherapy. A large, bulky tumor may contain areas that are poorly vascularized, and these areas will be exposed to suboptimal concentrations of chemotherapeutic agents. Similarly, these areas are poorly oxygenated, so that radiation therapy, which requires adequate oxygenation to achieve maximal cell kill, will be less effective. Surgical removal of these bulky tumors may eliminate areas that could be relatively resistant to radiation and chemotherapeutic treatment.


Gynecology_Novak

Gynecology_Novak. Larger tumor masses tend to be composed of a higher proportion of cells that are either non-dividing or in the “resting” phase (i.e., G0 cells, which are essentially resistant to the therapy). A low growth fraction is characteristic of bulky tumor masses, and cytoreductive surgery can result in smaller residual masses with a relatively higher growth fraction. Goals of Cytoreductive Surgery The principal goal of cytoreductive surgery is removal of all of the primary cancer and, if possible, all metastatic disease. If resection of all metastases is not feasible, the goal is to reduce the tumor burden by resection of all individual tumors to an optimal status. Griffiths initially proposed that all metastatic nodules should be reduced to less


Gynecology_Novak

Gynecology_Novak. Figure 37.12 Survival of patients with stage IIIC epithelial ovarian cancer based on the maximal size of residual tumor after exploratory laparotomy and tumor resection. (From Heintz APM, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. Twenty-sixth annual report of the results of treatment of gynaecological cancer. Int J Gynecol Oncol 2006;95(suppl 1):S161–S192, with permission.) than 1.5 cm in maximal diameter and showed that survival was significantly longer in patients for whom this was achieved (144).


Gynecology_Novak

Gynecology_Novak. Hacker and Berek demonstrated that patients whose largest residual lesions were less than 5 mm had a superior survival rate, which was substantiated by Van Lindert et al. (145–148). The median survival of patients in this category was 40 months, compared with 18 months for patients whose lesions were less than 1.5 cm and 6 months for patients with nodules greater than 1.5 cm. Patients whose disease is completely resected to no macroscopic (microscopic only) residual disease have the best overall survival (149) (Fig. 37.12). Approximately 30% to 40% of patients in this category will be free of disease at 5 years. The resectability of the metastatic tumor is usually determined by the location of the disease. Optimal cytoreduction is difficult to achieve in the presence of extensive disease on the diaphragm, in the parenchyma of the liver, along the base of the small bowel mesentery, in the lesser omentum, or in the porta hepatis.


Gynecology_Novak

Gynecology_Novak. The ability of cytoreductive surgery to inﬂuence survival is limited by the extent of metastases before cytoreduction, presumably because of the presence of phenotypically resistant clones of cells in large metastatic masses. A patient whose metastatic tumor is very large (i.e., >10 cm before cytoreductive surgery) has a shorter survival than those with smaller areas of disease (147,149). Extensive carcinomatosis, the presence of ascites, and poor tumor grade, even with lesions that measure less than 5 mm, may shorten the survival (150–153). Exploration The supine position on the operating table may be sufficient for surgical exploration of most patients. For patients with extensive pelvic disease and for whom a low resection of the colon may be necessary, the low lithotomy position should be used. Debulking operations should be performed through a vertical incision to gain adequate access to the upper abdomen and to the pelvis.


Gynecology_Novak

Gynecology_Novak. After the peritoneal cavity is opened, ascites ﬂuid, if present, should be evacuated. In some centers, ﬂuid is submitted for in vitro research studies, such as molecular analyses. In cases of massive ascites, careful attention must be given to hemodynamic monitoring, especially for patients with borderline cardiovascular function. The peritoneal cavity and retroperitoneum are thoroughly inspected and palpated to assess the extent of the primary tumor and the metastatic disease. All abdominal viscera must be palpated to exclude the possibility that the ovarian disease is metastatic, particularly from the stomach, colon, or pancreas. If optimal status is not considered achievable, extensive bowel and urologic resections are not indicated, except to overcome a bowel obstruction. Removal of the primary tumor and omental cake is usually both feasible and desirable.


Gynecology_Novak

Gynecology_Novak. Pelvic Tumor Resection The essential principle of pelvic tumor removal is the retroperitoneal approach. To accomplish this, the retroperitoneum is entered laterally, along the surface of the psoas muscles, which avoids the iliac vessels and the ureters. If the uterus is present, the procedure is initiated by bilateral division of the round ligaments. The peritoneal incision is extended cephalad, lateral to the ovarian vessels within the infundibulopelvic ligament, and caudally toward the bladder. With careful dissection, the retroperitoneal space is explored, and the ureter and pelvic vessels are identified. The pararectal and paravesicular spaces are identified and developed, as described in Chapter 36.


Gynecology_Novak

Gynecology_Novak. The peritoneum overlying the bladder is dissected to connect the peritoneal incisions anteriorly. The vesicouterine plane is identified, and with careful sharp dissection the bladder is mobilized from the anterior surface of the cervix. The ovarian vessels are isolated, doubly ligated, and divided. Hysterectomy is then performed. The ureters must be carefully displayed to avoid injury. During this procedure, the uterine vessels can be identified. Ligation of the uterine vessels Figure 37.13 The resection of the pelvic tumor may include removal of the uterus, tubes, and ovaries, as well as portions of the lower intestinal tract. The arrows represent the plane of resection. (From Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:465, with permission.) and the remainder of the tissues within the cardinal ligaments completes the hysterectomy and resection of the contiguous tumor.


Gynecology_Novak

Gynecology_Novak. Because epithelial ovarian cancers tend not to invade the lumina of the colon or bladder, it is usually feasible to resect pelvic tumors without having to resect portions of the lower colon or the urinary tract (154,155). Resection of a small portion of the bladder may be required and, if so, a cystotomy should be performed to assist in resection of the disease (155). Intestinal Resection Resection of focal areas of disease involving the small or large intestine should be performed if that would permit the removal of all or most of the abdominal metastases and leave the patient with optimal disease at the end of the cytoreduction. Apart from the rectosigmoid colon, the most frequent sites of intestinal metastasis are the terminal ileum, the cecum, and the transverse colon. Resection of one or more of these segments of bowel may be necessary (154,156).


Gynecology_Novak

Gynecology_Novak. If the disease surrounds the rectosigmoid colon and its mesentery, that portion of the colon may have to be removed in order to clear the pelvic disease (Fig. 37.13) (154). When the pararectal space is identified in such patients, the proximal site of colonic involvement is identified, the colon and its mesentery are divided, and the rectosigmoid is removed along with the uterus en bloc. A reanastomosis of the colon is performed.


Gynecology_Novak

Gynecology_Novak. Omentectomy Advanced epithelial ovarian cancer often completely replaces the omen-tum, forming an “omental cake.” This disease may be adherent to the parietal peritoneum of the anterior abdominal wall, making entry into the abdominal cavity difficult. After freeing the omentum from any adhesions to parietal peritoneum, adherent loops of small intestine are freed by sharp dissection. The omentum is lifted and pulled gently in the cranial direction, exposing the attachment of the infracolic omentum to the transverse colon. The peritoneum is incised to open the appropriate plane, which is developed by sharp dissection along the serosa of the transverse colon. Small vessels are ligated with hemoclips. The omentum is separated from the greater curvature of the stomach by ligation of the right and left gastroepiploic arteries and ligation of the short gastric arteries (Fig. 37.14).


Gynecology_Novak

Gynecology_Novak. Figure 37.14 Separation of the omentum from stomach and transverse colon. Arrow, the direction of the initial surgical approach. (From Heintz APM, Berek JS. Cytoreductive surgery for ovarian carcinoma. In: Piver MS, ed. Ovarian malignancies. Edinburgh, UK: Churchill Livingstone, 1987:134, with permission.) The disease in the gastrocolic ligament can extend to the hilus of the spleen and splenic ﬂexure of the colon on the left and to the capsule of the liver and the hepatic ﬂexure of the colon on the right. Usually, the disease does not invade the parenchyma of the liver or spleen, and a plane can be found between the tumor and these organs. It will occasionally be necessary to perform splenectomy to remove all the omental disease (157).


Gynecology_Novak

Gynecology_Novak. Resection of Other Metastases Other large masses of tumor located on the parietal peritoneum should be removed, particularly if they are isolated masses and their removal will permit optimal cytoreduction. Resection of extensive disease from the surfaces of the diaphragm is neither practical nor feasible, although solitary metastases may be resected, the diaphragm sutured, and a chest tube placed for a few days (157,158). The use of the Cavitron Ultrasonic Surgical Aspirator (CUSA) and the argon beam coagulator may facilitate resection of small tumor nodules, especially those on ﬂat surfaces (159,160).


Gynecology_Novak

Gynecology_Novak. There was no randomized prospective study performed to define the value of primary cytoreductive surgery, but all retrospective studies indicate that the diameter of the largest residual tumor nodule before the initiation of chemotherapy is significantly related to progression-free survival in patients with advanced ovarian cancer (163). Quality of life may be significantly enhanced by removal of bulky tumor masses from the pelvis and upper abdomen (166). An analysis of the retrospective data indicates that, when performed by gynecologic oncologists, successful operations are feasible in 70% to 90% of patients (152,153). Major morbidity is approximately 5% and operative mortality is 1% (156,161,162). Intestinal resection in these patients does not appear to increase the overall morbidity caused by the operation (156).


Gynecology_Novak

Gynecology_Novak. In a meta-analysis of 81 studies of women who underwent cytoreductive surgery for advanced ovarian cancer, Bristow et al. documented that the extent of debulking correlated with incremental benefits in survival (i.e., the greater the percentage of tumor reduction, the longer the survival). Each 10% increase in cytoreduction equaled a 5.5% increase in median survival (163). Women whose cytoreduction was greater than 75% of their tumor burden had a median survival of 33.9 months compared with 22.7 months for women whose tumors were cytoreduced less than 75% (p < 0.001). The performance of a pelvic and para-aortic lymphadenectomy in patients with stage III disease does not prolong survival, based on the results of a large prospective, randomized trial (164).


Gynecology_Novak

Gynecology_Novak. A prospective randomized study of “interval” cytoreductive surgery was carried out by the European Organisation for the Research and Treatment of Cancer (EORTC). Interval surgery was performed after three cycles of platinum-combination chemotherapy in patients whose primary attempt at cytoreduction was suboptimal. The initial surgery for most of these patients was not an aggressive attempt to debulk their tumors. Patients in the surgical arm of the study demonstrated a survival benefit when compared with those who did not undergo interval debulking (165). The risk of mortality was reduced by more than 40% in the group that was randomized to the debulking arm of the study. Based on these data, the performance of a debulking operation as early as possible in the course of the patient’s treatment should be considered the standard of care (166).


Gynecology_Novak

Gynecology_Novak. A prospective phase III study of interval cytoreductive surgery was conducted by the GOG; the patients entered on the trial had a maximal attempt at tumor resection at their initial surgery (167). The randomized findings showed no difference between the patients who had an additional attempt at debulking after three cycles of chemotherapy compared with those who did not. The median survival of the 216 women who underwent interval cytoreduction was 32 months compared with 33 months for the 209 women who did not undergo surgical cytoreduction. There is evidence that the survival of women with advanced ovarian cancer is improved when the surgeon is specifically trained to perform cytoreductive surgery and when there is centralization of care (168–171). Whenever feasible, patients with advanced ovarian malignancy should be referred to a subspecialty unit for primary surgery, and every effort should be made to attain as complete a cytoreduction as possible.


Gynecology_Novak

Gynecology_Novak. Stage I Epithelial Ovarian Cancer Early Stage, Low Risk Guthrie et al. studied the outcome of 656 patients with early-stage epithelial ovarian cancer (140). Patients who had stage IA, grade 1 cancer and did not receive radiation or chemotherapy did not die of their disease; indicating that adjuvant therapy is unnecessary. The GOG carried out a prospective, randomized trial of observation versus melphalan for patients with stage IA and IB, grades 1 and 2 disease (114). Five-year survival for each group was 94% and 96%, respectively, confirming that adjuvant treatment did not improve survival. Therefore, no adjuvant chemotherapy is recommended for these patients. Early Stage, High Risk


Gynecology_Novak

Gynecology_Novak. Early Stage, High Risk In patients whose disease is high risk (e.g., more poorly differentiated or in whom there are malignant cells either in ascites ﬂuid or in peritoneal washings), additional therapy is indicated. Most investigators recommend chemotherapy for these patients (172–185). Chemotherapy for patients with early-stage high-risk epithelial ovarian cancer can be either single agent or multiagent. Some researchers question the wisdom of overly aggressive chemotherapy in women with early-stage disease, suggesting that the evidence for a durable impact on survival is marginal (174,175,181). The risk of leukemia with alkylating agents and platinum make the administration of adjuvant therapy hazardous unless there is a significant benefit (186,187).


Gynecology_Novak

Gynecology_Novak. Because cisplatin, carboplatin, cyclophosphamide, and paclitaxel (Taxol) are active single agents against epithelial ovarian cancer, these drugs are administered in various combinations. There are some series in which cisplatin or cyclophosphamide (PC) or both have been used to treat patients with stage I disease (176–181). In a GOG trial of three cycles of cisplatin and cyclophosphamide versus intraperitoneal chromic phosphate (32P) in patients with stage IB and IC disease, the progression-free survival of women receiving the platinum-based chemotherapy was 31% higher than those receiving the radiocolloid (178). Similar results were reported by a multicenter trial performed in Italy by the Gruppo Italiano Collaborativo Oncologica Ginecologica (GICOG) for progression-free survival, although there was no overall survival advantage (179).


Gynecology_Novak

Gynecology_Novak. Two large parallel randomized phase III clinical trials were conducted on women with early-stage disease: the International Collaborative Ovarian Neoplasm Trial 1 (ICON1) and the Adjuvant Chemotherapy Trial in Ovarian Neoplasia (ACTION) (188,189). In the ICON1 trial, 477 patients from 84 centers in Europe were entered. Patients of all stages were eligible for the trial if, in the opinion of the investigator, it was unclear whether adjuvant therapy would be of benefit. Most patients were considered to have stage I and IIA disease, but optimal surgical staging was not required, and it is likely that a significant number of these women had stage III disease. Adjuvant platinum-based chemotherapy was given to 241 patients, and no adjuvant chemotherapy was given to 236 patients. The 5-year survival was 73% in the group who received adjuvant chemotherapy compared with 62% in the control group (hazard ratio [HR] = 0.65, p = 0.01) (189).


Gynecology_Novak

Gynecology_Novak. In the ACTION trial, 440 patients from 40 European centers were randomized; 224 patients received adjuvant platinum-based chemotherapy, and 224 patients did not (188). Patients with As I and IIa, grades 2 and 3 were eligible. Only about one-third of the total group was optimally staged (151 patients). In the observation arm, optimal staging was associated with a better survival (HR = 2.31, p = 0.03), and in the suboptimally staged patients, adjuvant chemotherapy was associated with an improvement in survival (HR = 1.78, p = 0.009). In optimally staged patients, no benefit of adjuvant chemotherapy was seen. In the ACTION trial, the benefit from adjuvant chemotherapy was limited to the patients with suboptimal staging, suggesting that patients benefit only if they had a likelihood of occult microscopic dissemination.


Gynecology_Novak

Gynecology_Novak. When the data from the two trials were combined and analyzed, a total of 465 patients were randomized to receive platinum-based adjuvant chemotherapy and 460 to observation until disease progression (190). After a median follow-up of more than 4 years, the overall survival was 82% in the chemotherapy arm and 74% in the observation arm (HR = 0.67, p = 0.001). Recurrence-free survival was better in the chemotherapy arm: 76% versus 65% (HR = 0.64, p = 0.001). The results of this analysis must be interpreted with caution, because most of the patients did not undergo thorough surgical staging, but the findings suggest that platinum-based chemotherapy should be given to patients who were not optimally staged.


Gynecology_Novak

Gynecology_Novak. Carboplatin is widely used instead of cisplatin, as it is equivalent in efficacy and much better tolerated with significantly fewer side effects (191). A randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in 457 patients with early stage epithelial ovarian carcinoma was conducted by the GOG (192). An unexpectedly large number of patients (126 patients, 29%) had incomplete or inadequately documented surgical staging in this study. The recurrence rate for six cycles was 24% lower (HR = 0.76; confidence interval [CI], 0.5– 1.13; p = 0.18) versus three cycles, but this was not statistically significant. The estimates of probability of recurrence at 5 years were 20.1% for six cycles and 25.4% for three cycles. The authors concluded that three cycles of adjuvant carboplatin and paclitaxel was a reasonable option for women with high-risk early stage ovarian cancer. The current GOG trial includes patients with high-risk stage I and stage II disease,


Gynecology_Novak

Gynecology_Novak. adjuvant carboplatin and paclitaxel was a reasonable option for women with high-risk early stage ovarian cancer. The current GOG trial includes patients with high-risk stage I and stage II disease, and offers three cycles of carboplatin and paclitaxel followed by a randomization to either observation versus 26 weeks of weekly low-dose (40 mg/m2) paclitaxel. High-risk stage I is defined as stage IA or IB, grade 3, stage IC, or clear cell carcinomas.


Gynecology_Novak

Gynecology_Novak. The recommendations for therapy follow: Patients with high-grade, high-risk stage I epithelial ovarian cancer should be given adjuvant chemotherapy. The type depends on the patient’s overall health and medical comorbidities Treatment with carboplatin and paclitaxel chemotherapy for three to six cycles is used in these patients, whereas single agent carboplatin may be preferable for older women and patients with other medical comorbidities. Systemic multiagent chemotherapy is the standard treatment for metastatic epithelial ovarian cancer (193–217). After the introduction of cisplatin in the latter half of the 1970s, platinum-based combination chemotherapy became the most frequently used treatment regimen in the United States. Paclitaxel became available in the 1980s, and this drug was incorporated into the combination chemotherapy in the 1990s (192–196). Comparative trials of paclitaxel, cisplatin, and carboplatin are summarized below.


Gynecology_Novak

Gynecology_Novak. In a meta-analysis performed on studies of patients with advanced-stage disease, those patients given cisplatin-containing combination chemotherapy were compared with those treated with regimens that did not include cisplatin (197). Survival differences between the groups were seen from 2 to 5 years, with the cisplatin group having a slight survival advantage, but this difference disappeared by 8 years. A major advance in the treatment of advanced-stage disease was the incorporation of paclitaxel into the chemotherapeutic regimens in the late 1990s. A series of randomized, prospective clinical trials with paclitaxel-containing arms defined carboplatin and paclitaxel as the standard treatment protocol in advanced epithelial ovarian cancer, although there are data to support intraperitoneal chemotherapy in selected patients (194,195,201,202).


Gynecology_Novak

Gynecology_Novak. Reporting the GOG data (Protocol 111), McGuire et al. showed that the combination of cisplatin (75 mg/m2) and paclitaxel (135 mg/m2) was superior to cisplatin (75 mg/m2) and cyclophosphamide (600 mg/m2), each given for six cycles (194). In suboptimally resected patients, the paclitaxel-containing arm produced a 36% reduction in mortality. These data were verified in a trial conducted jointly by the EORTC, the Nordic Ovarian Cancer Study Group (NOCOVA), and the National Cancer Institute of Canada (NCIC), in which patients with both optimal and suboptimal disease were treated (195). In this study, the paclitaxel-containing arm produced a significant improvement in both progression-free interval and overall survival in both optimal and suboptimal groups. Based on these two studies, paclitaxel is included in the primary treatment of all women with advanced-stage epithelial ovarian cancer, unless there are contraindications to paclitaxel, such as preexisting peripheral neuropathy.


Gynecology_Novak

Gynecology_Novak. A three-arm comparison of paclitaxel (T) versus cisplatin (P) versus PT in suboptimal stage III and IV patients (Protocol 132) showed equivalency in the three groups, but crossover from one drug to the other was permitted (196). The study showed that the combination regimen was better tolerated than the sequential administration of the agents in suboptimally resected patients. The second-generation platinum analogue, carboplatin, was developed to have less toxicity than its parent compound, cisplatin. In early trials, carboplatin had lower overall toxicity (204). Fewer gastrointestinal side effects, especially nausea and vomiting, were observed than with cisplatin, and there was less nephrotoxicity, neurotoxicity, and ototoxicity. Carboplatin is associated with a higher degree of myelosuppression (206).


Gynecology_Novak

Gynecology_Novak. The dose of carboplatin is calculated by using the area under the curve (AUC) and the glomerular filtration rate (GFR) according to the Calvert formula (207). The target AUC is 5 to 6 for previously untreated patients with ovarian cancer.


Gynecology_Novak

Gynecology_Novak. Two randomized, prospective clinical studies compared the combination of paclitaxel and carboplatin to paclitaxel and cisplatin (201,202). In both studies, the efficacy and survivals were similar, but the toxicity was more acceptable with the carboplatin-containing regimen. In the first trial, GOG Protocol 158, the randomization was carboplatin AUC = 7.5 and paclitaxel 175 mg/m2 over 3 hours versus cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 over 24 hours (Fig. 37.15). The disease progression-free survival of the carboplatin-containing arm was 22 months versus 21.7 months for the control arm (201). The gastrointestinal and neurotoxicity of the carboplatin arm were appreciably lower than that of the cisplatin arm. A similar result was obtained in a large randomized trial in Germany, in which the dose of carboplatin was AUC = 6 and paclitaxel was 185 mg/m2 over 3 hours compared with the same dose of paclitaxel and cisplatin 75 mg/m2 (202). Based on these data, the preferred regimen in


Gynecology_Novak

Gynecology_Novak. the dose of carboplatin was AUC = 6 and paclitaxel was 185 mg/m2 over 3 hours compared with the same dose of paclitaxel and cisplatin 75 mg/m2 (202). Based on these data, the preferred regimen in patients with advanced-stage disease is the paclitaxel plus carboplatin combination (203).


Gynecology_Novak

Gynecology_Novak. The ICON3 trial was a study of 2,074 women with all stages of ovarian cancer, including 20% who had stage I or II disease (208). Carboplatin plus paclitaxel was compared with two non-paclitaxel regimens, carboplatin (70%), or cyclophosphamide, Adriamycin, and cisplatin (CAP) (30%). The regimens were chosen before randomization and based on the clinical preference of the treating physician. One-third of patients who received carboplatin or CAP subsequently received second-line paclitaxel, and this additional chemotherapy was often given before clinical progression. With a median follow-up of 51 months, the carboplatin plus paclitaxel and the control groups had a similar progression-free survival (0.93) and overall survival (0.98). The median survival for the paclitaxel plus carboplatin and control groups was 36.1 and 35.4 months, respectively. The median duration of progression-free survival was 17.3 and 16.1 months, respectively. The researchers concluded that single agent carboplatin


Gynecology_Novak

Gynecology_Novak. control groups was 36.1 and 35.4 months, respectively. The median duration of progression-free survival was 17.3 and 16.1 months, respectively. The researchers concluded that single agent carboplatin and CAP were as effective as paclitaxel and carboplatin for first-line chemotherapy. Because carboplatin as a single agent had a lower toxicity than the other regimens and the median survival (33 months) was similar in the prior trial (ICON2) that compared carboplatin and CAP as first-line treatment, the researchers suggested that carboplatin alone was the preferred therapy (209).


Gynecology_Novak

Gynecology_Novak. The design of the study limited the interpretation of the results and was criticized, because patients with FIGO stages I to IV disease were included, the extent of primary surgery was variable, and the majority (85%) of patients who relapsed after single-agent carboplatin or CAP received paclitaxel. The results of this study did not change the practice in the United Kingdom where the study was predominantly carried out.


Gynecology_Novak

Gynecology_Novak. Docetaxel has a different toxicity profile from paclitaxel. The SCOT-ROC (Scottish Gynaecological Cancer Trials Group) study randomly assigned 1,077 women with stages Ic to IV epithelial ovarian cancer to carboplatin with either paclitaxel or docetaxel (210). The efficacy of docetaxel appeared to be similar to paclitaxel: The median progression-free survival was 15.1 months versus 15.4 months, and the docetaxel group had fewer neurologic effects, arthralgias, myalgias, and extremity weakness than the paclitaxel group. The docetaxel plus carboplatin regimen was associated with significantly more myelosuppression and its consequences (i.e., serious infections and prolonged grade 3 to 4 neutropenia). Additional study is necessary to determine whether docetaxel should supplant paclitaxel in the primary treatment of epithelial ovarian cancer. CHAPTER 37 Ovarian, Fallopian Tube, and Peritoneal Cancer


Gynecology_Novak

Gynecology_Novak. CHAPTER 37 Ovarian, Fallopian Tube, and Peritoneal Cancer Treatment residual disease Alive Dead Patients cisplatin/paclitaxel mirco 83 61 144 cisplatin/paclitaxel macro 87 168 255 carboplatin/paclitaxel micro 88 49 137 carboplatin/paclitaxel macro 57 198 255 0 12 24 36 48 60 Proportion surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0A 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 Figure 37.15 Survival of patients with stage III epithelial ovarian cancer treated with carboplatin and paclitaxel versus cisplatin and paclitaxel: a Gynecologic Oncology Group study. 0.2 0.1


Gynecology_Novak

Gynecology_Novak. Figure 37.15 Survival of patients with stage III epithelial ovarian cancer treated with carboplatin and paclitaxel versus cisplatin and paclitaxel: a Gynecologic Oncology Group study. 0.2 0.1 A: Survival by treatment. B: Survival by treatment group (micro vs. macro). (From Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol 2003;21:3194–3200, with permission; Berek JS, Hacker NF. Berek & Hacker’s Gynecologic Oncology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:475, with permission.)


Gynecology_Novak

Gynecology_Novak. An Intergroup, international trial—GOG 182/Southwest Oncology Group (SWOG) 182/ICON5—compared the standard combination of carboplatin and paclitaxel with these drugs in combination with gemcitabine, topotecan,or liposomal doxorubicin in sequential doublets or triplets (211). The study showed that the addition of any these three drugs to the standard chemotherapy with carboplatin and paclitaxel did not improve progression-free survival or overall survival.


Gynecology_Novak

Gynecology_Novak. A randomized, prospective GOG study (Protocol 104) of intraperitoneal cisplatin versus intravenous cisplatin (100 mg/m2), each given with 750 mg/m2 cyclophosphamide, was performed jointly by the SWOG and the GOG in patients with minimal residual disease (212). The intraperitoneal cisplatin arm had a somewhat longer overall median survival than the intravenous arm, 49 versus 41 months (p = 0.03). In the patients with minimal residual disease (<0.5 cm maximal residual), paradoxically, there was no difference between the two treatments, 51 versus 46 months (p = 0.08).


Gynecology_Novak

Gynecology_Novak. In a follow-up GOG study (Protocol 114), the dose-intense arm was initiated by giving a moderately high dose of carboplatin (dose AUC = 9) for two induction cycles, followed by intraperitoneal cisplatin 100 mg/m2 and intravenous paclitaxel 135 mg/m2 over 24 hours, versus intravenous cisplatin 75 mg/m2 and intravenous paclitaxel 135 mg/m2 (213). The dose-intense arm results were slightly better—the disease progression-free median survival was 27.6 months compared with 22.5 months for the control arm (p = 0.02). There was no difference in overall survival (52.9 months versus 47.6 months, p = 0.056). Based on this study, it was unclear whether dose intensification with intraperitoneal cisplatin has a sustained long-term impact on the survival of these patients.


Gynecology_Novak

Gynecology_Novak. A third randomized prospective GOG study (Protocol 172) compared intraperitoneal cisplatin and paclitaxel versus intravenous cisplatin and paclitaxel (214). The combination of cisplatin 75 mg/m2 and paclitaxel 135 mg/m2 given intravenously every 3 weeks was compared with paclitaxel 135 mg/m2 intravenous day 1, followed by cisplatin 100 mg/m2 intraperitoneal day 2, and paclitaxel 60 mg/m2 intraperitoneal day 8 every 3 weeks, each given for six cycles.


Gynecology_Novak

Gynecology_Novak. Although 83% of the patients randomized to intravenous chemotherapy completed all six cycles of therapy, only 42% of those treated with intraperitoneal chemotherapy completed the six cycles, principally because of catheter-related complications. For patients in either group who could not complete the therapy because of cisplatin-related toxicity, the chemotherapy was switched to intravenous carboplatin. Comparing the intravenous and intraperitoneal arms, the median duration of progression-free survival was 18.3 and 23.8 months, respectively (p = 0.05). The median duration of overall survival in the intravenous-therapy and intraperitoneal-therapy groups was 49.7 and 65.6 months, respectively (p = 0.03) (214). Quality of life was significantly worse in the intraperitoneal-therapy group before cycle four and 3 to 6 weeks after treatment but not 1 year after treatment. A summary of the intraperitoneal catheter-related issues in this trial was presented (215).


Gynecology_Novak

Gynecology_Novak. Based on these randomized trials, the intraperitoneal route of administration for cisplatin and paclitaxel chemotherapy in the primary treatment of optimally resected stage III ovarian cancer is an acceptable therapeutic alternative to intravenous chemotherapy with carboplatin and paclitaxel (216). There are no reports of randomized direct comparisons of this intraperitoneal regimen to intravenous carboplatin and paclitaxel or to intraperitoneal carboplatin and paclitaxel. Intraperitoneal therapy can be used in patients with optimally resected tumors who have a good performance status and are in overall good health. Because intraperitoneal chemotherapy is more cumbersome and has a higher morbidity than intravenous therapy, the use of this technique of drug delivery should be individualized after thorough discussion with the patient.


Gynecology_Novak

Gynecology_Novak. The Japanese GOG randomized 637 patients with ovarian cancer to receive carboplatin AUC 6 and paclitaxel 180 mg/m2 every 3 weeks or the same dose of carboplatin and 80 mg/m2 paclitaxel every week for at least six cycles (217). The median progression-free survival was 28 months in the dose-dense arm and 17 months in the control group, and they reported relatively little difference in toxicity between the two arms and that grade 3 to 4 neurotoxicity in particular was very low. In the 417 patients who had stage III disease, about half had less than 1 cm maximum residual disease, similar to the patients in GOG 172. There is no subgroup analysis to determine whether these optimally debulked patients fared better with dose-dense paclitaxel, but the hazard ratio for recurrence was 0.69 for stage III as a group. These findings are very encouraging but need to be validated in another study. There is good evidence that weekly paclitaxel is more effective than paclitaxel every 3 weeks in breast


Gynecology_Novak

Gynecology_Novak. III as a group. These findings are very encouraging but need to be validated in another study. There is good evidence that weekly paclitaxel is more effective than paclitaxel every 3 weeks in breast cancer and the Japanese GOG study suggests that the same may apply to ovarian cancer. This important question is being studied in GOG and other studies comparing intravenous dose-dense treatment with intraperitoneal chemotherapy.