Familial Ovarian Cancer

Familial hereditary ovarian cancer currently falls into three categories:

• 1.
  

  Site-specific familial ovarian cancer

  
  
• 2.
  

  Hereditary breast-ovarian cancer syndrome, in which there is an increased incidence of breast and ovarian carcinomas alone or in combination

  
  
• 3.
  

  Lynch syndrome type II, in which family members may develop a variety of cancers, including colorectal, endometrial, and ovarian cancer

Inherited genetic mutations are associated with approximately 10% of women who develop ovarian cancer. The mutation is inherited in an autosomal-dominant fashion (maternal or paternal transmission), and multiple family members are affected over several generations. First-degree relatives (mother or sister) are frequently involved.

True hereditary ovarian cancer and breast cancer mainly result from mutations of BRCA1 and BRCA2 genes. Individuals with these mutations ( BRCA1 and BRCA2 ) generally have a germline mutation (inherited mutated copy of the gene) in contrast to the more common somatic mutation (noninherited, or acquired) in most patients with ovarian cancer. BRCA1 mutations are located on the long arm of chromosome 17q, and BRCA2 mutations are located on chromosome 13q12. Lynch II syndrome arises as a result of inherited mutation in a family of DNA repair genes (MSH2, MLH1, PMS1, PMS2); this group accounts for only a small number of inherited ovarian cancers. Initial evaluation of these germline mutations suggested an estimated risk of ovarian cancer of 39% to 46% for carriers of the BRCA1 mutation but a lower rate of 10% to 20% for carriers of the BRCA2 mutation. With more than 400 mutations identified in the BRCA1 and BRCA2 genes along with multiple polymorphisms, estimating risk is difficult. In most women with a strong family history who do develop ovarian cancer, the disease is sporadic in nature and not inherited. Houlston and colleagues evaluated 391 women who were self-referred to a screening clinic for familial ovarian cancer. Of these women, 290 (74%) appeared to have no clear inheritance pattern, and there was no increased risk of cancer in the first-degree relatives. There were 82 (21%) pedigrees compatible with multisite cancer family syndrome with a relative risk of about 6, or development of ovarian cancer in 1 of 16. In the 19 families with site-specific ovarian cancer, the relative risk for first-degree relatives was 39, with a lifetime risk of 1 in 2. Kerlikowske and associates reviewed published studies of familial ovarian cancers and used ovarian cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER) database to estimate lifetime probabilities of ovarian cancer in these families. They noted that the lifetime probability of ovarian cancer for a 35-year-old woman was 1.6% in an individual without a family history of ovarian cancer. It increased to 5% if she had one relative and 7% if she had two relatives with ovarian cancer. These and other studies by Bourne and colleagues were based on family history pedigree and preceded BRCA1 and BRCA2 testing.

Claus and associates, using a previously fit autosomal-dominant genetic model, evaluated the Cancer and Steroid Hormone Study of 4730 patients with breast cancer aged 20 to 54 years and 4688 control subjects to estimate the proportions of breast and ovarian cases in the general population that are likely to result from breast and ovarian cancer susceptibility genes. About 10% of patients with ovarian cancer in the general population were estimated to be carriers of a breast or ovarian cancer susceptibility gene. The risks for ovarian cancer in carriers to the age of 60 years and 80 years were estimated to be about 10% and 27%, respectively. Carriers were predicted to have at least a 15-fold age-specific risk of ovarian cancer compared with noncarriers. Some ethnic groups appear to be at high risk for gene mutation, and the Ashkenazi Jews have been most extensively studied. In a large study by Struewing and associates, 5318 Jewish subjects had BRCA1 and BRCA2 evaluated, identifying 120 carriers. Carriers had a significantly elevated risk, with an estimated risk of 2% by age 50 years and 16% by age 70 years compared with the noncarrier risk of 0.4% by 50 years and 1.6% by 70 years. Metcalfe and colleagues performed BRCA testing for three founder mutations in 2080 self-identified Jewish women and found the BRCA mutation rate to be 1% (22 women) in an unselected population.

Frank and associates evaluated 283 women with breast cancer before age 50 years or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis for BRCA1 followed by BRCA2 analysis. Mutations were identified in 94 women (39%), including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian cancer. Mutations were noted in 24 of 38 women (63%) who had ovarian cancer. In women from breast–ovarian cancer families, 30 of the germline mutations occurred in BRCA2 . Of note in this study, the authors did not find Ashkenazi ancestry significantly increased in the identification of BRCA1 or BRCA2 mutation, suggesting the importance of a strong family history.

In considering women at high risk, two questions should be addressed: (1) Who should be tested? and (2) Are there screening or prophylactic measures that can be applied to decrease the risk? A family history of breast or ovarian cancer, particularly before the age of 50 years in a first-order relative, and Ashkenazi Jewish ancestry, are risk factors for BRCA1 or BRCA2 mutations. Family history, both maternal and paternal, should be obtained (three generations is desired), and age at diagnosis should be noted. Pathology reports or death certificates verify accuracy of history; there can be considerable errors from history alone. Lifetime empirical risks can be determined from this information and may suggest that testing for a gene mutation is indicated. The extensive evaluation of family history and counseling should be done before genetic testing. Interpretation and plan of action that will influence medical management should be discussed in detail before genetic testing is performed. Testing of family members known to have cancer before testing of the cancer-free members is recommended. If a suspect mutation is found in the family member with cancer, the relatives without cancer can be tested for that specific mutation. If the family member with cancer does not have a mutation, other relatives probably will not benefit from testing. In one study, women sought DNA testing most commonly because of concern about the potential cancer risk to their children and secondly for their own cancer surveillance and prevention.

In a consensus statement of the Cancer Genetics Studies Consortium, annual or semiannual screening with transvaginal ultrasonography (TVS) and determination of serum carcinoma antigen 125 (CA-125) levels beginning at age 25 to 35 years are recommended for BRCA1 mutation carriers. Both of these tests carry relatively high false-positive and false-negative rates with low positive predictive value. Narod and associates found that oral contraceptives protected against ovarian cancer in patients with mutation in either the BRCA1 or BRCA2 gene.

Risk-reducing salpingo-oophorectomy after completion of childbearing, or age 40 years, in women at high genetic risk is associated with a significant reduction in the risk of BRCA1- or BRCA2 -associated ovarian cancer. A National Institutes of Health (NIH) Consensus Conference recommended that women with two or more first-degree relatives with ovarian carcinoma be offered prophylactic oophorectomy after completion of childbearing or age 35 years. Prophylactic oophorectomy does not prevent subsequent primary peritoneal cancer, in which failure rates of 4% to 5% at 20 years after risk-reducing salpingo-oophorectomy (RRSO) were reported by Finch and colleagues. Rebbeck and associates clarified risk reduction estimates in their 2009 meta-analysis. They found RRSO was associated with an 80% risk reduction in BRCA1- or BRCA2 -associated ovarian, fallopian tube and peritoneal cancer, and a 50% risk reduction in BRCA1- or BRCA2 -associated breast cancer.

A 2005 study by Pal and colleagues suggested that previous studies may have underestimated the frequency of BRCA1 and BRCA2 mutations. Of 209 patients with invasive cancer, 32 patients (15%) had mutations of BRCA1 ( n = 20) or BRCA2 ( n = 12). Based on their data, they suggested it may be reasonable to offer genetic counseling to any woman with an invasive, nonmucinous epithelial ovarian cancer, and subsequent studies have supported this observation. A 2014 Society of Gynecologic Oncologists (SGO) Clinical Practice Statement on Genetic Testing for Ovarian Cancer recommended women diagnosed with epithelial ovarian, tubal, and peritoneal cancers receive genetic counseling and be offered genetic testing even in the absence of a family history.

The Gynecologic Oncology Group (GOG) has conducted a study (GOG 199) of 2605 women at increased risk for developing ovarian cancer, either by known BRCA mutation or family history risk factors. Patients were enrolled after choosing either prophylactic oophorectomy or screening, and both groups followed with CA-125 levels and Risk of Ovarian Cancer Algorithm (ROCA) assessment. The study was designed to evaluate both the prospective incidence of new and occult ovarian cancers and to assess the ROCA and quality of life. In 2014, Sherman and colleagues reported a portion of the analysis of high risk women older than 30 years of age who elected RRSO. Clinically occult cancers were detected in 2.6% of high risk women ( BRCA1 mutation carriers, 4.6%; BRCA2 mutations carriers, 3.5%; noncarriers, 0.5%), and further results from this trial will be forthcoming.

Borderline Malignant Epithelial Neoplasms

Over the past 4 decades, investigators have described a subset of epithelial ovarian tumors whose histologic and biologic features lie between those of clearly benign and frankly malignant ovarian neoplasms. These borderline malignant neoplasms account for approximately 15% of all epithelial ovarian cancers and share molecular characteristics with low-grade ovarian cancers. They have also been called proliferative cystadenomas and tumors of low malignant potential and are more completely discussed in Chapter 10 . Compared with invasive epithelial ovarian cancer, epithelial borderline tumors affect a younger population and may have a 10-year survival rate approaching 95% (see Chapter 10 ). Although symptomatic recurrence and death may rarely develop as late as 20 years after therapy, these neoplasms are correctly labeled as being of low malignant potential. Most gynecologic oncologists recommend conservative therapy, especially in patients who are desirous of further childbearing and have stage IA disease (see Chapter 10 ). We have found surgical excision of disease the most effective therapy and when necessary have used repeated explorations, reserving chemotherapy for patients who develop ascites or whose tumor changes histologic features or demonstrates rapid growth ( Fig. 11.9 ).

Algorithm for the management of borderline epithelial ovarian neoplasms. BSO, Bilateral salpingo-oophorectomy; TAH, total abdominal hysterectomy.

Treatment of Malignant Epithelial Neoplasms

The most common epithelial cancers of the ovary are histologically categorized as serous, mucinous, endometrioid, and clear cell (mesonephroid) types ( Figs. 11.10 to 11.13 ). Most large studies demonstrate that these different histologic types have similar outcomes with existing therapy, stage for stage and grade for grade. Mucinous and endometrioid subtypes are more commonly found in earlier stages. There are ongoing studies to investigate targeted therapies in certain cell types, most notably mucinous and clear cell cancers. Based on our current data, however, prognosis, survival, and therapy for these various forms of epithelial cancer will be considered collectively.

Papillary serous adenocarcinoma of ovary. Histologic appearance with prominent fibrous stalks and non–mucin-producing epithelial cells.

Mucinous adenocarcinoma of ovary. Microscopic appearance. Note the tall, columnar, mucin-producing cells.

Endometrioid adenocarcinoma of the ovary. Histologic appearance with columnar and pseudostratified epithelial cells showing prominent elongated hyperchromatic nuclei.

Clear cell adenocarcinoma of the ovary. Microscopic view showing hobnail or peg cells.

The unifocal theory of ovarian epithelial cancer growth suggests that the disease initially grows locally, invading the capsule and mesovarium, and then invades adjacent organs by local extension and lymphatic spread. Cells on the surface exfoliate into the peritoneal cavity, where they circulate and implant on free peritoneal surfaces. Local and regional lymphatic metastasis may involve the uterus, fallopian tubes, and pelvic and aortic lymph nodes.

Woodruff suggested a multifocal mechanism of disease spread, whereby the entire coelomic epithelium can give rise to this lesion after exposure to carcinogenic agents that enter the peritoneal cavity from the vagina through the fallopian tubes. Indeed, the lesion could then originate in a multifocal distribution, “like a measles rash,” over large portions of the coelomic epithelium. Although the early precursors leading to advanced ovarian cancer are incompletely understood, more current molecular evidence favors the unifocal origin theory.

In the past decade, as risk-reducing salpingo-oophorectomy has become more common, a moderate body of literature suggests that a significant percentage of “ovarian cancers” may actually arise in the fallopian tube fimbria with metastasis to the ovaries. Kindelberger and colleagues have reported a potential causal relationship based on identification of tubal intraepithelial carcinomas (TIC) and analysis of p53 mutations therein.

Regardless of origin, the most important prognostic variable for each patient is the extent, or “stage,” of disease. A staging system has been devised that allows treatment results in patients with similar prognostic factors to be compared among different institutions. Survival is affected by the cancer stage, grade of differentiation, gross findings at surgery ( Table 11.14 ), amount of residual tumor after surgery, and additional treatment required.

Stage III

In addition to surgical staging, every reasonable effort should be made to remove all visible metastatic tumors. Retrospective studies have strongly suggested that the survival rate in patients with stage III disease is related to the amount of residual tumor after surgery, such that patients with no macroscopic residual tumor appear to have the best prognosis after primary chemotherapy ( Table 11.17 and Fig. 11.14 ). Most centers prefer combination platinum-based chemotherapy for this group of patients because of the excellent response rates reported in the literature (see later section on combination chemotherapy and IP therapy).

TABLE 11.17

Relationship of Residual Tumor Size and Median Survival (Months)

Author	Patients ( n )	Optimal (<2 cm)	Suboptimal (>2 cm)
Griffiths et al.	102	28	11
Wharton et al.	104	27	15
Hacker et al.	47	22	6
Sutton et al.	56	39	22

 

Survival in patients with stage IIIc disease by completeness of surgery ( n = 1059).

(From International Federation of Gynecology and Obstetrics. Annual Report on the Results of Treatment in Gynecological Cancer, vol 23. Stockholm, 1998, Author.)

The duration of multiple-agent therapy is usually six cycles. If after primary chemotherapy the patient has no clinical evidence of disease (clinical complete response), a second-look procedure was often considered in the past to ascertain the presence of subclinical residual disease. However, a secondary data analysis of GOG 158 suggested no apparent outcome advantage from second-look surgery. For the most part, second-look surgery is no longer recommended.

Stage IV

The ideal management of stage IV disease is to remove as much cancer as possible and to administer chemotherapy after surgery. The role and benefit of surgical cytoreduction in these patients is detailed in the next section. The OS is worse for this group of patients than for those of other stages, as expected ( Fig. 11.15 ).

Obviously malignant cases of ovarian carcinoma. Cumulative proportion surviving by stage.

(From International Federation of Gynecology and Obstetrics. Annual Report on the Results of Treatment in Gynecological Cancer, vol 22. Stockholm, 1994, Author.)

Maximal Surgical Effort

The goal of primary surgery for advanced ovarian cancer should be to remove all visible tumor and to use all reasonable surgical means to do so ( Fig. 11.16 ). In the 1970s, Griffiths and coworkers evaluated the importance of postsurgical tumor residual by using a multiple linear regression equation with survival as the dependent variable to control simultaneously for the multiple therapeutic and biologic factors that contribute to the ultimate outcome in the individual patient. The most important factors proved to be histologic grade of the tumor and size of the largest residual mass after primary surgery. In Griffiths et al.’s original study, the operation itself contributed nothing to survival unless it effected reduction in the size of the largest residual tumor mass below the limit of 1.6 cm.

Survival rates stage for stage in patients in whom all tumor was surgically removed versus patients in whom not all tumor was completely removed.

(From Aure JC, Hoeg K, Kolstad P. Clinical and histologic studies of ovarian carcinoma. Long-term follow-up of 990 cases. Obstet Gynecol 1971;37:1.)

Cytoreductive or “debulking” procedures have gained considerable attention in the management of ovarian cancer. The concept is to reduce the residual tumor burden to a level at which subsequent chemotherapy can be most effective. A careful dissection by a well-trained gynecologic oncologist can often remove disease that on first impression appear to be unresectable ( Fig. 11.17 ). Removal of large ovarian masses and omental involvement may reduce the tumor burden by 80% to 99%. The theoretical value of debulking procedures lies in reducing the number of tumor cells and the advantage this affords to adjuvant therapy. This is especially relevant in bulky chemosensitive solid tumors such as ovarian cancer, in which removal of large numbers of cells in the resting phase (G0) may propel the residual cells into the more vulnerable proliferating phases. Several careful retrospective studies have repeatedly demonstrated improved survival rates in patients who can be surgically reduced to minimal tumor burden. The GOG has attempted to better define primary cytoreductive surgery with a detailed analysis of the results of surgery in patients with advanced disease. Their initial study compared survival of the patients with stage III disease who were found at surgery to have abdominal disease of 1 cm or smaller with that of patients found to have disease larger than 1 cm but whose tumors were surgically cytoreduced to 1 cm or less. If surgery was the only important factor, survival should have been equivalent in both groups. This was not the case. Patients found to have small-volume disease survived longer than did patients who had cytoreduction to small-volume disease at surgery, suggesting that the tumor biology also carries prognostic significance. In a second study, GOG investigators evaluated the effect of the diameter of the largest residual disease on survival in patients with suboptimal cytoreduction. They demonstrated that cytoreduction so that the largest residual mass was 2 cm or less resulted in a significant survival benefit, but all residual diameters larger than 2 cm had equivalent survival ( Fig. 11.18 ). Therefore, unless the mass could be cytoreduced to 2 cm or less, residual diameter did not influence survival. In evaluating optimal and suboptimal cytoreduction, these GOG investigators showed that three distinct groups emerged: microscopic (no visible) residual, residual disease of less than 2 cm, and residual disease of greater than 2 cm ( Fig. 11.19 ). It is clear from these studies that whereas patients with microscopic disease had a 4-year survival rate of about 60%, patients with gross disease 2 cm or less had a 4-year survival rate of 35%. However, patients whose disease could not be cytoreduced to 2 cm or less had a 4-year survival rate of less than 20%. Most striking, however, was the failure of cytoreductive surgery to improve survival unless the largest diameter of residual disease was 2 cm or less. The effect of maximal cytoreductive surgery can be seen in the percentage of negative second-look procedures ( Table 11.18 ).

A large omental cake of ovarian cancer exceeding 25 cm in greatest measurement.

Survival by maximal diameter of residual disease.

(From Hoskins WJ, McGuire WP, Brady MF, et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 1994;170:974.)

Survival by residual disease, Gynecologic Oncology Group protocols (PR) 52 and 97.

(From Hoskins WJ, McGuire WP, Brady MF, et al. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 1994;170:974.)

An inverse correlation between the amount of residual disease after surgery and OS has been consistently associated. In 2002, Bristow and associates published a meta-analysis of published studies at the time, in which the impact of cytoreduction was clearly demonstrated. By comparing currently available studies of advanced ovarian cancer patients undergoing surgical cytoreduction, they demonstrated that for each 10% increase in the proportion of patients undergoing optimal cytoreduction, the median survival rate increased by 5.5% to 6%. Although the current accepted definition of “optimal cytoreduction” is no visible residual tumor smaller than 1 cm in greatest dimension, the best reported outcomes occur in patients who have complete cytoreduction or no visible residual disease.

In an effort to remove visible tumor deposits and achieve optimal cytoreduction, gynecologic oncologists frequently perform radical surgical procedures beyond those required for standard staging. Eisenkop and associates described 163 consecutive patients assigned to stage IIIC and stage IV. Complete cytoreduction could be performed in 86% of patients using an array of radical procedures. The overall median survival time was 54 months, but it was 62 months in those whose tumors were optimally debulked. Aletti and colleagues reported that for patients cytoreduced to low-volume residual disease, their favorable survival was directly associated with the need for radical surgery. Two sites that often require radical operations to clear are tumor metastases to the bowel and to the upper abdomen. Multiple investigators have reported the utility and safety of large or small bowel resection, which may be necessary in up to 50% of cases to achieve optimal cytoreduction and has been associated with a subsequent improvement in survival. Upper abdominal cytoreduction has also been shown to be safe and effective but may require additional training or assistance. Cliby and colleagues reported procedures such as liver resection, splenectomy, and diaphragm resection to be possible and associated with an acceptable morbidity. Chi and coinvestigators demonstrated that the addition of upper abdominal procedures to achieve optimal cytoreduction resulted in a median survival time longer than 5 years, which was comparable to that of patients who did not require these extensive procedures for optimal cytoreduction. Improvements in surgical cytoreduction have developed in consort with additional advances in intensive care and postoperative care, allowing additional benefits for our ovarian cancer patients.

The role of cytoreductive surgery in stage IV cancers has been investigated. Several studies have suggested that optimal debulking can be performed in many of these patients with beneficial effect. Liu and associates described 47 patients with stage IV cancers, of which 14 (30%) were optimally debulked to less than 2 cm residual. The median survival time was 37 months in the patients in whom the cancer was optimally debulked compared with 17 months in the patients in whom the cancer was suboptimally debulked. A study by Chi and colleagues identified 92 patients; optimal debulking was achieved in 45% with a median survival time of 40 months compared with 18 months for suboptimal debulking. A recent ancillary study by the GOG demonstrated that the ability to achieve cytoreduction to less than 5 cm residual disease in stage IV patients rendered some survival advantage, although the most favorable subgroup was patients reduced to no visible residual disease. Aletti and colleagues also demonstrated that using radical procedures to perform cytoreduction to no visible residual disease resulted in median survival times longer than 3 years in stage IV patients. For patients known or suspected to have thoracic metastases, the use of video-assisted thoracic surgery (VATS) can be diagnostic, potentially therapeutic, or both. Positive findings on VATS may allow for intrathoracic cytoreduction in select cases or may indicate which patients are best served with neoadjuvant chemotherapy as a result of unresectable pleural disease.

Even though cytoreductive surgery consistently appears to have therapeutic value, controversy continues. The primary unresolved issue is whether the poor prognosis with bulky disease is caused by the presence of increased tumor burden (in which case cytoreductive surgery is of potential benefit) or whether it is associated with differences in tumor biology or a decreased sensitivity to chemotherapeutic regimens. (If these possibilities are indeed the case, cytoreductive surgery is not likely to have a major impact on survival.) The implication is that patients who have disease that can be cytoreduced are a select group with good prognoses on the basis of factors independent of the surgery. Furthermore, if chemotherapy is delayed because of complications of surgery, this may have a deleterious effect on long-term survival. The percentage of patients with advanced ovarian cancer who can effectively undergo cytoreductive surgery seems to range from 43% to 87%, depending on the investigators reporting. This difference may not only reflect the individual skills of the surgeons but also may be influenced by different referral patterns and other selection factors. Neoadjuvant chemotherapy has been investigated as a means by which to address this issue; these studies are described in the subsequent section.

The role of lymphadenectomy in patients with advanced disease continues to be debated. Lymph node involvement is common in patients with advanced disease (>50%); the question is whether lymphadenectomy improves survival. It has been suggested by some that metastases in lymph nodes do not respond well to chemotherapy, and therefore these potential metastatic sites should be removed. Opponents state that recurrence most frequently occurs in the peritoneal cavity, and therefore lymph node status has little impact on the overall disease course. Several studies have come to somewhat different conclusions. Parazzini and associates evaluated 456 women with stage III or IV disease entered in a prospective randomized chemotherapy trial. There were 161 patients with positive nodes. They noted grade 3 tumors to have a greater number with positive nodes compared with grade 1 or grade 2 tumors. This was also true of stage IV compared with stage III cancer. They did not find a difference in survival between those with positive nodes and those with negative nodes. Scarabelli and colleagues evaluated lymph node status in 98 patients with stage IIIC to IV disease who had no gross residual disease after surgery compared with 44 patients who did not undergo lymphadenectomy. Survival was significantly improved if lymphadenectomy was done (Cox analysis). In 2005, Panici and coinvestigators reported their prospective multicenter analysis of 427 advanced ovarian cancer patients randomly assigned to lymphadenectomy or removal of bulky nodes only. Although progression-free survival (PFS) was improved in patients undergoing lymphadenectomy, OS was not different. The 2005 retrospective analysis of 889 patients enrolled in the Scottish Randomised Trial in Ovarian Cancer (SCOTROC-1) was conducted. The analysis demonstrated that optimal debulking (<2 cm) was more commonly achieved in patients accrued from the United States, Europe, and Australia than in patients recruited from the United Kingdom (71% vs. 58%). Comparison of the UK and non-UK patients who had no visible residual disease demonstrated a better survival for the non-UK patients, and the authors attributed this to the fact that non-UK patients more commonly underwent primary lymphadenectomy, suggesting a potential therapeutic benefit. It has been our practice to do pelvic and aortic lymphadenectomy routinely if the patient’s tumor can be optimally debulked. Benefits of lymphadenectomy in patients with bulky residual disease remain questionable. It currently seems appropriate that patients with a diagnosis of advanced ovarian cancer should undergo resection of all masses when technically feasible.

Because a suboptimal surgical effort confers no survival benefit and adds only postoperative morbidity, accurate methods to determine which patients could be successfully resected would be useful. Both preoperative imaging and initial laparoscopy have been investigated as methods to determine the likelihood of success. Most imaging series have used preoperative CT scan to assess factors that could predict an optimal cytoreduction. Although sets of radiographic risk factors have been described, these have had poor predictive value because the majority of patients (62%–86%) identified as having “poor prognostic indicators” have been able to undergo optimal cytoreduction. Similarly, laparoscopy in advanced ovarian cancer has limitations in terms of how complete an assessment of the IP space is possible, and metastases at port sites have been reported. Wang and associates reviewed the literature to determine risk factors that may contribute to early recurrence at the port site. Of the gynecologic cancers, ovarian cancer was the most common malignant neoplasm with subsequent port site metastasis. Metastasis to the port site was more common if ascites and IP carcinomatosis were present. The earliest time from laparoscopy to port site metastasis was 8 days; however, the clinical significance of port site metastases is unclear because they often clinically resolve with systemic therapy.

Whether a suboptimal primary surgery can be improved upon by subsequent surgical cytoreduction after chemotherapy is controversial. The EORTC group reported its initial experience with interval debulking surgery in patients with advanced ovarian carcinoma after unsuccessful primary cytoreductive surgery. Patients received three courses of cisplatin and cyclophosphamide and were then randomly assigned to receive interval debulking surgery or no further surgery. All patients received six courses of chemotherapy. There were 278 patients evaluated, and the median survival rate was 26% versus 20% (surgery vs. no surgery; P = 0.012). Debulking surgery was an independent prognostic factor in multivariate analysis. After adjustment for all prognostic factors, surgery reduced the risk of death by 33% ( P = 0.008). GOG investigators conducted a similar study. This study (GOG 152) enrolled 550 patients, all of whom had initial primary surgery by a gynecologic oncologist. Patients who were suboptimally debulked (residual tumor >1 cm) received three cycles of paclitaxel plus cisplatin. Patients were randomized to continued chemotherapy or to a secondary surgical cytoreduction and then continued chemotherapy. Neither the PFS nor the relative risk of death was improved with the additional interval surgery. The authors speculate that the patients in the GOG study may also have undergone more aggressive primary surgery than the patients in the EORTC study, and this may have accounted for the difference in results. Most important, one could summarize these two studies by concluding that patients with advanced ovarian cancer are deserving of at least one maximal effort at cytoreduction, preferably by a gynecologic oncologist.

Although a maximal primary surgical effort appears to be a cornerstone of potential long-term survival, the timing of the surgical effort remains a focus of debate. In patients with borderline performance status, based on age, compromising medical disease, and extensive effusions (especially pleural or pericardial), and in patients with extensive abdominal disease, unlikely to be effectively debulked, strong consideration should be given to initiating therapy with neoadjuvant chemotherapy. After two to four cycles, a good clinical response to chemotherapy may provide an opportunity for an effective surgical debulking with an acceptably low complication rate. Before initiating chemotherapy, the diagnosis of ovarian, tubal, or peritoneal cancer should be confirmed by cytology or minimally invasive surgery. Neoadjuvant chemotherapy treatment (followed by surgical debulking) results have been reported in small retrospective reports of between 20 and 90 patients and generally report survival outcomes similar to those of patients who have been suboptimally cytoreduced. A meta-analysis of these studies by Bristow et al. and Chi et al. demonstrated that the use of neoadjuvant chemotherapy was associated with a reduction in survival of approximately 4 months with every preoperative cycle, implying that surgical intervention should be performed as soon as is feasible. However, Vergote and colleagues have reported results from the large randomized EORTC noninferiority trial of patients with advanced ovarian cancer treated with primary surgery followed by chemotherapy versus neoadjuvant chemotherapy for three cycles followed by surgical cytoreduction and three additional cycles of chemotherapy. Complete resection of all macroscopic disease was the strongest predictor of OS. They demonstrated comparable survival outcomes (~29 months in both arms), and overall the results favored neoadjuvant chemotherapy given the lower surgical morbidity compared with the primary surgery group. Another trial evaluating the role of neoadjuvant chemotherapy, Chemotherapy Or Upfront Surgery in Ovarian Cancer Patients (CHORUS), randomized women with stage III or IV ovarian cancer to receive upfront surgery followed by six cycles of chemotherapy (carboplatin and paclitaxel) or three cycles of chemotherapy, surgery, and then three additional cycles of completion chemotherapy. A total of 550 women were evaluated, and the OS time was 22.6 months in the primary surgery group compared with 24.1 months in the primary chemotherapy group. The authors also reported a lower rate of grade 3 or 4 postoperative adverse events and deaths in the primary chemotherapy group, concluding that the primary chemotherapy approach is noninferior to the primary surgery approach. Although the neoadjuvant approach is a reasonable option for some patients, it is important to recognize several criticisms to the study. Both studies reported low rates of primary optimal cytoreduction (~40% in both studies) and low median OS compared with other contemporary ovarian cancer trials. Therefore, neoadjuvant chemotherapy has not been widely adopted as an equivalent primary treatment option in the United States, and further studies are ongoing.

Role of Radiation Therapy

With improvements in chemotherapy and surgery for ovarian cancer, radiation therapy rarely plays a role in primary therapy. The systemic pattern of spread makes effective radiation therapy difficult, and with bulky residual disease, radiation therapy is particularly ineffective. Studies by the GOG and others demonstrated the extent to which the addition of radiation did not improve outcomes even before the current era of highly active chemotherapy. Some special problems are listed in Table 11.19 . The entire abdomen must be considered at risk; therefore, the volume that must be irradiated is large, resulting in multiple limitations for the radiotherapist. However, consideration of radiotherapy for specific histologies and isolated recurrences is being further studied. Dose restrictions are listed in Table 11.20 .

Radioisotopes

Numerous trials have been conducted comparing IP 32P with or without pelvic radiation with whole abdominal radiation or single-agent chemotherapy in various clinical settings of ovarian cancer. Because IP 32P has failed to demonstrate improved outcomes, can be associated with increased complications, and is “technique intensive,” it is rarely considered for contemporary treatment planning.

Chemotherapy

The evolution of chemotherapy agents for advanced ovarian cancer over the past 30 years has been significant. Ovarian cancer was one of the first solid malignant tumors demonstrating responsiveness to chemotherapy. Effectiveness of the various chemotherapy treatments has been measured by response rates (usually complete plus partial responses), negative second-look rates, PFS, and OS. All of these outcome measures can be subject to error. Even survival outcomes can be compromised by the fact that many patients receive a number of variously active chemotherapy treatments over their treatment history.

The earliest agents used for the treatment of ovarian carcinoma (1970–1980) were predominantly the alkylating agents melphalan (also called phenylalanine mustard, Alkeran, L-PAM, and L-sarcolysin), cyclophosphamide, chlorambucil, and thiotepa. Response rates were usually reported in the 20% to 60% range, but median survival rates for patients with advanced ovarian cancer were often in the range of 10 to 18 months, quite inferior to most outcomes from today’s clinical trials. Antimetabolites, such as 5-fluorouracil and methotrexate, were also used in many of the earlier trials, especially in combination with alkylating agents. The contemporary use of these agents in epithelial ovarian cancer is rare to nonexistent.

The late 1970s and 1980s saw the introduction of combination chemotherapy regimens, such as Hexa CAF (hexamethylmelamine, cyclophosphamide, doxorubicin, and 5-fluorouracil) and CAP (cyclophosphamide, doxorubicin, and cisplatin). By the early 1980s, combination therapy was the standard treatment for most patients. The 1980s also witnessed the introduction of cisplatin and later carboplatin. The introduction of these platinum compounds increased response rates to the 50% to 80% range and increased median survival periods to the 12- to 30-month range in most studies. The wide range was often attributable to select patient populations, with the “suboptimal” debulked patients having the 12- to 18-month survival times and the “optimal” debulked patients having the 18- to 30-month survival times. The platinum compounds have remained an integral component of treatment to this day.

The 1990s saw the introduction of paclitaxel, an agent first extracted from the stripped bark of the Pacific yew tree, Taxus brevifolia. Paclitaxel, now chemically synthesized, demonstrated a new mechanism of action by promoting microtubular assembly and stabilizing tubulin polymer formation, thus inhibiting rapidly dividing cells from completing the mitotic process. The initial single-agent paclitaxel response rates in patients with refractory ovarian cancer were in the 25% to 35% range. Contemporary drug development continues to look at new formulations of the taxane group. Docetaxel in several studies has shown equivalent efficacy to paclitaxel with a different side effect profile, and other modified taxanes such as Abraxane and CT-2103 have been evaluated .

The past 2 decades have also seen the introduction of additional cytotoxic agents with demonstrated activity in ovar­ian cancer, including topotecan, a topoisomerase I-inhibitor; a pegylated liposomal encapsulated form of doxorubicin; and gemcitabine. These three drugs were tested in the frontline setting by the GOG 182/ICON-5 clinical trials, discussed later.

For the past decade, there has been considerable interest in developing agents targeting specific molecular targets. Two important categories of targeted therapies in ovarian cancer have been angiogenesis inhibitors, of which bevacizumab has been most widely studied, and poly(ADP-ribose) polymerase (PARP) inhibitors. Immune therapies continue to be in development and will continue to be a therapeutic focus in the next decade.

Clinical Trials

The relatively low rates of response to most single agents stimulated investigators to search for combination schedules. In the “modern” era, platinum-based combinations have proved to be the most successful. Pertinent clinical trials relating to early-stage disease are discussed earlier in this chapter, and the following discussion focuses on trials for advanced ovarian cancer.

Development of ovarian cancer combination chemotherapy through the 1980s and 1990s saw transition from doxorubicin–cyclophosphamide (AC), to cyclophosphamide–doxorubicin–cisplatin (CAP), to cyclophosphamide-platinum, and finally to taxane–platinum as the evolving standard of care. The trials performed by the GOG as well as European investigators were primarily responsible to developing these standards. In 1986, GOG 47 reported results comparing CAP to AC, with improved response rate, response duration, and PFS but not OS in the whole cohort. Subgroup analysis of patients with measurable disease (227 of 440 assessable patients) did show improved OS, and the potential advantage of incorporating platinum therapy was recognized. GOG 52 evaluated CAP versus cyclophosphamide–cisplatin alone in optimally cytoreduced patients and demonstrated equivalent PFS and OS endpoints. With less toxicity by withholding doxorubicin, cyclophosphamide–cisplatin became the “standard” arm for many clinical trials in the late 1980s and early 1990s. Before abandoning doxorubicin completely, four trials were considered in a meta-analysis that specifically evaluated the benefit of doxorubicin in ovarian cancer. Considering only pathologic complete responses, the study showed a constant small benefit for CAP, highest in the North-West Oncology Group (GONO) and Danish Ovarian Cancer Group (DACOVA) studies. By pulling together these data in a meta-analysis, it was possible to detect a statistically significant benefit of pathologic complete responses (6%) and OS (7%) with CAP. However, because in three trials the dose intensity was greater for CAP than for cyclophosphamide–cisplatin, to what extent the benefit of CAP is from greater dose intensity or from doxorubicin itself remains unsolved.

In the 1990s, paclitaxel became available on trial, and GOG 132 evaluated 614 patients with suboptimally debulked cancer who were treated in a three-arm protocol comparing cisplatin alone, paclitaxel alone, and a combination of the two drugs. Neither PFS nor OS was different among the three arms, but significant crossover to the other drug in the single-drug arms muddled somewhat the clarity of the outcome data. Some interpreted the results of this study to indicate that a platinum agent should be a component of primary therapy. With some evidence for efficacy, the paclitaxel–cisplatin combination was compared to the existing standard, cyclophosphamide–cisplatin. The GOG 111 study randomized 386 patients with large-volume disease to paclitaxel–cisplatin versus cyclophosphamide–cisplatin. In the paclitaxel arm, administration of paclitaxel before cisplatin was important to optimize response and minimize toxicity. In terms of therapeutic efficacy, the cisplatin–paclitaxel arm produced a significantly greater overall response rate (73% vs. 60%) and clinical complete response rate, but the frequency of pathologic complete response was similar between the two arms. The paclitaxel arm showed significant improvements in PFS (18 vs. 13 months) and OS (38 vs. 24 months). The risk of progression was 32% lower among those treated with the paclitaxel regimen, and the risk of death was 39% lower ( Fig. 11.20 ). A European-Canadian Intergroup trial (OV-10) had a study design similar to GOG 111, testing the replacement of cyclophosphamide with paclitaxel. This study included patients with optimal and suboptimal stage IB, IIB, III, and IV. Again, the clinical response rate was superior for the paclitaxel arm (59% vs. 45%), with a subsequent 25% reduction in the rate of death. The combination of paclitaxel and cisplatin became the standard for combination first-line chemotherapy for the treatment of epithelial ovarian carcinoma.

Survival by treatment group.

(Modified from McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1. Copyright © 1996 Massachusetts Medical society. All rights reserved. Adapted 2006 with permission.)

When combined with cisplatin, paclitaxel requires an extended infusion interval (24 hours) to prevent unacceptable neuropathy. This administration schedule was inconvenient, prompting many community providers to replace cisplatin with carboplatin, with which paclitaxel did not require this extended infusion. Several groups conducted equivalency trials to compare paclitaxel (175–185 mg/m ² ) and carboplatin (AUC 5–7.5) with the standard cisplatin–paclitaxel regimen. The GOG conducted GOG 158 on the optimal (<1 cm) patient population as a noninferiority trial. The relative risk (RR) of progression on the paclitaxel plus carboplatin arm was equivalent (RR = 0.88; 95% CI, 0.–-1.03), and toxicity was greater on the paclitaxel plus cisplatin arm. Similar findings regarding therapeutic equivalence and toxicity preference for carboplatin over cisplatin were reported by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Ovarian Cancer Study Group. The combination of intravenous (IV) paclitaxel and carboplatin replaced paclitaxel and cisplatin as the standard first-line chemotherapy for ovarian cancer.

Care must always be taken in interpreting response rates as a correlate for survival rates. Too often a chemotherapeutic regimen will produce an excellent response rate but not affect the OS rate. Therefore, the clinician must await longer term studies of combination chemotherapy to accurately understand its impact on survival of patients. Omura and colleagues reported a sobering analysis of two large GOG studies of multiagent chemotherapy in epithelial ovarian cancer. In this analysis of 726 women with stage III or stage IV disease, excellent follow-up had been obtained. The authors concluded that the impact of chemotherapy to date had been modest. Fewer than 10% of their patients were progression free at 5 years, and late failures continued to occur, even beyond 7 years. Sutton and coworkers reported a 7% disease-free survival rate at 10 years. Unfortunately, the superiority of any particular combination of chemotherapeutic agents as reflected by statistically significant improvement in long-term survival remains unproved. Although carboplatin appears to be the most active agent in epithelial cancer of the ovary, there is still controversy that combining it with other agents improves outcome.

In vitro testing of chemotherapy resistance or sensitivity has been investigated for at least 3 decades without clarification of its role in either primary or recurrent disease. Multiple technologies are currently in use, and there is a need to identify the relative value of this testing modality.

Dose-intense Chemotherapy

Dose intensity refers to the amount of chemotherapy to which a cancer is exposed per unit of time; this is generally assumed to be reflected by the dose of drug in milligrams per square meter of body surface area per unit of time. The theory is well grounded in preclinical work showing that as the concentration of drug in culture medium increases, the fraction of surviving cancer cells decreases logarithmically. The cell kill for a particular drug frequently follows a sigmoidal curve, indicating a point at which continued dose escalation will yield little improvement in results. To determine whether dose intensity is important clinically, randomized trials are needed. The GOG did design such a trial in patients with large-volume, advanced disease. A total of 458 patients were entered into the study and were randomly assigned to low-dose cisplatin 50 mg/m ² plus cyclophosphamide 500 mg/m ² every 3 weeks for eight cycles or high-dose cisplatin 100 mg/m ² plus cyclophosphamide 1000 mg/m ² every 3 weeks for four cycles (same total dose in half the time). In patients with measurable disease, the overall response and clinical complete response rates were equivalent. There was no difference in PFS or OS in the subsets of patients with measurable or nonmeasurable disease. The results of this study did not support the concept that increased dose intensity will produce greater therapeutic effect of cisplatinum or cyclophosphamide. Colombo and associates reported a randomized trial in patients with advanced disease who were given cisplatin 75 mg/m ² every 3 weeks for six cycles or cisplatin 50 mg/m ² per week for 9 weeks (same total dose in half the time). Again, no significant differences were seen in clinical or pathologic complete response rates, PFS, or OS. Although neither of these randomized trials of pure dose intensity in cisplatin showed an advantage for a higher dose intensity across a clinically relevant range of doses, other lines of evidence have been cited to support the use of higher dose schedules.

In trials conducted by the National Cancer Institute (NCI) of the United States, even higher dose intensities of cisplatin in conjunction with hypertonic saline to protect the kidneys had been stated to yield higher response rates than more standard doses. A closer examination of these data reported by Rothenberg and coworkers shows confusing results. In patients with large-volume disease, the NCI regimen complete response rates were no different (11% vs. 12%) than the GOG results with CAP, as reported by Omura, regimens with a 3.3-fold difference in dose intensity of cisplatin. In patients with small-volume disease, the NCI regimen complete response rates were not statistically different (38% vs. 30%) from the GOG results with a two-drug combination of cisplatin plus cyclophosphamide, as reported by Omura in 1989. There appears to be no evidence from these data to support the importance of dose intensity of cisplatin over a 3.3-fold range of doses. At least 11 randomized trials have compared standard doses of carboplatin- or cisplatin-based chemotherapy with double doses of the same platinum analogs. Most of these trials showed no advantage in most outcome parameters. A second meta-analysis of the Levin and Hryniuk meta-analysis (in which it appeared that dose intensity had a positive impact on response rate and survival) suggested that platinum dose intensity is unimportant, although intensity of all administered drugs is important, as is tumor residual volume at initiation of therapy.

Katsumata and colleagues from the Japan GOG reported their results of their phase III trial in advanced ovarian cancer evaluating IV carboplatin and paclitaxel dosed every 3 weeks versus IV carboplatin with weekly dose-dense paclitaxel. For each 3-week cycle of therapy, the weekly dose-dense arm received 240 mg/m ² of paclitaxel versus 180 mg/m ² of paclitaxel in the control arm. PFS and 3-year OS were significantly improved in the weekly paclitaxel arm (28 vs. 17 months, 72% vs. 65%), with a higher incidence of grade III and IV anemia. Pignata and colleagues reported results from the similar Multicentre Italian Trials in Ovarian Cancer 7 (MITO-7) trial but showed no difference in PFS or OS for weekly versus pacli­taxel every 3 weeks. GOG investigators for GOG 262 investigated this question of carboplatin plus weekly paclitaxel versus paclitaxel every 3 weeks in a similar manner to the Japanese Gynecologic Oncology Group (JGOG), with the addition of with or without bevacizumab in each arm. Preliminary results reported no difference in PFS between the arms if bevacizumab was received, but without bevacizumab, the weekly paclitaxel arm had improved PFS.

For 2 decades, high-dose chemotherapy with autologous bone marrow transplantation (ABMT) or peripheral blood stem cell support has been reported for several solid tumors, and there has been a tendency for improved response rates but a relatively short period of disease-free survival in most of the reports reviewed. Many reports show that even in advanced cases, the most important factor for long-term survival after high-dose chemotherapy is the completeness of the primary cytoreductive surgery. Most of the reports in the literature with high-dose chemotherapy with ABMT have been phase II trials of patients with a mixed response to first-line chemotherapy. The best response and survival have been in patients who had had a complete response to pretransplantation chemotherapy. The MD Anderson group reported its experience of 96 patients undergoing transplantation, of whom 43% were in clinical remission. The overall 6-year survival rate was 38% and was 53% in the clinical remission group. Bengala and colleagues reported the results of the European Group for Blood and Marrow Transplantation (EBMT) for 91 patients in first com­plete remission treated with high-dose chemotherapy and ABMT. The median survival time was 44 months, and they were unable to identify a subgroup more likely to benefit. These reported median survival times are not significantly better than that with use of paclitaxel as second-line therapy. However, the toxicity of high-dose chemotherapy is a serious concern, as is the additional expense. Although interesting, it appears that targeting of patients for high-dose therapy with bone marrow support cannot be considered standard therapy and should only be done as part of an established national protocol so that information can be obtained to increase our knowledge of this therapy.

Immunotherapy

In the past 3 decades, there has been considerable interest in combining chemotherapy with immunotherapy for better results in patients with epithelial cancer of the ovary. The GOG and others have investigated immunomodulating agents such as Corynebacterium parvum and bacille Calmette-Guérin (BCG). Results have been conflicting as to whether nonspecific immunostimulation combined with chemotherapy improves survival.

The potential role of immune response modifiers in the treatment of ovarian cancer has been investigated. Ovarian cancer is a suitable model for biologic therapies because the peritoneal cavity is capable of mounting an inflammatory response to many stimuli, and this response has been shown to induce an antitumor effect. Early experimental observations confirmed that ovarian cancer is a suitable prototype tumor in which to evaluate novel immunotherapeutic and chemoimmunotherapeutic approaches. Berek and coworkers have reported that recombinant interferon alfa has clinical activity in patients with small-volume residual disease. Numerous phase II trials, using substances such as tumor necrosis factor, interleukin-2, and the like, along with other studies using combinations of cytokines have failed to demonstrate significantly improved outcomes. Combining biologic immune response modifiers with standard chemotherapy has proved to be more difficult than initially conceived because of overlapping toxicities. In view of this, it seems prudent to await proven efficacy before attempting to launch the phase III trials with biologic immune response modifiers.

Recent results from trials using programmed cell death protein 1 (PD-1) inhibitors, such as nivolumab and avelumab, have shown some promise. PD-1 is a T-cell “programmed cell death” receptor on T cells that can blocked by a tumor-secreted ligand, inactivating the T cell and allowing the cancer to evade the host immune system. Competitive blockade of this ligand should allow improved cancer immune regulation, and initial results reported by Brahmer and associates in melanoma, non–small cell lung cancer, renal cell cancer, and ovarian cancer were promising. Hamanishi and colleagues have reported their initial results with nivolumab in a cohort of patients with platinum-resistant ovarian cancer, with an encouraging safety profile and activity, including two durable responses. NRG Oncology and others have open trials investigating this mechanism in ovarian cancer. We await the results of these endeavors as to whether these novel treatments will show the same promise in ovarian cancer that has been demonstrated thus far in melanoma.

Intraperitoneal Chemotherapy

Ovarian cancer is predominantly a disease limited to the peritoneal cavity for most patients. For some chemotherapeutic agents, IP administration offers pharmacokinetic advantages, including high IP drug concentration and longer exposure in the peritoneal cavity. Although IP chemotherapy proposals date back decades, it has only been over recent years that the accumulated clinical trial data favor this approach.

Results from randomized trials, listed in Table 11.21 , summarize the experience of clinical trials conducted since the mid-1980s. These studies, all primary therapy trials, compare IV chemotherapy with combined IV and IP chemotherapy. The initial IP study demonstrating that IP chemotherapy may represent a survival advantage was a combined Southwestern Oncology Group (SWOG)/GOG trial (SWOG 8501 and GOG 104). The study compared IV cisplatin and IV cyclophosphamide with IP cisplatin and IV cyclophosphamide in patients with less than 2-cm-diameter residual disease. The IP arm produced a median survival of 49 months compared with 41 months for the IV arm, with an HR of 0.77. However, critics pointed out that the subsequent introduction of paclitaxel to our frontline treatment may have neutralized this apparent advantage for IP therapy. The other concern is that accrual was extended beyond the initial study design for patients with 0- to 0.5-cm residual disease, and still this subgroup failed to demonstrate superior survival (51 months vs. 46 months; HR, 0.80). One would have expected the treatment difference to be most pronounced in this patient subgroup. Partly because of these issues, IP therapy was not uniformly supported as producing a survival advantage over the current IV standard, carboplatin-paclitaxel.

TABLE 11.21

Randomized Trials Comparing Intravenous Versus Intraperitoneal First-Line Treatment of Ovarian Cancer

Study Identifier (Author, Year Published)	Control Regimen	Experimental Regimen	Target Population	Patients ( n )	Median Duration of Survival for Control Regimen (Months)	Median Duration of Survival for Experimental Regimen (Months)
SWOG/GOG-104 ( )	Cisplatin 100 mg/m 2 IV, ctx 600 mg/m 2 IV q 3 weeks × 6	Cisplatin 100 mg/ m 2 IP, ctx 600 mg/m 2 IV q 3 weeks × 6	Stage III ≤2 cm residual	546	41	49
Greek ( )	Carboplatin 350 mg/m 2 IV, ctx 600 mg/m 2 IV q 3 weeks × 6	Carboplatin 350 mg/m 2 IV, ctx 600 mg/m 2 IV q 3 weeks × 6	Stage III ≤or >2 cm residual	90	52	63
GONO ( )	Cisplatin 50 mg/m 2 IV, ctx 600 mg/m 2 IV, epidox 60 mg/m 2 IV q 4 weeks × 6	Cisplatin 50 mg/m 2 IP, ctx 600 mg/m 2 IV, epidox 60 mg/m 2 IV q 4 weeks × 6	Stage II or IV <2 cm residual	113	25	26
GOG-114/SWOG ( )	Cisplatin 75 mg/m 2 IV, tax 135 mg/m 2 (24 hr) IV q 3 weeks × 6	Carboplatin AUC 9 IV q 28 days × 2, cisplatin 100 mg/m 2 IP, tax 135 mg/m 2 (24 hr) IV q 3 weeks × 6	Stage III ≤1 cm residual	462	51	67
Taiwan ( )	Cisplatin 50 mg/m 2 IV, ctx 500 mg/m 2 IV epi/adr 50 mg/m 2 IV q 3 weeks × 6	Cisplatin 100 mg/m 2 IV, ctx 500 mg/m 2 IV, epi/adr 50 mg/m 2 IV q 3 weeks × 6	Stage III ≤1 cm residual	118	48	43
GOG-172 (Armstrong et al., 2006)	Cisplatin 75 mg/m 2 IV, tax 135 mg/m 2 (24 hr) IV q 3 weeks × 6	Tax 135 mg/m 2 (24 hr) IV, cisplatin 100 mg/m 2 IP, tax 60 mg/m 2 IV on day 8q 3 weeks × 6	Stage III ≤1 cm	415	49	67

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