ca ovary

1827

93 Ovaries and Fallopian TubesDeborah Armstrong

S U M M A R Y O F K E Y P O I N T S

Celomic Epithelial CarcinomaBasic Characteristics• Ninety percent of the 23,300 new

cases and 13,900 deaths annually in the United States

• Derived from celomic epithelium lining the peritoneal cavity, most commonly from that which invests the ovary

• Most common route of spread: dissemination throughout peritoneal cavity

• Signifi cant prognostic factors: age, histologic type and grade, extent of disease at diagnosis

Screening and Prophylaxis• High-risk individuals: those with one or

more fi rst-order relatives with ovarian carcinoma

• No proven effective screening tests available, although transvaginal sonography and serial CA-125 and proteomic serum patterns under evaluation

• Prophylactic oophorectomy still of no proven value

Initial Evaluation and Management• Emphasis in initial evaluation placed on

the peritoneal cavity, an emphasis requiring exploratory laparotomy in those not clearly stage IV

• Minimum requirements for appropriate laparotomy: surgery through an incision adequate to inspect the entire peritoneal surface, multiple peritoneal biopsies in the absence of gross extrapelvic disease, and a maximal attempt at surgical cytoreduction, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy

Management of Advanced (Stage III–IV) Disease• After surgery, systemic therapy to

include at least a platinum compound• Combination chemotherapy favored by

the weight of evidence, preferred combination being paclitaxel-carboplatin: paclitaxel (175 mg/m2 intravenously over 3 hours) followed by carboplatin (area under the curve, 6 to 7.5 intravenously) repeated every 3 weeks for six cycles

• Controversial issues: the roles of new agents, the role of dose-intense therapy supported by marrow reconstitution, the role of intraperitoneal therapy, and the role of maintenance paclitaxel

Management of Limited (Stage I–II) Disease• After careful exploratory laparotomy,

patients divided into low-risk and high-risk groups on the basis of the presence of one or more high-risk features: poorly differentiated neoplasm, extracystic tumor, positive peritoneal washings, ascites, or extraovarian disease

• Those who are at low risk of recurrence (no high-risk features): total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy followed by observation

• Those who are at high risk of recurrence (one or more high-risk features): the same surgery as in those who are at low risk followed by adjuvant platinum-based chemotherapy (paclitaxel/carboplatin for three cycles)

Salvage Therapy for Recurrent Disease• Patients divided into platinum-sensitive

and platinum-resistant groups• Platinum-sensitive patients (responded

to initial platinum-based therapy and experienced at least a 6-month platinum-free interval before relapse): retreatment with taxane/platinum combination

• Platinum-resistant patients (progressed on platinum-based therapy, best response to platinum-based therapy

stable disease, or relapsed during or within 6 months of platinum-based therapy): treatment with drugs that produce responses (weekly paclitaxel, docetaxel, pegylated liposomal doxorubicin, oral etoposide, topotecan, tamoxifen, gemcitabine, navelbine, ifosfamide)

• Offering no proven advantage over intravenous therapy at standard doses to these patients: intraperitoneal therapy, high-dose therapy with marrow reconstitution, radiation therapy, and biologic agents

Germ Cell CancersBasic Characteristics• Germ cell cancers make up 5% of all

cancers of the ovary in the United States

• Histologies: dysgerminomas and nondysgerminomas (endodermal sinus tumors, mixed cell tumors, immature teratomas, embryonal carcinomas, and choriocarcinomas)

• Tumor markers are an important means of detecting early recurrence and monitoring the progress of therapy: α-fetoprotein and human chorionic gonadotropin

• For management purposes, two major groups of patients: (1) stages I to III completely resected and (2) incompletely resected stage III to IV disease

Stages I to III Completely Resected• Initial management: complete resection

of disease• Adjuvant therapy: combination

chemotherapy (either bleomycin/ etoposide/cisplatin or vincristine/ actinomycin/cyclophosphamide)

Stages III to IV Incompletely Resected• Systemic therapy: bleomycin/etoposide/

cisplatin

1828 Part III: Specifi c Malignancies

INTRODUCTIONCancers of the ovary and fallopian tube together account for most deaths resulting from cancer of the female genital tract. This statistic relates primarily to the fact that, unlike other common malignant gynecologic neoplasms (cancers of the endometrium and cervix), cancers of the ovary and fallopian tube are fi rst seen at relatively advanced stages of disease because of the lack of an effective early diagnostic test. Ovarian cancers are far more common than tubal malignancies and provide most of the data on which the management of both malignancies is based. This chapter fi rst addresses cancers of the ovary extensively, followed by a discussion of cancers of the fal-lopian tube.

CANCER OF THE OVARYCancer of the ovary will be newly diagnosed in more than 23,300 women in the United States each year and will cause the death of more than 13,900 American women annually.1 The lifetime likeli-hood that ovarian cancer will develop in a woman is estimated to be between 1 in 60 and 1 in 70, with a higher frequency associated with certain familial syndromes.2–5 This group of cancers includes three major types: celomic epithelial carcinoma of the ovary, germ cell neoplasms, and stromal tumors. Each of these groups is discussed separately.

Celomic Epithelial Carcinoma

Almost 90% of cancers of the ovary are celomic epithelial carcinoma, which is one of the three most common gynecologic cancers. Man-agement of these lesions evolves from an understanding of certain basic aspects of the disease process.

Basic CharacteristicsCLINICALLY RELEVANT DISEASE FEATURES. Celomic epithelial carcinomas may arise in any part of the peritoneal cavity, although most appear to arise from the celomic epithelium that invests the ovary during embryonic development. The reasons for the preference for ovarian celomic epithelium are not entirely clear. It has been speculated that repeated rupture and repair of this portion of the celomic epithelium with the process of ovulation afford a greater opportunity for mutations that lead to malignancy. Such speculation is supported by observations that associate multiple preg-nancies and the use of birth control pills, which suppress ovulation, with a decreased risk for ovarian carcinoma.6

Furthermore, most of these lesions arise in invaginated epithelium in areas of repair after ovulation, developing as though within a cyst. The process eventually penetrates the capsule of the ovary, forms tumor excrescences on the surface of the ovary, and then disseminates primarily by direct spread throughout the peritoneal cavity. Subse-quent spread via lymphatic and hematogenous dissemination also occurs. This pattern of evolution of the disease is refl ected in the

International Federation of Gynecology and Obstetrics (FIGO) staging system7 (Table 93-1), in which the most common stage at presentation is stage III, characterized by spread outside the pelvis to involve the peritoneal cavity. Because the process is an intra-abdom-inal disease that produces few symptoms before intraperitoneal dis-semination and is not amenable to early diagnosis by currently available screening techniques, essentially 70% to 75% of patients are fi rst seen with advanced (stage III or IV) rather than limited (stage I or II) disease.

Several characteristics of celomic epithelial carcinomas distinguish their clinical management from that of the other two common gyne-cologic cancers: endometrial cancer and cervical cancer. First, the primary route of spread, dissemination throughout the peritoneal cavity, opens the possibility for therapy directed toward the perito-neal cavity. Second, unlike the other two common gynecologic cancers, these lesions usually are fi rst seen at a relatively advanced stage (stage III or IV), which necessitates a larger role for systemic

All• Close follow-up after chemotherapy,

including monthly assessments of tumor markers, physical examination, and chest radiography

Rare Malignant Ovarian Tumors• Fewer than 5% of ovarian cancer:

granulosa cell tumors, thecoma-fi broma tumors, Sertoli-Leydig cell tumors, gynandroblastomas, and steroid cell tumors

• Treatment of choice: surgical resection with little known about the use of radiation or systemic therapy as either adjuvant treatment or management for advanced or recurrent disease

Cancer of the Fallopian Tube• Rare (300 cases annually in the

United States), with more than 90% of all cases papillary serous adenocarcinomas

• Pattern of spread similar to that of celomic epithelial carcinoma of the ovary

• Surgical resection the mainstay for most patients with disease confi ned to the fallopian tube

• Radiation or chemotherapy reserved for cases with penetration to or beyond the serosa, with evidence favoring management similar to that used for advanced ovarian carcinoma

Table 93-1 International Federation of Gynecology and Obstetrics Staging System for Ovarian Carcinoma

Stage Description

I Growth limited to the ovaries

IA One ovary; no ascites; capsule intact; no tumor on external surface

IB Two ovaries; no ascites; capsule intact; no tumor on external surface

IC One or both ovaries with either surface tumor; ruptured capsule; or ascites or peritoneal washings with malignant cells

II Pelvic extension

IIA Involvement of uterus and/or tubes

IIB Involvement of other pelvic tissues

IIC Stage IIA or IIB with factors as in stage IC

III Peritoneal implants outside pelvis and/or positive retroperitoneal or inguinal nodes

IIIA Grossly limited to true pelvis; negative nodes; microscopic seeding of abdominal peritoneum

IIIB Implants of abdominal peritoneum ≤2 cm; nodes negative

IIIC Abdominal implants >2 cm and/or positive retroperitoneal or inguinal nodes

IV Distant metastases

Data from the New FIGO stage grouping.7

1829Ovaries and Fallopian Tubes • CHAPTER 93

therapy in the management of these cases. Finally, the volume of residual disease at initiation of systemic therapy infl uences the sub-sequent response to chemotherapy and survival. The smaller the largest residual nodule, the more likely it is that the disease will regress with drug therapy8–11 (Table 93-2) and the more likely it is that the patient will live longer12–14 (Table 93-3).

Other disease characteristics have been observed to infl uence outcome (Table 93-4). Shortened survival is associated with older age15 and more poorly differentiated disease. These factors do not, however, affect therapeutic decisions except for the role of histologic grade in limited disease, a role that is discussed later in the chapter. Histologic subtype also affects survival: Patients who have clear cell or mucinous carcinomas have shorter survival, whereas those with tumors of low malignant potential (“borderline carcinomas”) have a markedly better survival. These subtypes constitute fewer than 10% of all celomic epithelial tumors. Because no alternative therapeutic choice offers greater benefi t for mucinous or clear cell carcinomas, these histologic types do not currently infl uence therapeutic deci-sions. Conversely, tumors of low malignant potential do infl uence therapeutic choices, as will be discussed.

TUMORS OF LOW MALIGNANT POTENTIAL. Celomic epithelial tumors of low malignant potential account for approxi-mately 15% of ovarian carcinomas.16 Patients with these lesions tend to be younger than those with invasive ovarian carcinoma (average age at onset: 49 years).17 The sine qua non of the diagnosis is the absence of invasion of the stroma.18 The vast majority of cases display serous or mucinous histology with bilaterality in roughly one third of serous tumors.

Recognition of these tumors is important because both prognosis and management differ greatly, in comparison to standard manage-ment of invasive ovarian carcinomas.19–21 In general, management should begin with an exploratory laparotomy and resection of as much disease as possible. Pathology should be reviewed carefully to ensure that no areas of invasive carcinoma are present.22 After surgery, patients should be observed until such time as the disease begins to

behave in a more aggressive fashion. At that point, chemotherapy may be used, although its effi cacy in this setting is not clear.

EXTRAOVARIAN PERITONEAL SEROUS PAPILLARY CARCINOMA. It has long been recognized that celomic epithelial carcinomas can arise in portions of the peritoneal cavity other than the surface of the ovaries. The Gynecologic Oncology Group (GOG) undertook a study of these extraovarian peritoneal papillary serous carcinomas to determine whether they responded in a fashion similar to that of standard treatment for celomic epithelial carcinomas of the ovary.23 The study of 47 women with these extraovarian celomic epithelial carcinomas showed that when the data are compared with results of treatment of ovarian carcinomas with the same chemo-therapy, similar response rates, surgical complete response rates, and survivals are observed. This is the basis on which these lesions are now included in trials of chemotherapy for ovarian carcinoma.

INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS STAGE. The factor that most infl uences management is the extent of disease at diagnosis (stage). This discus-sion is organized accordingly: A general approach to initial evaluation and surgical management is followed by a discussion of the role of chemotherapy both in previously untreated patients with advanced disease and in patients with recurrent or persistent disease. The man-agement of patients with limited lesions is then considered.

Initial Evaluation and ManagementPatients with celomic epithelial carcinomas generally are fi rst seen with complaints of a full or heavy sensation in the pelvis or with increasing abdominal girth. Unfortunately, these symptoms usually refl ect the presence of advanced disease. Efforts directed to earlier diagnosis have largely been unsuccessful, with the possible exception of the application of certain tools to patient populations that are at high risk for the development of ovarian carcinoma.

HIGH-RISK PATIENTS, SCREENING, AND GENETIC TESTING. Within the past decade, interest in using family history to identify patients who are at high risk of developing ovarian carci-noma has escalated.2,24–26 Data now suggest that women with one fi rst-order relative with ovarian carcinoma have a 3.6-fold higher risk than that of the general population. For those who have two or more relatives with ovarian carcinoma, at least one of whom is a fi rst-order relative, risk is considerably higher, with estimates as great as 50% or better reported but not necessarily substantiated.

Certain hereditary syndromes have been described.3,25 These include hereditary breast and ovarian cancer syndromes associated with changes at chromosome 17q (BRCA1) and at chromosome 13q (BRCA2) and hereditary nonpolyposis colon cancer syndromes

Table 93-2 Impact of Volume of Residual Disease on Pathologic Complete Response to Combination Chemotherapy in Patients with Advanced Ovarian Carcinoma

Regimen Minimal Bulky

PAC (GOG)8,9 45/137 (33%) 13/107 (12%)

PAC (Ehrlich et al.)10 5/17 (30%) 5/39 (13%)

HCAP (Greco et al.)11 18/21 (86%) 3/29 (10%)

CHEX-UP (Young et al.)12 5/14 (36%) 5/37 (14%)

CHEX-UP, cyclophosphamide + hexamethylmelamine + 5-fl uoruracil + cisplatin; HCAP, hexamethylmelamine + cyclophosphamide + doxorubicin + cisplatin; PAC, cisplatin + doxorubicin + cyclophosphamide.

Table 93-3 Impact of Volume of Residual Disease on Survival in Patients with Advanced Ovarian Carcinoma

Regimen Minimal (months) Bulky (months)

PAC (GOG)8,9 42 19

L-PAM (GOG)13,14 33 13

L-PAM, melphalan; PAC, cisplatin + doxorubicin + cyclophosphamide.

Table 93-4 Prognostic Factors in Ovarian Carcinoma

Factor Description

Age Older patients have poorer survival.

Grade Poorly differentiated lesions are associated with poorer survival.

Histologic type Clear cell and mucinous histologies are associated with poorer survival. Tumors of low malignant potential imply a much better survival.

Stage More extensive disease, as refl ected in the FIGO staging system, produces poorer survival.

Volume of disease In patients with stage III disease, larger volume of residual disease leads to poorer survival.


(Lynch syndrome II with an association with colon and endometrial cancers as well), which exhibit hMLH1, hMSH2, and hPMS2 muta-tions. These familial ovarian cancers typically appear at a younger age than does sporadic ovarian carcinoma and, despite pathologic factors that should portend a poor survival, predict a signifi cantly better survival than that associated with sporadic ovarian cancer of the same stage.4,5,25–29 Both hereditary breast/ovarian syndrome and hereditary nonpolyposis colon cancer syndromes appear to be vertically trans-mitted by an autosomal dominant mode, with incomplete pene-trance. Familial ovarian cancer registries have now identifi ed a number of women who either fi t one of these syndromes or have at least one fi rst-order relative with ovarian cancer.

These observations raise at least four signifi cant questions with regard to management. First, should prophylactic oophorectomy be recommended to women who are at high risk? The largest experience with prophylactic oophorectomy comes from the Gilda Radner Familial Ovarian Cancer Registry. To date, 324 women with at least one fi rst-order relative with ovarian cancer have undergone prophy-lactic oophorectomy. The relatively short follow-up evaluation of most of these women shows that in six, celomic epithelial carcinomas of the peritoneal cavity have developed, for an overall rate of 1.8%.30 Although this rate is low, it exceeds the rate of ovarian carcinoma in the general population. Other reports have documented the occur-rence of primary peritoneal neoplasms in women who have previously undergone oophorectomy.31 This fi nding raises questions about the value of prophylactic oophorectomy in preventing the development of celomic epithelial carcinomas. No prospective trials have been conducted to examine this question. The weight of evidence suggests that the procedure should not be routinely recommended until further follow-up is available to determine whether a further signifi -cant increase in the incidence of peritoneal malignancies will occur. The exception to this might be women who have a true hereditary syndrome with a very high risk of developing ovarian carcinoma, although no clinical trial documents the value of prophylactic oopho-rectomy even in this population.32,33

Second, how should patients who are at high risk be monitored? More simply put, do we have valid screening tests? Family history clearly identifi es a high-risk population. Logic dictates that screening leading to early diagnosis would result in a higher cure rate. The problem is the lack of evidence that any monitoring technique yields early diagnosis at a reasonable rate. Both CA-125 and transvaginal sonography have been recommended for screening. Evidence is lacking that CA-125 leads to early diagnosis.4 By contrast, trans-vaginal sonography has proved capable of identifying ovarian carci-noma at a limited stage in two series.5,30 The drawback of the technique is that 15 to 40 laparotomies have to be done to diagnose one case of limited ovarian carcinoma. At least for the present, neither approach can be recommended for routine screening, although selected high-risk patients, with a clear understanding of the atten-dant diffi culties, can be screened with transvaginal sonography.34,35

More recently, new technology has offered some hope of an effec-tive approach to screening for ovarian carcinoma. Investigators at the U.S. National Cancer Institute reported the use of proteomic patterns in serum to identify patients with ovarian cancer.36 In a population of 50 patients with ovarian cancer and 66 patients with nonmalignant disease, the test reportedly had a sensitivity of 100%, a specifi city of 95%, and a positive predictive value of 94% for correctly identifying those with or without ovarian cancer. Unfortunately, the calculation of the positive predictive value did not take into account the preva-lence of the disease in the target population. When this defi ciency is corrected, the true positive predictive value is 1%, not 94%. This is less than the positive predictive value that has been reported for the use of CA-125 alone.37 Before proteomic patterns can be recom-mended to screen for ovarian carcinoma, further retrospective and prospective studies are required.

Third, should patients with positive family histories be offered genetic testing? Approximately 10% of ovarian carcinoma is associ-

ated with inheritance of an autosomal dominant genetic mutation and a resultant strong family history of ovarian carcinoma and certain other associated cancers, such as breast cancer.38 These cases fall into two broad categories. The fi rst is commonly called the breast and ovarian cancer syndrome and is associated with mutations at two loci: BRCA1 on chromosome 17q21 (75% to 90% of breast and ovarian cancer syndrome) and BRCA2 on chromosome 13q12 (10% to 25% of breast and ovarian cancer syndrome). In published series, these mutations account for approximately 7% of ovarian carcinoma. The second is commonly called the hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome and is associated with mutations that include three known genes: hMSH1 (45% to 50% of cases of HNPCC syndrome), hMLH1 (45% to 50% of cases of HNPCC syndrome), and hPMS2 (fewer than 5% of cases of HNPCC syn-drome). These lesions account for approximately 3% of ovarian carcinoma.

Although the risk of inheriting a mutation from a parent carrier is 50%, the actual risk of developing a cancer varies from as high as 80% to 85% to as low as 16% for different mutations.38 This vari-ability of risk and the previously discussed controversy about the effi cacy of prophylactic oophorectomy raise questions about the role of genetic testing in individuals with family histories of ovarian car-cinoma. The American Society of Clinical Oncology recently issued an updated policy statement about genetic testing and cited three criteria for determining when genetic testing should be offered (Table 93-5).39 Such testing should be done only if counseling before and after the test is available to discuss such issues as the risks and ben-efi ts of genetic testing as well as the effi cacy, or lack thereof, of interventions that are prompted by the tests.

Fourth, might interventions other than prophylactic oophorec-tomy be effi cacious in high-risk women? Oral contraceptives have been reported to reduce the risk of ovarian carcinoma by as much as 50% after prolonged (>10 years) use.40–42 At least some reports suggest that the effects of such oral contraceptive use on cancer incidence differ between women with positive family histories and those with a true hereditary syndrome associated with BRCA1 or BRCA2,43,44 with an actual increase in breast cancer risk among those BRCA1 or BRCA2 women who take tamoxifen for chemoprevention.45 Although this implies a need for caution, at least one study reports that pro-longed oral contraceptive use reduces the risk of ovarian cancer in women with pathogenic mutations in the BRCA1 or BRCA2 gene,46 whereas another study shows no impact, negative or positive, of oral contraceptives on ovarian cancer risk.47 In the absence of clear-cut evidence for a benefi t, the role of oral contraceptives to prevent ovarian cancer is not established; hence, they should not be used for such a purpose at present.

Use of other hormones also has been evaluated. At least some reports show a direct correlation between postmenopausal estrogen-replacement therapy and risk for development of ovarian carcinoma with a relative risk ranging from 1.59 to 2.81.48–50 This correlation

Table 93-5 Criteria for Offering Genetic Testing*

• Individual has personal or family history features suggestive of a genetic cancer susceptibility condition.

• Test can be adequately interpreted.

• Results will aid in diagnosis or infl uence the medical or surgical management of the patient or family members at hereditary risk of cancer.

*Genetic testing must include pretest and post-test counseling, including a discussion of the risks and benefi ts of testing and the interventions prompted by the testing.

Data from ASCO Working Group on Genetic Testing for Cancer Susceptibility: American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 2003;21:2397–2406.


appears to hold only for patients who take estrogen only and not for those who take a combined estrogen/progesterone regimen. Other studies have failed to fi nd such a correlation.51 In women who are survivors of ovarian cancer, no evidence has been found that estrogen use increases the likelihood of relapse or shortens survival.52

Finally, one report assessed the relationship between raloxifene and risk for ovarian carcinoma.53 This study was actually a meta-analysis of seven randomized placebo-controlled trials of raloxifene involving a total of 9837 women. The relative risk associated with the use of raloxifene was 0.50. This suggests that there is no adverse effect, but it does not prove a benefi cial effect.

In summary, no scientifi cally proven screening approach exists for ovarian carcinoma. In addition, no clear role is seen for the use of interventions in the high-risk patient, although the ovarian consensus statement recommends the use of screening with transvaginal sonog-raphy and prophylactic oophorectomy in women with true hereditary syndromes. The basis for this recommendation is expert opinion and not appropriate defi nitive trials.

INITIAL EVALUATION. The initial evaluation of patients with suspected ovarian carcinoma, after the usual history, physical exami-nation, laboratory testing, and CA-125, should be directed toward a detailed assessment of the abdominal cavity. Although a variety of imaging techniques for the abdominal cavity are now available, including sonography, computed tomography (CT), magnetic reso-nance imaging (MRI), and special isotopic scanning techniques, none provides the level of detailed study necessary for accurate staging of ovarian carcinoma. At the very least, CT scanning of the abdominal cavity, chest radiography, and bone scanning should be done.

Unless this evaluation demonstrates evidence of disease outside the abdominal cavity, exploratory laparotomy is an essential part of the initial evaluation of the patient. The laparotomy should be done through an incision that is adequate to evaluate the entire peritoneal surface, including the undersurface of the diaphragm and the right paracolic gutter, as well as the para-aortic lymph nodes. If no evidence of gross disease is found outside the pelvis, multiple biopsies of the peritoneal surface should be obtained. Many patients in whom the disease is apparently confi ned to the pelvis will have evidence of microscopic seeding of the abdominal peritoneum in one or more biopsies. At the conclusion of this procedure, accurate staging of the disease will have been accomplished and will serve to direct further management.

Therapeutic Role of SurgeryThe volume of residual disease is related both to response to chemo-therapy and to survival. As a result, the standard of care of patients with ovarian carcinoma with disease that is confi ned to the abdomi-nal cavity is to resect as much disease as possible at initial laparotomy. This approach applies to patients with limited disease that can be completely removed as well as to patients with advanced disease that can be only partially resected. Data on which this approach has been based are retrospective analyses showing that patients who initiate chemotherapy with small-volume disease (no nodule larger than 2 cm in diameter remaining in the abdominal cavity) have both a higher frequency of pathologic complete response and a superior survival with chemotherapy8,10–14,54 (see Tables 93-2 and 93-3).

Several major questions have been raised about the value of cyto-reductive surgery in patients with advanced disease that is not ame-nable to a “curative” resection. First and foremost, detractors have pointed out that approximately one half of the population of patients with small-volume disease consists of patients with stage IIIA or IIIB disease—patients who already have small-volume disease at the time the abdomen was opened without any surgical cytoreduction. Accord-ing to this line of reasoning, the improved results in small-volume disease relate entirely to this portion of the patients who presumably have biologically less aggressive disease. A retrospective analysis of a GOG database of patients with small-volume disease provided some

support for this view.14 Operative notes on the population in the database were reviewed to separate the patients into two groups: those who had stage IIIA or IIIB disease and those who had stage IIIC disease that was successfully surgically cytoreduced to small-volume residual disease. Patients who required surgical cytoreduction had an inferior survival in comparison with those who already had small-volume disease at the time the abdomen was opened. Although this investigation shows a difference between these two patient groups, it does not prove that surgical cytoreduction has no value, in the absence of a population for comparison in which chemotherapy was started with large-volume disease.

The only way to address the question of the value of cytoreductive surgery is to conduct a randomized trial in which all patients are randomized to surgical cytoreduction or no surgical cytoreduction and are then analyzed by intent to treat. No such study assessing initial surgical cytoreduction has been successfully completed. However, two prospective randomized phase III trials have evaluated the role of interval cytoreduction55,56 (Table 93-6).

In a European trial by the European Organization for Research and Treatment of Cancer,55 patients with advanced disease received three courses of cisplatin plus cyclophosphamide and were then ran-domized to receive either three more courses of the same chemo-therapy or interval cytoreductive surgery, followed by three more cycles of cisplatin plus cyclophosphamide. The group that received interval cytoreductive surgery demonstrated a statistically signifi -cantly superior progression-free and overall survival.

A GOG study56 took patients with stage IIIC disease who had undergone an aggressive attempt at initial surgical cytoreduction and still had large-volume disease remaining and randomized them to either six cycles of paclitaxel plus cisplatin or three cycles of paclitaxel plus cisplatin followed by interval surgical cytoreduction and then three more cycles of paclitaxel plus cisplatin. This trial showed no difference between the two study arms.

The most rational interpretation of these two studies rests on an understanding of the differences in study execution. In the European trial, initial surgery was performed by surgeons with varied training backgrounds and, in many instances, probably did not represent true aggressive attempts at surgical cytoreduction. In the GOG study, conversely, virtually every patient underwent an initial attempt at aggressive surgical cytoreduction by a trained gynecologic oncologist. What the two trials show is that patients with a less than optimal initial attempt at surgical cytoreduction benefi t from interval bulk reduction, whereas those who undergo an aggressive initial surgery

Table 93-6 Results of Two Studies of Interval Surgical Cytoreduction

Parameter All IDS No IDS

EORTC STUDY55

Patients 408 150 149

Response after three cycles

Complete response rate 17%

Partial response rate 55%

Progression-free survival 15 months 12.5 months

Survival 27 months 19 months

GOG STUDY56

Patients 425 216 209

Progression-free survival 10.5 months 10.8 months

Survival 32 months 33 months

IDS, interval debulking surgery.


and still have large-volume disease do not benefi t from interval surgery.

On the basis of the weight of current evidence, patients, except for those with obvious stage IV disease, should undergo an initial laparotomy with intent to carry out maximal surgical cytoreduction. This should improve response to chemotherapy as well as survival. Those who have a less aggressive initial operation should be consid-ered for interval surgical cytoreduction.

Management of Advanced DiseasePatients with stage III or IV disease, on completion of initial surgery, should receive systemic therapy for control of disease. For-tunately, celomic epithelial carcinoma is a chemosensitive disease—hence the signifi cant therapeutic options for patients with advanced disease.

ACTIVE AGENTS. A number of cytotoxic agents as well as bio-logic and hormonal agents have activity against celomic epithelial neoplasms6–8,10–15,24–26,54 (Table 93-7). Response rates that have been reported for each of the active agents vary as a result of several factors: (1) volume of residual disease in the patient population at the initia-tion of therapy, (2) dose and schedule of the agent under study, and (3) whether the patient population has received prior cytotoxic therapy to which the neoplasm has become clinically resistant, as evidenced by clinical progression during therapy. With the reserva-tion that these factors cannot be sorted out in many of the single-agent studies that have been reported, it is possible to point to certain active cytotoxic drugs of major interest: the platinum compounds, the taxanes, the mustard-type alkylating agents, the anthracyclines (including pegylated liposomal encapsulated doxorubicin), the topoi-somerase I inhibitors, oral etoposide, gemcitabine, vinorelbine, and hexamethylmelamine. In addition, among hormonal and biologic agents, interferon-α, interferon-γ, and tamoxifen display activity. Among these, the platinum compounds and paclitaxel deserve spe-cifi c comment because of their current major relevance to front-line therapy for newly diagnosed disease.

Platinum Analogs. The platinum analogs are the most system-atically evaluated and active cytotoxic drugs. Cisplatin demonstrates clear-cut activity in patients with no prior chemotherapy, as well as in those who are refractory to prior alkylating agents.57–61 Carbopla-tin produces less neurotoxicity and nephrotoxicity than does cispla-tin, in exchange for thrombocytopenia as the dose-limiting adverse effect, and exhibits activity similar to that seen with cisplatin.61

Taxanes. Paclitaxel, a diterpenoid extracted from the bark of Taxus brevifolia (the Western yew tree), acts to enhance tubulin polymeriza-tion and microtubule stability and hence to produce microtubule bundling throughout the cell.62 This stability leads to inhibition of the dynamic reorganization of the microtubular structure of the cell before cell division. This unique mechanism of action accounts for the apparent lack of cross-resistance between this drug and the plat-inum analogs.

Paclitaxel demonstrated signifi cant activity in four phase II trials in patients who had received prior platinum-based combination che-motherapy63–66 (Table 93-8). In two of the four trials, responses were documented in both platinum-sensitive and platinum-resistant patients. Adverse effects, including myelosuppression, hypersensitiv-ity reactions, and signifi cant arrhythmias requiring continuous cardiac monitoring during therapy, were frequent and severe but manageable and resulted in no deaths attributable to toxicity. The occurrence of signifi cant anaphylactic episodes in the initial experience with the drug led to the use of premedication with steroids and H1 and H2 blockers in the phase II trials, with the resultant virtual elimination of signifi cant hypersensitivity reactions. The dose-limiting toxicity is myelosuppression, which, with 24-hour infusions, is severe but brief.

The other taxane, docetaxel, has been less extensively evaluated.67–71 Activity appears to be similar to that of paclitaxel. Whether toxicity differs signifi cantly awaits publication of random-ized trials that have evaluated this, but on the basis of data available to date, docetaxel could be less neurotoxic but more myelosuppressive.

In summary, a variety of drugs have activity against ovarian car-cinoma. The most important of these are the platinum compounds and the taxanes. Other agents of particular interest exhibit the ability to obtain responses in patients who have progressed on paclitaxel-platinum front-line therapy and include oral etoposide, topotecan, tamoxifen, gemcitabine, navelbine, ifosfamide, and possibly doxil.

COMBINATION CHEMOTHERAPY. An extensive series of questions had to be addressed to evolve effective regimens for the treatment of advanced ovarian carcinoma after surgical cytoreduc-

Table 93-7 Active Single Agents in Celomic Epithelial Carcinoma of the Ovary*

PATIENTS

Drug N Percent†

Alkylating agents57 1371 33

Ifosfamide57,213–215 98 15

Cisplatin57–59 190 32

Carboplatin57,60,61 82 24

Oxaliplatin243 45 16

Paclitaxel63–66 157 35

Docetaxel67–71 423 29

Doxorubicin57 102 33

5-Fluorouracil57 126 29

Methotrexate57 34 18

Mitomycin57 49 16

Hexamethylmelamine175–182 296 23

Topotecan121,122,183–185 352 17

Irinotecan186 29 17

Pegylated liposomal doxorubicin119,120,187–190 557 18

Oral etoposide118,191–194 193 28

Gemcitabine123–125 109 16

Vinorelbine195–199 156 22

Dihydroxybusulfan57 26 27

Galactitol57 39 15

5-Fluorouracil/leucovorin200 44 14

Mitoxantrone201 33 15

Treosulfan202 80 19

Oral trofosfamide203 31 16

Progestins57 176 12

Tamoxifen204–206 141 14

Prednimustine57 36 28

Mifepristone207 34 26

Interferon-α57 21 19

Interferon-γ57 14 29

Trastuzumab127 41 7

*Response rate >15%.†Response rate percentage.Data from references 48–71, 120–125, 175–200, 213–215, and 243.


tion. Over the last two decades, the major themes that have keyed the development of current therapy include the evolution of plati-num-based combination chemotherapy, assessment of the value of dose intensity, the defi ning of the role of paclitaxel, the determination of which platinum compound to use, and the ascertainment of the role, if any, of maintenance or consolidation therapy for those who respond to front-line therapy. Each of these issues is discussed, and a brief look at other signifi cant issues follows.

Evolution of Platinum-based Combination Chemo-therapy. A multitude of trials have made a fi rm case for the value of combination chemotherapy compared with treatment with single agents. The most signifi cant of these studies were three large, rando-mized trials.8,9,54 The conclusions from these three GOG studies, supported by other trials of systemic therapy, formed the basis for practice at the end of the 1980s.72

The fi rst two GOG trials were successive studies in patients with bulky advanced disease8,54 (Table 93-9). The fi rst of these (GOG Protocol 22) compared melphalan alone with either melphalan plus hexamethylmelamine or doxorubicin plus cyclophosphamide.54 The only statistically signifi cant difference that was observed was a greater

clinical complete response rate in the patients who were treated with doxorubicin plus cyclophosphamide, as compared with those who received melphalan alone. This was the basis for selection of the two-drug combination as the control arm of the second trial (GOG Protocol 47), which compared doxorubicin plus cyclophos-phamide with the same two drugs plus cisplatin.8 Results showed a statistically signifi cant improvement in clinical complete response rate, overall response rate, progression-free interval, and survival in the patients who were treated with the three-drug cisplatin-based combination.

The third critical study (GOG Protocol 52), in patients with minimal residual disease (defi ned as patients with stage III disease and no nodules larger than 1 cm in diameter), compared the three-drug combination with cisplatin plus cyclophosphamide9 (Table 93-10). The pathologic complete response rates, as documented at second-look laparotomy, were not signifi cantly different, nor were any differences noted in progression-free interval or survival.

By the late 1980s, these three trials made a strong case for the combination of cisplatin plus cyclophosphamide as the standard che-motherapy for advanced or recurrent ovarian carcinoma. Four other studies focusing on the substitution of carboplatin for cisplatin expanded somewhat the meaning of standard chemotherapy.73–76 These studies compared the relative effi cacy of cisplatin-based versus carboplatin-based regimens (Table 93-11). The trial of the Southwest Oncology Group compared cyclophosphamide (600 mg/m2) plus either cisplatin (100 mg/m2) or carboplatin (300 mg/m2) in patients with bulky stage III or IV disease.73 The study showed no signifi cant differences between the two regimens with regard to response rate, progression-free interval, or survival. The toxicities of the two regi-mens was different, the cisplatin regimen producing greater adverse effects. The National Cancer Institute of Canada trial compared essentially the same regimens, except for a slightly lower cisplatin dose of 75 mg/m2, with similar results.75

The study conducted by the Gynaecological Cancer Cooperative Group for the European Organization for Research and Treatment of Cancer compared two four-drug combinations consisting of cyclo-phosphamide, doxorubicin, and hexamethylmelamine with either cisplatin or carboplatin.74 No signifi cant differences were noted with regard to response rate, progression-free interval, or survival.

The trial that was conducted by investigators at the Mayo Clinic is fl awed by a major design problem.76 The dose intensity of carbo-platin is well below that of cisplatin in the other arm, making it diffi cult to determine whether the differences in progression-free interval and survival favoring the cisplatin regimen were related to a different platinum compound or to a lower dose intensity of the carboplatin. This study has two other features that distinguish it from the other three trials. The number of patients in the trial is consider-ably smaller and included 65% with small-volume disease.

Table 93-8 Phase II Trials of Taxol as Salvage Therapy in Patients with Ovarian Carcinoma

Investigators No. of Patients Response Rate (%)

McGuire et al.65 40 30

Sensitive 15 40

Resistant 25 24

GOG (Thigpen et al.)63 43 35

Sensitive 16 44

Resistant 27 30

Einzig et al.64 30 20

Kohn et al.66 44 48

Table 93-9 Results of Two GOG Studies of Combination Chemotherapy in Large-Volume Advanced Ovarian Carcinoma

GOG PROTOCOL 22 GOG PROTOCOL 47

Parameter L-PAM AC AC PAC

Patients 64 72 120 107

CRR 20% 32% 26% 51%

Total response (CRR + PRR)

37% 49% 48% 76%

CRR 4/23 13/39

PCR/total 3% 12%

Duration 8 months 10 months 9 months 15 months

Median survival 12 months 14 months 16 months 20 months

AC, doxorubicin (50 mg/m2) plus cyclophosphamide (500 mg/m2), both intravenous, every 3 weeks, for eight courses; CRR, complete response rate; L-PAM, melphalan (0.2 mg/kg/day orally), for 5 days every 4 to 6 weeks, for 10 courses or 18 months; PAC, cisplatin (50 mg/m2) plus doxorubicin and cyclophosphamide as in AC, all intravenous, every 3 weeks, for eight courses; PCRR, pathologic complete response rate; PRR, partial response rate.

Data from references 8 and 54.

Table 93-10 Results of a GOG Study of Minimal Residual Stage III Ovarian Carcinoma

Parameter PAC PC

Patients 173 176

Early recurrence 19 30

Refused second look 36 37

Residual disease 73 67

Pathologic complete response (%) 45 (26%) 42 (24%)

PAC, cisplatin (50 mg/m2) plus doxorubicin (50 mg/m2) plus cyclophosphamide (500 mg/m2), all intravenous every 3 weeks, for eight cycles; PC, cisplatin (50 mg/m2) plus cyclophosphamide (1000 mg/m2), both intravenous, every 3 weeks, for eight cycles.

Data from reference 9.


In summary, these seven randomized trials8,9,54,73–76 defi ned four major concepts about standard chemotherapy for advanced ovarian carcinoma as of 1990. First, combination chemotherapy is superior to single-agent therapy. Second, platinum-based combination che-motherapy offers signifi cant advantages over non-platinum-based regimens. Third, carboplatin offers certain advantages over cisplatin in terms of altered and more tolerable toxicity with no diminution in effi cacy. Finally, two-drug combinations of a platinum compound and an alkylating agent offer benefi ts that are equivalent to those that are achieved with more complex regimens. Three major themes dominated clinical research in the 1990s in attempts to improve further on systemic therapy for advanced disease: dose intensity, the

development of combinations of a platinum compound and pacli-taxel, and the choice of platinum compound.

Dose Intensity. Although debated to some extent, the concept of the importance of dose intensity to the success of chemotherapy in the management of celomic epithelial carcinomas of the ovary has been generally well accepted among oncologists. In vitro data support the effi cacy of increasing drug levels in enhancing cell kill in cultures of ovarian cancer cells.77 In patients who have experienced recurrence after prior platinum-based chemotherapy for ovarian carcinoma, responses to higher doses of the same platinum compound78 or to greater exposure as a result of intraperitoneal administration79 have been cited as evidence that enhanced dose can result in response when lower doses have failed. The use of hypertonic saline to permit esca-lation of cisplatin dose to 200 mg/m2 per course in combination with cyclophosphamide has been reported to yield high response rates that are superior to those achieved with lower-dose regimens.80 Finally, meta-analyses have been reported to show a correlation between dose intensity of platinum and response.81,82 These kinds of evidence have provided strong support for the value of dose intensity in the treat-ment of ovarian carcinoma.

At fi rst glance, the case for dose intensity would appear to be very solid. However, several signifi cant questions remain. First, with regard to reported responses of “refractory” ovarian carcinoma to higher doses of drug, it is becoming increasingly apparent that such responses occur not in patients whose disease progresses with the lower-dose therapy but rather in patients in whom recurrent disease develops some time after they have completed prior therapy. For example, Ozols and colleagues83 reported a series of 30 patients with “refractory” ovarian carcinoma who were treated with high-dose car-boplatin (800 mg/m2 per 35 day cycle). Although eight responses were observed, Ozols and colleagues also noted that “no responses were observed from high-dose carboplatin in [9] patients who had progres-sive disease during prior therapy with a cisplatin-based regimen.” Similar observations emerge from second-line phase II studies of intraperitoneal chemotherapy. In other words, patients whose tumors are clinically resistant to platinum-based chemotherapy do not benefi t from treatment with higher doses of the same or similar drugs.

Second, the reported improvement in response rate that was seen with high-dose cisplatin regimens has been reappraised in light of the signifi cant neurotoxicity that emerged from these studies.80 Although this is not a randomized comparison, it is instructive to compare the results of GOG studies with regimens using 50 mg/m2 of cisplatin in the combination regimen with results of using high-dose cisplatin. In patients with minimal residual stage III disease (no nodule >2 cm remaining), the high-dose regimen (cisplatin 200 mg/m2 plus cyclo-phosphamide 1000 mg/m2 repeated every 4 weeks) yielded a patho-logic complete response rate of 38%,80 whereas the GOG regimen (cisplatin 50 mg/m2 plus cyclophosphamide 1000 mg/m2 every 3 weeks) yielded a pathologic complete response rate of 30%.9 In patients with bulky stage III or stage IV disease, the high-dose regimen (the same as was noted earlier) yielded a pathologic complete response rate of 12%,80 whereas the GOG regimen (cisplatin 50 mg/m2 plus doxorubicin 50 mg/m2 plus cyclophosphamide 500 mg/m2 repeated every 3 weeks) yielded a pathologic complete response rate of 11%.8 Thus, no evidence exists that the high-dose cisplatin regimen yielded a superior result, even though the dose intensity of the plat-inum compound as a function of dose and time was 3 times as high.

Third, although a dose-intensity meta-analysis conducted by Levin and Hryniuk81 indeed documented a dose-response relation for cisplatin, this relation held only over the range of 0.4 to 0.8. For purposes of this meta-analysis, the “standard” regimen used a cispla-tin dose equivalent to 15 mg/m2 per week. The dose-response rela-tion for cisplatin thus held over a range of 6 mg/m2 per week to 12 mg/m2 per week. This equates to a highest dose of 36 mg/m2 every 3 weeks. This meta-analysis thus supplied no support for the use of

Table 93-11 Randomized Trials Comparing Cisplatin-based with Carboplatin-based Combination Chemotherapy in Advanced, Predominantly Large-Volume Ovarian Carcinoma

Study and RegimenResponse Rate (%) Survival

ALBERTS ET AL73 (342 PATIENTS)

Carboplatin (300 mg/m2), every 4 weeks CCR, 34 20 months

Cyclophosphamide (600 mg/m2), every 4 weeks

PCR, 12

Cisplatin (100 mg/m2), every 4 weeks CCR, 27 17 months


PCR, 7

TEN BOKKEL HUININK ET AL74 (339 PATIENTS)

Cyclophosphamide (100 mg/m2 PO), days 14–28

CCR, 24 107 weeks

Hexamethylmelamine (150 mg/m2 PO), days 14–28

Doxorubicin (35 mg/m2 IV), day 1

Carboplatin 350 mg/m2 IV), day 1

Cyclophosphamide (100 mg/m2 PO), days 14–28

CCR, 23 108 weeks

Hexamethylmelamine (150 mg/m2 PO), days 14–28

Doxorubicin (35 mg/m2 IV), day 1

Cisplatin (20 mg/m2 IV), days 1–5

PATER ET AL75 (447 PATIENTS)

Carboplatin (300 mg/m2), every 4 weeks PCR, 13 24 months


Cisplatin (75 mg/m2), every 4 weeks PCR, 18 23 months


EDMONDSON ET AL76 (103 PATIENTS)

Carboplatin (150 mg/m2), every 4 weeks 20 months


Cisplatin (60 mg/m2), every 4 weeks 27 months


CCR, clinical complete response; PCR, pathologic complete response.


doses higher than those used by the GOG in their relatively low-dose cisplatin regimens.

An extended meta-analysis by the same investigators82 included more studies in the higher dose range. This study demonstrated the superiority of combination chemotherapy over single agents and also noted a correlation between response and cisplatin dose up to a level of 25 mg/m2/week (or 75 mg/m2 every 3 weeks). In this analysis, the investigators also suggested that total dose delivered might be as important as dose intensity. Neither meta-analysis, however, offered any evidence supporting the importance of total dose nor of a cor-relation between response and dose intensity for any drug other than cisplatin; nor was either meta-analysis able to support the importance of cisplatin dose intensity beyond 25 mg/m2/week.

These considerations raise serious questions about the value of dose-intense regimens in the treatment of ovarian carcinoma. Address-ing these issues appropriately requires randomized prospective trials. Eight such studies have been reported (Table 93-12).84–91

Studies Showing No Advantage from Dose Intensity. GOG Protocol 9784 randomized patients with large-volume disease defi ned

as having nodules larger than 1 cm or stage IV disease to receive either eight cycles of cisplatin (50 mg/m2) plus cyclophosphamide (500 mg/m2) every 3 weeks or four cycles of cisplatin (100 mg/m2) plus cyclophosphamide (1000 mg/m2) every 3 weeks. A total of 458 eligible patients was randomized, of whom 130 had measurable disease. Prognostic features were evenly distributed between the two treatment arms. If the prescribed low dose is assigned a dose intensity of 1.0, the actual received dose intensity for the low-dose regimen was 0.95, and that for the high-dose regimen was 1.90. A twofold difference in dose intensity was thus achieved. No difference in total dose received was noted between the two arms as planned.

With regard to response, of 60 patients assigned to the high-dose arm, 19 (32%) achieved a clinical complete response, 16 (27%) achieved a partial response, 18 (30%) had stable disease, and 7 (12%) experienced increasing disease. The overall response rate for the high-dose arm was thus 59%. Of 70 patients assigned to the low-dose arm, 27 (39%) achieved a clinical complete response, 18 (26%) achieved a partial response, 24 (34%) had stable disease, and 1 (1%) experi-enced increasing disease. The overall response rate for the low-dose arm was thus 65%. No statistically signifi cant differences were noted between the two arms with regard to response.

With regard to progression-free interval and survival, all 458 patients were included in the analysis. Median progression-free inter-vals for the low-dose and high-dose regimens were 12 and 13 months, respectively, whereas median survivals were 24 and 21 months, respectively. No signifi cant differences were observed in either parameter.

The high-dose regimen was associated with more severe or life-threatening (grade III or IV) toxicity, which included more leukope-nia (82% versus 40%), more thrombocytopenia (22% versus 1%), more anemia (9% versus 2%), more nausea and vomiting (16% versus 3%), and more nephrotoxicity (5% versus 1%). Very few cases of grade III or IV neurotoxicity were seen.

This GOG study was designed as a pure dose-intensity study only in patients with large-volume disease. No evidence exists that a twofold increase in dose intensity yields any greater patient benefi t over the range of doses used in this trial for patients with large-volume disease, but it is clear that the higher-dose regimen was more toxic.

A Gruppo Interregionale Collaborativo in Ginecologia Onco-logica trial86 randomized 306 patients with advanced disease to either cisplatin 75 mg/m2 every 3 weeks for six cycles or cisplatin 50 mg/m2 weekly for 9 weeks. The actual received dose intensity of the high-dose regimen was twice that of the low-dose regimen, and no differ-ences existed in the total dose delivered in either arm of the trial. In contrast to the GOG study, 45% of the patients in this study had small-volume advanced disease. No signifi cant differences were observed between the arms with regard to pathologic complete response (24% high-dose versus 28% low-dose), progression-free interval (21 versus 18 months), and survival (36 versus 33 months). Like the GOG study, this was a trial of pure dose intensity, because each regimen delivered the same total dose of drug. Also like the GOG trial, this study provides no support for the importance of dose intensity over the range of cisplatin dose intensity from 25 mg/m2/week to 50 mg/m2/week.

A North-West Oncology Group trial87 randomized 145 patients with large-volume advanced disease to receive cyclophosphamide 600 mg/m2 plus epirubicin 60 mg/m2 plus either cisplatin 50 mg/m2 or cisplatin 100 mg/m2 every 4 weeks for six cycles. In contrast to the GOG and Gruppo Interregionale Collaborativo in Ginecologia Oncologica trials, this study called for the delivery of twice as much total dose of cisplatin in the high-dose regimen. Actual received dose intensity achieved a 2 : 1 ratio between the high-dose and low-dose regimens and evaluated the range of cisplatin dose intensity from 12.5 mg/m2/week to 25 mg/m2/week. No signifi cant differences were noted with regard to clinical response (57.5% high-dose versus 61.1% low-dose), pathologic complete response (9.6% high-dose versus

Table 93-12 Eight Randomized Trials of Platinum Dose Intensity in Advanced Ovarian Carcinoma

Trial Platinum DIResponse Rate (%) Survival

SHOWING NO DIFFERENCE

GOG84 Cisplatin, 16.7 mg/m2/week

65 21 months

Cisplatin, 33.3 mg/m2/week

59 24 months

GICOG86 Cisplatin, 25 mg/m2/week

61 33 months

Cisplatin, 50 mg/m2/week

66 36 months

GONO87 Cisplatin, 12.5 mg/m2/week

61 24 months

Cisplatin, 25 mg/m2/week

58 29 months

London88 Carboplatin, AUC 6 57 HR: 0.91

Carboplatin, AUC 12 63

Danish89 Carboplatin, AUC 8 33% 3 years

Carboplatin, AUC 4 30% 3 years

Austrian90 Cisplatin, 25 mg/m2/week

42 38 months

Cis, 25 mg/m2 + Carbo 75 mg/m2/week

39 42 months

SHOWING A DIFFERENCE

Scottish85 Cisplatin, 16.7 mg/m2/week

34 27% 4 years

Cisplatin, 33.3 mg/m2/week

61 32% 4 years

Hong Kong91 Cisplatin, 15–20 mg/m2/week

30 30% 3 years

Cisplatin, 30–40 mg/m2/week

55 60% 3 years

DI, dose intensity; HR, hazard ratio.Data from references 84–91.


18.1% low-dose), progression-free interval (18 months high-dose versus 13 months low-dose), and survival (29 months high-dose versus 24 months low-dose). The high-dose regimen was clearly more toxic. The trial provides no support for the importance of either dose intensity or total dose over the range of cisplatin dose intensity that was tested (12.5 mg/m2/week to 25 mg/m2/week).

A London GOG trial88 randomized 241 patients with either small-volume or large-volume advanced disease to single-agent car-boplatin dosed to an area under the curve (AUC) of either 6 for six courses or 12 for four courses at 4-week intervals. In the high-dose arm, dose intensity was doubled, and total dose increased by 22%. No signifi cant differences were noted with respect to response (63% high-dose versus 57% low-dose), progression-free interval (hazard ratio, 0.98), and survival (hazard ratio: 0.91). This trial also provides no support for the importance of dose intensity or total dose over the range that was tested.

In a Danish Ovarian Cancer Group trial,89 Danish investigators randomized 222 patients with advanced ovarian carcinoma to carbo-platin dosed to an AUC of either 4 or 8 every 4 weeks for six cycles. No differences were observed with respect to pathologic complete response or survival.

An Austrian trial90 approached the problem of platinum dose intensity by combining cisplatin and carboplatin. A total of 253 patients with stages IC to IV disease were randomized either to cis-platin 100 mg/m2 plus carboplatin 300 mg/m2 or to cisplatin 100 mg/m2 plus cyclophosphamide 600 mg/m2 monthly for six cycles. Actual received dose intensity for platinum was 1.6-fold greater with the cisplatin/carboplatin regimen. The platinum-intensifi ed regimen produced more myelosuppression, ototoxicity, and gastrointestinal toxicity. The cisplatin/carboplatin regimen produced a response rate of 39%, a complete response rate of 26%, a progression-free median survival of 22 months, and an overall median survival of 42 months. These results were not signifi cantly different from those that were seen with the cisplatin/cyclophosphamide regimen: 42% response rate, 26% complete response rate, 25-month median progression-free survival, and 38-month median overall survival. This trial thus failed to confi rm an advantage for a 1.6-fold increase in platinum dose intensity.

These observations contradict the dogma that higher-dose sched-ules yield better results. Several possible explanations may be found. First, total dose instead of dose intensity could be important. At least four of the six studies, however, used differences in both dose inten-sity and total dose and showed no advantage. Second, dose intensity may be relatively ineffective in large-volume disease and still yield better results in patients with small-volume disease. All but the GOG trial, however, included patients with small-volume disease, with no advantage noted in the small-volume subset. Third, a twofold increase in dose intensity may be too small to permit observation of differ-ences. Finally, and perhaps most devastatingly, once a certain thresh-old has been reached, further escalation in dose intensity may yield no further benefi t.

Studies Showing an Advantage for Dose Intensity. A study from the Scottish Gynaecology Cancer Trials Group85 randomized 159 patients with stages IC to IV disease to cyclophosphamide 750 mg/m2 plus either cisplatin 50 mg/m2 or cisplatin 100 mg/m2 every 3 weeks. Actual received dose intensity for the higher-dose regimen versus the lower-dose regimen was 1.8 to 1. The lower-dose regimen produced signifi cantly less neurotoxicity. At 4 years of follow-up, 32% of those receiving the higher-dose regimen were alive compared to 27% of those on the lower-dose regimen. The ratio of deaths among those receiving the higher-dose regimen versus that of those receiving the lower-dose regimen was 0.52 at 2 years and 0.68 at 4.75 years. These results suggest that in contrast to results in the previous fi ve studies, an advantage that diminished with time occurred for the higher-dose regimen. The investigators’ conclusion was that the optimal dose of cisplatin would be 75 mg/m2 every 3 weeks.

This trial has major problems. First, 49 (31%) of the 159 patients had stage IC or II disease. The heterogeneous patient population resulting from the inclusion of these limited-disease patients makes interpretation of results very diffi cult, especially when one considers the relatively small total number of patients in the study. Second, the actual difference in 4-year survival of less than 6% is not impressive; and the relative death rate of the higher-dose regimen versus the lower-dose regimen after the fi rst 2 years is 1.30. The overall advan-tage for the higher-dose regimen is signifi cant only at P = 0.061. Finally, the choice of 75 mg/m2 every 3 weeks as the optimal dose of cisplatin does not follow from the results of the study, which did not deal with the recommended dose.

A Hong Kong trial91 is the smallest of the randomized studies, with only 50 patients entered. The patient population is not well characterized. Cisplatin doses on the two regimens were 60 mg/m2 and 120 mg/m2, respectively. The higher-dose regimen yielded a response rate of 55% and a 3-year survival rate of 60% as compared with lower-dose results of a response rate of 30% and a 3-year survival rate of 30%. Even though these results suggest that the higher-dose regimen offered an advantage, the size of the trial and the poor char-acterization of the patient population make the conclusions less convincing.

Conclusions Regarding Dose Intensity. In conclusion, the case for the use of regimens with greater dose intensity, especially greater dose intensity of the platinum compound, is unclear at best. To understand the apparent contradiction between in vitro data and clinical results, one must look to certain basic principles on which the concept of the value of dose intensity is based. By using a somatic mutation theory for drug resistance, Coldman and Goldie92 postulated that the failure to cure a patient of malignancy results from either the failure to eradicate all drug-sensitive cells because of insuffi cient drug dose intensity or the emergence of cells that were resistant to the drug regimen. Enhanced dose intensity functions in two ways to improve the likelihood of cure: (1) eradicating all sensitive cells and (2) eliminating cells that are likely to mutate to resistance before such mutations take place. No evidence exists that drug resistance can be overcome in vivo by enhancement of dose intensity over the range that can be clinically achieved.

If these considerations are translated into simple terms, increasing dose intensity yields increasing clinical response rates up to the point at which all sensitive cells have been eradicated. Further increase in dose intensity cannot be expected to yield further improvement in results over the currently achievable range. The only basis on which an increased cure rate can be expected from dose escalation is that the drugs are started before the emergence of resistant cells, an unlikely circumstance in patients with advanced disease.

Role of PaclitaxelPaclitaxel, a new agent with a unique mechanism of action, has sig-nifi cant activity in ovarian carcinoma as second-line therapy with a response rate in excess of 20% in patients, regardless of prior response to platinum-based chemotherapy. These results marked paclitaxel as probably non-cross-resistant with the platinum compounds and alkylating agents and suggested a major role for the drug in fi rst-line treatment of ovarian carcinoma. These data prompted four major randomized trials testing paclitaxel in front-line combination chemotherapy.

GOG Protocol 11193 randomized 386 newly diagnosed patients with large-volume advanced ovarian carcinoma to six cycles of cis-platin 75 mg/m2 plus either cyclophosphamide 750 mg/m2 or pacli-taxel 135 mg/m2 over a 24-hour period preceding the cisplatin. The paclitaxel-based regimen proved superior in regard to overall response rate (73% versus 60%, P = 0.01), clinical complete response rate (51% versus 31%, P = 0.01), percentage grossly disease free at second-look laparotomy (40% versus 24%, P = 0.001), progression-free survival (median, 18 versus 13 months, P < 0.001), and overall


survival (median, 38 versus 24 months; P < 0.001; Table 93-13). Analysis of comparative risk demonstrated a 33% reduction in mor-bidity and mortality with the addition of paclitaxel to fi rst-line che-motherapy. Although increased myelosuppression, cardiac problems, and alopecia were found with the paclitaxel-based regimen, no major clinical consequences occurred. In particular, the frequency of grade III or IV neurotoxicity was the same with the two regimens. The conclusion of the GOG is that paclitaxel plus cisplatin is the new standard of care for ovarian carcinoma.

In OV-10,94 a Canadian/European consortium randomized patients with advanced disease to either cyclophosphamide 750 mg/m2 plus cisplatin 75 mg/m2 every 3 weeks for six to nine cycles or paclitaxel 175 mg/m2 over a 3-hour period followed by cisplatin 75 mg/m2 every 3 weeks for six to nine cycles. This trial shows supe-riority for the paclitaxel/cisplatin regimen with regard to response rate (59% versus 45%), clinical complete response rate (41% versus 27%), progression-free survival (15.5 months versus 11.5 months), and overall survival (35.6 months versus 25.8 months). This study confi rms GOG 111 and conclusively establishes paclitaxel plus a platinum compound as the standard of care.

GOG Protocol 13295 was completed before availability of the fi nal analysis of GOG Protocol 111. This trial randomized 613 newly diagnosed patients with large-volume advanced disease to six cycles of either cisplatin 100 mg/m2 every 3 weeks, paclitaxel 200 mg/m2

over a 24-hour period every 3 weeks, or paclitaxel plus cisplatin, as in GOG Protocol 111 (Table 93-14). No differences were observed among the three arms with respect to survival. The paclitaxel regimen arm was inferior with respect to response and progression-free sur-vival. It is important to note, however, that this trial did not serve as a confi rmatory trial for GOG Protocol 111 for a very important reason. At the time of accrual to GOG Protocol 111, paclitaxel was not commercially available in the United States, whereas it was com-mercially available at the time of accrual to GOG Protocol 132. Very few of the patients on the nonpaclitaxel regimen in GOG Protocol 111 received paclitaxel at the time of fi rst relapse. Conversely, vast majority of patients on the single-agent regimens of GOG Protocol 132 received the other drug before progression of disease. This pattern of second-line therapy blunts differences among the three regimens.

International Collaborative Ovarian Neoplasm (ICON3)96 (Table 93-15) is the most recently completed of the four trials and the largest (2074 patients). Several features of this trial distinguish it from the other three and dictate how this study should be evaluated. First, the study included patients with all stages of disease, I to IV. Patients with stage I to II disease represent 20% of the patients; hence, the patient population is very heterogeneous. Second, the regimens are not as well defi ned as those in the other three trials. A choice was made between two regimens for the control arm, and the arms that involved carboplatin allowed a range of AUC doses as long as a minimum was met. That a choice of control regimens was made is perhaps not such a problem as it might have been, because the results of a randomized trial comparing the two has since been reported as showing no differences.97 Third, the randomization was 2 : 1 favoring

Table 93-13 Results of GOG Protocol 111 and EORTC/NCIC OV 10: Cisplatin plus Either Cyclophosphamide or Taxol

GOG 111* OV 10†

TP CP TP CP

Clinical response rate 73% 60% 59% 45%

Clinical complete response rate 51% 31% 41% 27%

Grossly disease-free second look 40% 24% — —

Pathologic complete response 26% 20% — —

Progression-free survival 18 months 13 months 15.5 months 11.5 months

Overall survival 38 months 24 months 35.6 months 25.8 months

*TP, paclitaxel 135 mg/m2/24 hours plus cisplatin 75 mg/m2 every 3 weeks; CP, cyclophosphamide 750 mg/m2 plus cisplatin 75 mg/m2 every 3 weeks. Each regimen given for six cycles; all differences statistically signifi cant except pathologic complete response, for which P = 0.08.

†TP, paclitaxel 175 mg/m2/3 hours plus cisplatin 75 mg/m2 every 3 weeks; CP, cyclophosphamide 750 mg/m2 plus cisplatin 75 mg/m2 every 3 weeks. Each regimen given for up to nine cycles; all differences statistically signifi cant.

Data from references 93 and 94.

Table 93-14 Results of GOG Protocol 132: Comparison of Cisplatin versus Paclitaxel versus Cisplatin plus Paclitaxel

P T TP

Clinical response rate

67% 42% 66%

Clinical complete response rate

42% 21% 43%

Progression-free survival

16.4 months 10.8 months 14.1 months

Overall survival 30.2 months 25.9 months 26.3 months

P, cisplatin 100 mg/m2 every 3 weeks; T, paclitaxel 200 mg/m2/24 hours every 3 weeks; TP, paclitaxel 135 mg/m2/24 hours plus cisplatin 75 mg/m2 every 3 weeks. Each regimen given for six cycles. Only statistically signifi cant differences are in failure rates: Paclitaxel alone is inferior to the other two.


Table 93-15 Results of ICON3: Comparison of Carboplatin or CAP versus Paclitaxel versus Carboplatin plus Paclitaxel

Control* TP†

Progression-free survival 16.1 months 17.3 months

Overall survival 36.1 months 35.4 months

*Control regimens included carboplatin or CAP every 3 weeks: carboplatin AUC minimum 5; CAP, cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, cisplatin 50 mg/m2.

†TP, paclitaxel 175 mg/m2/3 hours, carboplatin AUC minimum 5 every 3 weeks. Each regimen given for six cycles.



the control arm, so twice as many patients were assigned to the control regimens as to paclitaxel plus carboplatin. Fourth, quality control was not as tight as in the other three trials. No pathology review is planned. Surgical requirements were nonexistent. No audit of data is planned. These factors detract from the credibility of this trial in comparison with the other three.

The trial shows no signifi cant differences between the control regimens and the experimental regimen in terms of progression-free and overall survival. This contradicts the results of GOG 111 and OV 10. The defi ciencies of the study, however, are such that this trial should not detract from the results of the earlier studies.

Conclusions from these four studies should be based not only on the study results, but also on the quality of the study design and execution. Two trials (GOG 111 and OV 10) show a clear advantage for a taxane/platinum combination. One trial (GOG 132) shows no difference, but crossover before progression in all likelihood means that the study actually evaluated concurrent versus sequential use of the two agents. Even in this setting, the concurrent arm was judged to be the treatment of choice because the overall toxicity was less with the concurrent regimen. The last trial (ICON3) has a number of design problems and lack of data audits; hence, its contrary result should be regarded circumspectly. On the basis of these consider-ations, the current standard of care should be a combination of paclitaxel plus a platinum compound.

Choice of Platinum CompoundInitial studies of paclitaxel in front-line therapy involved regimens with cisplatin. Interest in substitution of carboplatin for cisplatin results from the ease of administration and decreased nonhematologic toxicity associated with carboplatin. Concerns about the use of car-boplatin with paclitaxel focused on an interaction between the two agents.98 This interaction decreases the amount of thrombocytopenia that was observed with carboplatin such that suppression is less severe, and recovery is usually complete by 3 weeks instead of 4, as is seen with carboplatin alone. The mechanism for this interaction is not yet clear; hence, it is not clear whether the same mechanism might also result in tumor protection. This correlation would result in less effi cacy than is observed with paclitaxel/cisplatin. This concern led to three phase III trials comparing paclitaxel plus cisplatin with paclitaxel plus carboplatin.99–101

The Dutch trial99 randomized 208 advanced-disease patients to paclitaxel 175 mg/m2/3 hours plus either cisplatin 75 mg/m2 or car-boplatin AUC 5 every 3 weeks for at least six cycles. No differences in effi cacy were observed, and the carboplatin-based regimen had a better toxicity profi le. However, the study was too small to permit defi nite conclusions to be drawn about therapeutic equivalence between the two regimens.

The AGO trial100 randomized 798 advanced-disease patients to paclitaxel 185 mg/m2/3 hours plus either cisplatin 75 mg/m2 or car-boplatin AUC 6 every 3 weeks for six cycles. No differences were observed between the two regimens with regard to progression-free or overall survival, though small trends favored the cisplatin regimen. The cisplatin-based regimen was more toxic and produced a signifi -cantly inferior quality of life.

GOG Protocol 158101 randomized 798 patients with small-volume residual advanced disease to either paclitaxel 135 mg/m2/24 hours plus cisplatin 75 mg/m2 or paclitaxel 175 mg/m2/3 hours plus carbo-platin AUC 7.5. This study differs from the other two in several important ways. First, the use of the 24-hour infusion of paclitaxel with cisplatin served to decrease the amount of neurotoxicity that was seen with the cisplatin-based regimen. Second, as a result of the 24-hour infusion, the dose of paclitaxel was different in the two regimens. Third, and most important, the dose of carboplatin was substantially higher in this trial. The study showed no difference in progression-free and overall survival between the two regimens, but a strong trend favored the carboplatin-based regimen, with a hazard ratio for survival of 0.86. As a result of the escalated dose of carbo-

platin, the toxicity of the carboplatin-based regimen was substantially greater than that reported in the other two trials and did not differ greatly from that seen with the cisplatin-based regimen.

Conclusions from these three trials point to no major differences in effi cacy between paclitaxel/cisplatin and paclitaxel/carboplatin. The observed trends, however, raise serious questions about the optimal dose of carboplatin in combination with paclitaxel. At the very least, in combining carboplatin with paclitaxel, an AUC of 6 of carboplatin should be used, and serious consideration should be given to the higher AUC of 7.5.

Consolidation or Maintenance TherapyFor patients with advanced ovarian carcinoma, response rates now approach 90%, clinical complete response rates reach 75%, and median survivals range from 26 months for patients with bulky residual disease to more than 60 months for patients with small-volume residual disease. Despite these excellent results, almost 75% of those who achieve a clinical complete response will relapse eventu-ally and die of their disease.

In addition to the continuing effort to improve further the clini-cal complete response rate, investigators have conducted studies of ways to consolidate or maintain these responses. Over the last 20 years, none of these studies had produced a positive result.102 The most recent reports focused on consolidation after six initial cycles of paclitaxel plus carboplatin with four cycles of topotecan.103,104 Neither study showed any advantage for the consolidation therapy. No evi-dence now supports a role for consolidation therapy.

The one exception to the plethora of negative studies is a recent phase III randomized trial of extended duration paclitaxel as main-tenance therapy.105 This study differs from prior trials in two sig-nifi cant respects. First, only patients who responded to front-line therapy with a clinical complete response were eligible. Second, evi-dence suggests that extension of the duration of paclitaxel therapy could be benefi cial. This includes anecdotal reports of responses to paclitaxel that did not develop until as late as the twelfth cycle of therapy and preclinical observations of an antiangiogenic effect of paclitaxel over a prolonged period of treatment.106

Originally designed to accrue 450 patients with clinical complete responses to paclitaxel/platinum and to randomize these patient to either 3 or 12 additional monthly cycles of paclitaxel 175 mg/m2/3 hours, the study was closed early because of extreme differences in progression-free survival favoring the 12 additional cycles (Table 93-16). Because of patient choice to cross over to the 12-cycle regimen after study closure, survival is not assessable. Toxicity was obviously greater in the 12-cycle regimen, but only 13 patients in the entire study dropped out because of toxicity. Although one study requires confi rmation, the trial should certainly prompt discussion of this issue with each patient, and the evidence poses a convincing case for using 12 additional cycles of paclitaxel monthly as maintenance therapy. Whether 12 cycles is enough could be questioned because

Table 93-16 Results of SWOG and GOG Intergroup Study of Maintenance Therapy*

3 Cycles 12 Cycles

Patients 107 115

Recurrences 34 20

Progression-free survival† 28 months 21 months

*Comparison of 3 versus 12 cycles of monthly paclitaxel in those with clinical complete response to front-line paclitaxel plus cisplatin.105

†The difference in progression-free survival was statistically signifi cant (P = 0.0023).


of the observation of an increase in recurrence rate after cessation of the paclitaxel on each arm.

Current Standard of CareOn the basis of the series of studies cited over the last two decades, a solid case points to the combination of paclitaxel 175 mg/m2/3 hours plus carboplatin AUC 6 to 7.5 every 3 weeks for six cycles as the current standard of care. With this approach, an overall response rate of 95%, a clinical complete response rate of 75%, a pathologic complete response rate of 50%, a progression-free survival of 15 to 24 months, and an overall survival of 26 to more than 60 months should result. These results will vary according to the volume of residual disease; patients with small-volume residual disease (no nodule left >2 cm diameter) experienced better outcome.

After this, the issue of maintenance therapy with 12 cycles of paclitaxel should be discussed with the patient. Patient preference will play a large role in determining whether an individual patient will receive maintenance therapy.

Controversies and IssuesStudies of patients with advanced disease address a number of addi-tional issues: optimal paclitaxel schedule, intraperitoneal chemother-apy, high-dose chemotherapy with stem cell support, integration of new agents (both cytotoxic and biologic) into front-line therapy, the role of second-look laparotomy, and the role of CA-125 in assessing response and progression.

Paclitaxel was initially studied in a number of different schedules, from weekly to every-3-week schedules and from 1-hour to 120-hour infusion durations. By 1990, investigators were exclusively using a 24-hour infusion given every 3 weeks because of the higher incidence of hypersensitivity reactions with shorter infusions. Since then, shorter and longer infusions as well as weekly schedules have been studied.

A great deal of interest focused on the potential for shorter infu-sions because of the inconvenience of 24-hour infusions. A landmark phase III trial of 3-hour versus 24-hour infusions of paclitaxel as a single agent in relapsed ovarian cancer established the feasibility of short infusions preceded by premedication to prevent hypersensitivity reactions.107 The study dispelled the myth that the 24-hour infusion had superior effi cacy by showing no difference in response rate, progression-free survival, and overall survival. In terms of toxicity, the 3-hour infusion produced signifi cantly less myelosuppression in exchange for increased neurotoxicity and other nonhematologic toxicities.

The theoretical advantages of even longer infusions also have been examined. Two studies of 96-hour infusions, prompted by sugges-tions in breast cancer that this length of infusion produced responses in some patients for whom shorter infusions had failed, defi ned no role for this approach. Markman and colleagues108 treated 30 patients, for whom either a 3-hour or a 24-hour infusion had failed, with a 96-hour infusion of a total dose of 140 mg/m2, to be repeated every 3 weeks. No objective responses were observed, although the regimen was well tolerated. Subsequently the GOG randomized patients with newly diagnosed advanced ovarian carcinoma to either paclitaxel 135 mg/m2/24 hr plus cisplatin 75 mg/m2 every 3 weeks for six cycles or paclitaxel 120 mg/m2/96 hours plus cisplatin 75 mg/m2 every 3 weeks for six cycles.109 No differences in effi cacy were observed. Therefore, no reason exists to use a 96-hour infusion in the treatment of ovarian carcinoma.

Of potentially greater interest is a weekly schedule of paclitaxel. An initial phase I study of 40 to 100 mg/m2/1 hour of paclitaxel weekly demonstrated that this approach was feasible and also sug-gested potential activity (four responses among 13 patients).110 This study also suggested that these weekly infusions produced fewer adverse effects. Subsequently, a phase II trial treated 53 patients with paclitaxel 80 mg/m2/1 hour weekly and reported 13 (25%) responses.111 A randomized phase III trial of weekly versus every-3-

week paclitaxel (67 mg/m2/3 hours weekly versus 200 mg/m2/3 hours every 3 weeks), however, showed no difference in effi cacy and a small advantage for the weekly regimen in terms of toxicity.112 It should be pointed out that the dose of the every-3-week schedule is higher than is generally used in ovarian carcinoma, and this might account for the greater toxicity seen with that schedule.

In summary, these data on schedule taken together provide the following points that should be considered in the application of paclitaxel to the treatment of ovarian carcinoma. First, effi cacy does not appear to be affected by schedule. Second, toxicity does vary with schedule. Longer infusions produce more myelosuppression, whereas shorter infusions produce more nonhematologic toxicity, such as neurotoxicity. With appropriate premedication, hypersensitivity does not appear to be a major problem regardless of infusion duration. Finally, although the weekly schedule is certainly effi cacious and feasible, it appears to offer insuffi cient advantage in general to justify the greater inconvenience of weekly treatments.

Intraperitoneal ChemotherapyIn an effort directed at achieving ever greater dose intensity, three randomized trials involving intraperitoneal therapy have been reported. The fi rst of these studies, an Intergroup study of the South-west Oncology Group and the GOG, randomized 654 patients with small-volume residual disease to cyclophosphamide 600 mg/m2 intravenously plus cisplatin 100 mg/m2 either intravenously or intra-peritoneally.113 Results show a statistically signifi cant small survival advantage and less tinnitus, clinical hearing loss, and neurotoxicity for patients on the intraperitoneal regimen. The study has a fl aw in execution (extension of the accrual goal to increase the size of a subset and then an analysis using all patients, an approach that introduces statistical bias) but does suggest an advantage for intraperitoneal chemotherapy. Somewhat counterintuitively, the study shows that the treatment advantage exists only in patients with somewhat larger nodules (0.5 to 2.0 cm) rather than in the expected 0- to 0.5-cm subgroup.

GOG Protocol 114,114 a second Intergroup trial involving intra-peritoneal therapy, randomized small-volume patients to either pac-litaxel plus cisplatin as given in GOG Protocol 111 or two cycles of carboplatin dosed to an AUC of 9 at 4-week intervals followed by six cycles of paclitaxel 135 mg/m2 intravenously over 24 hours fol-lowed by intraperitoneal cisplatin 100 mg/m2 every 3 weeks. The 523 patients with no nodule larger than 1-cm diameter were randomized to study. The intraperitoneal regimen was superior with regard to progression-free survival (median: 27.6 versus 22.5 months, P = 0.02), but only a marginal difference in overall survival was observed (median: 52.9 versus 47.6 months, P = 0.056).114 The gain in effi -cacy, similar to that seen in the prior intraperitoneal study,113 came at the expense of signifi cantly more toxicity of all types on the intra-peritoneal regimen.

The third intraperitoneal study, GOG Protocol 172,115 random-ized 417 small-volume (<1.0-cm nodules) patients to either paclitaxel plus cisplatin, as given in GOG Protocol 111, or six cycles of pacli-taxel 135 mg/m2 intravenously over 24 hours on day 1, intraperito-neal cisplatin 100 mg/m2 on day 2, and intraperitoneal paclitaxel 60 mg/m2 on day 8, with the regimen repeated every 3 weeks. Tox-icity was dramatically greater on the intraperitoneal regimen, to such an extent that a substantial portion of the patients were unable to complete six cycles of therapy. Analysis of survival awaits suffi cient deaths. Progression-free survival, however, is superior on the intra-peritoneal regimen, with a hazard ratio of 0.73.

These three trials make the case that intraperitoneal chemotherapy yields a superior survival compared with standard intravenous che-motherapy in patients with small-volume residual advanced ovarian carcinoma. This benefi t is bought at the expense of signifi cantly more toxicity, to such an extent that a substantial portion of the patients cannot complete six cycles of therapy. At least at present, the toxicity of the intraperitoneal regimens tested precludes their routine clinical


use. Current efforts are directed at the development of less toxic intraperitoneal regimens that preserve the apparent survival benefi t of the approach.

STEM CELL-SUPPORTED HIGH-DOSE CHEMOTHER-APY. The alternative to intraperitoneal chemotherapy for the achievement of higher dose intensity is the use of stem cell-supported high-dose chemotherapy. As with the use of this approach in other cancers, most studies are small and uncontrolled and show high response rates but short response durations and short survivals.116 The largest study to date reports on the use of stem cell-supported high-dose chemotherapy in 421 patients for whom prior chemotherapy failed.117 The population had an average age of 48 years, and 59% were platinum sensitive. The reported response rate was 70% (47% complete response and 23% partial response). The 2-year progres-sion-free survival rate was 12%, and the 2-year overall survival rate was 35%. Although these numbers appear promising, patients with similar demographic and disease features fare considerably better with either intraperitoneal chemotherapy or standard intravenous chemotherapy.

To settle the issue of the role of high-dose chemotherapy with stem cell support, a randomized phase III trial should be conducted. Two attempts, one in Europe and one in the United States, have failed to accrue suffi cient patients. Until such a trial demonstrates the value of this approach, high-dose therapy should be reserved for clinical trials, preferably phase III clinical trials.

INTEGRATION OF NEW CYTOTOXIC AND BIOLOGIC AGENTS INTO FRONT-LINE THERAPY. The last 10 years saw a veritable explosion of discovery of new agents, both cytotoxic and biologic, with activity in ovarian carcinoma. Many of these agents are active in patients with disease that is still platinum sensitive, but activity in platinum-resistant disease is minimal or nonexistent. Of particular interest for incorporation into front-line therapy are those agents that have activity in patients who have progressed on or shortly after completion of a paclitaxel/platinum front-line regimen. Such agents may be considered at least partially clinically non-cross-resistant with the taxanes and platinum compounds and thus may add additional benefi t to front-line regimens.

At least four cytotoxic agents have activity in patients with “pac-litaxel/platinum-resistant” disease: oral etoposide,118 pegylated lipo-somal doxorubicin,119,120 topotecan,121,122 and gemcitabine.123–125 These four agents have been the focus of efforts by an international consortium to integrate one or more into front-line therapy. Oral etoposide was dropped from further efforts because of the occurrence of three cases of acute myeloid leukemia among 52 patients in the study of paclitaxel plus carboplatin plus escalating duration of pro-longed oral etoposide.126 The other three agents are being evaluated in an ongoing GOG/Gynecologic Cancer Intergroup trial (Table 93-17) that assesses the impact of a third agent added either as a component of a triplet or as part of a sequential doublet.

Biologic agents that are of interest as part of front-line therapy now include tyrosine kinase inhibitors (Iressa); monoclonal antibod-ies that target either epidermal growth factor receptor (C-225), HER2-neu (trastuzumab), or vascular endothelial growth factor (bevacizumab); agents that reverse resistance (cyclosporine and val-spodar); and interferon-γ. Of these, data are available on trastu-zumab, cyclosporine, valspodar, and interferon-γ.

The GOG studied trastuzumab in a population of patients with recurrent or refractory ovarian carcinoma.127 Of a total of 837 patients who were screened, 95 overexpressed HER2-neu (2+/3+ by immuno-histochemistry). Of these 95 patients, 41 were eligible and assessable and agreed to participate in the trial. Among the 41 patients who were treated with trastuzumab, one complete and two partial responses resulted. Investigators concluded that HER2-neu overexpression occurred less frequently than had previously been reported (12%

instead of 25%) and that treatment with trastuzumab had at best modest activity (7%).

The GOG also evaluated cyclosporine (cyclosporin A) for poten-tial ability to reverse resistance to cisplatin.128 Preclinical data had suggested that cyclosporin A could inhibit P-glycoprotein and reverse MDR-mediated resistance to cisplatin. Among 26 patients with platinum-resistant disease, only three responses to cisplatin plus cyclosporin A occurred. These data were considered insuffi cient jus-tifi cation for further study. A related compound (cyclosporine D analog), valspodar, subsequently underwent a phase II and a phase III study of its ability to reverse MDR-mediated resistance to pacli-taxel. The GOG phase II study129 administered the combination to 58 patients with clinical resistance to paclitaxel. Five responses resulted and prompted the performance of a phase III trial by an international consortium.130 This phase III study in patients with newly diagnosed ovarian carcinoma sought to determine whether the concurrent administration of valspodar with paclitaxel/carboplatin produced results that are superior to that of chemotherapy alone. The study report showed no signifi cant differences in effi cacy or toxicity. All trends in both effi cacy and toxicity favored the chemotherapy-alone regimen. These three trials suggest that these two compounds have no signifi cant role in the management of ovarian carcinoma.

Studies of interferon-γ report signifi cant activity against ovarian carcinoma by either intraperitoneal or intravenous routes.131 These results prompted a phase III trial of cyclophosphamide/cisplatin with or without interferon-γ administered by the subcutaneous route.132 Although this study had to be stopped prematurely because of the emergence of paclitaxel/carboplatin as the new standard of care, the trial did show a statistically signifi cant difference in progression-free survival favoring the interferon-γ regimen. As a result, interferon-γ is being evaluated in an ongoing phase III trial of paclitaxel/carboplatin with or without interferon-γ.

Among other biologic agents, agents that are directed against vascular endothelial growth factor attract the greatest interest because of studies suggesting that high levels of vascular endothelial growth factor in tumor specimens are associated with a poorer prognosis.133 At this point, however, no data defi ne a clear role for any biologic agent.

ROLE OF CA-125. CA-125, a mucin-like glycoprotein, increases in response to disturbances of the celomic epithelium. The marker is most closely associated with the assessment of patients with ovarian carcinoma. As was discussed earlier, the marker has no defi ned role in the early detection of ovarian carcinoma. The major clinical role is the assessment of disease status in patients receiving treatment for advanced disease.134 Because of the diffi culty in accurately assessing tumor response in a neoplasm often confi ned to the peritoneal cavity, interest has developed in defi ning ways to use CA-125 levels to

Table 93-17 Schema for GOG Protocol 182: An International Trial of the Addition of a Third Agent to Front-Line Therapy

Regimen I: Paclitaxel plus carboplatin × 8 cycles

Regimen II: Paclitaxel plus carboplatin plus gemcitabine × 8 cycles

Regimen III: Paclitaxel plus carboplatin plus PLD × 8 cycles (PLD given every other cycle)

Regimen IV: Gemcitabine plus carboplatin × 4 cycles followed by paclitaxel plus carboplatin × 4 cycles

Regimen V: Topotecan plus carboplatin × 4 cycles followed by paclitaxel plus carboplatin × 4 cycles

PLD, pegylated liposomal doxorubicin.Accrual goal: 4000 patients.


determine response.135 Current proposals focus on defi nitions based on a 50% or 75% decrease of CA-125 levels during the course of therapy and are currently under review by a committee of the Gynecologic Cancer Intergroup.136

Until standard defi nitions are developed, the marker should be confi ned to allowing a rough idea of whether disease is responding and should not be used as a response criterion. Decreasing CA-125 levels suggest a favorable response of tumor to therapy, whereas increasing levels suggest progression of disease. Certain principles should guide such a use. First, no single CA-125 value should dictate management decisions; a series of increasing or decreasing values (usually three or more) should be required. Second, changes in the CA-125 level should not result in action until the changes are cor-roborated by other objective evidence.

SECOND-LOOK LAPAROTOMY. Second-look laparotomy is an exploratory laparotomy that is performed at the conclusion of front-line chemotherapy. The purpose of the procedure is to deter-mine disease status accurately so that decisions regarding further management can be made.137 Patients who are selected as candidates for second-look laparotomy are usually in one of two categories: those with a clinical complete response to front-line therapy and those who are potential candidates for secondary surgical cytoreduction. Among patients who undergo second-look laparotomy, 40% will have no pathologic evidence of disease, yet half of those with a pathologic complete response will relapse.138,139

After widespread use in the 1980s, second-look laparotomies are now performed less frequently. Reasons that are cited for decrease in use of the procedure usually focus on the failure of studies to show that patients who undergo second-look laparotomy have improved survival as a result. The most recent and largest study evaluating second-look laparotomy101,140 came from data that were collected in a study of paclitaxel/carboplatin versus paclitaxel/cisplatin in patients with small-volume residual stage III ovarian carcinoma (GOG Pro-tocol 158). Institutions were required to specify whether women with clinical complete responses on the study would undergo second-look laparotomy at the conclusion of the protocol-assigned therapy. Roughly half of the patients who were entered in the study did undergo the procedure. GOG investigators compared the outcome for patients who did or did not have a second look. No differences were observed; hence, the investigators concluded that second-look laparotomy was of no value.

The problem with the study is the same fl aw that has been seen in other reported studies. The potential value of second-look lapa-rotomy lies in the information gleaned from the procedure. What determines whether that value is realized is the value of the manage-ment decision that is made on the basis of the information. The proper study should specify the management choice to be made for each fi nding at second look so that the study evaluates the package of second-look plus a specifi ed management versus no second look. In conclusion, second-look laparotomy is currently not recommended for routine clinical use (Box 93-1).

Summary of Management of Advanced DiseasePatients with advanced ovarian carcinoma should undergo an initial attempt at surgical cytoreduction followed by chemotherapy. The best evidence shows that paclitaxel combined with carboplatin is the regimen of choice. On completion of initial chemotherapy, the use of an additional 12 cycles of paclitaxel monthly as maintenance therapy should be discussed with the patient. Dose-intense regimens, intraperitoneal therapy, and the addition of a third agent to front-line therapy offer no established advantage and hence should be reserved for clinical trials.

Management of Limited DiseasePatients with stage I or II disease compose approximately 25% of all patients with celomic epithelial carcinoma of the ovary. Only a small

proportion of these are ever entered into clinical trials, however; hence until recently, it was diffi cult to provide defi nitive guidelines for the management of these patients. Recent randomized trials form the basis of current management principles.

GENERAL CONSIDERATIONS. Certain characteristics of the primary lesion are important in determining the prognosis of the patient with limited disease: histologic grade, location of the primary tumor, ascites, peritoneal cytology, and, to a lesser extent, histologic type. These characteristics permit separation of the patient popula-tion into those who are at low risk of recurrence and those who are at high risk141 (Table 93-18). Patients who are at low risk of recur-rence exhibit all the following characteristics: one or both ovaries involved, grade I or II (well or moderately differentiated), intracystic (no tumor on the external surface of the ovary), no ascites, negative peritoneal cytology, and no extraovarian disease. Patients who are at high risk have any one of the following characteristics: grade III (poorly differentiated), extracystic (tumor on the surface of the ovary), ascites, positive peritoneal cytology, or extraovarian (stage II) disease. Patients who are at low risk of recurrence have a 5-year survival rate that exceeds 90%, whereas those who are at high risk have a substantially lower survival rate.142

The assignment of a patient to a risk category should be based on a careful exploratory laparotomy performed through an incision that permits the exploration of the entire abdominal contents. Ascites should be noted, and samples for cytology should be taken. In the absence of ascites, peritoneal washings for cytology should be obtained. The capsule of the tumor should be inspected for excres-cences, dense adherence, or rupture. The peritoneal surface should be carefully examined for implants of tumor. Areas that require par-ticular attention include the undersurface of the diaphragm, the paracolic gutters, and the omentum. Biopsies should be obtained of any suggestive lesion and, in the absence of suggestive areas, of mul-tiple sites. The para-aortic nodes should be examined and sampled. Finally, after inspection of the entire peritoneal surface, a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy should be carried out.

Box 93-1. THERAPEUTIC DECISIONS IN NEWLY DIAGNOSED CELOMIC EPITHELIAL CARCINOMA

Newly diagnosed patients with celomic epithelial carcinoma of the ovary must be carefully staged so that appropriate treatment decisions can be made. This necessitates an exploratory laparotomy in all patients but those who have obvious stage IV disease. At laparotomy, as much disease as possible should be resected. Decisions are then governed by the surgical stage of the disease.

For patients with stage I or II disease, total abdominal hysterectomy and bilateral salpingo-oophorectomy should be done. This should be followed by adjuvant therapy if any of the following are present: poorly differentiated disease (grade III), tumor excrescences on the surface of the ovary, ascites, positive peritoneal cytology, or extraovarian disease. The adjuvant therapy of choice at our institution is platinum-based chemotherapy: carboplatin (AUC 7.5 intravenously) after paclitaxel (175 mg/m2/3 hours intravenously) every 3 weeks for three cycles. At the conclusion of treatment, close observation will suffi ce.

For patients with stage III or IV disease, an aggressive attempt at surgical cytoreduction should be followed by platinum-based combination chemotherapy for six cycles. The optimal regimen is the combination of paclitaxel 175 mg/m2 over a 3-hour period plus carboplatin AUC 6 to 7.5 every 3 weeks for six cycles. At the conclusion of initial chemotherapy, the physician should discuss the issue of maintenance paclitaxel 175 mg/m2 over a 3-hour period monthly for 12 cycles.


Because selection of therapy will be based on risk category, a detailed staging procedure is mandatory. In a series of 100 patients who were referred after initial laparotomy-based diagnosis of stage I or II ovarian carcinoma and then reexplored, 31 patients were found to have more advanced disease than was noted at initial laparotomy. Such upstaging can have a signifi cant impact on choice of therapy.

MANAGEMENT. The initial approach to patients with limited disease should be surgical resection of disease. This should be com-bined with a careful staging laparotomy that defi nes in detail the anatomic extent of disease. However, controversy characterizes rec-ommendations for the use of adjuvant therapy after surgical resection. At least three different approaches have been used in uncontrolled trials: abdominopelvic radiation therapy, intraperitoneal radioactive chromic phosphate (32P), and chemotherapy.

Radiation Therapy. The use of radiation therapy in the manage-ment of ovarian carcinoma fell into disfavor because of two fl awed approaches to its use: pelvic radiation therapy as an adjuvant to surgical resection of stage I disease143,144 and abdominopelvic radia-tion therapy in patients with gross disease. The fi rst approach failed because a signifi cant proportion of the patients who were treated with pelvic fi elds already had at least microscopic disease outside the pelvis. The second approach attempted the eradication of disease that was too bulky to handle with the doses that were achievable to a whole-abdominal fi eld. Results with abdominopelvic radiation therapy as an adjuvant treatment in patients with stage I through III disease and no gross residual suggest that the potential role of radiation therapy should be reconsidered.

Investigators at the Princess Margaret Hospital in Toronto, Ontario, Canada, randomized patients with stage I, stage II, and minimal residual stage III disease to either abdominopelvic radiation to a total of 22.5 cGy by a moving-strip technique or pelvic radiation with or without chlorambucil. Patients with stage III disease were not randomized to pelvic radiation alone. The study demonstrated clear superiority for abdominopelvic radiation.145 A follow-up trial that compared abdominopelvic radiation by a moving-strip and open fi eld technique showed no difference.146

A subsequent analysis of patients who received abdominopelvic radiation in these two studies looked at the results in patients who

were at intermediate or high risk of recurrence on the basis of histo-logic type, grade, and stage.147 Of 211 patients who were at interme-diate risk, only 60 were assigned to stage I; the 5-year survival rate was 75%. Of 88 patients who were at high risk of recurrence, there were 72 stage III patients and 16 stage II patients; the 5-year survival rate was 32%. Two groups of patients did not benefi t from abdom-inopelvic radiation: those with stage I grade I disease and those with large-volume disease (nodules >2 cm).

An important problem with these studies is the lack of careful surgical staging, as evidenced by the large number (155 of 325) of patients who were assigned to stage II, an uncommon stage in appro-priately evaluated patients. This is a major inconsistency in a patient population that purports to serve as the basis for determining prognostic features that can identify low-risk, intermediate-risk, and high-risk patient subsets.

Despite the questionable nature of the surgical staging, the Prin-cess Margaret Hospital experience makes a strong case for a role for abdominopelvic radiation in the management of patients with limited disease who are at signifi cant risk for recurrence. The comparisons with pelvic radiation with or without chlorambucil do not permit conclusions as to the relative merits of abdominopelvic radiation versus chemotherapy because the chemotherapy that was used con-sisted of suboptimal doses of a single alkylating agent.

Supporting these observations are a number of uncontrolled reports in the literature.148,149 These experiences confi rm that patients with gross disease, particularly those with nodules greater than 2 cm in diameter, do not benefi t signifi cantly from radiation.

In contrast to these experiences is one earlier M.D. Anderson Hospital trial of 149 patients with stage I, II, or minimal residual stage III disease who were randomized to either abdominopelvic radiation by the moving-strip technique or oral melphalan. A 10-year follow-up evaluation showed no difference in survival.150 The study has been criticized for imbalances in prognostic factors favoring the chemotherapy regimen and for problems with the radiation tech-nique used.

On the basis of current evidence, abdominopelvic radiation cannot be recommended as adjuvant therapy in limited disease. Studies suggesting effi cacy have critical fl aws. However, further study is indicated on the basis of the Princess Margaret Hospital experience.

Radioactive Isotopes. The intraperitoneal administration of radioactive isotopes to treat limited-stage ovarian cancer after surgical resection has been proposed as a promising approach.151–157 Early studies were characterized by small numbers of patients accrued over many years, lack of control groups, and inadequate surgical staging. Despite these limitations, reported survival rates were suffi ciently high to include this modality as one treatment regimen in three major randomized trials described.142,158,159

This approach is based on the facts that ovarian carcinoma spreads initially primarily by intraperitoneal seeding and that 32P is an emitter of beta-radiation, which has a maximum tissue penetration of 3 to 4 mm, with an effective penetration of probably no more than 2 mm. Whereas 32P could not be expected to be effective in patients with visible disease, it might well be an effective agent in patients with microscopic or no documentable residual disease after surgical resection. Uncontrolled trials in limited disease as well as reports of effi cacy in patients who have achieved a pathologic complete response of more advanced disease with initial chemo-therapy supported the possible effi cacy of this approach.149 A subse-quent randomized trial (GOG Protocol 95) comparing intraperitoneal 32P with cyclophosphamide/cisplatin showed a superior progression-free survival with chemotherapy and also highlighted distribution problems and bowel toxicities associated with 32P. The GOG inves-tigators concluded that chemotherapy was the preferred treatment for high-risk limited ovarian carcinoma and essentially laid to rest any role for 32P.160

Table 93-18 Risk Groups for Limited Ovarian Carcinoma

Group Characteristics

Low risk Grade I or II disease

Intact capsule

No tumor on external surface

Negative peritoneal cytology

No ascites

Growth confi ned to ovaries

High risk* Grade III disease

Ruptured capsule

Tumor on external surface

Positive peritoneal cytology

Ascites

Growth outside ovaries

*If any high-risk factors are present, the patient is considered high risk.Data from Young RC, Walton L, Ellenberg SS, et al: Adjuvant therapy in stage I and

stage II epithelial ovarian cancer: results of two prospective randomized trials. N Engl J Med 1990;322:1021–1027.


Single Alkylating Agents. Single alkylating agents, most com-monly melphalan, appear to offer benefi t in uncontrolled trials.150,160 One series compared melphalan with abdominopelvic radiation and showed similar survival between the two regimens and an advantage for melphalan because of less toxicity.150 The other study retrospec-tively evaluated 50 patients with limited disease accrued over a 13-year period and treated with single-agent melphalan.160 The survival rate at 2 years was 98%, and that at 4 years was 94%. Consistency of surgical staging techniques was not documented in the report. To draw defi nite conclusions about the effi cacy of melphalan from these reports is impossible, but survival fi gures suggest that melphalan could be an effective adjuvant therapy.

RANDOMIZED TRIALS. Superseding the previously described uncontrolled trials are nine major randomized trials comparing modalities as adjuvant therapy in patients with limited disease: GOG Protocol 1, a National Cancer Institute of Canada Clinical Trials Group study, two critically important trials from the combined efforts of the Ovarian Cancer Study Group and the GOG, two European trials, two additional studies of the GOG, and the com-bined analysis of two European trials (ICON1/ACTION).

GOG Protocol 1. GOG Protocol 1, conducted during 1970 to 1976, was a phase III trial of patients with stage I ovarian carci-noma.144 Although all patients underwent exploratory laparotomy, routine exploration of the diaphragm, lymph node sampling, perito-neal cytology, and omentectomy were not required because the importance of these procedures as a part of careful staging was not fully understood. After surgical resection of disease, patients were randomized to either no further therapy, pelvic radiation to 50 cGy, or chemotherapy consisting of melphalan (0.2 mg/kg/day orally) for 5 days every 4 weeks. Of the 168 patients who were entered into the study, only 86 were both eligible and evaluable, a major problem.

An analysis of prognostic factors showed an even distribution of prognostic factors, except that the control arm contained a greater percentage of favorable histology and stage IA. Among 29 patients who were randomized to no further therapy, fi ve (17%) recurrences were found; among 23 patients who were given pelvic radiation, seven (30%) had a recurrence; and among 34 patients who received melphalan, only two (6%) had recurrence. The difference between melphalan and pelvic radiation was signifi cant (P < 0.05).

This trial suggests that patients with limited disease benefi t from the use of adjuvant melphalan, but fl aws in study execution and the relatively small number of evaluable patients prevent defi nitive con-clusions. The results do indict pelvic radiation as an inadequate approach. The analysis of prognostic factors also points to the impor-tance of grade, histologic type, and extracystic tumor in determining patient outcome.

National Cancer Institute of Canada Clinical Trials Group Study. This investigation of patients with stage I or IIA high-risk (defi ned by rupture of a malignant ovarian cyst, poorly differentiated disease, extracystic excrescences of tumor, or positive peritoneal cytology), stage IIB, or stage III with disease confi ned to the pelvis158 randomized subjects to pelvic radiation to 45 cGy plus either abdominal radiation to 22.5 cGy, radioactive chromic phos-phate 15 mCi intraperitoneally, or melphalan (8 mg/m2/day orally) for 4 days every 4 weeks for 18 months. Of 257 eligible and evaluable patients, 107 were randomized to abdominopelvic radiation, 106 to pelvic radiation plus melphalan, and 44 to pelvic radiation plus intraperitoneal 32P. The arm including intraperitoneal chromic phos-phate was closed early because of an unacceptably high incidence of delayed toxicity. No differences in disease-free or overall survival or in recurrence rate were noted among the three arms. The investigators concluded that the survival results of all three arms point to the need for further improvement in adjuvant therapy.

Ovarian Cancer Study Group and GOG Studies. These studies were conducted from 1976 to 1986.142 The fi rst study, OCSG/GOG Protocol 7601, randomized 81 patients with stage I disease at low risk of recurrence (defi ned as those patients with well- or moderately well-differentiated intracystic lesions associated with no extraovarian neoplasm, no ascites, and negative peritoneal cytol-ogy after a careful and detailed exploratory laparotomy) to either no further therapy (38 patients) or melphalan 0.2 mg/kg/day orally for 5 days every 4 weeks for up to 12 cycles (43 patients). At a median follow-up in excess of 6 years, only six deaths had been observed: four in the control arm and two in the melphalan arm. Five recur-rences have been observed: four in the control arm and one in the melphalan arm. No signifi cant differences in recurrence rate, disease-free survival, and survival were noted between the two arms (Table 93-19).

The second trial, OCSG/GOG Protocol 7602, involving 141 patients with stage I high-risk disease (defi ned as having one or more high-risk feature—that is, poorly differentiated disease, extracystic tumor, ascites, positive peritoneal cytology, or extraovarian lesions—or stage II disease completely resected) randomized subjects to either intraperitoneal radioactive chromic phosphate 15 mCi (73 patients) or melphalan (0.2 mg/kg/day orally) for 5 days every 4 weeks for up to 12 cycles (68 patients). At a median follow-up of more than 6 years, 34 (24%) recurrences were seen, 16 (22%) of 73 in the 32P arm and 18 (26%) of 68 in the melphalan arm. Over the same period, 31 (22%) deaths occurred, 16 (22%) of 73 in the 32P arm and 15 (22%) of 68 in the melphalan arm. The 5-year disease-free survival rate for both arms is 80%. No signifi cant differences between arms are present in regard to recurrence rate, disease-free survival, or overall survival (Table 93-20).

Table 93-19 Results of OCSG and GOG Protocol 7601*

Observation Melphalan

Patients 38 43

Recurrences 4 1

Deaths 4 2

Disease-free 5-year survival rate 91% 98%

Overall 5-year survival rate 94% 98%

*Randomized trial of patients who were at low risk of recurrence.Data from Young RC, Walton L, Ellenberg SS, et al: Adjuvant therapy in stage I and


Table 93-20 Results of OCSG and GOG Protocol 7602*

Intraperitoneal 32P Melphalan

Patients 73 68

Recurrences 14 13

Deaths 16 15

Disease-free 5-year survival rate

80% 80%

Overall 5-year survival rate 78% 81%

*Randomized trial of patients at high risk of recurrence.Data from Young RC, Walton L, Ellenberg SS, et al: Adjuvant therapy in stage I and



Italian Trial. An Italian trial,161 reported in 1992, grouped patients with limited disease into three categories: a low-risk group including stage IA G1 and stage IB G1 with no extracystic involve-ment (93 patients), an intermediate-risk group including stage IAG2–3 and stage IBG2–3 with no extracystic involvement (91 patients), and a high-risk group including stage I patients with extra-cystic involvement (185 patients; Table 93-21). Patients in the low-risk group were followed up on no active treatment after surgical resection and demonstrated a 5-year disease-free survival rate of 90% with fi ve relapses and three disease-related deaths.

Patients in the intermediate-risk group were randomized to either cisplatin 50 mg/m2 every 4 weeks for six cycles, or no further treat-ment after surgical resection. The 5-year disease-free survival rate was 76% in the cisplatin arm and 58% in the control arm. Eighteen relapses and nine disease-related deaths were observed. The difference in disease-free survival was signifi cant (P < 0.05) in favor of the cisplatin arm.

Patients in the high-risk group were randomized to either cispla-tin (50 mg/m2) every 4 weeks for six cycles or chromic phosphate (15 mCi intraperitoneally). The 5-year disease-free survival rate in the cisplatin arm was 84% versus 61% in the 32P arm, a difference that was statistically signifi cant (P < 0.01) in favor of the cisplatin arm. Forty relapses and 25 disease-specifi c deaths were observed.

Norwegian Study. A Norwegian study162 that was reported in 1992 randomized 265 patients with stage I limited disease to either cisplatin or intraperitoneal 32P, as in the Italian trial. The trial is dif-fi cult to interpret on the basis of the only report to date because of the inclusion of patients with borderline lesions (low malignant potential) and because of a failure to separate patients into low-risk and high-risk groups.

GOG Protocol 95. The GOG randomized 205 patients with high-risk limited disease after complete surgical resection to adjuvant therapy consisting of either intraperitoneal 32P or three cycles of cyclophosphamide 1000 mg/m2 plus cisplatin 100 mg/m2.163 The

recurrence-free rate at 5 years was 77% on the chemotherapy regimen versus 66% with 32P. The estimated relative risk is 0.693, favoring the chemotherapy regimen (P = 0.075). The 5-year survival rate was 84% for the chemotherapy and 76% for the 32P group. Patients receiving the intraperitoneal 32P experienced problems with distribu-tion of the compound in the abdominal cavity and also with bowel toxicities. The GOG concluded from these data that chemotherapy represented the preferred treatment (Table 93-22).

ICON1/Action. The combined efforts of the ICON and the European Organization for Research and Treatment of Cancer pro-duced a combined analysis of two randomized studies of adjuvant chemotherapy in patients with limited disease.164 Both groups required that patients have stage I to IIA disease and that patients be randomized after surgical resection to either no further therapy or adjuvant chemotherapy containing a platinum compound. Of 925 patients who were randomized to the two studies, at a median follow-up of 4 years, 245 patients had either died or experienced recurrence of disease. The recurrence-free survival rate at 5 years was 76% in the chemotherapy arm and 65% in the observation arm (relative risk: 0.64, P = 0.001). The overall 5-year survival rate was 82% in the chemotherapy arm and 74% in the observation arm (relative risk: 0.67, P = 0.008). This study marks the fi rst report of improved overall survival with chemotherapy and establishes chemotherapy as the standard of care after surgery in patients with high-risk limited disease (Table 93-23).

GOG Protocol 157. The GOG randomized 457 patients with high-risk limited ovarian carcinoma after complete surgical resection to paclitaxel 175 mg/m2/3 hours plus carboplatin AUC 7.5 every 3 weeks for either three or six cycles.165 The basis for this trial included the prior studies that showed an advantage for chemotherapy in high-risk limited disease163,164 and the randomized trials that estab-lished paclitaxel/carboplatin as the standard of care for advanced

Table 93-21 Results of a Randomized Trial Involving 369 Patients with Stage I Ovarian Carcinoma

Treatment Relapses Deaths

5-Year Disease-Free Survival Rate (%)

Group A: IAiG1 and IBiG1 (N = 93)

5 3

No further therapy 90

Group B: IAiG2–3 and IBiG2–3 (N = 91)*

18 9

No further therapy 58

Cisplatin 76

Group C: IAii, IBii, and IC (N = 185)†

40 25

32P 61

Cisplatin 84

i, no extracystic tumor; ii, extracystic tumor.*In group B, the disease-free survival rate is signifi cantly different (P < 0.05) in

favor of cisplatin.†In group C, the disease-free survival rate is signifi cantly different (P < 0.01) in

favor of cisplatin.Data from Bolis G, Colombo N, Favalli G, et al: Randomized multicenter clinical

trials in stage I epithelial ovarian cancer [abstract]. Proc ASCO 1992;11:225.

Table 93-22 Results of GOG Protocol 95*

Intraperitoneal 32P CP† Relative Risk

Patients 98 107

Recurrence free at 5 years

66% 77% 0.693‡

Alive at 5 years 76% 84%

*Randomized trial of patients at high risk of recurrence.163

†Cyclophosphamide 1000 mg/m2 plus cisplatin 100 mg/m2. Repeat every 3 weeks times 3.

‡P = 0.075.

Table 93-23 Results of ICON and ACTION*

Observation Chemotherapy Relative Risk

Patients 460 465

Recurrence free at 5 years

65% 76% 0.64†

Alive at 5 years

74% 82% 0.67‡

*Randomized trial of patients at high risk of recurrence.†P = 0.001.‡P = 0.008.Data from Vergote I, Trimbos B, Guthrie D, et al: Results of a randomized trial in

923 patients with high-risk early ovarian cancer, comparing adjuvant chemotherapy with no further treatment following surgery [abstract]. Proc ASCO 2001;20:201a.


disease.93,94,100,101 The chemotherapy regimen that was adopted was the one used in GOG Protocol 158.101 A large proportion of the patients failed to meet the surgical requirements of the trial (107 of 457, or 23%), so the study was analyzed both with and without these patients. Both analyses showed a reduction in recurrence rate that did not reach statistical signifi cance (relative risk: 0.69 without the surgical exclusions and 0.77 with the exclusions, neither of which was statistically signifi cant). Both also showed no signifi cant difference in survival at 5 years (79% compared to 84% in group without exclu-sions; Table 93-24).

CONCLUSIONS. The results of the nine randomized trials provide guidelines for the management of patients with limited disease. First, the trials demonstrate the importance of careful surgi-cal staging to establish the patient’s risk of recurrence. Second, patients who are at low risk of recurrence have a 5-year survival rate exceeding 90% with or without adjuvant therapy. Additional treat-ment after surgical resection does not appear to be indicated. Third, patients who are at high risk of recurrence appear to benefi t from adjuvant therapy. The weight of evidence supports the use of cispla-tin-based chemotherapy as the adjuvant therapy of choice. Although defi nitive statements about regimen and duration are diffi cult, it would seem reasonable to use paclitaxel/carboplatin, as in GOG Protocol 157, for at least three cycles of therapy (Box 93-2).

Management of Recurrent, Persistent, or Progressive DiseaseAlthough debate continues about the optimal choice of drugs, dose schedule, and route of administration, platinum-based combination chemotherapy yields the following results in patients with advanced disease:93,94,100,101 an overall response rate of 95%, a clinical complete response rate of 75%, a pathologic complete response rate of 40% to 50%, a 10-year survival rate of 15% to 40%, and a recurrence rate after clinical complete response of 75% and after pathologic complete response of 40% to 60%. Patients who initiate front-line therapy with small-volume residual disease will fare better than those who start chemotherapy with large-volume residual disease. The fact remains, however, that a majority (60% to 75%) of patients with ovarian carcinoma will require further therapy for recurrent, persis-tent, or progressive disease. The factors that affect the choice of that therapy and the specifi c options available are now considered.

RECURRENT DISEASE POPULATION. Long-term follow-up evaluation of 726 women who were treated for ovarian carcinoma on GOG protocols166,167 identifi ed a number of characteristics associated with increased likelihood of recurrence: clear cell or mucinous histol-ogy, non-platinum-based treatment, poor performance status, older age, higher stage, clinically measurable disease, larger residual tumor volume, and ascites. In addition, an analysis of those factors that predict recurrence after pathologic complete response168 shows that

histologic grade is an important determinant of relapse rate, with grade I having a relapse rate of 22%; grade II, 39%; and grade III, 56%.

None of these factors provides guidance in the selection of appro-priate subsequent therapy. However, an additional factor that does appear to provide a basis for choosing salvage therapy is the result of immediately preceding therapy. Patients who respond to previous platinum-based therapy and who demonstrate a signifi cant treat-ment-free interval have a high probability of responding again to platinum-based treatment.169–174 Patients who progressed during or shortly after completion of platinum-based therapy are unlikely to respond to further treatment with a platinum compound and should be considered for therapy with non-cross-resistant agents.63–71,118–125,127,175–207Discussion of salvage therapy is based on this division of patients into “sensitive” and “resistant” populations based on responsiveness to initial platinum-based treatment (Table 93-25).

MANAGEMENT OF PLATINUM-SENSITIVE PATIENTSImportance of Treatment-Free Interval. Until recently, most studies of patients who have recurrent, persistent, or progressive disease after initial chemotherapy focused on identifi cation of the activity of new drugs or approaches as a basis for the subsequent testing of these active regimens in phase III studies of front-line therapy. As a result, determination of optimal therapy for this setting was extrapolated from data that had been collected for other purposes. These efforts have led to the conclusion that the most important determinant of the likelihood of a response in the setting of progres-sive, persistent, or recurrent disease is the treatment-free interval.

Succinctly stated, the duration of the interval from the conclusion of preceding therapy to the need for further therapy infl uences the likelihood of the patient’s responding to the chosen further therapy.

Table 92-24 Results of GOG Protocol 157*

TP 3 3 Cycles*

TP 3 6 Cycles†

Relative Risk

Patients 213 216

Recurrence free at 5 years 75% 81% 0.77‡

Alive at 5 years 79% 84%

*Randomized trial of patients at high risk of recurrence.†Paclitaxel 175 mg/m2/3 hours plus carboplatin AUC 7.5. Repeat every 3 weeks.‡P = 0.109.Data from Bell J, Brady M, Lage J, et al: A randomized phase III trial of three versus

six cycles of carboplatin and paclitaxel as adjuvant treatment in early stage ovarian epithelial carcinoma: a Gynecologic Oncology Group study [abstract]. Gynecol Oncol 2003;88:156.

Box 93-2. THERAPEUTIC CHOICES IN RECURRENT, PERSISTENT, OR PROGRESSIVE CELOMIC EPITHELIAL CARCINOMA

Choices of therapy for progressive, persistent, or recurrent celomic epithelial carcinoma of the ovary hinge on the patient’s response to front-line therapy. Patients who respond to initial chemotherapy, who become disease free, and who experience a treatment-free interval of 6 months or longer are highly likely, at recurrence, to be responsive to platinum-based salvage therapy. These platinum-sensitive patients should be retreated with a platinum-based combination regimen. The currently preferred regimen is carboplatin AUC 6 to 7.5 intravenously after paclitaxel 175 mg/m2/3 hours intravenously every 3 weeks. Patients who fail to respond should be deemed platinum resistant and treated accordingly. Those who respond and become disease free with a treatment-free interval of at least 6 months should once again receive platinum-based therapy.

Patients whose disease progresses while they are receiving initial therapy, who have persistent disease at the conclusion of initial treatment, or whose tumor recurs within 6 months of initial therapy should be regarded as platinum resistant. These patients should be treated with regimens that induce responses in platinum-resistant disease. Repeated platinum-based therapy is not indicated. Single agents that achieve responses in resistant patients include weekly paclitaxel, docetaxel, pegylated liposomal doxorubicin, oral etoposide, topotecan, tamoxifen, gemcitabine, navelbine, and ifosfamide. No evidence supports the use of combinations in resistant patients. Therapy should be continued until disease progression or achievement of complete response.

Approaches that should be reserved for clinical trials only include high-dose therapy with autologous bone marrow transplantation or peripheral stem cell support, intraperitoneal therapy, and biologic agents.


The longer the interval, the greater is the likelihood of a response.173 To illustrate this principle, four among many studies are examined.

In the fi rst example, intravenous cisplatin-based therapy as salvage treatment was evaluated retrospectively in 72 patients with measur-able disease who had received at least two cisplatin- or carboplatin-based regimens and had demonstrated a platinum-free interval of at least 4 months between the completion of the fi rst regimen and initiation of the second.173 The overall response rate was 43% (31 of 72 with 10 pathologic complete responses). The response rate increased as the platinum-free interval increased. In patients with an interval of 5 to 12 months, the response rate was 27% (5% pathologic complete responses); in those with an interval of 13 to 24 months, it was 33% (11% pathologic complete responses); and in those with an interval of more than 24 months, it was 59% (pathologic complete responses, 22%).

In the second example, a salvage regimen of weekly cisplatin combined with either epirubicin or etoposide174 yielded a 60% response rate (25% complete response) with a median duration of response of 7 months and a median survival of 13.5 months in 40 patients who had responded to initial platinum-based therapy. The longer the disease-free interval before relapse, the greater was the likelihood of response.

In the third example, the combination of carboplatin (300 mg/m2) on day 8 preceded by cyclophosphamide (100 mg/m2/day) on days 1 to 7 in 28 patients produced nine objective responses (fi ve complete and four partial).171 Six of these responses (46%) occurred among 13 patients who were initial responders and hence platinum sensitive. Only three responses (20%) were observed among the 15 platinum-resistant patients. The relatively high response rate among the platinum-resistant group may be accounted for by the response defi nitions, because the platinum-resistant group included patients with platinum-free intervals of up to 12 months’ duration.

The fourth example evaluated the platinum analog iproplatin at an initial dose of 270 mg/m2 in patients with recurrent disease after prior cisplatin or carboplatin treatment.172 Among 78 resistant patients, nine responses (three complete and six partial, 12%) were observed. Among the 19 sensitive patients, fi ve responses (two com-plete and three partial, 26%) were observed.

These four examples demonstrate that patients who respond to platinum-based therapy initially and relapse after a signifi cant plati-num-free interval have a high likelihood of responding again to intravenous platinum-based treatment. The correct defi nition of a signifi cant platinum-free interval is unclear, although the data suggest that the longer the interval, the more likely is the response. Most studies use the interval of 6 months as the point that defi nes platinum sensitivity.

Choice of Regimen. The principle of the treatment-free interval appears to apply regardless of the drug or regimen that is chosen.120 Virtually all active drugs tested to date appear to fare better in the platinum-sensitive group than in the platinum-resistant group. The

frequency of response, however, does appear to depend on the drug chosen. For any given point along the plot of treatment-free interval, the frequency of response to platinum-based therapy is 1.5 to 2.0 times greater than that reported with nonplatinum agents or regi-mens.122,171–174,185,187 In addition, the duration of response and survival is better with platinum-based regimens than with alternative, non-platinum-containing regimens.208

Debate has focused on whether a platinum compound as a single agent offered a less toxic and equally effi cacious alternative to com-bination chemotherapy in the setting of platinum-sensitive disease. A phase III trial has directly addressed this question. ICON4 ran-domized patients with platinum-sensitive disease, defi ned as a treat-ment-free interval from prior therapy of at least 6 months, to a platinum-containing regimen with or without a taxane.209 The vast majority of patients received either single-agent carboplatin or a combination of paclitaxel/carboplatin. The analysis showed that the patients receiving the taxane/platinum regimen had a superior response rate (66% versus 54%, P = 0.06), a superior progression-free survival (50% progression-free versus 40% at 1 year, hazard ratio = 0.76; P < 0.001), and a superior overall survival (57% alive versus 50% at 2 years, hazard ratio = 0.82; P = 0.023; Table 93-26). This is the fi rst study in the second-line setting to show a survival advan-tage for combination chemotherapy over a single agent and estab-lishes a taxane/platinum combination as the preferred treatment for patients with platinum-sensitive disease. (A confi rmatory trial will be required to make this the standard of care.)

Dose-Intense Second-Line Chemotherapy. Studies of dose-intense approaches to salvage chemotherapy for ovarian carci-noma117,210–212 purport to show an advantage for such approaches based on the observation of responses in the recurrent-disease situa-tion. The problem with the interpretation of many of these reports is the lack of information on prior response to platinum-based treat-ment. Without such data, one cannot determine whether the observed responses occurred only in platinum-sensitive patients at a rate that is expected with standard IV platinum therapy or whether platinum-resistant patients are responding to the higher-dose schedules.

Two reports169,170 do provide this critical information. The fi rst of these is a study of high-dose carboplatin (800 mg/m2 intravenously) every 5 weeks in 30 patients who had previously been treated with cisplatin.169 Eight objective responses (27%) were observed, none in patients with progressive disease during platinum-based therapy.

The second report examined retrospectively two phase II trials of salvage cisplatin-based intraperitoneal therapy.170 Among 89 patients, 52 were considered platinum sensitive, and 37 were considered plat-inum resistant. Among the sensitive patients, 29 (56%) developed an objective response; 17 were pathologic complete responses. Among the resistant patients only four responded (11%), all partially.

These two reports suggest that the increase in dose intensity that is achievable by dose escalation or intraperitoneal administration of drug

Table 93-25 Defi nitions of Platinum-Sensitive and Platinum-Resistant Patients for Decision Making in Salvage Treatment

Group Description

Platinum sensitive Initial response to platinum

Platinum-free interval: >6 months

Platinum resistant Progression on platinum

Best response stable to prior platinum

Relapse <6 months after prior platinum

Table 93-26 Results of ICON and OVAR 2.2*

PlatinumTaxane/Platinum

Relative Risk

Patients 410 392

Response 54% 66%

Progression free at 1 year 40% 50% 0.76†

Alive at 2 years 50% 57% 0.82‡

*Randomized trial of patients with platinum-sensitive recurrent disease.†P < 0.001.‡P = 0.023.Data from Schwartz P, Keating G, MacLusky N, et al: Tamoxifen therapy for

advanced ovarian cancer. Obstet Gynecol 1982;59:583–588.


cannot overcome true clinical resistance. Although this does not rule out the ability of an even greater dose intensity to overcome resistance, the fact that intraperitoneal drug administration with a fairly signifi -cant enhancement of drug exposure to cells did not yield a signifi cant response rate in resistant patients certainly argues against the likeli-hood that other dose-intense programs will succeed. Conversely, the activity of these approaches in sensitive patients is on the same order as that reported with standard intravenous doses of platinum-based regimens.116 There is little evidence so far to support the routine clinical use of such dose-intense approaches in the salvage setting.

Conclusions. Evidence supports the use of platinum-based therapy to treat patients with recurrent disease who responded to prior platinum-based therapy and experienced at least a 6-month treatment-free interval before recurrence. In such a setting, platinum-based therapy is far more likely to produce a response than is any alternative. Furthermore, recent evidence supports the use of a taxane/platinum-based combination regimen. The goal of therapy in this setting should be both improvement in survival and palliation. Dose-intense approaches do not appear to offer any advantage over standard intravenous doses.

MANAGEMENT OF PLATINUM-RESISTANT PATIENTS. Successful management of platinum-resistant patients (less than 6-month treatment-free interval after a preceding platinum-based regimen) depends on the identifi cation of agents that are non-cross-resistant with the platinum compounds. Until 1989, essentially no such agents had been identifi ed. Now a number of agents have been shown to produce objective responses in patients who have failed to respond to platinum-based initial therapy. Among these are paclitaxel,57,63–66 docetaxel,67–71 pegylated liposomal dox-orubicin,119,120,187–190 oral etoposide,118,191–194 topotecan,121,122,183–185 tamoxifen,204–206 gemcitabine,123–125 vinorelbine,195–199 and ifos-famide.57,213–215 Although each of these agents appears to be more active in platinum-sensitive patients, major interest has been gener-ated primarily by their activity in resistant patients.

In platinum-resistant patients, paclitaxel achieves responses in 24% to 30% of patients in phase II trials.63–66 This agent is clearly the treatment of choice in patients whose disease has failed to achieve an objective response to initial platinum-based regimens. Because pacli-taxel is now a part of standard front-line therapy, current focus is on agents that have activity in patients who have disease that is resistant to both the platinum compounds and paclitaxel. Six agents have dem-onstrated such activity: docetaxel, weekly paclitaxel, pegylated liposo-mal doxorubicin, topotecan, oral etoposide, and gemcitabine.

To date, no evidence suggests an advantage for combination che-motherapy over single-agent therapy in the platinum-resistant setting; hence, platinum-resistant patients should be treated with single-agent therapy consisting of one of the six agents that have demonstrated activity against resistant disease. The goal in this setting is palliative because no evidence indicates that therapy in this setting prolongs survival.

Other potential options for treatment of resistant ovarian carci-noma include more dose-intense therapy, biologic agents, and hor-mones. The lack of evidence supporting the value of more dose-intense approaches has been described. Insuffi cient data are available to estab-lish the value of biologic agents in resistant disease.

CONCLUSIONS REGARDING SALVAGE THERAPY. The current management of patients with ovarian carcinoma who have recurred after initial platinum-based chemotherapy rests on consid-eration of the results of the initial chemotherapy. Patients who respond to the initial platinum-based therapy and relapse after a platinum-free interval should be considered clinically sensitive to further platinum-based treatment. Recent evidence suggests that combination chemotherapy with a taxane/platinum combination produces a superior response rate and better progression-free and

overall survival. Such therapy will yield response rates as high as 60%, with up to 25% of patients achieving a complete response and also median survivals that exceed 2 years. No evidence indicates that more dose-intense approaches yield better results in these patients than results with standard intravenous schedules.

Patients who fail to respond to initial platinum-based therapy or who relapse shortly after completion of initial therapy should be regarded as clinically resistant to further platinum-based treatment. These patients should be treated with drugs that have been shown to have activity against resistant disease: weekly paclitaxel, docetaxel, pegylated liposomal doxorubicin, oral etoposide, topotecan, tamoxifen, gemcitabine, navelbine, and ifosfamide. No evidence exists that combi-nations of these drugs are more effective than single-agent therapy.

CONTROVERSIAL ISSUES. Two specifi c situations in the man-agement of patients with recurrent, persistent, or progressive disease deserve further comment: patients who have a rising CA-125 level as the only evidence of recurrence or progression and potential candi-dates for secondary surgical cytoreduction.

Patients with Increasing CA-125 Only. With the advent of the widespread use of CA-125 to monitor patients with ovarian carcinoma, an increasingly common situation to confront the physi-cian is that of the patient who develops an increasing CA-125 level but is otherwise free of any evidence, objective or otherwise, of recur-rence and is asymptomatic. Because of the high level of awareness of CA-125, patients naturally obsess about their CA-125 values and often demand that the physician intervene with therapy in such a situation. Unanswered as yet is the question as to what is the best choice for these patients: treatment or observation until the develop-ment of other objective evidence of disease or of symptoms.

Until recently, all treatment in the second-line setting was regarded as purely palliative. In such circumstances, the rationale for waiting until the patient developed either symptoms or other objective evi-dence of recurrence, which was almost always followed shortly there-after by symptoms, was obvious. Except for patients who demanded treatment, the general recommendation was that treatment should await the onset of symptoms or the appearance of other objective evidence of disease.

With the report of the results of ICON4/OVAR 2.2209 and the demonstration that survival could be improved by treatment in the platinum-sensitive setting, the question of immediate treatment should be revisited. As of this writing, no such study is under way; hence, treatment decisions must be made in the absence of defi nitive evidence. The best recommendation is to discuss the issue with the patient. In the absence of a preference on the patient’s part, a policy of watchful waiting until the development of symptoms would seem to be most prudent.

Potential Candidates for Secondary Surgical Cyto-reduction. Secondary surgical cytoreduction is debulking that is performed in the patient with recurrent, persistent, or progressive disease before the use of second-line chemotherapy.216 Mixed results have been reported with secondary debulking.217,218 The benefi t appears to depend on careful selection of candidates for the proce-dure. Patients whose disease can be surgically cytoreduced to the point at which no gross disease remains appear to be the patients who benefi t from the procedure.219 The procedure should therefore prob-ably be reserved for those patients in whom the surgeon feels that complete resection of all gross disease can be achieved. To some extent, the benefi t that is observed also depends on the availability of chemotherapy that will follow the procedure and to which the patient is likely to be sensitive.

Special SituationsThe natural history and spread patterns of celomic epithelial carci-nomas of the ovary create at least two special circumstances with


which the clinician must deal: intestinal obstruction and malignant effusions.

INTESTINAL OBSTRUCTION. Up to one half of patients with ovarian carcinoma develop symptoms of gastrointestinal obstruc-tion (nausea, vomiting, abdominal pain, and obstipation), most com-monly related to progressive cancer rather than to adhesions.220,221 Small bowel and, to a lesser extent, colonic and gastric outlet obstruc-tion can occur. Nonoperative management with intravenous hydra-tion, intestinal intubation, and parenteral hyperalimentation is acceptable initial management, but only 10% to 30% of cases of true obstruction will be relieved by such an approach; the majority of patients who are so relieved develop recurrent obstruction within 1 month.222,223

Surgical management of intestinal obstruction is the remaining option if no relief is obtained with noninvasive measures. If surgery is used indiscriminantly, median survival after such an approach is uniformly less than 8 months and not dramatically different from that seen in patients who are managed without surgery. The selection of patients to be considered for surgery will depend on several fea-tures: performance status, contraindications to general anesthesia, and availability of effective postoperative chemotherapy. Particularly in patients who are still potentially sensitive to chemotherapy, surgi-cal relief of the obstruction is warranted.224

MALIGNANT EFFUSIONS. Although malignant effusions asso-ciated with ovarian carcinoma can involve any one of three cavities (peritoneal, pleural, or pericardial), only the fi rst two are suffi ciently common to warrant detailed consideration. With regard to the fi rst of these, ascites is by far the most common of the effusions. At initial diagnosis, ascites is frequent but seldom severe enough to require specifi c intervention and usually responds to systemic chemotherapy with resolution after one to two cycles of treatment.225 For cases that are resistant to systemic chemotherapy and productive of signifi cant problems, paracentesis provides symptomatic relief. Intraperitoneal bleomycin226,227 and peritoneovenous shunts228,229 have been used in particularly troublesome cases, but success is temporary and most often related to concomitant chemotherapy the patient received.

Pleural effusions occur in 25% to 30% of patients and are cyto-logically positive for malignant cells in 75% of cases.230 When symp-tomatic, these effusions should be approached with thoracentesis. For patients who are receiving fi rst-line chemotherapy, the pleural effu-sion usually responds and does not become a recurring problem, whereas patients with recurrent disease and associated pleural effu-sion, particularly those with platinum-resistant disease, can experi-ence major problems with rapid reaccumulation of fl uid after thoracentesis. In such cases, drainage of the fl uid with a thoracostomy tube can provide complete resolution of the problem in 36% to 55% of patients.231,232 Instillation of sclerosing agents such as tetracycline, talc, or bleomycin can signifi cantly improve the rate at which com-plete resolution is observed.233 Patients with persistent problems after all these measures can be considered for pleurectomy or thorascopic pleurodesis.234,235

Germ Cell CancersApproximately 5% of ovarian cancer consists of germ cell carcinomas, which are classifi ed into two broad groups: dysgerminomas and non-dysgerminomas236 (Table 93-27). The same staging system as that used for celomic epithelial carcinomas is used for these tumors. Management begins with exploratory laparotomy to determine extent of disease and to permit surgical resection if possible. Subsequent treatment depends on histology and fi ndings at laparotomy that place patients into one of two groups: those with stage I to III disease that has been completely resected and those with incompletely resected stage III and IV disease. Therapeutic decisions, however, are based on comparisons with historic controls, because these lesions are suf-fi ciently uncommon that randomized trials are not feasible.

Tumor MarkersOvarian germ cell tumors produce markers in most cases. α-Fetoprotein elevations have been noted in patients with endodermal sinus tumors, immature teratomas, mixed germ cell tumors, embryo-nal carcinomas, and polyembryomas. Elevations of human chorionic gonadotropin have been observed with choriocarcinomas, embryonal carcinomas, polyembryomas, mixed cell tumors, and, less commonly, dysgerminomas. These markers are useful in assessing response to chemotherapy and in monitoring patients who are in complete remis-sion for evidence of recurrence.

Stage I to III Completely ResectedIn patients with completely resected stage I, II, or III endodermal sinus tumors, mixed cell tumors, embryonal carcinomas, choriocar-cinomas, and immature teratoma, the recurrence rate is high enough to warrant adjuvant therapy. The largest experience with adjuvant chemotherapy is that of the GOG in studies evaluating adjuvant VAC (vincristine, actinomycin D, and cyclophosphamide) and adju-vant BEP (bleomycin, etoposide, and cisplatin).237–239

The relative value of these regimens is best established by com-parison with historic data on no adjuvant therapy (Table 93-28), which shows a steady increase in the percentage of patients remaining disease free at 16 months of follow-up, as treatment progresses from no adjuvant through VAC to BEP. On the basis of these data, adjuvant BEP is the treatment of choice for patients with completely resected stage I to III disease and specifi c histologies: immature teratoma grade II and III, endodermal sinus tumor, mixed cell tumor, embryonal carcinoma, and choriocarcinoma. For other histologic types, data are insuffi cient to permit defi nitive conclusions (Box 93-3).

Stage III Incompletely Resected and Stage IV DiseaseAt least two chemotherapy regimens are active in patients with advanced or recurrent disease: VAC and PVB (cisplatin, vin-blastine, and bleomycin)239 (Table 93-29). The cisplatin-based com-bination yields higher response rates and a greater percentage of patients who remain disease free for extended periods. The current study of the GOG evaluates a combination of bleomycin, etoposide, and cisplatin.

Rare Malignant Ovarian Tumors

Accounting for fewer than 5% of all malignant ovarian tumors are a variety of rare ovarian neoplasms, including granulosa cell tumors,

Table 93-27 Classifi cation of Ovarian Germ Cell Carcinomas

Dysgerminoma

Nondysgerminoma

Teratoma

Immature

Mature

Monodermal or specialized

Endodermal sinus tumor

Embryonal carcinoma

Choriocarcinoma

Polyembryoma

Mixed cell tumors

Data from Gershenson DM, Malone JM Jr: Chemotherapy for malignant germ cell tumors of the ovary. In Deppe G (ed): Chemotherapy of Gynecologic Cancer, 2nd ed. New York, Wiley-Liss, 1990, pp 217–239.


thecoma-fi broma tumors, Sertoli-Leydig cell tumors, gynandroblasto-mas, and steroid cell tumors. Such lesions are best treated with surgi-cal resection if only limited disease is present. Appropriate management of more advanced disease is unclear. Although both radiation therapy and chemotherapy have been used in the management of advanced disease and as adjuvant therapy for limited disease, evidence is largely anecdotal. It is therefore not possible to make defi nitive recommenda-tions for the management of more advanced cases.

CANCER OF THE FALLOPIAN TUBEThe fallopian tube is the least common site of origin in the female genital tract for cancer. The most common histologic type of cancer, accounting for 90% of all malignancies of the tube, is papillary serous adenocarcinoma, but even this type is rare, with only 300 cases reported annually in the United States. The pattern of spread is similar to that seen with celomic epithelial lesions of the ovary, dis-semination throughout the peritoneal cavity being perhaps the most important route of spread; hence, it is often diffi cult to distinguish between ovarian and fallopian tube primary tumors. Criteria have been set for lesions that are designated to be of fallopian tube origin:240,241 The main tumor arises from the endosalpinx and is in the tube; the histologic pattern shows a papillary pattern; a transition zone between benign and malignant epithelium must be demon-strable if the wall is involved; and the ovaries and endometrium must be either normal or less involved than the tube.

As a refl ection of the propensity of tubal cancer to spread by intraperitoneal dissemination, 5-year survival rates correlate well with the degree to which the primary lesion penetrates the wall of the tube: 91% for intramucosal lesions, 53% for those with mucosal wall inva-sion, and 25% or less for lesions that penetrate the tubal serosa.242 The actual staging system that is used, however, is a modifi cation of the FIGO staging system for ovarian cancer (see Table 93-1).

In contradistinction to ovarian cancer, fallopian tube cancers tend to be fi rst seen at an earlier stage of development: roughly 33% as stage I, 33% as stage II, and 33% as more advanced disease. The mainstay of therapy for patients with limited disease is surgical resec-tion. Whether postoperative radiation therapy is of value as an adju-vant treatment in patients whose tumors have been completely resected is unclear in the absence of a randomized trial. If radiation therapy does have a role, it would seem to be in patients who have no gross disease. Studies of chemotherapy in fallopian tube carcinoma are anecdotal. Agents that have been noted to produce responses are the same that have been noted to be active in celomic epithelial

Table 93-28 GOG Trials of Adjuvant Chemotherapy for Ovarian Germ Cell Carcinoma

Therapy

Endometrial Sinus Tumor and Mixed Cell Tumor Immature Teratoma

No adjuvant 34/165 (21%)* 36/56 (64%)

VAC† 53/82 (65%) 59/70 (84%)

BEP‡ 30/31 (97%) 18/19 (95%)

*Percentage of patients remaining disease free at a median follow-up of 16 months after completion of therapy.

†VAC, vincristine (1.5 mg/m2 intravenously, maximum 2 mg), every 2 weeks, × 12, actinomycin D (350 µg/m2/day intravenously) × 5 days every 4 weeks × 6, and cyclophosphamide (150 mg/m2/day intravenously) × 5 days every 4 weeks × 6.

‡BEP, bleomycin (20 U/m2 intravenously, maximum 30 units) per week × 9, etoposide (100 mg/m2/day intravenously) × 5 every 3 weeks × 3, and cisplatin (20 mg/m2/day intravenously) × 5 every 3 weeks × 3.

Data from Slayton RE, Park RC, Silverberg SG, et al: Vincristine, dactinomycin and cyclophosphamide in the treatment of malignant germ cell tumors of the ovary: a Gynecologic Oncology Group study: a fi nal report. Cancer 1985;56:243–248; Williams S, Blessing J, Liao S, et al: Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group. J Clin Oncol 1994;12:701.

Box 93-3. THERAPEUTIC DECISION IN NEWLY DIAGNOSED GERM CELL CARCINOMAS

Patients with germ cell carcinomas should be divided into two groups: those with stage I to III disease that has been completely resected and those with incompletely resected stage III and IV disease. After complete resection, patients with endodermal sinus tumor, mixed cell tumor, embryonal carcinoma, choriocarcinoma, or immature teratomas, grade II or III, should receive adjuvant therapy consisting of VP-16 100 mg/m2/day intravenously plus cisplatin 20 mg/m2/day intravenously for 5 days every 3 weeks for three cycles and bleomycin 30 units intravenously weekly for the 9 weeks of the three cycles. Second-look laparotomy at the conclusion of therapy is unnecessary if all clinical evidence of disease has disappeared and if both α-fetoprotein and human chorionic gonadotropin levels are normal.

Patients with incompletely resected stage III and IV disease, regardless of histologic type, should be treated with four cycles of the combination described earlier. Those with complete remission, including normalization of α-fetoprotein and human chorionic gonadotropin, can be followed with no further treatment. Those with persistent disease will require further therapy with other active agents, but the precise nature of this therapy has not been defi ned. Other active drugs include actinomycin D, ifosfamide, and other alkylating agents, anthracyclines, methotrexate, and the vinca alkaloids.

Because most tumors produce either α-fetoprotein or human chorionic gonadotropin or both, therapy should be monitored with the appropriate markers. Subsequent follow-up management of complete responders also should include the marker(s) that were positive.

Table 93-29 GOG Trials of Two Three-Drug Combinations in Incompletely Resected Stage III and IV Germ Cell Carcinomas of the Ovary

Histology and Therapy

Complete Response

Partial Response

Disease Free

Immature teratoma

VAC* — — 4/8 (50%)

PVB† 2/9 (22%) 2/9 (22%) 12/24 (50%)

Endodermal Sinus Tumor and Mixed Cell Tumor

VAC — — 3/14 (21%)

PVB 13/24 (54%) 8/24 (33%) 31/58 (53%)

Dysgerminoma

PVB 3/4 (75%) 1/4 (25%) 7/8 (88%)

Choriocarcinoma

PVB 2/3 (67%) 1/3 (33%) 2/3 (67%)

*VAC, vincristine (1.5 mg/m2 intravenously, maximum 2 mg), every 2 weeks × 12, actinomycin D (350 µg/m2/day intravenously), × 5 days every 4 weeks × 6, and cyclophosphamide (150 mg/m2/day intravenously), × 5 days every 4 weeks × 6.

†PVB, vinblastine (12 mg/m2 intravenously) every 3 weeks × 4, bleomycin (20 U/m2 intravenously, maximum 30 units) per week, and 12 cisplatin (20 mg/m2/day intravenously), × 5 every 3 weeks × 3–4.

Data from Williams SD, Blessing JA, Moore DH, et al: Cisplatin, vinblastine, and bleomycin in recurrent ovarian germ cell tumors: a trial of the Gynecologic Oncology Group. Ann Intern Med 1989;3:22–27.


carcinoma of the ovary. It would seem reasonable to base the choice of systemic therapy in advanced or recurrent disease on extrapolation from data in ovarian carcinoma (Box 93-4).

FUTURE DIRECTIONSThe development of additional information about the nature and management of germ cell cancers and rarer malignant tumors of the ovary as well as fallopian tube cancer will continue to be restricted by the low frequency of these lesions. With regard to celomic epithe-lial carcinomas of the ovary, however, progress should continue to be rapid. Current and future investigational efforts focus on several distinct areas: biology of ovarian carcinoma, screening and early detection, the proper role of surgery, new agents and their role in systemic therapy, and the role of dose-intense approaches.

First, with regard to the biology of ovarian carcinoma, specifi c studies are seeking (1) to characterize factors associated with ovarian carcinoma and its outcome, such as specifi c genetic defects associated with hereditary ovarian carcinoma, various oncogenes, and DNA ploidy; (2) to identify features that are predictive of the likelihood of developing ovarian carcinoma; and (3) to ascertain the biologic reasons for the observation that more aggressive disease is associated with older patients. As these and other investigations expand the understanding of the basic nature of ovarian carcinoma, the develop-ment of better and more specifi c methods for early detection and treatment of the disease should become possible. Where this line of work will ultimately lead is speculative but exciting.

Second, the evolution of effective techniques for screening for and early detection of ovarian carcinoma has a high priority in ovarian carcinoma, the only one of the major gynecologic cancers for which

early detection is not the rule. Most interest centers on the potential for transvaginal sonography, especially when enhanced by color-fl ow Doppler, to permit earlier detection of disease. The recent report of potential value for proteomic patterns in the serum for early detection of ovarian carcinoma has focused on the biologic front as well. Con-fi rmation of the value of such approaches must await larger trials.

Third, although the effi cacy of initial surgical cytoreduction in patients with stage III disease has been accepted on the basis of ret-rospective analyses, prospective trials are needed to address several important questions. Two trials of interval surgical cytoreduction at the midpoint of a series of chemotherapy courses suggest a role for this procedure in patients with a less than optimal initial surgical effort. Prospective randomized trials of initial or secondary surgical cytoreduction have not been performed. Investigations of the relative merits of each of these approaches versus no surgery are needed, as well as trials evaluating which of these points in the therapy represents the optimal time to introduce surgical resection into the management of advanced disease. Such studies are diffi cult to conduct because of the widespread acceptance of the role of surgical cytoreduction in ovarian carcinoma.

Fourth, efforts continue to investigate the role of new agents in the management of ovarian carcinoma. Current interest continues to center on further delineation of the role of a number of promising new cytotoxic and biologic agents. The plethora of new agents with activ-ity in patients who are clinically resistant to the platinum compounds and paclitaxel opens the possibility for the addition of clinically non-cross-resistant drugs to front-line paclitaxel/platinum therapy. Defi n-ing the role of these new agents is of paramount importance.

Finally, dose intensity continues to command signifi cant interest. Three basic ways to enhance the dose intensity have been proffered: escalation of dose within the range that can be achieved without marrow reconstitution, high-dose chemotherapy with support of autologous bone marrow transplant or peripheral stem cell transfu-sion, and, in the case of ovarian carcinoma, intraperitoneal adminis-tration of drug. Eight randomized trials of dose escalation over a standard range of doses have been completed. Six show no advantage to a doubling of dose intensity, and the other two have major design problems. Further exploration of this approach seems unwarranted.

Although uncontrolled studies and anecdotal reports of high-dose chemotherapy with marrow reconstitution appear promising, the highly selected nature of the patients and the expense of the proce-dures mandate that randomized, comparative trials demonstrate the superiority of this approach over standard therapy before it can be considered a valid part of the therapeutic armamentarium.

Intraperitoneal administration of drug, although it has been under study for more than a decade, still has no defi ned role in manage-ment. In the salvage setting, it appears to have no advantage over intravenous therapy. In the setting of fi rst-line treatment, three large randomized trials in patients with small-volume disease show small advantages at the expense of markedly enhanced toxicity. The fi nal determination of the role, if any, for intraperitoneal therapy awaits the development of less toxic regimens. If a role for intraperitoneal therapy exists, data show that it will be in only those patients with extremely small-volume disease or perhaps no residual disease; hence, its role will be a very narrow one.

In conclusion, the future holds the promise of continuing advances in the management of patients with celomic epithelial carcinoma of the ovary. Although the explosion of knowledge of the basic nature of the disease holds the greatest potential for improvement, the iden-tifi cation of an effective screening technique, the clarifi cation of the role of surgery in advanced disease, and the introduction of exciting new biologic and cytotoxic agents offer the promise of better treat-ment in the immediate future. The great promise of dose-intense regimens, which are still worthy of further investigation, suffers from a growing body of evidence that no advantage is obtained at least over the clinically achievable range of doses unsupported by marrow reconstitution.

Box 93-4. THERAPEUTIC DECISIONS IN FALLOPIAN TUBE CARCINOMAS

Firm recommendations on the management of fallopian tube carcinomas are diffi cult because of the lack of extensive clinical studies. With the best evidence available, four basic groups of patients are found.

Intramucosal Lesions OnlyFor patients with intramucosal lesions only, cure is excellent with surgical resection. Patients should undergo total abdominal hysterectomy and bilateral salpingo-oophorectomy and should be monitored closely with no further therapy.

Mucosal Wall InvasionFor patients with mucosal wall invasion, the recurrence rate is approximately 50%. These patients are candidates for adjuvant therapy, but no data support the use of such treatment. If adjuvant therapy is to be used, choices similar to those for high-risk ovarian carcinoma seem reasonable. If radiation therapy is to be used, it would seem appropriate to treat the entire abdominal cavity. A preferable approach would be the use of platinum-based chemotherapy, on the assumption that this disease responds similarly to the response of celomic epithelial carcinoma.

Penetration of the SerosaFor patients with penetration of the serosa but no gross spread, the recurrence rate exceeds 75%. An even stronger case for the use of adjuvant therapy can be made. The choices are similar to those noted earlier.

Metastatic DiseaseFor patients with obvious spread of disease to locoregional and distant sites, platinum-based chemotherapy is a reasonable choice. The overall strategy should be similar to that used for patients with advanced or recurrent celomic epithelial carcinoma of the ovary.


REFERENCES 1. Jemal A, Thomas A, Murray T, Thun M: Cancer

statistics, 2002. CA Cancer J Clin 2002;52:23–47. 2. Lynch HT, Watson P, Lynch JF, et al: Hereditary

ovarian cancer: heterogeneity in age at onset. Cancer 1993;71:573–581.

3. Lynch HT, Casey MJ, Shaw TG, Lynch JF: Hereditary factors in gynecologic cancer. Oncologist 1998;3:319–338.

4. Rubin SC, Benjamin I, Behbakht K, et al: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 1996;335:1413–1416.

5. Buller RE, Anderson B, Connor JP, et al: Familial ovarian cancer. Gynecol Oncol 1993;51:160–166.

6. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Epithelial ovarian cancer and combined oral contraceptives. Int J Epidemiol 1989;18:538–545.

7. The new FIGO stage grouping for primary carcinoma of the ovary (1985). Gynecol Oncol 1986;25:383–385.

8. Omura G, Blessing J, Ehrlich C, et al: A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. Cancer 1986;57:1725–1730.

9. Omura G, Bundy B, Berek J, et al: Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1989;7:457–465.

10. Ehrlich C, Einhorn L, Williams S, et al: Chemotherapy for stage III-IV epithelial ovarian cancer with cis-dichlorodiammine-platinum. II: Adriamycin, and cyclophosphamide: a preliminary report. Cancer Treat Rep 1979;63:281–288.

11. Greco F, Julian C, Richardson R, et al: Advanced ovarian cancer: brief intensive combination chemotherapy and second-look operation. Obstet Gynecol 1981;58:199–205.

12. Young R, Howser D, Myers C, et al: Combination chemotherapy (CHex-UP) with intraperitoneal maintenance in advanced ovarian adenocarcinoma. Proc ASCO 1981;22:465.

13. Gall S, Bundy B, Beecham J, et al: Therapy of stage III (optimal) epithelial carcinoma of the ovary with melphalan or melphalan plus Corynebacterium parvum (a Gynecologic Oncology Group study). Gynecol Oncol 1986;25:26–36.

14. Hoskins W, Bundy B, Thigpen T, Omura G: The infl uence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992;47:159–166.

15. Thigpen T, Brady M, Omura G, et al: Age as a prognostic factor in ovarian carcinoma: the Gynecologic Oncology Group experience. Cancer 1993;71:606–614.

16. Colgan T, Norris H: Ovarian epithelial tumors of low malignant potential: a review. Int J Gynecol Pathol 1983;1:367–382.

17. Pecorelli S, Odicino F, Maisoneuve P, et al: Carcinoma of the ovary. J Epidemiol Biostat 1998;3:75–102.

18. Russell P: Surface epithelial-stromal tumors of the ovary. In Kurman R (ed): Blaustein’s Pathology of the Female Genital Tract. New York, Springer-Verlag, 1994, pp 705–782.

19. Menzin A: Update on low malignant potential ovarian tumors. Oncology 2000;14:897–906.

20. Burger C, Prinssen H, Baak J, et al: The management of borderline epithelial tumors of the ovary. Int J Gynecol Cancer 2000;10:181–197.

21. Sykes P, Quinn M, Rome R: Ovarian tumors of low malignant potential: a retrospective study of 234 patients. Int J Gynecol Cancer 1997;7:218–226.

22. Sengupta P, Shanks J, Buckley C, et al: Require-ment for expert histopathological assessment of ovarian cancer and borderline tumours. Br J Cancer 2000;82:760–762.

23. Bloss J, Brady M, Liao S, et al: Extraovarian peritoneal serous papillary carcinoma: a phase II trial of cisplatin and cyclophosphamide with comparison to a cohort with papillary serous ovarian carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2003;89:148–154.

24. Piver MS, Baker TR, Jishi MF, et al: Familial ovarian cancer: a report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry (1981–1991). Cancer 1993;71:582–588.

25. Srivastava A, McKinnon W, Wood M: Risk of breast and ovarian cancer in women with strong family histories. Oncology 2001;15:889–902.

26. Watson P, Butzow R, Lynch H, et al: The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2001;82:223–228.

27. Boyd J, Sonoda Y, Federici M, et al: Clinicopatho-logic features of BRCA-linked and sporadic ovarian cancer. JAMA 2000;283:2260–2265.

28. Ben David Y, Chetrit A, Hirsh-Yechezkel G, et al: Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 2002;20:463–466.

29. Cass I, Baldwin R, Varkey T, et al: Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 2003;97:2187–2195.

30. Piver MS, Jishi MF, Tsukada Y, et al: Primary peritoneal carcinoma after oophorectomy in women with a family history of ovarian cancer. Cancer 1993;71:2751–2755.

31. Eisen A, Rebbeck T, Wood W, Weber B: Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer. J Clin Oncol 2000;18:1980–1995.

32. Kerlikowske K, Brown J, Grady D: Should women with familial ovarian cancer undergo prophylactic oophorectomy? Obstet Gynecol 1992;80:700–707.

33. Scheuer L, Kauff N, Robson M, et al: Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 2002;20:1260–1268.

34. ACOG Committee on Gynecologic Practice: The role of the generalist obstetrician-gynecologist in the early detection of ovarian cancer. Gynecol Oncol 2002;87:237–239.

35. NIH Consensus Development Panel on Ovarian Cancer: Ovarian cancer: screening, treatment, and follow-up. JAMA 1995;273:491–497.

36. Petricoin E, Ardekani A, Hitt B, et al: Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002;359:572–577.

37. Jacobs I, Davies A, Bridges J, et al: Prevalence screening for ovarian cancer in postmenopausal women by CA-125 measurement and ultrasonography. Br Med J 1993;306:1030–1034.

38. Boyd J: Molecular genetics of hereditary ovarian cancer. Oncology 1998;12:399–406.

39. ASCO Working Group on Genetic Testing for Cancer Susceptibility: American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 2003;21:2397–2406.

40. Gwinn M, Lee N, Rhodes P, et al: Pregnancy, breast feeding, and oral contraceptives and the risk of epithelial ovarian cancer. J Clin Epidemiol 1990;43:559–568.

41. Weiss N, Lyon J, Liff J, et al: Incidence of ovarian cancer in relation to the use of oral contraceptives. Int J Cancer 1981;28:669–671.

42. Parazzini F, La Vecchia C, Negri E, et al: Oral contraceptive use and the risk of ovarian cancer: an Italian case control study. Eur J Cancer 1991;27:594–598.

43. Grabrick D, Hartmann L, Cerhan J, et al: Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer. JAMA 2000;284:1791–1798.

44. Ursin G, Henderson B, Haile R, et al: Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 1997;57:3678–3681.

45. Eeles R, Powles T, Ashley S, et al: BRCA1, BRCA2 mutation and pedigree analysis to determine genetic risk in the UK Royal Marsden Hospital Tamoxifen Prevention Trial [abstract]. Br J Cancer 2000;83(suppl 1):25.

46. Narod S, Risch H, Moslehi R, et al: Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998;339:424–428.

47. Modan B, Hartge P, Hirsh-Yechezkel G, et al: Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:235–240.

48. Risch H: Estrogen replacement therapy and risk of epithelial ovarian cancer. Gynecol Oncol 1996;63:254–257.

49. Rodriguez C, Patel A, Calle E, et al: Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001;285:1460–1465.

50. Lacey J, Mink P, Lubin J, et al: Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334–341.

51. Sit A, Modugno F, Weissfeld J, et al: Hormone replacement formulations and risk of ovarian carcinoma. Gynecol Oncol 2002;86:118–123.

52. Guidozzi F, Daponte A: Estrogen replacement therapy for ovarian carcinoma survivors. Cancer 1999;86:1013–1018.

53. Neven P, Goldstein S, Ciaccia A, et al: The effect of raloxifene on the incidence of ovarian cancer in postmenopausal women. Gynecol Oncol 2002;85:388–390.

54. Omura G, Morrow P, Blessing J, et al: A randomized comparison of melphalan versus melphalan plus hexamethylmelamine versus Adriamycin plus cyclophosphamide in ovarian carcinoma. Cancer 1983;51:783–789.

55. van der Burg MEL, van Lent M, Buyse M, et al: The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. N Engl J Med 1995;332:629.

56. Rose P, Nerenstone S, Brady M, et al: A phase III randomized study of interval secondary cytoreduction in patients with advanced stage ovarian carcinoma with suboptimal residual disease: a Gynecologic Oncology Group study [abstract]. Proc ASCO 2002;21:201a.

57. Thigpen JT: Single agent chemotherapy in the management of ovarian carcinoma. In Alberts DS, Surwit EA (eds): Ovarian Carcinoma. Boston, Martinus Nijhoff, 1985, pp 115–146.

58. Wiltshaw E, Kroner T: Phase II trial of cis-dichlorodiammineplatinum (II) (NSC-119875) in advanced adenocarcinoma of the ovary. Cancer Treat Rep 1976;60:55–60.

59. Thigpen T, Lagasse L, Homesley H, et al: Cisplatinum in the treatment of advanced or recurrent adenocarcinoma of the ovary: a phase II study of the Gynecologic Oncology Group. Am J Clin Oncol 1983;6:431–435.


60. Kjorstad K, Bertelsen K, Slevin M, et al: Phase II trial of carboplatin in ovarian cancer. Proc ASCO 1986;5:116.

61. Pecorelli S, Bolis G, Vassena L, et al: Randomized comparison of cisplatin and carboplatin in advanced ovarian cancer. Proc ASCO 1988;7:136a.

62. Rowinsky EK, Donehower RC, Jones RJ, Tucker RW: Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res 1988;48:4093–4100.

63. Thigpen T, Blessing J, Ball H, et al: Phase II trial of taxol as second-line therapy for ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1994;12:1748–1753.

64. Einzig A, Wiernik P, Sasloff J, et al: Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma. J Clin Oncol 1992;10:1748–1756.

65. McGuire W, Rowinsky E, Rosenshein N, et al: Taxol: a unique antineoplastic agent with signifi cant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 1989;111:273–279.

66. Kohn E, Sarosy G, Bicher A, et al: Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst 1994;86:18–24.

67. Verschraegen C, Sittisomwong T, Kudelka A, et al: Docetaxel for patients with paclitaxel-resistant mullerian carcinoma. J Clin Oncol 2000;18:2733–2739.

68. Francis P, Schneider J, Hann L, et al: Phase II trial of docetaxel in patients with platinum-refractory advanced ovarian cancer. J Clin Oncol 1994;12:2301–2308.

69. Kaye S, Piccart M, Aapro M, et al: Phase II trials of docetaxel (Taxotere) in advanced ovarian cancer: an updated review. Eur J Cancer 1997;33:2167–2170.

70. Rose P, Blessing J, Ball H, et al: A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2003;88:130–135.

71. Piccart M, Gore M, Ten Bokkel Huinink W, et al: Docetaxel: an active new drug for treatment of advanced epithelial ovarian cancer. J Natl Cancer Inst 1995;87:676–681.

72. Thigpen T, Vance R, Lambuth B, et al: Chemo-therapy for advanced or recurrent gynecologic cancer. Cancer 1987;60:2104–2116.

73. Alberts DS, Green SJ, Hannigan EV, et al: Improved effi cacy of carboplatin plus cyclophos-phamide versus cisplatin plus cyclophosphamide: preliminary report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV suboptimal ovarian cancer, abstracted. Proc ASCO 1989;8:151.

74. ten Bokkel Huinink WW, van der Burg MEL, van Oosterom AT, et al: Carboplatin in combination therapy for ovarian cancer. Cancer Treat Rev 1988;15(suppl B):9–15.

75. Pater J: Cyclophosphamide/cisplatin versus cyclophosphamide/carboplatin in macroscopic residual ovarian cancer: initial results of a National Cancer Institute of Canada Clinical Trials Group trial, abstracted. Proc ASCO 1990;9:155.

76. Edmondson JH, McCormack GM, Wieand HS, et al: Cyclophosphamide-cisplatin versus cyclophosphamide-carboplatin in stage III-IV ovarian carcinoma: a comparison of equally myelosuppressive regimens. J Natl Cancer Inst 1989;81:1500–1504.

77. Alberts DS, Young L, Mason NL, et al: In vitro evaluation of anticancer drugs against ovarian cancer at concentrations achievable by intraperitoneal administration. Semin Oncol 1985;12:38–42.

78. Ozols R, Corden B, Jacob J, et al: High-dose cisplatinum in hypertonic saline. Ann Intern Med 1984;100:19–24.

79. Howell S, Zimm S, Markman M, et al: Long-term survival of advanced refractory ovarian carcinoma patients with small-volume disease treated with intraperitoneal chemotherapy. J Clin Oncol 1987;5:1607–1612.

80. Ozols R: High dose therapy with cisplatin and its analogs in ovarian cancer: current status and future studies. ASCO Educ Book 1987, pp 69–70.

81. Levin L, Hryniuk WM: Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 1987;5:756–767.

82. Levin L, Simon R, Hryniuk W: Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis. J Natl Cancer Inst 1993;85:1732–1742.

83. Ozols RF, Ostchega Y, Curt G, Young RC: High-dose carboplatin in refractory ovarian cancer patients. J Clin Oncol 1987;5:197–201.

84. McGuire WP, Hoskins WJ, Brady MF, et al: Assessment of dose-intensive therapy in suboptimally debulked ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 1995;13:1589–1599.

85. Kaye S, Lewis C, Paul J, et al: Randomized study of two doses of cisplatin and cyclophosphamide in epithelial ovarian cancer. Lancet 1992;340:329–333.

86. Colombo N, Pittelli M, Parma G, et al: Cisplatin dose intensity in advanced ovarian cancer: a randomized study of conventional dose versus dose-intense cisplatin monochemotherapy [abstract]. Proc ASCO 1993;12:255.

87. Conte P, Bruzzone M, Carnino F, et al: High-dose versus low-dose cisplatin in combination with cyclophosphamide and epidoxorubicin in suboptimal ovarian cancer: a randomized study of the Gruppo Oncologico Nord-Ouest. J Clin Oncol 1996;14:351–356.

88. Gore M, Mainwaring P, Macfarlane V, et al: Randomized trial of dose-intensity with single agent carboplatin in patients with epithelial ovarian cancer. J Clin Oncol 1998;16:2426–2434.

89. Jakobsen A, Bertelsen K, Andersen JE, et al: Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group Study. J Clin Oncol 1997;15:193–198.

90. Dittrich C, Obermair A, Kurz C, et al: Prospective randomized trial of cisplatin/carboplatin versus conventional cisplatin/cyclophosphamide in epithelial ovarian cancer: fi rst results of the impact of platinum dose intensity on patient outcome [abstract]. Proc Am Soc Clin Oncol 1996;15:279.

91. Ngan H, Choo Y, Cheung M, et al: A randomized study of high-dose versus low-dose cisplatin combined with cyclophosphamide in the treatment of advanced ovarian cancer. Chemotherapy 1989;35:221–227.

92. Coldman A, Goldie J: Impact of dose-intense chemotherapy on the development of permanent drug resistance. Semin Oncol 1987;14:29–33.

93. 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;334:1–6.

94. Piccart MJ, Bertelsen K, James K, et al: Randomized Intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000;92:699–708.

95. Muggia FM, Braly PS, Brady MF, et al: Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a

Gynecologic Oncology Group study. J Clin Oncol 2000;18:106–115.

96. The International Collaborative Ovarian Neoplasm (ICON) Group: Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. Lancet 2002;360:505–515.

97. The International Collaborative Ovarian Neoplasm (ICON) Group: ICON2: randomised trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer. Lancet 1988;352:1571–1576.

98. Pertussini E, Ratajczak J, Majka M, et al: Investigating the platelet-sparing mechanism of paclitaxel/carboplatin combination chemotherapy. Blood 2001;97:638–644.

99. Neijt J, Engelholm S, Tuxen M, et al: Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 2000;18:3084–3092.

100. DuBois A, Lueck H, Meier W, et al: Cisplatin/paclitaxel vs carboplatin/paclitaxel in ovarian cancer: update of an Arbeitsgemeinschaft Gynaekolgische Onkologie study group trial [abstract]. Proc ASCO 1999;18:356a.

101. Ozols R, Bundy B, Fowler J, et al: Randomized phase III study of cisplatin/paclitaxel versus carboplatin/paclitaxel in optimal stage III epithelial ovarian cancer: a Gynecologic Oncology Group trial [abstract]. Proc ASCO 1999;18:356a.

102. Ozols R: Maintenance therapy in advanced ovarian cancer: progression-free survival and clinical benefi t. J Clin Oncol 2003;21:2451–2453.

103. Pignata S, Deplacido S, Scambia G, et al: Topotecan vs nihil after response to carboplatin and paclitaxel in advanced ovarian cancer: early results of the MITO-1 study [abstract]. Proc ASCO 2003;22:446.

104. Pfi sterer J, Lotholary A, Kimmig R, et al: Paclitaxel/carboplatin vs. paclitaxel/carboplatin followed by topotecan in fi rst-line treatment of ovarian cancer FIGO stages IIB-IV: interim results of a gynecologic cancer Intergroup phase III trial of the AGO Ovarian Cancer Study Group and GINECO [abstract]. Proc ASCO 2003;22:446.

105. Markman M, Liu P, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 2003;21:2460–2465.

106. Browder T, Butterfi eld C, Kraling B, et al: Antiangiogenic scheduling of chemotherapy improves effi cacy against experimental drug-resistant cancer. Cancer Res 2001;60:1878–1886.

107. Eisenhauer E, ten Bokkel Huinink W, Swenerton K, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 1994;12:2654–2666.

108. Markman M, Rose P, Jones E, et al: Ninety-six-hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens. J Clin Oncol 1998;16:1849–1851.

109. Hurteau J: Personal communication on behalf of the GOG.

110. Fennelly D, Aghajanian C, Shapiro F, et al: Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 1997;15:187–192.

111. Markman M, Hall J, Spitz D, et al: Phase II trial of weekly single-agent paclitaxel in platinum/


paclitaxel-refractory ovarian cancer. J Clin Oncol 2002;20:2365–2369.

112. Andersson H, Boman K, Ridderheim M, et al: An updated analysis of a randomized study of single agent paclitaxel given weekly vs every 3 weeks to patients with ovarian cancer treated with prior platinum therapy [abstract]. Proc ASCO 2000;19:380a.

113. Alberts DS, Liu PY, Hannigan EV, et al: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950–1955.

114. Markman M, Bundy B, Alberts D, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperito-neal cisplatin in small-volume stage III ovarian carcinoma: an Intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:1001–1007.

115. Armstrong D, Bundy B, Baergen R, et al: Randomized phase III study of intravenous paclitaxel and cisplatin versus intravenous paclitaxel, intraperitoneal cisplatin and intraperitoneal paclitaxel in optimal stage III epithelial ovarian cancer: a Gynecologic Oncology Group trial (GOG 172) [abstract]. Proc ASCO 2002;21:201a.

116. Thigpen T: Dose-intensity in ovarian carcinoma: hold, enough? J Clin Oncol 1997;15:1291–1293.

117. Stiff P, Veum-Stone J, Lasarus H, et al: High-dose chemotherapy and autologous stem-cell transplantation for ovarian cancer: an autologous blood and marrow transplant registry report. Ann Intern Med 2000;133:504–515.

118. Rose P, Blessing J, Mayer A, Homesley H: Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1998;16:405–410.

119. Muggia F, Hainsworth J, Jeffers S, et al: Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modifi cation by liposomal encapsulation. J Clin Oncol 1997;15:987–993.

120. Gordon A, Granai C, Rose P, et al: Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 2000;18:3093–3100.

121. ten Bokkel Huinink W, Gore M, Carmichael J, et al: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997;15:2183–2193.

122. Bookman M, Malmstrom H, Bolis G, et al: Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 1998;16:3345–3352.

123. Friedlander M, Millward M, Bell D, et al: A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol 1998;9:1343–1345.

124. Shapiro J, Millward M, Rischin D, et al: Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 1996;63:89–93.

125. Lund B, Hansen O, Theilade K, et al: Phase II study of gemcitabine in previously treated ovarian cancer patients. J Natl Cancer Inst 1994;86:1530–1533.

126. Rose P, Rodriguez M, Waggoner S, et al: Phase I study of paclitaxel, carboplatin, and increasing days of prolonged oral etoposide in ovarian, peritoneal,

and tubal carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2000;18:2957–2962.

127. Bookman M, Darcy K, Clarke-Pearson D, et al: Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol 2003;21:283–290.

128. Manetta A, Blessing J, Hurteau J: Evaluation of cisplatin and cyclosporin A in recurrent platinum-resistant ovarian cancer: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol 1998;68:45–46.

129. Fracasso P, Brady M, Moore D, et al: Phase II study of paclitaxel and valspodar in refractory ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2001;19:2975–2982.

130. Joly F, Mangioni C, Nicolleto M, et al: A phase 3 study of PSC 833 in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary cancer of the peritoneum [abstract]. Proc ASCO 2002;21:202a.

131. Pujade-Lauraine E, Guastalla J, Colombo N, et al: Intraperitoneal recombinant interferon gamma in ovarian cancer patients with residual disease at second-look laparotomy. J Clin Oncol 1996;14:343–350.

132. Windbichler G, Hausmaninger H, Stummvoll W, et al: Interferon-gamma in the fi rst-line therapy of ovarian cancer: a randomized phase III trial. Br J Cancer 2000;82:1138–1144.

133. Paley P, Staskus K, Gebhard K, et al: Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer 1997;80:98–106.

134. Markman M: The role of CA-125 in the management of ovarian cancer. Oncologist 1997;2:6–9.

135. Bridgewater J, Nelstrop A, Rustin G, et al: Comparison of standard and CA-125 response criteria in patients with epithelial ovarian cancer treated with platinum or paclitaxel. J Clin Oncol 1999;17:501–508.

136. Rustin G, Nelstrop A, Bentzen S, et al: Selection of active drugs for ovarian cancer based on CA-125 and standard response rates in phase II trials. J Clin Oncol 2000;18:1733–1739.

137. Berek J, Hacker N, Lagasse L, et al: Second look laparotomy in stage III epithelial ovarian cancer: clinical variables associated with disease status. Obstet Gynecol 1984;64:207–212.

138. Potter M, Hatch K, Soong S, et al: Second look laparotomy and salvage therapy: a research modality only? Gynecol Oncol 1992;44:3–9.

139. Podratz K, Kinney W: Second-look operation in ovarian cancer. Cancer 1993;71:1551–1558.

140. Greer B, Bundy B, Ozols R, et al: Implications of second-look laparotomy in the context of Gynecologic Oncology Group Protocol 158: a non-randomized comparison using an explanatory analysis [abstract]. Gynecol Oncol 2003;88:156.

141. Day TG, Smith JP: Diagnosis and staging of ovarian carcinoma. Semin Oncol 1975;2:217–222.

142. Young RC, Walton L, Ellenberg SS, et al: Adjuvant therapy in stage I and stage II epithelial ovarian cancer: results of two prospective randomized trials. N Engl J Med 1990;322:1021–1027.

143. Bush RS, Allt WEC, Beale FA, et al: Treatment of epithelial carcinoma of the ovary: operation, irradiation and chemotherapy. Am J Obstet Gynecol 1977;127:692–704.

144. Hreshchyshyn MM, Park RC, Blessing JA, et al: The role of adjuvant therapy in stage I ovarian cancer. Am J Obstet Gynecol 1980;138:139–145.

145. Dembo AJ, Bush R, Beale F, et al: The Princess Margaret study of ovarian cancer: stages I, II and asymptomatic III presentation. Cancer Treat Rep 1979;63:249–254.

146. Dembo AJ, Bush R, Beale F, et al: A randomized clinical trial of moving strip versus open fi eld whole abdominal irradiation in patients with invasive epithelial cancer of ovary. Proc Am Soc Clin Oncol (abstract C571).

147. Dembo AJ: Abdominopelvic radiotherapy in ovarian cancer: a 10-year experience. Cancer 1985;55:2285–2290.

148. Martinez A, Schray M, Howes A, Bagshaw M: Postoperative radiation therapy for epithelial ovarian cancer: the curative role based on a 24-year experience. J Clin Oncol 1985;3:901–911.

149. Haas J, Mansfi eld C, Hartman G, et al: Results of radiation therapy in the treatment of epithelial carcinoma of the ovary. Cancer 1980;46:1950–1956.

150. Smith J, Rutledge F, Delclos L: Postoperative treatment of early cancer of the ovary: a random trial between postoperative irradiation and chemotherapy. Natl Cancer Inst Monogr 1975;42:149–153.

151. Allen C: Adjunctive irradiation treatment for ovarian carcinoma. Northwest Med 1967;66:1040–1044.

152. Aure J, Hoeg K, Kolstad P: Radioactive colloidal gold in the treatment of ovarian carcinoma. Acta Radiat Ther Phys Biol 1871;10:399–407.

153. Buchsbaum H, Keetel W, Latourette H: The use of radioisotopes as adjunct therapy of localized ovarian cancer. Semin Oncol 1975;2:247–251.

154. Decker D, Webb M, Holbrook M: Radiocolloid treatment of epithelial cancer of the ovary: late results. Am J Obstet Gynecol 1973;115:751–758.

155. Hilaris B, Clark D: The value of postoperative intraperitoneal injection of radiocolloids in early cancer of the ovary. Am J Roentgenol 1971;112:749–754.

156. Pezner R, Stevens K, Tong D, et al: Limited epithelial carcinoma of the ovary treated with curative intent by the intraperitoneal installation of radiocolloids. Cancer 1987;42:2563–2571.

157. Piver S, Lele S, Bakshi S, et al: Five and ten year estimated survival and disease-free rates after intraperitoneal chromic phosphate: stage I ovarian adenocarcinoma. Am J Clin Oncol 1988;11:515–519.

158. Klaassen D, Shelley W, Starreveld A, et al: Early stage ovarian cancer: a randomized clinical trial comparing whole abdominal radiotherapy, melphalan, and intraperitoneal chromic phosphate: a National Cancer Institute of Canada Clinical Trials Group report. J Clin Oncol 1988;6:1254–1263.

159. Spencer R, Marks R, Fenn J, et al: Intraperitoneal P-32 after negative second-look laparotomy in ovarian carcinoma. Cancer 1989;63:2434–2437.

160. Gallion H, Van Nagell J, Donaldson E, et al: Adjuvant oral alkylating chemotherapy in patients with stage I epithelial ovarian cancer. Cancer 1989;63:1070–1073.

161. Bolis G, Colombo N, Favalli G, et al: Randomized multicenter clinical trials in stage I epithelial ovarian cancer [abstract]. Proc ASCO 1992;11:225.

162. Vergote I, Kaern J, Trope C: Adjuvant treatment of stage I ovarian cancer: how can we prevent overtreatment? Proc ASCO 1992;11:225.

163. Young R, Brady M, Nieberg R, et al: Randomized clinical trial of adjuvant treatment of women with early (FIGO I–IIA high risk) ovarian cancer [abstract]. Proc ASCO 1999;18:357a.

164. Vergote I, Trimbos B, Guthrie D, et al: Results of a randomized trial in 923 patients with high-risk early ovarian cancer, comparing adjuvant


chemotherapy with no further treatment following surgery [abstract]. Proc ASCO 2001;20:201a.

165. Bell J, Brady M, Lage J, et al: A randomized phase III trial of three versus six cycles of carboplatin and paclitaxel as adjuvant treatment in early stage ovarian epithelial carcinoma: a Gynecologic Oncology Group study [abstract]. Gynecol Oncol 2003;88:156a.

166. Neijt JP, ten Bokkel Huinink WW, van der Burg ME, et al: Long-term survival in ovarian cancer: mature data from The Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer 1991;27:1367–1372.

167. Omura GA, Brady MF, Homesley HD, et al: Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 1991;9:1138–1150.

168. Rubin SC, Hoskins WJ, Saigo PE, et al: Prognostic factors for recurrence following negative second-look laparotomy in ovarian cancer patients treated with platinum-based chemotherapy. Gynecol Oncol 1991;42:137–141.

169. Ozols RF, Ostchega Y, Curt G, Young RC: High-dose carboplatin in refractory ovarian cancer patients. J Clin Oncol 1987;5:197–201.

170. Markman M, Reichman B, Hakes T, et al: Responses to second-line cisplatin-based intraperitoneal therapy in ovarian cancer: infl uence of a prior response to intravenous cisplatin. J Clin Oncol 1991;9:1801–1805.

171. van der Burg ME, Hoff AM, van Lent M, et al: Carboplatin and cyclophosphamide salvage therapy for ovarian cancer patients relapsing after cisplatin combination chemotherapy. Eur J Cancer 1991;27:248–250.

172. Weiss G, Green S, Alberts DS, et al: Second-line treatment of advanced measurable ovarian cancer with iproplatin: a Southwest Oncology Group Study. Eur J Cancer 1991;27:135–138.

173. Markman M, Rothman R, Hakes T, et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 1991;9:389–393.

174. Zanaboni F, Scarfone G, Presti M, et al: Salvage chemotherapy for ovarian cancer recurrence: weekly cisplatin in combination with epirubicin or etoposide. Gynecol Oncol 1991;43:24–28.

175. Manetta A, Tewari K, Podczaski E: Hexamethylmelamine as a single second-line agent in ovarian cancer: follow-up report and review of the literature. Gynecol Oncol 1997;66:20–26.

176. Vergote I, Himmelmann A, Frankendal B, et al: Hexamethylmelamine as second-line therapy in platin-resistant ovarian cancer. Gynecol Oncol 1992;47:282–286.

177. Markman M, Blessing J, Moore D, et al: Altretamine in platinum-resistant and platinum-refractory ovarian cancer: a Gynecologic Oncology Group phase II trial. Gynecol Oncol 1998;69:226–229.

178. Moore D, Valea F, Crumpler L, et al: Hexamethylmelamine/altretamine as second-line therapy for epithelial ovarian carcinoma. Gynecol Oncol 19932;51:109–112.

179. Rustin G, Nelstrop A, Crawford M, et al: Phase II trial of oral altretamine for relapsed ovarian carcinoma: evaluation of defi ning response by serum CA125. J Clin Oncol 1997;15:172–176.

180. Keldsen N, Havsteen H, Vergote I, et al: Altretamine in the treatment of platinum-resistant ovarian cancer: a phase II study. Gynecol Oncol 2003;88:118–122.

181. Malik I: Altretamine is an effective palliative therapy of patients with recurrent epithelial ovarian cancer. Jpn J Clin Oncol 2001;31:69–73.

182. Rosen G, Lurain J, Newton M: Hexamethyl-melamine in ovarian cancer after failure of

cisplatin-based multiple-agent chemotherapy. Gynecol Oncol 1987;27:173–179.

183. Kudelka A, Tresukosol D, Edwards C, et al: Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 1996;14:1552–1557.

184. Creemers G, Bolis G, Gore M, et al: Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol 1996;14:3056–3061.

185. McGuire W, Blessing J, Bookman M, et al: Topotecan has substantial antitumor activity as fi rst-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2000;18:1062–1067.

186. Bodurka D, Levenback C, Wolf J, et al: Phase II trial of irinotecan in patients with metastatic epithelial ovarian cancer or peritoneal cancer. J Clin Oncol 2003;21:291–297.

187. Gordon A, Fleagle J, Guthrie D, et al: Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001;19:3312–3322.

188. Markman M, Kennedy A, Webster K, et al: Phase 2 trial of liposomal doxorubicin (40 mg/m2) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. Gynecol Oncol 2000;78:369–372.

189. Rose P, Maxson J, Fusco N, et al: Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages. Gynecol Oncol 2001;82:323–328.

190. Campos S, Penson R, Mays A, et al: The clinical utility of liposomal doxorubicin in recurrent ovarian cancer. Gynecol Oncol 2001;81:206–212.

191. Hoskins P, Swenerton K: Oral etoposide is active against platinum-resistant epithelial ovarian cancer. J Clin Oncol 1994;12:60–63.

192. Seymour M, Mansi J, Gallagher C, et al: Protracted oral etoposide in epithelial ovarian cancer: a phase II study in patients with relapsed or platinum-resistant disease. Br J Cancer 1994;69:191–195.

193. Markman M, Hakes T, Reichman B, et al: Phase 2 trial of chronic low-dose oral etoposide as salvage therapy of platinum-refractory ovarian cancer. J Cancer Res Clin Oncol 1992;119:55–57.

194. Tuxen M, Lund B, Hansen O, et al: Oral etoposide in elderly previously untreated ovarian cancer patients with residual disease. Int J Gynecol Cancer 1997;7:213–217.

195. George M, Heron J, Kerbrat P, et al: Navelbine in advanced ovarian epithelial cancer: a study of the French Oncology Centers. Semin Oncol 1989;16(2, suppl 4):30–32.

196. Sorensen P, Hoyer M, Jakobsen A, et al: Phase II study of vinorelbine in the treatment of platinum-resistant ovarian carcinoma. Gynecol Oncol 2001;81:58–62.

197. Burger R, DiSaia P, Roberts J, et al: Phase II trial of vinorelbine in recurrent and progressive epithelial ovarian cancer. Gynecol Oncol 1999;72:148–153.

198. Gershenson D, Burke T, Morris M, et al: A phase I study of daily ×3 schedule of intravenous vinorelbine for refractory epithelial ovarian cancer. Gynecol Oncol 1998;70:404–409.

199. Bajetta E, Leo A, Biganzoli L, et al: Phase II study of vinorelbine in patients with pretreated advanced ovarian cancer: activity in platinum-resistant disease. J Clin Oncol 1996;14:2546–2551.

200. Look K, Muss H, Blessing J, Morris M: A phase II trial of 5-fl uorouracil and high-dose leucovorin in recurrent epithelial ovarian carcinoma: a

Gynecologic Oncology Group study. Am J Clin Oncol 1995;18:19–22.

201. Markman M, Lichtman S, Homesley H, et al: Phase 2 trial of moderately high dose single agent mitoxantrone in platinum and paclitaxel-refractory ovarian cancer. Gynecol Oncol 1998;70:123–126.

202. Gropp M, Meier W, Hepp H: Treosulfan as an effective second-line therapy in ovarian cancer. Gynecol Oncol 1998;71:94–98.

203. Gunsilius E, Gierlich T, Mross K, et al: Palliative chemotherapy in pretreated patients with advanced cancer: oral trofosfamide is effective in ovarian carcinoma. Cancer Invest 2001;19:808–811.

204. Hatch K, Beecham J, Blessing J, Creasman W: Responsiveness of patients with advanced ovarian carcinoma to tamoxifen. Cancer 1991;68:269–271.

205. Shirey D, Kavanagh J, Gershenson D, et al: Tamoxifen therapy of epithelial ovarian cancer. Obstet Gynecol 1985;66:575–578.

206. Schwartz P, Keating G, MacLusky N, et al: Tamoxifen therapy for advanced ovarian cancer. Obstet Gynecol 1982;59:583–588.

207. Rocereto T, Saul H, Aikins J, Paulson J: Phase II study of mifepristone in refractory ovarian cancer. Gynecol Oncol 2000;77:429–432.

208. Cantu M, Buda A, Parma G, et al: Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to fi rst-line platinum-based regimens. J Clin Oncol 2002;20:1232–1237.

209. Ledermann J on behalf of ICON and AGO collaborators: Randomised trial of paclitaxel in combination with platinum chemotherapy versus platinum-based chemotherapy in the treatment of relapsed ovarian cancer (ICON4/OVAR 2.2). Proc ASCO 2003;22:446.

210. Ozols RF, Ostchega Y, Myers CE, et al: Cisplatin in hypertonic saline in refractory ovarian cancer. J Clin Oncol 1985;3:1246–1250.

211. Markman M: Intraperitoneal chemotherapy. Semin Oncol 1991;18:248–254.

212. McGuire WP, Rowinsky EK: Old drugs revisited, new drugs, and experimental approaches in ovarian cancer therapy. Semin Oncol 1991;18:255–269.

213. Sutton GP, Blessing JA, Photopoulos G, et al: Gynecologic Oncology Group experience with ifosfamide. Semin Oncol 1990;17(suppl 4):6–10.

214. Markman M, Hakes T, Reichman B, et al: Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease. J Clin Oncol 1992;10:243–248.

215. Markman M, Kennedy A, Sutton G, et al: Phase 2 trial of single agent ifosfamide/mesna in patient with platinum/paclitaxel refractory ovarian cancer who have not previously been treated with an alkylating agent. Gynecol Oncol 1998;70:272–274.

216. Berek J, Hacker N, Lagasse L, et al: Survival of patients following secondary cytoreductive surgery in ovarian cancer. Obstet Gynecol 1983;61:189.

217. Morris M, Gershenson D, Wharten T, et al: Secondary cytoreductive surgery for recurrent epithelial ovarian cancer. Gynecol Oncol 1989;34:334–338.

218. Janicke F, Holscher M, Kuhn W, et al: Radical surgery procedure improves survival time in patients with recurrent ovarian cancer. Cancer 1992;70:2129–2136.

219. Vaccarello L, Rubin S, Vlamis V, et al: Cytoreductive surgery in ovarian carcinoma patients with a documented previously complete surgical response. Gynecol Oncol 1995;57:61–65.

220. Lund B, Hansen M, Lundvall F, et al: Intestinal obstruction in patients with advanced carcinoma of


the ovaries treated with combination chemother-apy. Surg Gynecol Obstet 1989;169:213–218.

221. Krebs H, Helmkamp F: Management of intestinal obstruction in ovarian cancer. Oncology 1989;3:25–36.

222. Helmkamp B, Kimmel J: Conservative manage-ment of small bowel obstruction. Am J Obstet Gynecol 1985;152:677–679.

223. Krebs H, Goplerud D: The role of intestinal intubation in obstruction of the small intestine due to carcinoma of the ovary. Surg Gynecol Obstet 1984;158:467–471.

224. Piver S, Barlow J, Lele S, Frank A: Survival after ovarian cancer induced intestinal obstruction. Gynecol Oncol 1982;13:44–49.

225. Ozols R, Rubin S, Thomas G, et al: Epithelial ovarian cancer. In Hoskins W, Perez C, Young R (eds): Principles and Practice of Gynecologic Oncology, 3rd ed. Philadelphia, JB Lippincott, 2000, pp 981–1058.

226. Paladine W, Cunningham T, Sponzo R, et al: Intracavitary bleomycin in the management of malignant effusions. Cancer 1976;38:1903–1908.

227. Ostrowski M: An assessment of the long-term results of controlling the reaccumulation of malignant effusions using intracavity bleomycin. Cancer 1986;57:721–727.

228. Souter R, Wells C, Tarin D, Kettlewell M: Surgical and pathologic complications associated with peritoneovenous shunts in management of malignant ascites. Cancer 1985;55:1973–1975.

229. Edney J, Hill A, Armstrong D: Peritoneovenous shunts palliate malignant ascites. Am J Surg 1989;158:598–601.

230. Kerr V, Cadman E: Pulmonary metastases in ovarian cancer. Cancer 1985;56:1209–1213.

231. Johnston N: The malignant pleural effusion: a review of the cytopathologic diagnosis of 584 specimens from 472 consecutive patients. Cancer 1985;56:905–910.

232. O’Neill W, Spurr C, Muss H, et al: A prospective study of chest tube drainage and tetracycline sclerosis versus chest tube drainage in treatment of malignant pleural effusion. Proc ASCO 1980;21:349.

233. Austin E, Flye M: The treatment of recurrent malignant pleural effusion. Ann Thorac Surg 1979;28:190–203.

234. Martini N, Bains M, Beattie E: Indications for pleurectomy in malignant effusion. Cancer 1975;35:734–738.

235. Boutin C, Viallat C, Cargnino P, Farisse P: Thoracoscopy in malignant pleural effusions. Am Rev Respir Dis 1981;124:588–592.

236. Gershenson DM, Malone JM Jr: Chemotherapy for malignant germ cell tumors of the ovary. In Deppe G (ed): Chemotherapy of Gynecologic Cancer, 2nd ed. New York, Wiley-Liss, 1990, pp 217–239.

237. Slayton RE, Park RC, Silverberg SG, et al: Vincristine, dactinomycin and cyclophosphamide in the treatment of malignant germ cell tumors of the ovary: a Gynecologic Oncology Group study: a fi nal report. Cancer 1985;56:243–248.

238. Williams S, Blessing J, Liao S, et al: Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group. J Clin Oncol 1994; 12:701–706.

239. Williams SD, Blessing JA, Moore DH, et al: Cisplatin, vinblastine, and bleomycin in recurrent ovarian germ cell tumors: a trial of the Gynecologic Oncology Group. Ann Intern Med 1989;3:22–27.

240. Sedlis A: Primary carcinoma of the fallopian tube. Obstet Gynecol Surv 1961;16:209.

241. Yoonessi M: Carcinoma of the fallopian tube. Obstet Gynecol Surv 1979;34:257–270.

242. Schiller HM, Silverberg SG: Staging and prognosis in primary carcinoma of the fallopian tube. Cancer 1971;28:389.

ca ovary

Health & Medicine

high risk of therapy

intravenous therapy

intense therapy

highdose therapy

peritoneal cavity

germ cell cancers

low risk ofteratomas

role of dose