This chapter should be cited as follows: This chapter was last updated:
Deppe, G, Glob. libr. women's med.,
(ISSN: 1756-2228) 2009; DOI 10.3843/GLOWM.10253
October 2009

Ovarian carcinoma

Chemotherapy for Ovarian Cancer

Gunter Deppe, MD
Professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hutzel Hospital, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA

INTRODUCTION

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States. Of about 21,650 women diagnosed in 2008, 15,520 will die of this disease.1 Epithelial ovarian cancer comprises more than 90% of malignant ovarian neoplasms. The other two types are germ cell tumors and sex cord stromal tumors.

EPITHELIAL OVARIAN CANCER

The incidence of epithelial ovarian cancer increases with age and peaks in the eighth decade of life. Epidemiologic studies have identified that multiple pregnancies, breast-feeding and oral contraceptive use are associated with a decreased risk.2 In addition, approximately 10% of ovarian cancer results from inherited defects in the BRCA1, BRCA2 and nonpolyposis colorectal cancer genes. The lifetime risk of ovarian cancer in women with BRCA mutants is 28–40%.3 Bilateral salpingo-oophorectomy at 35–40 years of age is recommended for women with BRCA1 and BRCA2. The use of oral contraceptives is recommended until childbearing is complete.4, 5

The symptoms of ovarian cancer are nonspecific and often occur when the disease is already spread throughout the peritoneal cavity. Up to 75% of patients present with Stage III or IV disease. Abdominal discomfort, vague pains, abdominal fullness, bowel habit changes, early satiety, dyspepsia and bloating are frequent symptoms.6 Currently there is no proven screening modality for the early diagnosis of ovarian cancer. Serum Ca-125 measurement can be useful in detecting early recurrence or assessing response during chemotherapy. 

Although epithelial ovarian cancer can spread through lymphatic or hematogenous dissemination, it most commonly spreads by local shedding and implantation and growth on peritoneal surfaces. Comprehensive surgical staging (Table 1) is most important for determining appropriate adjuvant management. It should include cytologic evaluation of ascites or washings, visualization and smear/biopsy of the diaphragm, examination and biopsy of abdominal and pelvic peritoneum, and para-aortic and pelvic lymph node sampling.   

The surgical goals should include accurate staging and optimal cytoreduction of all visible tumors. Optimal debulking is defined as removal of all disease 1 cm or larger in diameter. The amount of residual disease after primary surgery is the most important factor that influences the survival of patients with advanced epithelial ovarian cancer.7 The range of expected rates of optimal cytoreduction for advanced-stage epithelial ovarian cancer varies widely and is surgeon dependent. Neoadjuvant chemotherapy and interval debulking have been used successfully for patients not found to be suitable for primary surgical debulking.8 Neoadjuvant chemotherapy is currently being evaluated in a prospective randomized trial.9

Table 1. FIGO staging system for primary carcinoma of the ovary

Stage    

Description
I Growth limited to ovaries
IA Growth limited to one ovary; no ascites. No tumor on the external surface; capsule intact
IB Growth limited to both ovaries; no ascites. No tumor on the external surfaces; capsule intact
IC* Tumor either stage IA or IB, but with tumor on surface of one or both ovaries; or with capsule ruptured; or with ascites present containing malignant cells or with positive peritoneal washings
II Growth involving one or both ovaries with pelvic extension
IIA Extension or metastases to the uterus, tubes, or both
IIB Extension to other pelvic tissues
IIC* Tumor either stage IIA or IIB, but with tumor or surface of one or both ovaries; or with capsules ruptured; or with ascites present containing malignant cells or with positive peritoneal washings
III Tumor involving one or both ovaries with peritoneal implants outside the pelvis or positive retroperitoneal or inguinal nodes. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis but with histologically proven malignant extension to small bowel or omentum
IIIA Tumor grossly limited to the true pelvis with negative nodes but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces
IIIB Tumor of one or both ovaries with histologically confirmed implants of abdominal peritoneal surfaces, none exceeding 2 cm in diameter. Nodes are negative
IIIC Abdominal Implants greater than 2 cm in diameter or positive retroperitoneal or inguinal nodes
IV Growth involving one or both ovaries with distant metastasis. If pleural effusion is present, there must be positive cytologic findings to allot a case to stage IV. Parenchymal liver metastasis equals stage IV


FIGO, International Federation of Gynecology and Obstetrics.
*To evaluate the impact on prognosis of the different criteria for allotting cases to stage IC or IIC, it would be of value to know (1) if rupture of the capsule was spontaneous or caused by the surgeon, or (2) if the source of malignant cells detected was peritoneal washings or ascites.

The prognosis of epithelial ovarian cancer depends on stage, histologic grade and type, volume of disease, age, performance status, and ploidy. Work continues in the identification of molecular markers of prognosis in ovarian cancer.

Chemotherapy of Early-Stage Epithelial Ovarian Cancer 

Approximately one-third of women with epithelial ovarian cancer are diagnosed with Stage I or II disease. Careful surgical staging determines the patient’s risk of recurrence (see Table 2).

Table 2. Risk factors for patients with early-stage epithelial ovarian cancer 

Low risk

Well or moderately differentiated and intact capsule
No tumor or external surface
No ascites
Negative peritoneal cytologic findings
No dense adhesions
No extraovarian disease

High risk

Poorly differentiated or ruptured capsule
Tumor on external surface
Ascites
Positive peritoneal cytologic findings
Dense adhesions
Extraovarian disease

Low risk patients have 5-year survival rates exceeding 90% and do not require adjuvant chemotherapy.10 However, high risk patients have a 20–30% risk of relapse and can benefit from adjuvant chemotherapy. The Gynecology Oncology Group studied high risk Stage I and II patients and compared 3 vs. 6 cycles of paclitaxel at 175 mg/mfor three hours plus carboplatin with an area under the curve (AUC) of 7.5. The estimated probability of surviving five years was 81% vs. 83%. The study concluded that after complete surgical staging, three cycles of paclitaxel plus carboplatin was reasonable treatment, with an additional three cycles of therapy resulting in only a modest reduction in risk of recurrence with a significant increase in toxicity.11 The GOG is currently evaluating three cycles of paclitaxel with carboplatin, with three cycles of the same combination followed by weekly paclitaxel for 26 weeks. 

In the United States, postoperative treatment with either paclitaxel plus carboplatin or participation in clinical trials is recommended for patients with early stage disease with high risk factors. 

Chemotherapy of Advanced Epipthelial Ovarian Cancer 

The standard treatment of advanced epithelial ovarian cancer consists of primary optimal cytoreductive surgery followed by chemotherapy.   

Before the 1980s, standard chemotherapy consisted of a single alkylating agent with response rates of 35–65% with a median survival rate of 10–14 months.12 Platinum-based combination chemotherapy, established in the late 1980s, was found to be superior to non platinum-based therapy.13 In the late 1980s and early 1990s, paclitaxel was established as an active agent in epithelial ovarian cancer. The Gynecologic Oncology Group (GOG) evaluated cyclophosphamide and cisplatin against cisplatin and paclitaxel. A significantly improved progression-free survival (18 months vs. 13 months) and overall survival (38 months vs. 24 months) was found on the cisplatin-paclitaxel arm.14 Carboplatin was developed as an alternative to cisplatin. Cisplatin and carboplatin achieved equal efficacy when combined with paclitaxel in a GOG trial. The cisplatin arm had more gastrointestinal, renal, and leukopenic toxicities, whereas thrombocytopenia was more frequent in the carboplatin arm.15

A five-arm study evaluating adding topotecan and gemcitabine to paclitaxel and carboplatin as a triplet regimen and in a sequential doublet regimen did not prolong progression-free survival.16 Although clinical complete remission is frequent, disease relapse will occur in most women with advanced-stage ovarian carcinoma after primary chemotherapy. Consolidation therapy with intraperitoneal radioactive32 P17 whole abdominal radiation therapy18 or high-dose chemotherapy with stem cell support19 did not improve survival. A randomized trial of 12 vs. 3 months of maintenance paclitaxel after complete response to initial surgery, followed by chemotherapy, improved progression-free survival, but not overall survival.20

GOG 212 is currently comparing 12 cycles of paclitaxel vs. 12 cycles of paclitaxel poliglumex vs. observation after a complete response to debulking surgery and chemotherapy. The current standard chemotherapy for patients with Stage III or IV epithelial ovarian and peritoneal cancer is intravenous carboplatin and paclitaxel.21

Chemotherapy for Recurrent Epithelial Ovarian Cancer  

Most patients with advanced stage epithelial ovarian cancer will eventually experience recurrence and will die of disease. Median survival upon recurrence is about two years.22 Cure is an unrealistic expectation. The primary goal of therapy is optimization of quality of life. Survival is not improved by earlier administration of chemotherapy to women with an asymptomatic recurrence.22 The role of secondary surgical reduction remains controversial. The best candidates for secondary cytoreduction are patients with one or two radiographic recurrence sites and a diagnosis-to-recurrence interval of 18 months or longer.23 Patients with a relapse-free interval of more than 6 months (platinum-sensitive) respond better to platinum and other chemotherapeutic agents than those who are platinum resistant (recurrence within 6 months of completion of therapy) or platinum refractory (progression while taking platinum as salvage therapy).

Two randomized trials showed better overall response rates with combination therapy (paclitaxel plus carboplatin or gemcitabine plus carboplatin) than with single-agent carboplatin in patients with platinum-sensitive recurrent epithelial ovarian cancer.24 Single agent carboplatin, however, remains a viable option in the treatment of patients with platinum-sensitive recurrent ovarian cancer. 

For patients with persistent toxicities from the prior treatments and those with platinum and taxane resistant disease, several agents have shown activity, including topotecan,25, 26 liposomal doxorubicin,27 gemcitabine,28, 29 oral etoposide,30 oral altretamine,31 ifosfamide,32 taxanes,33 vinorelbine,34, 35 docetaxel,36 Tamoxifen,37 megestrol acetate,38 and bevacizumab39, 40 (see Table 3). 

Responses generally are brief (3–6 months) and range from 3–35%. The issue of how many treatment regimens to use in patients with recurrent ovarian cancer is controversial. Patients need to decide whether to continue treatment or receive supportive care.22

Table 3.  Options for the treatment of recurrent epithelial ovarian cancer   

Agent

Overall response rate %

Reference

Pegylated liposomal doxorubicin

8.4–19.7

Gordon27

Topotecan weekly

12.4
31.0

Bookman25
Bhoola26

emcitabine

6.1–29.0

Ferrandima29
Mutch28

Ifosfamide

12.0

Markman32

Etoposide (oral)

27.0

Rose30

Docetaxel

22.0

Rose36

Vinorelbine

3.0–29.0

Rothenberg34
Burger35

Hexamethylmelamine (oral)

9.7

Keldsen31

Tamoxifen

9.6

Weiner37

Paclitaxel (weekly)

20.9

Markman33

Megestrol acetate

10.0

Veenhof38

Taxane retreatment

24.0–30.0

Thigpen41

Bevacizumab

16.0

Monk39
Burger40

Intraperitoneal Chemotherapy 

Platin and taxane-based intravenous chemotherapy following maximal surgical tumor debulking has been the standard treatment for patients with advanced stage epithelial ovarian cancer. Unfortunately relapse and loss of chemo-responsiveness are frequent. 

The propensity of epithelial ovarian cancer to remain confined to the peritoneal cavity for much of its natural history has prompted investigation into the efficacy of intra-peritoneal drug delivery. Pharmokinetic studies have shown that intra-peritoneal administration of chemotherapeutic agents results in several-fold increased drug concentrations (10–20 fold for cisplatin and >1000-fold for paclitaxel) in the peritoneal cavity compared with intravenous administration.42, 43, 44 Intra-peritoneal chemotherapy may expose peritoneal tumor to an increased concentration of drug for a prolonged period of time while reducing the systemic toxicities associated with intravenous therapy. However, uniform distribution of the drug may not occur because of adhesions that result from surgery. 

The localized high-dose therapy was tested in three sufficiently large phase III randomized trials comparing intravenous to intra-peritoneal chemotherapy.45, 46, 47 For patients with small-volume residual advanced epithelial ovarian cancer, improved progression-free and overall survival with increased but manageable toxicity was shown. 

The Gynecologic Oncology group randomized optimally cytoreduced patients with stage III epithelial ovarian cancer. Fifty percent received intravenous paclitaxel plus cisplatin, the other 50% were given intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel. 

Side effects, including Grade 3 and 4 pain, fatigue and hematologic, gastrointestinal and neurologic toxic effects were more common in the intraperitoneal therapy group. Only 42% of the patients in the intraperitoneal therapy group completed six cycles of the assigned therapy. The medium duration of overall survival in the intravenous-therapy and intraperitoneal therapy groups was 49.7 and 65.6 months, respectively.48 The 25% reduction in the risk of death was considered to be significant.  

Eight randomized trials (1819 patients) found that women who received an intra-peritoneal component to the chemotherapy had greater overall survival rates than women who did not receive such therapy. There may be greater serious toxicity with regard to gastrointestinal effects, pain, and fever but less cytotoxicity with the intraperitoneal route.49

Based on these combined results, the National Cancer Institute recommended that women with stage III epithelial ovarian cancer who undergo optimal surgical cytoreduction be considered for intraperitoneal chemotherapy.50 In spite of theoretical and pharmacologic advantages, the benefit of intraperitoneal therapy may have been overestimated. Intraperitoneal chemotherapy should be prospectively compared with a safer, much less toxic regimen of intravenous carboplatin plus paclitaxel in a prospective randomized trial.51

Given the quality of life and toxicity, intraperitoneal chemotherapy may be used in the first-line treatment for well informed, carefully selected patients with optimally debulked stage III epithelial ovarian cancer, if administered by physicians experienced in intraperitoneal chemotherapy. The decision to use it should be individualized.52, 53,     

New Treatment Modalities  

One of the strategies is to identify the genes and their resultant proteins that mediate resistance to chemotherapy. Women with chemo-resistant disease could be treated with alternative approaches.54,    

A major goal of current research in ovarian cancer is the identification of targeted therapies. Targeted therapy has the potential of providing less toxic, targeted inhibition of tumor growth. For ovarian cancer, targets include the inhibition of epidermal growth factor receptor (EGFR), inhibition of various kinases, and inhibition of angiogenesis. Phase II studies with Erlotinib,55, Gefitinib,56, and EMD 72000,57 in recurrent ovarian cancer demonstrated three partial responses in 98 patients. Protein kinase C is involved in the regulation of cell growth, proliferation, and inhibition of apoptosis. In ovarian cancer attempts to modulate protein kinase C activity have thus far been unsuccessful.   

Angiogenesis plays an important role in ovarian cancer. Vascular endothelial growth factor (VEGF) is over-expressed in patients with ovarian cancer and its expression is a negative prognostic factor.58 Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody against VEGF, which has shown activity in recurrent ovarian cancer.59  

A current GOG Phase III trial is comparing carboplatin and paclitaxel with either bevacizumab or placebo in previously untreated patients with suboptimal Stage III and IV epithelial ovarian cancer. 

Borderline Ovarian Neoplasms 

Borderline ovarian neoplasms account for 5–15% of epithelial ovarian tumors. They usually affect patients younger than 50 years of age and are mostly diagnosed at an early stage. Five-year overall survival rate for early stage disease is about 98% and ranges between 86–92% for advanced disease. 

Management is primarily surgical. For Stage I disease, fertility-sparing surgery can be performed.60, 61 There is no proven benefit from adjuvant chemotherapy, even in advanced-stage tumors with invasive implants.62 Cytoreductive  surgery is the recommended treatment for recurrent disease.61  

Chemotherapy for Malignant Ovarian Germ Cell Tumors 

Malignant ovarian germ cell tumors comprise approximately 20–25% of ovarian neoplasms overall and 5% of all malignant ovarian tumors.  Known characteristics of these tumors are their presentation at a young age (10–30 years), rapid growth, frequent production of tumor markers (human chorionic gonadotropin, alpha-fetoprotein, lactic dehydrogenase), predilection for hematogenous and lymphatic spread, and, with the exception of dysgerminomas, a predominantly unilateral involvement.   

Patients typically present with a palpable pelvic-abdominal mass and abdominal pain, usually due to hemorrhage, rupture or torsion of the ovarian tumor. Abdominal distention, vaginal bleeding and fever are seen less frequently.63,   

Histologically they can be divided into dysgerminomatous (the most common type and the equivalent in women of seminoma) and nondysgerminomatous tumors. The current classification system separates primitive germ cell tumors from biphasic or triphasic teratomes and monodermal teratomes and somatic-type tumors associated with dermoid cysts (see Table 4).      

Table 4.        Classification of malignant ovarian germ cell tumors

 I

Primitive germ cell tumors

A.  Dysgerminoma
B.  Yolk sac tumor
          Polyvesicular vitolline
          Glandular
          Hepatoid
C.  Embryonal carcinoma
D.  Polyembryoma
E.  Non-gestational choriocarcinoma
F.  Mixed germ cell carcinoma

 II

Biphasic or triphasic teratoma

A.  Immature
B.  Mature
          Solid
          Dermoid cyst
          Fetiform

 III

Monodermal teratoma and somatic-type tumors associated with biphasic or triphasic teratoma

A.  Thyroid
B.  Carcinoid
C.  Neuroectodermal
D.  Carcinoma
E.  Melanocytic
F.  Sarcoma
G.  Sebaceous
H.  Pituitary-type
I.   Retinal anlage

(modified from the WHO histologic classification of ovarian tumors, in: Tavassoli FA, Deville P: Pathology and genetics of tumors of the breast and female genital organs. Lyon, France, International Agency for Research on Cancer, 2003.)

Germ cell tumors of the ovary are staged surgically, following the same criteria delineated for epithelial ovarian cancer. Most of them are confined to the ovary at presentation. As a result, these patients are candidates for fertility-sparing surgery. Deviations from standard surgical staging did not increase survival. Surgical comprehensive restaging for patients inadequately staged was not recommended by the Pediatric Oncology Group.64

In the setting of advanced disease, resection of all gross tumors should be attempted. The benefit of cytoreductive surgery is less well established than for epithelial ovarian cancer. Malignant ovarian germ cell tumors have excellent chemosensitivity to platinum-based chemotherapy. 

Chemotherapy for Nondysgerminomatous Ovarian Germ Cell Tumors 

Postoperative combination chemotherapy is indicated for all nondysgerminomatous malignant ovarian germ cell tumors except those with an adequate surgically-staged IA, grade I pure immature teratoma. The first effective combination of vincristine, dactinomycin and cyclophosphamide was replaced by the combination of cisplatin, vinblastine and bleomycin, which proved to be more effective.65 Because of equal activity but less toxicity in testicular cancer patients, etoposide was substituted for vinblastine in combination chemotherapy for ovarian germ cell malignancies.66 The combination of bleomycin, etoposide, and cisplatin (BEP) produced long-term survival in approximately 80% of women with advanced-stage disease, and close to 100% in early-stage disease, and has become the standard chemotherapy for patients with malignant ovarian germ cell tumors.67, 68, 69, To decrease toxicity, a modified 3-day regimen was found to be safe and effective (see Table 5).70, 71 In the standard regimen, cisplatin and etoposide are usually administered over five days with weekly bleomycin.67

Table 5.  Chemotherapy regimen for malignant ovarian germ cell tumors71

                    BEP (repeated at 21-day intervals)

Drug combination

Dose

Route

Duration

Bleomycin

15 mg

IV

For 3 days

Etoposide

120 mg

IV

For 3 days

Cisplatin

40mg/m2

IV

For 3 days

Although the optimal number of chemotherapy cycles has not been established, for patients with completely resected disease, 4 cycles of BEP is recommended.69 Patients positive for tumor markers are being treated with two more cycles until after they achieve a status negative for tumor markers. Controversy still exists as to whether or not carboplatin can be substituted for cisplatin.72,    

The growing teratoma syndrome, a benign condition, should always be considered in the differential diagnosis of persistent tumor masses with normalization of tumor markers following chemotherapy or progressive increase in size of a mass during or after treatment with normalization of tumor markers. The treatment of growing teratoma syndrome should be complete surgical resection of the tumor.73 Historically, three cycles of adjuvant chemotherapy for patients with Stage I high grade ovarian germ cell tumors has been the general approach; however, reports in the pediatric literature suggest surgery plus surveillance in Stage I patients may be sufficient.74 A small percentage of patients with malignant ovarian germ cell tumors develop recurrence, usually within 24 months of primary diagnosis.63 Because of this rare occurrence, no standard treatments for recurrent tumor exist.   

Salvage chemotherapy for patients with recurrent testicular cancer consisted of four courses of vinblastine (or etoposide) plus ifosamide plus cisplatin, or three similar cycles followed by a single course of high-dose carboplatin plus etoposide plus cyclophosphamide.75 Long-term responses and potential cures by means of high dose chemotherapy, plus hematopoietic stem-cell rescue, have been described in patients with testicular cancers refractory to platinum-based chemotherapy or those not cured by salvage therapy with cisplatin-ifosfamide.76 Long-term disease-free survival is possible with paclitaxel plus gemcitabine in patients that progressed after high-dose chemotherapy.77 The majority of survivors of malignant ovarian germ cell tumors treated with platinum-based chemotherapy and fertility-sparing surgery retain their menstrual function and reproductive ability.78,

Chemotherapy for Dysgerminoma

Dysgerminomas of the ovary are the female counterpart of male seminoma. They are among the most radiosensitive and chemosensitive gynecologic malignancies. Dysgerminoma often contain synctiotrophoblastic cells which produce placental alkaline phosphatase and lactate dehydrogenase (LDH) which can be used for monitoring purposes.   

Early stage disease is managed by fertility preserving surgery. Adjuvant chemotherapy has replaced radiotherapy as standard postoperative treatment for advanced-staged dysgerminoma. The initial surgical procedure should include staging and possible tumor debulking, but the contralateral ovary, tube and uterus generally need not to be removed. Optimal chemotherapy has not been defined for dysgerminoma due to the rare occurrence. Reports of chemotherapy in other types of germ cell tumors and in seminomas of men are extrapolated to dysgerminomas. 

The experience of the Gynecologic Oncology Group was reported by Williams et al. As an alternative to cisplatin, etoposide and bleomycin (BEP), three courses of postoperative carboplatin and etoposide was administered to patients with completely resected dysgerminoma. The regimen was less toxic than BEP.70,   

Chemotherapy of Sex Cord Stromal Tumors

Sex cord-stromal tumors account for approximately 6–7% of all malignant ovarian neoplasms. They include granulosa cell tumors (at 70%, the most common), Sertoli-Leydig cell tumors, and gynandroblastomas (see Table 6).80  

These tumors may be hormonally active and patients often present with symptoms of either estrogen or androgen excess.  Potential useful tumor markers are serum levels of estradiol, testosterone, mullerian inhibitory substance, and Inhibin A and B. Inhibin B, a polypeptide hormone, predominantly secreted by granulosa cell tumors, has been found to be most helpful for the follow-up of granulosa cell tumors.81 More than 95% of granulosa cell tumors are diagnosed at Stage I.  The natural history is characterized by slow growth, local spread, and late recurrence.  Many patients with disease confined to the ovary are cured by surgery alone. Up to 25% of all patients develop recurrences some 5–20 years after the initial diagnosis. Patients with Stage III disease have a 5-year survival of only 0–22%.82

Table 6.  World Health Organization classification of sex cord stromal tumors 

 Granulosa stromal cell tumors
          Granulosa
          Adult
          Juvenile
     Thecoma-fibroma group
          Thecoma
          Fibro-sarcoma
          Sclerosing stromal tumor        

 Sertoli-Leydig cell tumors, androblastomas
        Sertoli-Leydig
          Well differentiated
          Moderately differentiated
          Poorly differentiated
               With heterologous elements
               Retiform
               Mixed

 Gynandroblastoma

 Sex cord tumor with anular tubules

 Unclassified

(Colombo N, Parma G, Zanagnolo V, et al: Management of ovarian stromal cell tumors. J Clin Oncol, 25:2944. 2007.)

Postoperative therapy must be considered for selected patients with Stage I granulosa cell tumors associated with large tumor size (>10-15 cm), high mitotic index (greater than 4–10 mitoses per 10 high-power fields) or preoperative tumor rupture.80

Adjuvant cytoxic chemotherapy is usually administered only to patients with post-surgical residual or with recurrent and metastatic disease.  Postoperative adjuvant chemotherapy is recommended for patients with Stage I Sertoli-Leydig cell tumors (poorly differentiated or containing heterologous elements) and for those with advanced disease of any histologic subtype. Though no standard chemotherapy regimen exists, several combinations with variable response rates have been reported (see Table 7).  

Hormonal therapy consisting of progestational agents with or without tamoxifen or gonadotropin-releasing hormone agonists has produced partial responses in a few patients with chemotherapy and/or radiation refractory disease.83, 84, 85 Freeman86 observed activity of anastrozole (aromatose inhibitor) therapy in two patients with recurrent ovarian adult granulosa cell tumors after failure of chemotherapy and leuprolide. 

Table 7.   Active chemotherapy regimens for ovarian sex cord stromal tumors 

Drugs

Number of patients
Response rate (%) Reference

Adriamycin
Cisplatin

2 100 Jacobs87

Cisplatin
Vinblastine
Bleomycin

11 82 Colombo88

Cyclophosphamide
Adriamycin
Cisplatin

10 60 Pectasides89

Bleomycin
Etoposide
Cisplatin

57 61 Homesley90
Paclitaxel 1 100 Tresukosol91
Paclitaxel – with or without another agent 30 42 Brown92

REFERENCES

1

Jemel A, Siegel R, Ward E, et al: Cancer Statistics 2008. Ca Cancer J Clin, 58:71. 2008

 

2

National Cancer Institute SEER: Cancer Stat Fact Sheets. Cancer of the Ovary Available at: http://seer.cancer.gov Accessed June 1, 2007

 

3

Frank TS: Testing for hereditary risk of ovarian cancer. Cancer Control, 6:327. 1999

 

4

Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prevention and observation of Surgical End points Study Group: Prophylactic oophorectomy in carriers of BRCA1 and BRCA2 mutations. N Engl J Med, 346:1616. 2002

 

5

Eisen A, Rebbeck TR, Wood WC, et al: Prophylactic surgery in women with a hereditary predisposition to breast and ovarian cancer. J Clin Oncol 18:1980. 2000

 

6

Goff BA, Mandel LS, Drescher CW, et al: Development of an ovarian cancer symptom index: Possibilities for earlier detection. Cancer 109:221. 2007

 

7

Bristow RE, Tomacruz RS, Armstrong DK, et al: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era. meta-analysis. J Clin Oncol, 20:1248. 2002

 

8

Hou, JY, Kelly MG, Yu H, et al: Neoadjuvant chemotherapy lessens surgical morbidity in advanced ovarian cancer and leads to improved survival in Stage IV disease. Gynecol Oncol, 105:211. 2007

 

9

Vergote I, Van Gorp T, Amant F, et al: Neoadjuvant chemotherapy for ovarian cancer. Oncology (Williston Park), 19:1615-1622. 2005

 

10

Trope C, Kaern J: Adjuvant chemotherapy for early-stage ovarian cancer: Review of the literature. J Clin Oncol, 25:2909. 2007

 

11

Bell J, Brady MF, Young RC, et al: Radomized phase III trial of three vs six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol, 102:432. 2006

 

12

Young RC, Hibbard SP, DeVita VT: The chemotherapy of ovarian carcinoma. Cancer Treat Rev, 1:99. 1974.

 

13

Williams CJ, Stewart L, Parmar M, et al: Meta-analysis of the role of platinum compounds in advanced ovarian carcinoma. The Advanced Ovarian Cancer Trialists Group. Semin Oncol, 19:120. 1992

 

14

McGuire WP, Haskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with Stage III and IV ovarian cancer. N Engl J Med, 334:1. 1996

 

15

Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected Stage III ovarian cancer: A Gyecologic Oncology Group study. J Clin Oncol, 21:3194. 2003

 

16

Bookman MA, GOG 0182-ICONS: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (CC) combination with gemcitabine (G) PEG-liposomal doxorubicin (D) or topotecan (T) in patients (pts) with advanced stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. (Abstract) J Clin Oncol, 24(185):5002. 2006

 

17

Varia MA, Stehman FB, Bundy BN, et al: Intraperitoneal radioactive phosphorus (32P) versus observation after negative second-look laparotomy for Stage III ovarian carcinoma: A randomized trial of the Gynecologic Oncology Group. J Clin Oncol, 21:2849. 2003

 

18

Sorbe B: Consolidation treatment of advanced ovarian carcinoma with radiotherapy after induction chemotherapy. Int J Gynecol Cancer, 13(2):192. 2003

 

19

Cure H, Battista C, Guastalla JP, et al: Phase III randomized trial of high-dose chemotherapy and peripheral blood stem cell support as consolidation in patients with advance ovarian cancer: Five-year follow-up of GINECO/FNCLCC/FGM-TC. Study (abstract) Proc Am Soc Clin Oncol, 23:449A, Abstr 5006. 2004

 

20

Markman M, Liu PY, 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, 21:2460. 2003

 

21

DuBois A, Quinn M, Thigpen T, et al: 2004 consensus statements in the management of ovarian cancer: Final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIC OCCC 2004). Ann Oncol, 16(8):viii7-viii12. 2005

 

22

Ozols RF: Treatment goals in ovarian cancer. Int J Gynecol Cancer, 15(1):3. 2005

 

23

Salani R, Santillan A, Zahurak ML, et al: Secondary cytoreductive surgery for localized, recurrent epithelial ovarian cancer: Analysis of prognostic factors and survival outcome. Cancer, 109:685. 2007

 

24

Pfisterer J, Plante M, Vergote I, et al: Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: An intergroup trial of the AGO-OVAR, the NCIC CTG and the EORTC GCG. J Clin Oncol, 26:4699. 2006

 

25

Bookman MA, Malstrom H, Bollis G et al: Topotecan for the treatment of advanced epithelial ovarian cancer: An open-label phase II study in patients treated after prior chemotherapy containing cisplatin or carboplatin and paclitaxel. J Clin Oncol 16: 3345, 1998

 

26

Bhoola SM, Coleman RL, Herzog T, et al: Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer. Gynecol Oncol, 95:564. 2004

 

27

Gordon AN, Fleagle JT, Guthrie D, et al: Recurrent epithelial ovarian carcinoma: A randomized Phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol, 19:3312. 2001

 

28

Mutch DG, Orlando M, Goss T, et al: Randomized Phase III trial of gemcitabine compared to pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol, 25:2811. 2007

 

29

Ferrandina G, Ludovisi M, Lorusso D, et al: Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol, 26:890. 2008

 

30

Rose PG, Blessing JA, Mayer AR et al: Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 16: 405, 1998

 

31

Keldsen N, Harsteen H, Vergote I, et al: Altretamine (hexamethylmelamine) in the treatment of platinum-resistant ovarian cancer: A Phase II study. Gynecol Oncol, 88:118. 2003

 

32

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

 

33

Markman M, Blessing J, Rubin SC, et al: Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: A Gynecologic Oncology Group study. Gynecol Oncol, 101:436. 2008

 

34

Rothenberg ML, Liu PY, Wilezynski S, et al: Phase II trial of vinorelbine for relapsed ovarian cancer: A Southwest Oncology Group study. Gynecol Oncol, 95:506. 2004

 

35

Burger RA, DiSaia PJ, Roberts JA, et al: Phase II trial of vinorelbine in recurrent and progressive epithelial ovarian cancer. Gynecol Oncol, 72:148. 1999

 

36

Rose PG, Blessing JA, Ball HG, et al: A Phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol, 88:130. 2003

 

37

Weiner SA, Alberts DS, Surwit EA, et al: Tamoxifen therapy in recurrent epithelial ovarian carcinoma. Gynecol Oncol, 27:208. 1987

 

38

Veenhof CH, van der Berg ME, Novy M, et al: Phase II study of high-dose megestrol acetate in patients with advanced ovarian carcinoma. Eur J Cancer, 30A:697. 1994

 

39

Monk BJ, Han E, Josephs-Corvan CA, et al: Salvage bevacizumab (rhu MAB VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer. Gynecol Oncol, 102:140. 2006

 

40

Burger RA, Sill MW, Monk BJ, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group study. J Clin Oncol, 25:5165. 2007

 

41

Thigpen JT, Blessing JA, Ball W, et al: Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: A Gynecologic Oncology Group study. Gynecol Oncol, 101:436. 2006

 

42

Francis P, Rowinsky E, Schneider J, et al: Phase I feasibility and pharmacologic study of weekly intraperitoneal paclitaxel: A Gynecologic Oncology Group Pilot Study. J Clin Oncol, 13:2961.1995

 

43

Howell SB, Pfeifle CL, Wung WE, et al: Intraperitoneal Cisplatin with systemic thiosulfate protection. J Clin Oncol, 13:2961. 1995

 

44

Markman M, Rowinsky E, Hakes T, et al: Phase I trial of intraperitoneal taxol. A Gynecologic Oncology Group Study. Ann Intern Med, 97:846. 1982

 

45

Markman M. Bundy BN, Alberts DS, et al: Phase III trial of standard dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume Stage III ovarian carcinoma: An intragroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19:1001. 2001

 

46

Alberts DS, Liu PY, Hannigan EV, et al: Intraperitoneal cisplatin plus intravenous cyclophospharmide versus intravenous cisplatin plus intravenous cyclophospharmide for Stage III ovarian cancer. N Engl J Med, 335:1950. 1996

 

47

Markman M, Walker JL: Intraperitoneal chemotherapy of ovarian cancer: A review with a focus on practical aspects of treatment. J Clin Oncol, 24:988. 2006

 

48

Armstrong DK, Bundy B, Wenzel L, et al: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med, 354:34. 2006

 

49

Jaoback K, Johnson N.: Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. The Cochrane Database of Systematic Reviews 2006, Issue 1, Art. No CD005340.pub. 2

 

50

National Institutes of Health. NCI issues clinical announcement for preferred methods of treatment for advanced ovarian cancer. January 2006 (Accessed March 23, 2006, at http://www.nih.gov/news/pr;jan2006/nci-04.htm.)

 

51

Ozols R.E., Bookman M.A., Young R.C.: Intraperitoneal chemotherapy for ovarian cancer. N Engl J Med, 354:1641. 2006

 

52

Cannistra SA: Intraperitoneal chemotherapy comes of age. N Engl J Med, 354:77. 2006

 

53

Intraperitoneal chemotherapy for ovarian cancer. ACOG. Committee opinion. Obstet. Gynecol. 111:249. 2008

 

54

Hartmann LC, Lu KH, Linette GP, et al: Gene expression profiles predict early relapse in ovarian cancer after platinum-paclitaxel chemotherapy. Clin Cancer Res, 11:2149. 2005

 

55

Gordon AN, Finkler N, Edwards RP, et al: Efficacy and safety of erlotinib, HCL, an epidermic growth factor receptor (HER/EGFR) tyrosine kinase inhibitor in patients with advanced ovarian carcinoma: Results from a Phase II multicenter study. Int J Gynecol Cancer, 15:785. 2008

 

56

Schilder RJ, Sill MW, Chen X, et al: Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: A Gynecologic Oncology Group study. Clin Cancer Res, 11:5539. 2008

 

57

Seiden MV, Burris HA, Matulonis V, et al: A Phase II trial of EMD 72000 (matuzumab), a humanized anti-EGFR monoclonal antibody, in patients with platinum-resistant ovarian and primary peritoneal malignancies. Gynecol Oncol, 104:727. 2007

 

58

Alvarez AA, Krigman HR, Whitaker RS, et al: The prognostic significance of angiogenesis in epithelial ovarian carcinoma. Clin Cancer Res, 5:587. 1999

 

59

Burger RA, Sill M, Monk BJ, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study (abstract). J Clin Onc, 23(1):5009. 2005

 

60

Fauvet R, Poncelet C, Boccara J, et al: Fertility after conservative treatment for borderline ovarian tumors. A French multicenter study. Fertil Steril, 83:284. 2005

 

61

Cadron L, Leunen K, Van Gorp T, et al: Management of borderline ovarian neoplasms. J Clin Oncol, 25:2928. 2007

 

62

Trope C, Kaern J, Vergote I, et al: Are borderline tumors of the ovary overtreated both surgically and systemically? A review of four prospective randomized trials including 253 patients with borderline tumors. Gynecol Oncol, 51:236. 1993

 

63

Gershenson DM:Management of ovarian germ cell tumors. J Clin Oncol, 25:2938. 2007

 

64

Billmire D, Vincour C, Rescorla F, et al: Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents. An intergroup study. J Pediatr Surg, 39:424; discussion 429. 2004

 

65

Gershenson DM, Kavanaugh JJ, Copeland LJ, et al: Treatment of malignant nondygerminomatous germ cell tumors of the ovary with vinblastine, bleomycin and cisplatin. Cancer, 57:1731. 1986

 

66

Williams SD, Birch E, Einhorn LH, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin and either vinblastine or etoposide. N Engl J Med, 316:1435. 1987

 

67

Gershenson DM, Morris M, Cangir A, et al:Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide and cisplatin. J Clin Oncol, 8:715. 1990

 

68

Williams SD: Ovarian germ cell tumors: An update. Semin Oncol, 25:407. 1998

 

69

Lu KH, Gershenson DM: Update on the management of ovarian germ cell tumors. J Reprod Med, 50:417. 2005

 

70

Lai C-W, Chang T-C, Hsueh S, et al: Outcome and prognostic factors in ovarian germ cell malignancies. Gynecol Oncol, 96:784. 2005

 

71

Dimopoulos MA, Papadimitriou C, Hamilos G, et al: Treatment of ovarian germ cell tumors with a 3-day bleomycin, etoposide and cisplatin regimen: A prospective multicenter study. Gynecol Oncol, 95:695. 2004

 

72

Stern JW, Brunin N: Prospective study of carboplatin-based chemotherapy for pediatric germ cell tumors. Med Pediatr Oncol, 39:163. 2002

 

73

Zagamé L, Pautier P, Drouillard P, et al: Growing teratoma syndrome after ovarian germ cell tumors. Obstet Gynecol, 108:503. 2006

 

74

Cushing B, Giller R, Ablin A, et al: Surgical resection alone is effective treatment for ovarian immature teratoma in children and adolescents: A report of the Pediatric Oncology Group and the Childrens’ Cancer Group. Am J Obstet Gynecol, 181(2):353. 1999

 

75

Pico JL, Rosti G, Kramar A, et al: A randomized trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumors. Ann Oncol, 16:1152. 2005

 

76

Einhorn LH, Williams SD, Chamness A, et al: High-dose chemotherapy and stem cell rescue for metastatic germ-cell tumors. N Engl J Med, 357:340. 2007

 

77

Einhorn LH, Brames MJ, Julian B, et al: Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol, 25:513. 2007

 

78

Gershenson DM, Miller AM, Champion VL, et al: Reproductive and sexual function after platinum-based chemotherapy in long-term ovarian germ cell tumor survivors: A Gynecologic Oncology Group study. J Clin Oncol, 25:2792. 2007

 

79

Williams SD, Kanderer J, Burnett FA, et al: Adjuvant therapy of completely resected dysgerminoma with carboplatin and etoposide: A trial of the Gynecologic Oncology Group. Gynecol Oncol, 95:490. 2004

 

80

Colombo N, Parma G, Zanagnolo V, et al: Management of ovarian stromal cell tumors. J Clin Oncol, 25:2944. 2007

 

81

Mom CH, Engelen MJA, Willemse PHB, et al: Granulosa cell tumors of the ovary: The clinical value of serum inhibin A and B levels in a large sincle center cohort. Gynecol Oncol, 105:365. 2007

 

82

Hines JF, Khalifa MA, Moore JL, et al: Recurrent granulosa cell tumor of the ovary 37 years after initial diagnosis: A case report and review of the literature. Gynecol Oncol, 60:484. 1996

 

83

Hardy RD, Bell JG, Nicely JC, et al: Hormonal treatment of recurrent granulosa cell tumor of the ovary: Case report and review of the literature. Gynecol Oncol, 96:865. 2005

 

84

Fishman A, Kudelka AP, Tresukosol D, et al: Leuprolide acetate for treating refractory or persistent ovarian granulosa cell tumor. J Reprod Med, 41:393. 1996

 

85

Briasoulis E, Karavasilis V, Pavlidis N: Megestrol activity in recurrent adult-type granulosa cell tumour of the ovary. Ann Oncol, 8:811. 1997

 

86

Freeman SA, Modesitt SC: Anastrozole therapy in recurrent ovarian adult granulose cell tumors. A report of two cases. Gynecol Oncol, 103:755. 2005.

 

87

Jacobs HJ, Deppe G, Cohen CJ: Combination chemotherapy of ovarian granulosa cell tumor with cisplatinum and doxorubicin. Gynecol Oncol, 14:294. 1982

 

88

Colombo N, Sessa C, Landoni F, et al: Cisplatin, vinblastine and bleomycin combination chemotherapy in metastatic granulosa cell tumor of the ovary. Obstet Gynecol, 67:265. 1986

 

89

Pectasides D, Alevizakos N, Athanassiou AE: Cisplatin-containing regimens in advanced or recurrent granulosa cell tumors of the ovary. Ann Oncol, 3:316. 1992

 

90

Homesley WD, Bundy BN, Hurteau JA, et al: Bleomycin, etoposide and cisplatin combination therapy of ovarian granulosa cell tumors and other stromal malignancies: A Gynecologic Oncology group study. Gynecol Oncol, 72:131. 1999

 

91

Tresukosol D, Kudelka AP, Edwards CL, et al: Recurrent ovarian granulosa cell tumor: A case report of a dramatic response to Taxol. Int J Gynecol Cancer, 5:156. 1998

 

92

Brown J, Shoartsman HS, Deavers MT, et al: The activity of toxanes compared with bleomycin, etoposide and cisplatin in the treatment of sex cord stromal ovarian tumors. Gynecol Oncol, 97:489. 2005

 
Back to Top