Chemotherapy for Ovarian Cancer

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.

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

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 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/m²  for 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 bevacizumab^{39, 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   

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

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 modified3-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)

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 

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